Biotech, Humanized.
2
Jun
2020

Digital Natives and Skilled Operators: Weaving Data Science Into Pharma R&D

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02 Jun 2020

David Shaywitz

An abiding challenge at the intersection of technology and pharma R&D is the need to bring together two historically disparate cultures. 

Tech companies tend to be led by engineers. Pharma R&D is generally run by chemists and biologists in the early stages, and by physicians further on in development.

Each of these domains has its own distinct language, culture and norms that don’t all neatly overlap on a Venn diagram.

It’s clear by this point that effective integration across these disciplines is both required and difficult. 

Data science is likely to make an impact on R&D when it’s perceived not as an exotic, novel capability, but rather when it becomes woven into the way medical researchers go about their daily work.   

This is how science progresses. In the 1980s, molecular biology was exotic, and clinician-scientists famously abandoned physiology to embrace it, as Brown and Goldstein classically described.  Today, molecular biology is a given, a standard part of the researcher’s toolbox, and the leaders of pharma R&D are all fluent with the standard tools and techniques.

I suspect data science today is where molecular biology was 40 years ago. It is now widely recognized as an incredibly powerful emerging tool, and many young physicians and medical scientists are eager to embrace it. 

Talent at intersection of medical research and data science is rare, and in high demand.  I think of people like Dr. Alvin Rajkomar, formerly of UCSF and now at Google; Dr. Krishna Yeshwant, at GV; Dr. Taha Kass-Hout, formerly of the FDA and now at Amazon; Dr. Andrew Trister, formerly at Apple, now leading the Innovative Technology Solutions team at the Gates Foundation; and Imran Haque, trained in computer science at Stanford and now at Recursion; among others. 

In what I suspect may be an early indication of where the puck is heading, Genentech recently announced what I believe is the first example of a “digitally native” researcher to lead a major pharma R&D group. The distinguished biotech drug discovery company recruited highly regarded computational biologist and systems biologist, Aviv Regev from the Broad Institute to run gRED (Genentech Research and Early Development). Her predecessor, Michael Varney, trained as an organic chemist. Varney’s predecessor in that high-powered, priority-setting role, Richard Scheller, was a molecular neurobiologist.  

To be sure, there are plenty of strong data scientists in pharma, but generally within data science-specific functions; at Genentech, Regev is responsible for all of early R&D. She isn’t being charged with running a science project, an innovation initiative, or some novel effort to link up disparate databases and see what happens. Her department must deliver actual drug candidates that move forward in development, and eventually become products that help patients.

Regev, known for her work in single-cell sequencing at high volumes, generating data that can be placed in a larger biological context, is the rare kind of individual who is equally comfortable at a computer science and molecular biology symposium. She inhabits several domains that seem critical for pharma’s future.

Digital natives like Regev remain extremely rare, though I suspect they will increasingly come to populate top pharma and medical research leadership roles – if data science is perceived to deliver on its promise (not a given). 

But “digital nativist” isn’t the only path to success. A second route is the “skilled orchestrator” – leaders who are knowledgeable, curious, and have a particular knack for effectively aligning health and tech talent against an objective. There’s a high degree of emotional intelligence that seems to be required, as well as an intuitive feel for both domains. A few role models spring to mind: Dr. Amy Abernethy (currently Deputy Commissioner of the FDA) and her leadership at Flatiron is one; Chris Gibson, the founder and CEO of Recursion seems like another.

Successful orchestration requires a common sense of mission; this is a much higher bar than most appreciate, requiring more than simply putting an engineer and a biologist in a room, say, or appending a data scientist onto a pharma product team. But a skilled orchestrator who can pull this off has the opportunity to leverage comparatively large pools of specialized tech and pharma talent, and doesn’t require all the competencies to reside in a single, remarkable person.

Whether through digital natives or skill orchestrators, it’s exciting to see pharma embrace the challenge of bringing data science to bear. The proof, however, will be in the pipeline.

2
Jun
2020

Puretech Focuses on the Long-Term Lung Complications in COVID-19 Survivors

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02 Jun 2020

Kshithija KJ Mulam, correspondent, Timmerman Report

All eyes are on the healthcare industry as biotech and pharmaceutical companies race like never before to develop antiviral treatments and vaccines to curtail the immediate and most severe effects of contracting the virus.

However, as new cases and unforeseen symptoms emerge, some scientists are shifting their focus to the extended repercussions of patients who survived their brush with COVID-19. The need is enormous and growing fast. The US now has almost 1.8 million cases of COVID-19. Scientists can only speculate about how many of them will come away with long-term damage, and what kind of long-term health effects may linger.

On May 28, Boston-based biotech PureTech Health announced plans to start a clinical trial specifically examining a proposed therapy, deupirfenidone (LYT-100), against pulmonary fibrosis in non-critically hospitalized patients with COVID-19.

This clinical trial, a randomized, placebo-controlled study of 150 patients, is scheduled to start before the end of September. Puretech says it’s one of the first to well-controlled studies to directly concentrate on the long-term complications of COVID-19 beyond the critical stage of the virus.

“What we’re seeing now with COVID-19, and again, obviously this data is changing by the day, is that upon discharge … a significant percentage of lung dysfunction is noted. Now what we don’t know yet is: does that regress or progress?” said Dr. Dennis Ausiello, director of the Center for Assessment Technology and Continuous Health (CATCH), former chief of medicine at Massachusetts General Hospital and a scientific advisor to PureTech Health’s team.

Dennis Ausiello, MD; director of the Center for Assessment Technology and Continuous Health (CATCH), former chief of medicine at MGH; scientific advisor to PureTech Health

“And so we’re using cues from previous epidemics, but even if a small percentage of those patients progress, and as said that the progression is largely a pro-inflammatory leading to a fibrotic process, then we could have a significant number of patients going forward over the next months or years with lung limitations. And so it’s in that context that we actually have a synchronized event here i.e. pretty uniform instances of a disease that has the potential to cause at least, in some subset of the population, significant post-recovery inflammation and ultimately fibrosis. And it’s in that context that this clinical trial is being designed.”

PureTech Health’s proposed therapy for these potential respiratory issues, deupirfenidone (LYT-100), builds upon a proven anti-fibrotic agent, pirfenidone. That drug, marketed by Roche / Genentech as Esbriet was approved by the FDA for idiopathic pulmonary fibrosis (IPF) in 2014. Researchers thought to try it for COVID-19 patients, based on the kind of lung fibrosis they saw in hospitalized patients with COVID-19.

“Some of the [pirfenidone] studies are of different design in terms of the length and goals and endpoints of the study,” said Michael Chen, senior director at PureTech Health. “I think it’s safe to say that relative to the vast majority of the trials targeting the acute treatment or antiviral or vaccine studies, there are very few looking more at the long-term complications that we’re targeting.”

LYT-100 is a deuterated version of pirfenidone, in which a hydrogen in the small-molecule is replaced with a heavier deuterium isotope. made into a twice-daily oral form. Early studies on LYT-100 suggest that the molecule might aid in preventing inflammation by targeting TGF-beta, TNF alpha, and IL6.

“[LYT-100] is a deuterated form of pirfenidone,” said Eric Elenko, chief innovation officer at PureTech Health. “What that really enables is better pharmacokinetic properties; this was seen in a single dose study in healthy volunteers where pirfenidone was compared to LYT-100, and greater exposure was seen at the same dose. Those pharmacokinetic benefits can then translate potentially into better tolerability and even potentially better efficacy at the same dose, so it’s really driven by this deuteration.”

Eric Elenko, chief innovation officer, Puretech Health

The clinical trial, which will take place over the course of three months, will focus on  potency and tolerability of LYT-100. The core subject group will primarily consist of COVID-19 patients post-hospitalization as they deal with any persisting respiratory issues in recovery. The expected aim of the study will be evaluated using standardized pulmonary function testing to evaluate the relative progression or regression of lung function.

The company chose to focus on pulmonary fibrosis based on past data related to pandemics of a similar scale and profile, most specifically the original SARS-CoV and the MERS-CoV pandemics that surfaced in 2002 and 2012 respectively; both of these viruses caused lung dysfunction that lasted  for years after the initial infection.

“If you also look at SARS and MERS, those [epidemics] also give a good way to peg the potential damage that might occur for survivors of these types of viral infections,” Elenko said. “You know there are reports of those sorts of patients having issues, so I think as particularly this first wave is coming in, and you have a first set of survivors, this issue of fibrosis and lung damage is starting to emerge.”

Other long-term fibrosis studies in COVID-19 patients, beyond PureTech Health’s, have begun to take shape in China in Wuhan and Guangzhou among other provinces.Early results were published recently in The Lancet and the European Respiratory Journal, but most of these studies are in their initial exploratory phases with little public information currently available.

Beyond fibrosis, other potentially concerning long-term implications of COVID-19 are surfacing globally. Recently, physicians have been observing instances of a Kawasaki-like disease occurring in tandem with COVID-19 infection, specifically targeting children and young adults who were previously perceived to be less likely to suffer severe consequences as a result of COVID-19 infection. Kawasaki disease occurs as a result of blood vessel inflammation, commonly known as vasculitis, and can have fatal results if left untreated, including cardiac issues and risk of aneurysms.

“So there are other [long-term] components [to consider], but keep in mind that fibrosis is often the end result of many pathological events, and so whether you’ve got almost always a pro-inflammatory process preceding fibrosis, and it’s in that context that you want to recover from the inflammation, you don’t want to recover with the progression of the fibrosis,” Dr. Ausiello said. “Fibrosis is a common pathological endpoint, largely irreversible, and that is not a good thing to happen to any organ or tissue.”

Kshithija (KJ) Mulam is a biomedical engineering and political science student at Columbia University in the City of New York. As a budding technical writer and scientific journalist, she is deeply interested in clinical medicine, AI, and law & policy, specifically their intersection in the biotechnology industry. 

31
May
2020

Dig Deep and Fight Hard Against Injustice. Here’s How

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31 May 2020

Rob Perez, chairman, Life Science Cares

If you are as sickened and outraged by the events that have occurred during the past week in our country as I am, you might be asking yourself a couple very important questions.

How did we get here?

What can I do to be a positive force for change?

The killing of George Floyd, an unarmed African American man, was an injustice at the hands of police caught on video. It can’t be unseen. As saddened as I am to see peaceful protests turn into violent riots in in the streets, I am not surprised. The economic boom has benefited some of us, but not all of us. It also created an ever widening gap between the life we lead and those who are similarly disadvantaged by the same economic, political, and justice system. 

You need only look at the COVID-19 pandemic. COVID-19 is killing African Americans at a rate that is ~three times higher than white people, according to a nonpartisan APM Research Lab study.

In Michigan, black people make up 14% of the state’s population, but account for 41% of coronavirus deaths.

In Illinois, black people make up 14% of the population, but account for 32.5% of coronavirus deaths.

In Louisiana, where black people make up about 33% of the population, Gov. John Bel Edwards said in early April they account for more than 70% of the state’s coronavirus deaths.

The COVID-19 pandemic isn’t just depriving black people of their lives – it’s taking away their livelihoods at a far greater rate. The economic toll has been hardest on the people who make the least money, and who are most vulnerable in our society.

Even in good times, African American unemployment is usually about double that of white Americans. During the pandemic, that gap has narrowed. At first glance, that may appear to be a good thing. But it’s deceiving, because it is actually because blacks are over-represented in low-wage jobs — mail carriers, fast food workers, health care auxiliary staff, etc. — who are more likely to stay on the job because they are deemed  “essential.” Many of these people, while taking home poverty-level wages, are being asked to put their own health on the line every day to keep our society running.

If you study your history, you will find that this type of injustice is the key driver behind most revolutions. Seeing anger and outrage pour out into our streets when another black man is killed senselessly on video, is to me, an expected result of an unfair system. It was sure to happen sooner or later.

So what do you and I do? 

The time for thoughts and prayers, or expressing outrage on social media, or talking to friends about how terrible things are, is over.

Those days of passive caring are in the past.

If you are not actively looking to make changes to the system that is producing these results, then you are complicit with the results it is producing. 

This is a hard thing to say out loud. It’s even harder for some people to hear. Many of us benefit greatly from having things stay the way they are, and tend to go about life without seeing this kind of deep, painful injustice on a regular basis.

Events like the killing of George Floyd can propel us to take the kinds of hard action that must be taken to dismantle systemic racism. During times like today when we are all saddened and frustrated with what we see as a broken system, we need to look in the mirror and ask ourselves how much we really care to see a different result. Those of us who look in the mirror and think “I’m not a racist” but are only passively supporting change, need to take another look in the mirror and think harder about what it’s really going to take to achieve the change we need.

The good news is that I know a lot of people want to care actively. Many people of good faith truly believe that the status quo is not acceptable. They just don’t really know how or what to do about it. 

As an African-American man past age 50, having grown up working class in Los Angeles and now having had a successful business career, I have a pretty unusual lens to look at both sides of this rather large gap. I know people are striving for better, and looking for effective ways to do so.

Here are a few tangible ways to make a real difference. The list is nowhere near comprehensive, but at least it provides some ideas:

VOTE!

As I’ve written previously, I believe that discrimination based on racial, gender, sexual orientation and other prejudicial lines needs to be a litmus test issue. Candidates for elected office who are not committed to basic human equality need to be voted out, regardless of how much we agree with them on other issues (taxes, etc). America has a long history of forgiving monstrous behavior in favor of supporting those who benefit our economic and social status quo.

If you want the system to change, this type of individualistic “what’s in it for me?” type of thinking has to end. 

If you want to care even more actively, then work to help those who are disenfranchised to register and vote easily.

Our political system has a long and sad history of suppressing the votes of people of color. In Milwaukee, some central city voters had to wait in line 2.5 hours to vote, because so few polling stations were open during the pandemic. How many of you would wait 2.5 hours to vote? I wouldn’t. No one should have to. This is not what our democracy is about. By the way, in nearby Madison, Wisc. – a smaller city with a much higher percentage of white people — three times as many polling stations remained open on election day. People there didn’t have to wait 2.5 hours.

This is wrong. It shouldn’t happen again in our country.

Hire

Many of us are walking examples of the American dream. We have great jobs, and have been given the chance to compete and succeed in the greatest industry in the world. For many of our brothers and sisters in underserved communities, access to the same dream is simply not available. Every time you hire from the same schools, from the same referral sources, using the same system, you are perpetuating the income gap that purportedly causes you so much frustration. Here are some tangible ways to break the cycle, and narrow the gap:

  1. For every intern you hire from a family friend or colleague, from your alma mater, or from the usual ways you find young talent, add one person of color, or person from an underserved socio-economic community to fill a similar role. Each time privilege and contacts are used to perpetuate the system, break the cycle by allowing someone in who would not have access otherwise.
  2. Mentor one person. In this time of virtual connections, this is as easy as it has ever been. Just find the time to connect with one person, electronically and voice to voice. Help them to understand your journey, and give them access to the same privilege that you provide to those who are currently in your circle of family, friends and colleagues. If you need help finding someone, Life Science Cares can help.
  3. Find talent everywhere. As a proud graduate of Cal State Los Angeles, I am continually irritated by the notion that the only smart people worth hiring are those who attended the “top” schools. There is no question that most students who attend the “top” schools are bright and worked their butt off to get there.But to assume that kids who are at state schools, community colleges, etc. are not as bright or talented is an absolute fallacy. If the hiring system of your company relies on school brand as the proxy for whether young people are smart and talented enough to succeed in your company, you are fooling yourself, and perpetuating the system of inequality that exists today. To stop it, you need to change that system by allowing access to your jobs to those students from the lesser-known schools who are not only just as smart, but who have proven to have the grit that correlates well to success in virtually all fields.
  4. Add a parallel hiring process. If your current system for hiring women and people of color is not producing the diversity that should be demonstrated in your workforce, don’t try and completely change your current system.Add a new one. I often hear people defend status quo hiring practices by saying it would take too much time, effort and money to completely revamp the way talent is brought into the organization. I get it. Keep the process you have in place, but add one or two unique activities that are specifically designed to offer opportunities to those who have little access to your jobs. (For a list of ideas, check out this previous blog.)
Promote

Every one of us had someone, or likely numerous people, who were willing to take a chance on us before we were proven. It is easiest to do that when the person we are entrusting look like us, and remind us of younger versions of ourselves.

While that is completely understandable, it serves to reinforce the status quo and create barriers that people may not even realize exist. To see real change, find one person who is different from you in your professional circle, and be their benefactor. This could mean advocating for their professional advancement, approving their project even though you’re not sure it will succeed, or standing up for them when they are being treated (consciously or unconsciously) unfairly.

Educate

The disparity between how students of color and white students are educated is a cornerstone of the current system. No tool is as effective in reducing the income gap than making high quality public K-12 education more accessible. Your ZIP code should not dictate your future earnings.

There are numerous programs, schools and organizations whose mission is to help students from underserved populations have access to quality education. Support them. Instead of giving your economic abundance to the schools and organizations that already have overflowing resources, (Harvard has a $41B endowment!) direct them to those that don’t, and those who are educating students who need a bridge to cross this divide. Instead of joining in the fund raising effort at your kids’ private school to build the next new gymnasium or library, how about giving to an organization that makes private school education accessible to a student who could never experience it otherwise. THAT creates a new system.

Engage

*****WARNING, WARNING….SHAMELESS PLUG AHEAD******

Signing petitions is nice. Writing checks is even better.

Caring actively requires more than this. 

If you really want to change the “system”, you must engage. Find an organization that seeks to make real change and spend some of your time getting your hands dirty. This will look different for all of us depending on where we are in life, but this is not the time to remain on the sidelines cheering. All of us have to get on the field and do something. 

Our mission at Life Science Cares, in Boston and in Philadelphia, is to be a vehicle for our biopharmaceutical industry to do just that. We are connected to nonprofits that do the best work in our cities in fighting poverty, enhancing education, and otherwise serving the most vulnerable people. We know that the people in the biopharmaceutical industry are extraordinary, and care deeply about humanity. We also realize that these extraordinary people are super busy, with their careers and with life, and likely don’t have the time to seek out the perfect organization that is worthy of their time and treasure. 

If that is you, and you really want change, give us a call or drop us a note. We will work tirelessly to connect you to an organization that will not only satisfy your desire to change the system, but also make a meaningful impact on those who that same system has left behind. 

If you already have a way to engage, terrific! Give it as much of your energy as you can muster, and encourage others to do the same. If you have other ideas on how folks can care actively, please post a comment to this blog, tag me in a Twitter note on your suggestion, or somehow make your ideas heard.

There is no better time than the present to change the world, and no better reminder than this week that it really needs changing.

31
May
2020

Adtech Data For Health: Time To Get Past The ‘Ick’ Factor

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31 May 2020

David Shaywitz

If you were responsible for the health of a large population, and could access just one of the following types of data, what would you choose (assuming all were acquired legally and responsibly)?

(a) Genetics and other –omics data;

(b) EHR data;

(c)  Consumer/adtech data.

For at least the last 20 years, we’ve been obsessively focused on the first two categories, as proponents of precision medicine were enthralled with the possibilities of what we could learn from genomics and other types of -omics data. Advocates for a learning healthcare system, meanwhile, tended to emphasize the value of medical record data. These efforts have yielded important progress. 

At the same time, if we’re being honest, we must acknowledge that these approaches haven’t (yet) delivered anything close to the envisioned healthcare transformation originally promised. Perhaps, we just need to be more patient.

While some academic groups have begun looking at consumer/adtech data, this information has remained largely off-limits for serious healthcare companies and researchers — mostly because it’s just too fraught, enmeshed as it is with ethical and legal landmines. The very existence of the copious amounts of data on consumer buying patterns and expressed affinities is viewed by some as intrinsically problematic. Many worry about the ecosystem in which these data were generated, concerned about the increasing pervasiveness of what sometimes called “surveillance capitalism.” 

According to some critics, these data shouldn’t even exist. Given the reality of their enduring presence, many believe we should do all we can to minimize their impact.

Similarly, I suspect some medical researchers viscerally view adtech data the same way they (and I) view the results of historically unethical experiments, like (to pick a deliberately extreme example, and risk invoking Godwin’s Law) Nazi doctor Josef Mengele’s notorious twin studies. The repugnant method in which Mengele’s data were obtained are generally felt to outweigh any potential utility; the results are not typically considered part of the scientific canon.

While Mengele analogy may be over the top, the discomfort towards this information is real, and consequently, most everyone in healthcare steers clear – well clear – of adtech data. Medical systems, to the extent they are even aware such data exist, are unlikely to go anywhere near them; it would risk reducing patient trust, with no apparent upside. (I’m sure the marketing department of medical systems are well-aware of these data, but have no interest in connecting this information with traditional health data.) 

Tech companies like Google and Amazon are keenly aware of consumer and adtech data; their business models and staggering valuations are built on these data. Yet, most large tech companies seem to have decided that they want to become trusted partners to healthcare. The business opportunity they see in this space doesn’t involve their traditional model of harvesting consumer data; rather, they hope to sell cloud computing and related services (like AI) to hospitals, drugmakers, health insurers and others. 

In their interactions with healthcare systems, Google, Amazon, and Microsoft each seem to go out of the way to emphasize the robust firewall between patient data and consumer data. At a recent healthcare conference, senior physician-executives at Microsoft and Google, for example, repeatedly emphasized the importance of trust and equity in all discussions of technology. These tech giants want healthcare data from clinical care and pharmaceutical research to be managed and analyzed on their respective cloud services. 

The tech companies evince little interest in “crossing the streams,” and somehow connecting adtech data and healthcare data. The goal is to be trusted stewards of the health industry’s sensitive data, and to help healthcare customers use analytical tools to extract greater value from this information. 

Apple, for its part, has never been particularly interested in monetizing individual data, but rather seems focused on providing a secure data ecosystem, so it can sell the devices that collect (Apple Watch) and integrate (iPhone) this information. 

Facebook, meanwhile, was exploring the possibility of integrating user and health data back in 2018. This work was happening largely out of public view for more than a year. As described by Sidney Fussell in The Atlantic in January 2020, Facebook had sent cardiologist Freddy Abnousi (current head of health technology at Facebook) on a mission:

“He was to get the Stanford University School of Medicine and the American College of Cardiology on board with a new project that would combine Facebook user information with hospital-patient data in order to influence patient outcomes. Facebook hoped it could leverage the cache of data users already give it – about their education, relationships, habits, spoken languages, employment status, and more, all of which have an enormous impact on health outcomes – to create a sort of subclinical health-care system, warning providers if, for example, a user recovering from surgery had a small support group.

Then came the Cambridge Analytica debacle, and with it a cascade of highly public inquires and privacy revelations that resulted in the cessation [of these efforts].”

The Cambridge Analytica scandal, in which Facebook user data was harvested without consent and ultimately used to inform political campaigns brought new scrutiny on many aspects of the social network’s business. In response, Fussell reports, Facebook opted to roll out a dramatically scaled-down version, “Facebook Preventive Health.” The capability is offered as an (opt-in) feature in the Facebook mobile app, and uses only two user data points: age and gender. 

Just a few months after The Atlantic report, Facebook still seems to be pursuing an ambitious health vision. Facebook’s Abnousi is currently hiring a Head of Health Tech Research, seeking “a world leader in outcomes research to develop and execute a digital health tech research agenda that is aimed at improving morbidity, mortality, cost, and inequity in health outcomes” (you can apply here).  This suggests that although Facebook told The Atlantic that the Preventive Health effort is unrelated to the original data sharing proposal, the underlying goal outlined in talks with Stanford and the American College of Cardiology has endured.

Without question, there’s a creepy, icky aspect to adtech data, information that speaks to our habits and predilections, and are collected every time we Like something on Facebook, purchase something on Amazon, or search for something on Google. 

Responsible health researchers typically seek to understand patients based on parameters like genetic sequence or physician notes or claim records – each of which could be exceptionally useful.  But meanwhile, reams of data describing our actual, real-world behaviors are now the exclusive provenance of advertisers seeking to hawk soda and politicians. Health scientists and hospital administrators, for the most part, seem to have a knee-jerk reaction against touching these data; concerned about the risks and anxious about the many uncertainties. But the inconvenient truth remains: our behavior and choices play an outsized role in determining our health – and adtech data may offer the most relevant window into this critical parameter.

From the perspective of a startup, the ickiness of the data, and its existence in a grey area, may represent an opportunity, since established healthcare companies and tech giants are likely to give these data wide berth, creating an opportunity for a startup in the model of Uber or PayPal willing to embrace and intelligently navigate the risk, as VC Josh Kopelman has described. 

A startup that could leverage adtech data and generate relevant health insights for traditional stakeholders could be an intriguing proposition. Think of all the research that seeks to elucidate the genetic basis for extreme phenotypes, including exceptional responders; imagine if there was a way to identify characteristics of patients most likely to maintain weight loss, or patients most likely to respond to treatment A vs treatment B.

Intriguing as these research questions are, figuring out the right business model for a startup in this space remains a critically important challenge.  

As a leading data guru told me:

“The main issue is what do you do with this information … that’s what I don’t think anyone has figured out. Let’s say you can figure out that [some factor] is correlated with a particular health outcomes, etc. — how does that actually change the course of care, or what pharma companies/payers/providers do?”

This feels to me like a solvable problem – and a worthy challenge. The risks can be responsibly managed. To the extent that we remain awash in ultra-granular, legally-obtained behavioral data, it seems a shame not to gainfully leverage this information for the improvement of human health.

28
May
2020

The Infodemic Summer

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28 May 2020

Luke Timmerman, founder & editor, Timmerman Report

The US death toll from COVID-19 exceeded 100,000 this week.

Another 40 million people are unemployed. 

We’ve been on this terrible trajectory for what seems like forever, with 20,000 new cases a day and 1,500 or so deaths every day. The New York Times lists 18 states where new cases are increasing and 19 states where cases are decreasing.

Memorial Day weekend came and went. People are stressed and fatigued and antsy and lonely and depressed. We’re all seeking social contact. Some are gathering outside in large groups without masks. Images of crowds were everywhere from the Georgia coast to the lakes of Missouri to the Montlake cut in Seattle.

Knowing what we know about how the virus transmits, and everything we’ve seen this spring, we can expect an increase of cases in 2-3 weeks. (See Otello Stampacchia’s May 26 analysis).

Will there be just a “blip” in new cases, in the optimistic scenario outlined by Tony Fauci, or will we see a Second Wave surge?

We don’t know yet. But we do know that a pharmaceutical intervention will not be riding to the rescue this summer. If we want to reduce the toll of suffering and death, we will have to get by with non-pharmaceutical interventions that have caused so much pain since March.

Another thing we do know is that our country is at war with itself. Many people can’t even speak to members of their own families. Many can’t speak to old friends across the partisan divide. Many, inhaling toxic fumes from our 24/7 online networks and extremists on cable TV, suspect bad faith and fraud and conspiracy everywhere. It strikes some people as hard to believe that anyone might mean well, make a mistake, and then try to fix it.

All of the bitterness and resentment and suspicion of other people’s motives makes it incredibly hard to mount the kind of consistent, disciplined, collective action response we need.

The consequences of the infodemic are here, staring us in the face.

This is a good time to re-think what kind of information commons we want to have in the 2020s and beyond. One place to start is by re-reading the late Neil Postman’s “Amusing Ourselves to Death: Public Discourse in the Age of Show Business.” It was written in 1985, when TV was king, and social media didn’t exist. It’s a brilliant, biting work of media criticism. But it doesn’t let us off the hook as citizens. It asks an uncomfortable question: are we willing to do the work of being citizens, or are we just empty consumers of entertainment and advertisements?

Even though Postman didn’t predict the nightmare of the entertainer-in-chief — that was too preposterous for the time — he correctly saw the conditions that made that rise possible.

I’d like to think we can reclaim what it means to be citizens. What are the responsibilities that come with that? What sort of work does this demand of us? What do we owe our fellow citizens? It means more than just showing up to vote once every four years.

Right now, a lot of people are wrestling with deep questions like this. In my more optimistic moments, I imagine that people will come out of this terrible time dedicated to others and to issues larger than themselves.  

Communication in the 21st Century

Headline: “Zuckerberg Says Twitter is Wrong to Fact-Check Trump.” Newsweek. May 27. (Daniel Villarreal).

Early in the pandemic, a reporter asked the President of the United States about the diagnostic testing failures and delays.

He replied: “I don’t take any responsibility at all.”

He’s not the only powerful man shirking his responsibility. So is the man in control of the most powerful information distribution network in human history.

Mark Zuckerberg, the Facebook founder and CEO, built an empire that siphoned away most of the revenue from advertising that used to support local news publishers all over the United States.

While Zuckerberg was demolishing the local news gathering engines that hold local officials accountable and build community tensile strength, he did nothing to fill the civic void. Zuckerberg, for years, has insisted Facebook is just a platform, and doesn’t really have to shoulder any responsibility of being a publisher. Grudgingly, the company has instituted a few bare-minimum policies to take down the worst kind of posts that incite imminent harm. These are expensive and tedious and difficult things that come with a publisher’s responsibility. It’s a big responsibility. Like making sure the things you publish are rooted in fact. Like adhering to basic standards of fairness. Like correcting your mistakes. Like giving a damn about serving your community with the kind of quality journalism that people need to make informed decisions in a democracy.

Instead of owning up to his role in hollowing out local media and doing something meaningful about it, Zuckerberg has spent years in a defensive crouch. This week, he threw some shade at Twitter. Twitter, like Facebook, is under pressure to behave like a responsible publisher. So Twitter started pointing out the baselessness of certain tweets by the President. That provoked Mr. Zuckerberg. Maybe he’s afraid that if citizens demand accountability from Twitter, they might also demand it of Facebook?

Zuckerberg went on offense. He told FOX News that “Facebook shouldn’t be the arbiter of truth of everything that people say online.”

I agree. It shouldn’t be the arbiter. No Internet company should be that big, and that unaccountable to the public. While we are free to speak out and consume on Mr. Zuckerberg’s propaganda-drenched social network, we’re also free to ignore it — even though persuasive design and algorithm enhancements make that psychologically very difficult. We’re also free to demand that Zuckerberg take responsibility as a publisher, or force him to do so through legislation.

It will take tenacity and discipline, but we can do that.

That won’t happen anytime in 2020, as lawmakers have other things to do. But if you want to do something positive right now to reverse the catastrophic degradation to our information system, I suggest permanently deleting your Facebook account and purchasing a subscription to your local newspaper.

Headline: “Sorry, No Mask Allowed. Some Businesses Pledge to Keep Out Customers Who Cover Their Faces.” Washington Post. May 28. (Teo Armus).

Some people don’t like being told to wear masks. But as things get more extreme, we now have businesses banning people from setting foot in their establishment if they choose to wear masks.

This can only happen in a society that cares little about others. Wearing a mask isn’t much to ask. We have got to take a deep breath as a people, and find a way to talk to each other, listen to each other, and help each other adopt the collective behaviors necessary to reduce the risks of the pandemic.

Headline: “Why Scientists Are Changing Their Minds and Disagreeing in the Pandemic.” CNBC. May 23. (Chrissy Farr).

With distrust on the rise, a fair bit is directed at scientists. Scientists need to be aware, and communicate with care.

Glancing at the headline above, you might say “duh, that’s how science works.” Of course, good scientists change their minds when presented with new evidence, or evidence that contradicts guidelines based on prior studies that have been overturned. But not everyone knows that. Scientists, and journalists, should take great care to communicate with humility and caution about what’s known and what’s not, and what’s the best course of action for the time being. Readers and viewers should know things could change if new evidence emerges, and it probably will with a virus that’s brand new to science.

Headline: “He Experienced a Severe Reaction to Moderna’s Covid-19 Vaccine Candidate. He’s Still a Believer.” STAT. May 26. (Matthew Herper)

Say what you want about reporting on an anecdotal adverse event in the midst of an ongoing clinical trial of global significance. I would rather wait to see the text and data tables from a mature analysis in the New England Journal of Medicine. When anecdotes dribble out in the middle of a trial, it injects bias for both investigators and participants. Then it can spread like cynicism wildfire.

See this young man’s succinct summary of what happened after this article ran about his experience on the Moderna vaccine.   

 

Merck on the Case

The big drugmaker company hasn’t been the loudest voice in the pharmaceutical world this spring, but it announced a series of aggressive moves after Memorial Day. The company:

  • Acquired Themis, a preclinical, private vaccine developer that has a partnership with the Institut Pasteur and the Center for Vaccine Research at the University of Pittsburgh. Merck said it plans to drive that SARS-CoV-2 vaccine candidate into clinical testing in 2020.
  • Agreed to collaborate with IAVI on a vaccine candidate that uses the same underlying technology platform that Merck used to make the first and only Ebola virus vaccine.
  • Obtained from Ridgeback Biotherapeutics the exclusive worldwide right to develop and commercialize EIDD-2801, an orally-available ribonucleoside analog drug that inhibits the replication of multiple RNA viruses including SARS-CoV-2.
  • Sought to pooh-pooh the ambitious expectations on vaccine development timelines.

Scientific Articles of Note

  • Remdesivir for the Treatment of COVID-19. Preliminary Report. New England Journal of Medicine. May 22. (John Beigel et al)
  • Deep Sequencing of B cell Receptor Repertoires from COVID-19 Patients Reveals Strong Convergent Immune Signatures. BioRxiv. May 20. (Jacob Galson et al)
  • Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. May 7. Cell. (Alba Grifoni et al)
  • Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies. May 15. Cellular & Molecular Immunology. (Chunyan Yi et al)
  • The Emergence of SARS-CoV-2 in Europe and the US. BioRxiv. May 23. (Michael Worobey et al)
  • Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. May 22. (Mandep Mehra et al)
  • Preventing Cytokine Storm May Ease Severe COVID-19 Symptoms. May 20. HHMI News. (Meghan Rosen, quoting Bert Vogelstein)
  • A National Open Genomics Consortium for COVID-19 Response. Centers for Disease Control and Prevention.

Science Features

Thoughts on Evidence in a Pandemic (Debate in Boston Review)

Humanity

  • Is It Safe for Me to Go Back to Work? Risk Stratification for Workers. New England Journal of Medicine. May 26. (Marc Larochelle)
  • Medical Residents Are Stressed to the Breaking Point. USA Today. May 26. (Ashely Alker)
  • AIDS Activist Larry Kramer Dies at 84. The Guardian. May 27. (Joanna Walters) See Also, “He Was a Force of Nature” a Set of Remembrances from Tony Fauci, Tom Frieden, Gregg Gonsalves, Harold Varmus and Rick Berke in STAT.

Testing

Wuhan, China, the original epicenter of the SARS-CoV-2 outbreak, reportedly ran 9 diagnostic tests in 10 days as it sought to gain clarity on where the virus is, so it can be isolated and give people the confidence necessary to resume activities of normal living. (WSJ coverage).

Treatments

Roche / Genentech said it has initiated a Phase III trial of its IL-6 inhibitor tocilizumab (Actemra) in combination with Gilead Sciences’ remdesivir as combo therapy for hospitalized patients with severe COVID-19 pneumonia. This would combine the Gilead drug’s antiviral effect with the antibody that suppresses cytokine storms which are known to cause major complications. Enrollment is expected to start in June, with 450 patients globally. Separately, Genentech said it’s close to completing enrollment in the Phase III Covacta study, and expects results this summer, to see how the IL-6 inhibitor alone performs for hospitalized COVID-19 patients.

Vaccines

GSK said it plans to scale up production to make 1 billion doses of vaccine adjuvants in 2021. These are the compounds that can boost the potency of vaccines to elicit robust immune responses, and which could be used to reduce the actual dose of vaccine protein per dose, thereby stretching out potentially limited supplies to a larger swath of Earth’s population. GSK said it believes more than one vaccine will be necessary, and that it’s working with partners to make adjuvants that will complement more than one vaccine candidate.

Gaithersburg, Maryland-based Novavax said it began enrolling 130 healthy adult volunteers in a randomized Phase 1/2 clinical trial of its SARS-CoV-2 vaccine candidate. The protein-based vaccine comes in a standard version, and with another version that includes a proprietary adjuvant designed to boost higher levels of neutralizing antibodies. A low and high dose are being evaluated, with and without the adjuvant. The study is being run at two sites in Australia. The program is funded by the Coalition for Epidemic Preparedness Innovations (CEPI).

Reuters had a detailed piece on the US plan to enroll 100,000 volunteers in COVID-19 vaccine studies in the hopes of hitting the extraordinary deadline of delivering a vaccine by the end of 2020. Dr. Larry Corey, principal investigator of the HIV Vaccine Trials Network based at Fred Hutch, was quoted in the story as one of experts designing trials. (Listen to Dr. Corey on this recent episode of The Long Run podcast).

US Healthcare Dysfunction

Read this piece by Dr. Sachin Jain and nod along about all the entrenched interests and how they stymie positive change in healthcare. To summarize, quoting Upton Sinclair: “It’s hard to get a man to understand something if the man’s salary depends on not understanding it.”

Financings

  • Sanofi said it intends to sell 23 million shares it holds in its longtime partner, Regeneron Pharmaceuticals. That deal will fetch a cool $13 billion. Regeneron will repurchase $5 billion of the shares, and Sanofi will keep about 400,000 shares, less than a 1 percent ownership stake in the company.
  • Vancouver, BC-based Abcellera, an antibody discovery company, raised $105 million in a Series B financing led by OrbiMed.
  • San Francisco-based Insitro, a company using machine learning to aid with drug discovery, raised $143 million in a Series B financing. Andreesen Horowitz led.
  • Seattle-based Variant Bio raised $16 million in a Series A financing led by Lux Capital. Andrew Farnum, who previously ran the $2 billion strategic investment fund at the Bill & Melinda Gates Foundation, joined as CEO. The company is working to develop drugs by studying the genes of people from understudied populations who are outliers for medically relevant traits. The company has projects focused on the Maori, in the Faroe Islands, in Pakistan, and with the Sherpa people who live at high-altitude in Nepal.
  • Boston-based Ginkgo Bioworks, a synthetic biology company, raised $70 million to develop tests for COVID-19.
  • Emeryville, Calif.-based Octant, a synthetic biology company developing small molecules for large numbers of GPCRs, raised $30 million in a Series A deal led by Andreesen Horowitz.
  • Seattle-based Good Therapeutics raised another $11 million to complete a $22 million Series A round, to advance its work on developing protein drugs that activate only in certain biological contexts. Roche Venture Fund and Rivervest Venture Partners participated.
  • Seattle-based Nautilus Biotechnology raised $76 million in a Series B financing. The company is developing a low-cost platform for analyzing the human proteome for drug discovery. Vulcan Capital, the investment company founded by the late Paul Allen, led.
  • Cambridge, Mass.-based Q32 Bio announced it has raised $46 million in a Series A financing to pursue biologic drugs for autoimmune diseases, starting with an IL-7 receptor inhibitor. Atlas Venture led the round, and was joined by OrbiMed Advisors, Abingworth and Sanofi Ventures. Michael Broxton was named CEO, and co-founder Shelia Violette is CSO and president of research.
  • San Francisco-based Syapse raised $30 million to work on real-world evidence for cancer trials.
  • Wayne, Penn.-based Palvella Therapeutics, a rare genetic disease drug developer, raised $45 million in a Series C.
  • San Diego-based Arena Pharmaceuticals raised $275 million in a stock offering priced at $50 a share.
  • Research Triangle Park, NC-based Biocryst Pharmaceuticals raised $100 million in a stock offering.
  • San Carlos, Calif.-based Iovance Biotherapeutics, a cancer immunotherapy company, announced plans to raise $500 million in a stock offering.
  • Deerfield Management committed as much as $130 million to support research at the University of Michigan.
  • Gaithersburg, MD-based Viela Bio raised $169 million in a stock offering for its autoimmune disease drug programs.
  • Alameda, Calif.-based Penumbra, a drug developer, raised $100 million in a stock offering.
  • Menlo Park, Calif.-based Geron raised $140 million in a stock offering.

Data That Mattered

Netherlands-based Argenx passed a Phase III clinical trial with its drug candidate efgartigimod for myasthenia gravis, a rare autoimmune disease that causes debilitating muscle weakness. About two-thirds of patients on the drug met the primary endpoint of improvement in activities of daily living, compared with about one-third of those on placebo. The company said it plans to submit an application for FDA approval by the end of 2020. Two days later, the company seized on the momentum in its share price to haul in $750 million through a stock offering.

South San Francisco-based Atara Biotherapeutics reported on Phase I results for an experimental T-cell therapy against the progressive form of multiple sclerosis, which is notoriously hard to treat. Results were from a Phase I trial of ATA188, an off-the-shelf T cell therapy candidate, designed to target B cells that carry the Epstein-Barr Virus, and which become a troublesome cell type attacking neuronal sheaths, causing the pain and misery of multiple sclerosis. It was a small study of 25 patients in four dose cohorts, but the company reported that the treatment was safe and patients saw improvements on disability out to 12 months of follow-up. Atara immediately sought to cash in on the data, raising $175.5 million in a stock offering a day later.

Roche/Genentech said it passed a Phase III clinical trial with a next-generation permanent refillable implant to deliver the VEGF inhibitor ranibizumab to the eyes of patients with the vascularized form of age-related macular degeneration. The new implant, about the size of a grain of rice, can be refilled with drug after a period of months. In this study, it was refilled after six months, and delivered similar results as the standard form that requires frequent injections of ranibizumab (Lucentis).

Merck said it passed a Phase III trial, in which its single-agent PD-1 inhibitor pembrolizumab (Keytruda) was found superior to standard chemotherapy in patients with microsatellite-instability high or mismatch repair deficient forms of metastatic colorectal cancer. The drug showed a 40 percent improvement on Progression Free Survival.

Deals

Hayward, Calif.-based Arcus Biosciences collected $175 million upfront from Gilead Sciences as part of a 10-year collaboration to work on Arcus’ treatments based on how tumors evade the immune system. Arcus, like so many other companies in this bull market biotech spring, followed up that news by announcing plans to raise more money from Wall Street.

Cambridge, Mass. and Montreal-based Repare Therapeutics collected a $65 million upfront payment from Bristol-Myers Squibb as part of a collaboration to work on the small company’s CRISPR-enabled synthetic lethal cancer drug discovery platform.

Chi-Med and Beigene announced a partnership to test combinations of a couple VEGF receptor inhibitors with Beigene’s PD-1 inhibitor for solid tumor cancers.

Roche acquired Stratos Genomics to advance its development of a nanopore-based DNA sequencer. Terms weren’t disclosed.

Moderna struck a deal with Luxembourg-based CordenPharma to provide lipid excipients for delivery of its SARS-CoV-2 vaccine candidate. Corden, a supplier to Moderna since 2016, said it will provide “large scale volumes.”

Regulatory Action

Regeneron Pharmaceuticals won clearance from the FDA to expand the label for its IL-4 and IL-13 inhibitor dupilumab (Dupixent) as a treatment for kids ages 6-11 with moderate to severe atopic dermatitis.

The FDA cleared Takeda’s brigatinib (Alunbrig) as a treatment for ALK-positive forms of metastatic non-small cell lung cancer.

Worth a Listen

Epidemiologist Marc Lipsitch on Whether We’re Winning or Losing Against COVID-19. 80,000 Hours Podcast

27
May
2020

The Recovery: A Long Road Ahead for Patients, Healthcare Workers, and Hospitals

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27 May 2020

Alex Harding, MD, associate, Atlas Venture

The Patient

As the patient rolls down the hall in her hospital bed, thankful to be getting out of this place alive, there are many things she can’t bring herself to think about now.

Spending 30 or so days in the hospital, mostly in the intensive care unit on a ventilator, will do that to a person.

Maybe someday later she’ll recall that hazy time she spoke with her husband and children. She’ll have to remember to thank the nurse who flipped her cell phone into speaker mode and held it out at arm’s length in a Ziploc bag, so she could hear their voices.

Somewhere in the back of her mind, there’s that terrible, unforgettable gasping sound of the machine pumping air into her lungs with the regularity of a metronome.

On this day, she isn’t exactly celebrating. She’s thinking more about the uncertain path ahead of her. Her medical team told her she’s better, but it doesn’t feel that way. She is being transferred from the hospital to a long-term acute care facility. This is the type of facility that has been in the news. She’s aware.

Once she’s settled at the new facility, there will be work to do. She will participate in three to five hours of physical and occupational therapy each day. She’s lost 40 pounds over the past month. Her muscles have shrunk so much she can barely lift a fork to her mouth; the thought of being able to walk again is a remote possibility. Her kidneys have stopped working. She is undergoing dialysis three times each week, which she will need to continue until her kidneys recover their function, if they ever do.

She is hoping to have her tracheostomy (a hole cut in her neck so that her vocal cords aren’t injured by the breathing tube) closed in the next week or two, but her doctor told her this morning it could take longer. It will leave a scar.

The uncertainty is the worst of it. Will she be allowed visitors in the new facility? How long until she can get home? Will she ever feel back to normal?

The Nurse

Watching his patient’s bed roll down the hall toward the elevator, the nurse finally has a chance to look around the unit where he’s spent half of his waking hours over the past four weeks.

He paused to appreciate the patient’s life had been saved. That is something to be thankful for. But it was only a pause, after weeks of being on constantly high alert.

It all started for him a month ago. He had received an email from his boss telling him he was being redeployed. He would no longer be answering patient phone calls for the primary care office where he worked. Instead, he was going to work in an intensive care unit taking care of patients with COVID-19. The front of the front line. He had chosen to get out of inpatient medicine 10 years ago. and had never expected—or wanted—to go back.

Those feelings had to be moved to the back burner. Now, after a month in the ICU, with his adrenaline and cortisol pumping, he took a breath. He felt a moment of pride, while watching the medical team rounding and other nurses checking on patients and responding to beeping ventilators. He was proud to be able to take care of some of the sickest patients with COVID-19. He has had patients like the one rolling down the hall, who have reached the brink of death and somehow managed to come back. He’s also seen many patients who have not come back, dying in their hospital beds alone, with no family to comfort and support them in their final hours.

He’s gotten used to the beeping machines, the constant orders to keep track of, the gown and face shield, and even the smothering N95 mask he wears all day long. But he hasn’t gotten used to the deaths. He’s seen more in a month than he had seen in his entire career in nursing before COVID-19.

He takes off his gown and checks his phone. Another email pops up from his boss. This time, he finds out he’s being called back to the primary care clinic in a week. His time in the intensive care unit is coming to an end.

His immediate reaction is relief, but guilt slowly seeps in.

The Unit

The oncology floor is slowly returning to normal. After five weeks as a ‘non-traditional intensive care unit’ treating only COVID-19 patients, cancer patients are coming back. Interspersed with patients on ventilators and multiple medications to keep their blood pressure up, are patients receiving chemotherapy infusions.

There are still ‘listeners’—people with medical training but no critical care expertise—stationed around the unit to hear any ventilator alarms beeping and notify the clinical teams. Critical care nurses and redeployed nurses from all over the hospital still mingle with the regular oncology nurses, but they are gradually peeling away as they get called back to their home service to resume non-COVID-19 patient care.

Hospital administrators tour the halls to see if the unit is prepared to transition fully back to cancer care. Patients admitted to the hospital for chemotherapy infusions are a vital source of income for the hospital. Getting more of these patients in will keep the lights on and the staff paid, enabling better medical care for all patients. The transition to resume normal care needs to happen fast, as the hospital’s revenues dropped drastically in the past month as all elective medical care was halted. This hospital, like all others in the area, lost millions of dollars in April. That can’t happen in May and June.

The COVID-19 pandemic is, of course, far from over. But the recovery must move ahead in parallel with the ongoing containment and treatment of new cases. The more new cases there are, the harder it will be on everyone.

Patients, healthcare workers, and hospitals themselves, are all beginning the recovery process. All face a set of new challenges.

No one knows what the long-term health consequences of COVID-19 are for patients. In speaking with friends and colleagues who have been seeing patients in follow-up after being discharged from the hospital, it seems like long term injury to the lungs is less of an issue than loss of muscle strength and potentially permanent loss of kidney function, and the psychological trauma of having come so near death in an unfamiliar environment without the support of family and friends.

Few patients are back to normal when they leave the hospital. It can take months of intensive physical therapy to regain muscle strength. Kidney function returns over weeks to months in some patients, but others will remain on dialysis to replace the function of their kidneys for the rest of their lives. I expect we will see a rise in post-traumatic stress disorder, or PTSD, cases after this crisis has diminished, no less serious than the PTSD affecting veterans of military combat. This will apply for both patients and healthcare workers.

Many healthcare workers have experienced the most difficult two months of their careers. Some have been pulled out of their regular jobs and redeployed to the front lines, doing work they haven’t done in years, if ever. Others have stopped working altogether. Orthopedic surgeons, for example, are largely idle since they cannot do their job over the phone and most orthopedic surgeries are non-emergent and have been postponed indefinitely.

The redeployed healthcare workers on the front lines have put themselves in danger while seeing many of their patients die of COVID-19. Certainly, they feel pride in helping in this crisis, but also fear about the danger posed to themselves from treating COVID-19 patients, and then potentially putting their families at risk. Many are continually frustrated about the poor coordination of response at the national level and the shortages of personal protective equipment that increase their personal danger. Now, they are also beginning to grieve for their patients who died. Many are returning to their home practices, but they are not—and may never be—returning to normal.

For other healthcare workers who aren’t on the front lines, they feel guilt that they haven’t been able to do more. Perhaps because of their medical specialty, perhaps because they are in a high-risk group or live with someone who is, they have been unable to take care of COVID-19 patients while their colleagues have. While it may seem trivial, the guilt of not serving can be just as acute as the grief among those who have.

Lastly, it is worth considering the well-being of hospitals themselves. As most healthcare services have stopped completely, the business of healthcare has taken a severe hit. Hospitals have high fixed costs (expensive facilities, salaried employees) that cannot be readily scaled back when patients aren’t coming in. The result is millions of dollars in losses each month. Some hospitals and health clinics won’t survive. Others with more resilient balance sheets will, but their ability to recover as institutions offering the best care across a range of specialties will depend upon being able to resume in-person medical care quickly.

Hospitals are already, cautiously, reopening specialty services. They must delicately balance wanting to reopen services for important but non-emergent medical services with the imperative of not facilitating the spread of infection among patients.

At Massachusetts General Hospital, where I work, outpatient services are restarting at a small fraction of their normal volumes to avoid crowded waiting rooms. Virtual care has made more headway into routine clinical practice in the last two months than it did over the decade leading up to COVID-19, and is surely going to remain an important component of management of outpatients for the long term.

It’s not just about the hospitals’ finances, either. Non-COVID-19 medical issues like heart failure and diabetes haven’t gone away, but instead have just been pushed off and temporized. Eventually those patients will need to be seen in person, and the hospitals need to devise a safe system to do so. Like the other aspects of the COVID-19 recovery, it is both a gradual process and an urgent one.

The recovery phase of this pandemic is less dramatic than the initial surge, but it is no less important to get right. Patients, healthcare workers, and hospitals have all been wounded. Healing will take our time, our understanding, and our best efforts to work together.

26
May
2020

Finding a Path in Biotech Venture Capital: Nina Kjellson on The Long Run

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26 May 2020

Today’s guest on The Long Run is Nina Kjellson.

Nina Kjellson, general partner, Canaan Partners

Nina is a general partner with Canaan Partners on the West Coast.

Her investing style leans toward high science, which you can see in portfolio companies like PACT Pharma, a company developing neoantigen targeted T cell therapies for cancer, Tizona Therapeutics, a targeted antibody developer for cancer, and Vineti, a software platform to help cell and gene therapy companies manage their supply chains and scale up with these intricate medicines.  

Nina is also a powerful advocate for helping women advance in biotech. She has developed her own platform with a podcast called Women who Venture, or WoVen, to amplify voices of strong women leaders. She organizes meetings for help women executives extend their networks.

As a successful VC who sits on a lot of company boards, she’s in a position to open doors and uplift people. She takes that role seriously.

I saw Nina do this at close range, when she joined me last summer on a trip to climb the highest peak in Africa, Mt. Kilimanjaro, as part of a group fundraiser for the Fred Hutchinson Cancer Research Center.

It was very important to me as the team captain to assemble a diverse, gender balanced group. Nina played a key role in helping make that happen.

Now before we start, this interview was recorded in early March. I was already sheltered in place, and a bit anxious, but we didn’t talk about the pandemic. I’ve held onto this conversation for a couple months to squeeze in more timely news-oriented episodes of The Long Run. This episode is more in the typical format of this show, which runs longer and discusses the guest’s personal journey.

I know everyone’s busy, but I think we need to have these kinds of deeply humanizing conversations to understand each other better as people, not just one-dimensional professionals who do X or Y.

I hope you enjoy the conversation. 

Now, please join me and Nina Kjellson on The Long Run.

26
May
2020

Miscommunications, Misapplied Policy & Misunderstood Liberty: Why the US Pandemic Response is in Trouble

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26 May 2020

Otello Stampacchia, founder, Omega Funds

On April 17 — seemingly a long time ago — I wrote about what steps would have to be taken in order to (cautiously) “reopen” US states from their various lock-downs and stay-at-home advisories.

The piece tried to focus on the “how”, versus the “when”.

By the early days of May, most states had begun re-opening, and now all 50 states are well along in the process. So how are we doing in terms of following through on the actions that we know can mitigate the spread? What can we expect in the next few months? How should we behave?

This follow-up piece will be divided in the following sections (I have been told I try to cram too much into everything I write, with excessively long sentences, such as this one: I am hoping making this a bit more structured might make easier to follow my writing. Fingers crossed.):  

  1. “Second wave” concerns.
  2. The importance of communication, compliance and behavior modifications in beating the pandemic.
  3. Public Service Announcement.
“Second Wave” Concerns

Medical Definition of “Second wave”: A phenomenon of infections that can develop during a pandemic: the disease infects one group of people first. Infections appear to decrease. And then, infections increase in a different part of the population, resulting in a second wave of infections.

Public health officials and policymakers are concerned about a “second wave” of the pandemic hitting, potentially with even greater force than the first. Most are focused on a timeline towards the fall / end of the year. Some of the (justified) concerns are centered about a renewed surge of COVID infections coinciding with a flu season of unknown severity, taxing healthcare systems even further. That would be bad news for sure.

Yogi Berra: “It’s tough to make predictions, especially about the future.”

Here is the really bad news: in my opinion (and being mindful of the quote above), we are going to see a continuous, substantial increase of infections and fatalities in the US starting (very, very roughly) early / late July, if not sooner. Quite likely, by August / September we might revisit the peaks of daily confirmed infections and fatalities we saw in April.

What am I basing such a pessimistic forecast on?

This bears repeating: this is a very infectious, new virus that spreads at an exponential rate. Please re-read my previous Timmerman Report articles discussing R0 and the rapid spread of the virus. I am still absorbing the visual shock of the historical New York Times front page for Sunday May 24, which listed names of roughly 1% of the dead across the US, in a stunning display covering several pages. I spent hours on its interactive version on the website. Scrolling through it, I was reminded that the total US death toll from COVID-19 was about 100 on Mar. 17. We are now on track to exceed 100,000 deaths by early next week, just as we are “re-opening”. It is easy to forget that.

Let that sink in for a second: 100,000 fatalities in two months.

Let’s also keep in mind that, as of right now, only / roughly a few percentage points, if that, of the US population has been exposed to the virus. Exposure rates appear to vary greatly from state to state, of course (with NY likely being the most exposed): that said, I would be personally shocked if it turns out that more than 3-5% of the US has been exposed as of right now. The problem is we will not know that for sure for a while yet.

For those of you who think this virus will stop circulating altogether over the summer: I would like to point you towards the rapidly escalating pandemic in South America, particularly in Brazil. Rio de Janeiro has had temperatures in the 60s-70s degrees Fahrenheit for a while and cases have spread very fast there for weeks now. Yes, we should expect some R0 reduction (driven by higher humidity, sunlight, etc.), but again it will not magically disappear.  

Another important statistic: back in March, two-thirds of US newly-confirmed cases were concentrated in just five states: NY, NJ, MA, CA, IL. The rest was mostly in MI and WA, which were also hit early (and very hard in the case of MI). Those states reacted early and with the strongest distancing guidelines and measures. At great economic cost, for sure. But they saved lives.

Last week, two-thirds of newly confirmed cases came from the other 45 US states: the virus has continued to spread widely across the country during those two months.

It’s not “just a New York thing” because the city is dense and has subways. It is accurate that highly dense urban areas were hit first and (so far) hardest, and that high population density “weaponizes” the virus. But other, less dense and even rural areas of the country are not “immune”. There is no existing immunity. The virus will keep spreading.

If we do not beat this virus everywhere, we won’t beat it anywhere.

Also an important contributor to my pessimism: since the virus started spreading in Jan / Feb in the US, we did not ramp up PCR (nucleic acid) or serological (antibody) testing to a sufficient scale to identify early on asymptomatic / symptomatic infection spreaders and thus limit the reach of the virus. There is an understandable supply scarcity of reagents needed to perform the tests at a scale that few previously imagined. In addition, a number of antibody tests have been faulty (to the point of being useless).

That said, a country with the technological prowess of the US should have figured this out months ago. We did not.

The importance of communication, compliance and behavior modifications (non-pharmaceutical interventions) in beating the pandemic

A final component leading me to my pessimistic predictions: there is no way we can beat this pandemic without clear, transparent, coherent communication by authorities, followed by the citizenship’s broad compliance with behavior modifications to reduce transmission. Assistance from drugs and (hopefully, one day) safe and effective vaccines will come, but we need to limit the damage and survive before the cavalry arrives.

Needless to say, almost all of those components are missing or confusing at the very least. The sacrifices of so many healthcare and other essential workers and the many people sheltering at home away from their families are potentially being squandered when a minority of the population refuses to comply. When enough come together in close proximity indoors, the math clearly shows that it increases the risk of “super spreader” events like the choir practice group in Skagit County, Washington.

As I am sure you have seen on the news from Memorial Day weekend, multitudes of people have celebrated the “end” of the lock-down and the long weekend by frolicking in large assemblies in swimming pools, beach town sidewalks, across the US. No masks to be seen. Social distancing nonexistent. This is unconscionable.

I want to express just how important those non-pharmacological interventions are by discussing briefly the Japanese experience and making a “compare & contrast” exercise between theirs and other countries’ response to the pandemic.

Japan has surprisingly managed to avoid a catastrophic outbreak, contrarily to most pundits’ predictions. It has the oldest population in the world, with very densely populated cities, and large public transportation networks used by most citizens. It also has very extensive travel links to China, so it is impossible to think that it was not seeded early in the pandemic.

Japan did not perform mass testing of its citizenship, like South Korea, nor did it impose restrictive lockdowns (hairdressers and restaurants have been kept open: for those who know me, I do care way more about the latter than the former, but not everybody is as follicularly challenged as I am). According to Worldometer’s dashboard, Japan has had only ~800 fatalities to date due to the virus. This is a miracle that cannot be overstated and that everybody is quite puzzled by.

Very early on (in late January), Japan activated its public health centers, which are heavily staffed with nurses trained in contact tracing. So, no fancy contact tracing app like Korea or Singapore, but old-fashioned shoe-leather epidemiology performed by an army of well-trained individuals. People with suspected symptoms, or in contact with people with suspected viral infections, were first screened for other respiratory viruses (influenza, RSV, etc.) and only if tested negative, were then tested for COVID, maximizing the use of scarce COVID test resources. Quarantines of infectious clusters were also sensibly put in place, like in Korea.

A huge emphasis was also put on behavior modification of the entire population to minimize infection spread: preventing one cluster of patients from creating another cluster.

To that extent, government and health authorities spread early, broadly and effectively a very simple message: “avoid the three Cs!”: 1) Closed spaces (with poor ventilation), 2) Crowded places (with many people nearby) and 3) Close-contact settings (such as close-range conversations).

Those recommendations are so sensible — and easy for people to remember — that there is no need, hopefully, to elaborate further. That said, they were given very prominently, very early, and very clearly, by the entire government apparatus as a single voice.

Finally, and essentially, the population broadly complied. Everybody wears masks at all times when walking outside. Nobody speaks loudly (or at all, actually) on their phones on subways / other means of public transportation / while walking down the street (yes, that was already the case in Japan even before the pandemic: I am hoping to sneak in some permanent behavioral modifications also in the US for after the pandemic).

There are probably other factors helping protect Japan from the worst. The population has arguably the lowest rate of obesity and diabetes in the developed world, but again that should be counter-balanced by the demographic skew towards elderly citizens. Who knows. But I am sure there are lessons to be learned here. And that you, non-mask-wearing runners in downtown residential Boston, should learn (that is where I live).

To summarize:

  1. Testing at scale would be very useful to contain the pandemic: in the US, we do not have large volumes of tests available yet;
  2. We could compensate for the lack of large-scale testing with a skilled contact-tracing infrastructure, thus reducing the spreading from one infected cluster to the other: in the US, we lack enough trained people; a tech-based solution is not available yet and might run into privacy and implementation concerns;
  3. We could have tried / try now to compensate with the issues in 1) and 2) above by implementing a sensible communication policy. Communication of the risks / benefits associated with each behavior, if implemented early, clearly and spread widely to ensure compliance, has shown benefits. It is clear to me that the communication effort in the US should probably be characterized as late, lackadaisical, and lacking in consistency and clarity across the various branches of government and public health policy agencies. There are now many instances, across a number of US states, of mistaken statistics provided to the public, concerning both testing volumes (confluence of PCR and serological testing) and undercounting of cases. Ruth Etzioni had another great piece in Timmerman Report about this recently.
Public Service Announcement (Part I)

First, a preamble: this gets into some cultural aspects that might be controversial. You might want to skip this next section if you find it disagreeable and go to PSA (Part II) with some more concrete suggestions. Those should be objectively useful, I hope.

According to the CDC, 45% of the US population has pre-existing conditions (diabetes, hypertension, obesity) that appear to increase severity and fatality outcomes when infected with the virus. This will certainly worsen the already dismal count of blood and treasure (or lives and livelihoods) that the country will have to disburse to get on the other side of this pandemic.

What I would like to discuss, and I am on very thin ice here, as I am a guest in this amazing country, is the role of pre-existing convictions in increasing infection spreading. A number of people in the US reflexively dismissed, early on, warnings coming from science journalists and healthcare / government about the virus. Some of that, certainly early on, might be based on partisan positioning, some of that might be due to a narrow / misguided interpretation of the “American exceptionalism” that seemed to think “it can’t happen here, because nothing like this has in anyone’s living memory.” (I want to state for the record that I do truly believe that this is indeed an incredible country). It might be also hard for people to truly understand the implications of a tragedy that has not yet affected them / their region. However, the virus does not care. It follows a biological imperative to reproduce and spread itself.

Equally, we need to face this pandemic as a challenge for us as a species, not as something to face as a jigsaw of disparate strata of society (or regions) with different socio-economic status, education, access to healthcare, etc. Again, the virus does not care. You should. Your behavior affects others. They might be more or less privileged than you, might be younger or older, it does not matter.

Let me briefly introduce Ayn Rand, celebrated author of “The Fountainhead” and “Atlas Shrugged.” Rand was the founder of a philosophical system named Objectivism (which I am not going to get into, but let’s say succinctly she was not the biggest champion of socialized medicine or collectivism, and she’s become a kind of hero to modern libertarians in the US).

Even Rand, skeptical of the role of government and a champion of individual rights as she was, discussed pandemics as situations where society (as a whole) needs to respond together for the benefit of the herd versus the narrow benefit of the individual. According to Rand, knowingly or negligently subjecting another person to infection with a deadly pathogen falls under the category of the initiation of physical force (like dumping toxic waste on another person’s property).

She makes the illustrative example of “Typhoid Mary,” an asymptomatic carrier of a typhoid fever. She was released from quarantine in 1910, but repeatedly broke her promise to stop working as a cook and ended up spreading the disease further. She eventually returned to quarantine (and spent decades there on an isolated island). It appears to me this is a case that pretty clearly falls under the governmental function of protecting individual rights (not to be infected by others).

This pandemic needs to be tackled as a societal response instead of an individualistic response. With a science-driven, probabilistic approach and using statistics instead of basing ourselves on pre-existing positions and convictions based on whatever politics we might belong to.

Public Service Announcement (Part II)

You will find below some suggestions for behaviors that might help identify different susceptibility risks and factors this summer as things re-open. These guidelines are not perfect, and, to quote Harvard Business School, “it depends” on your circumstances which of them are more relevant to you. The corollary to that, is that the trick is to know what it depends on. The important part is to understand that this is not a set of binary recommendations. Risk is on a sliding scale and different factors have different importance depending on your personal situation.

You are probably familiar with the known individual risk factors: age and pre-existing conditions are still the single largest contributors, as far as we know. I personally believe a medical history of inflammatory disorders (asthma, etc) also increases risk, but it is hard to quantify that or to find hard data on that. It stands to reason, though, since the single largest driver of fatalities appear to be driven by a hyperactive response of the immune system to the virus.

It is also very, very important to consider the sheer volume of virus (size of the viral “inoculum”) you are potentially exposing yourself to with your behavior: time spent in enclosed spaces, with a lot of people for long-term interactions, are very, very risky, obviously, especially if containing younger individuals who might have had promiscuous contacts with a large number of people beforehand, and might well be asymptomatic.

However, even open spaces are risky if in close physical contacts (handshakes, hugs, etc) with multiple parties. For example, we are learning from parts of developing world, like India and Brazil, that even belonging to a younger demographic does not protect individuals from severe prognosis and possibly fatality: so population density / inoculum size could outweigh young age / lack of pre-existing conditions.

Even the amount of physical distancing is relative. Say the person running / biking across from you happens to be a super-spreader, breathing heavily, with a tailwind at his back and close to you? It is impossible to calculate the risk. It is probably not 100%, but it is not 0% either. If you are young, vigorous, with an impeccable immune system (Are you? Really? How do you know?), and avoid touching your face and wash your hands when you are back at home after the run, your immune system is likely to beat this since you are probably not going to be exposed to too many copies of the virus. But you still could become an asymptomatic spreader and nobody would be able to check that.  

So, it’s great to walk outside and exercise, but unless you live in a desert with nobody around for miles, always carry a mask (and wear it in case you come across other individuals / groups), stay as far apart from other people as possible, avoid physical interactions unless you have isolated with these individuals for weeks, and don’t talk loudly on the phone without a mask while walking (or, ideally, ever).

This pains me personally as a Southern Italian, but again there are some lessons here from the Japanese: no touching, no hugging / kissing on the cheeks, no handshakes, no buffets, we should think of individually-wrapping snacks and cookies. All those behaviors limit infectious disease spreading. Civilizations in the Middle East and elsewhere have developed religious precepts prohibiting the consumptions of certain foods, mainly to avoid diseases.

The whole world is going through this tragedy like us: we should all learn from other experiences. The only thing that might move faster than this virus is information. And we all have a lot of things to learn.

Follow Otello Stampacchia on Twitter: @OtelloVC

This article expresses the personal views and perspectives of the author. The views and perspectives expressed here do not necessarily represent the views or perspectives of Omega Fund Management, LLC or any officer, director, partner, member, manager or employee of Omega Fund Management, LLC or any of its affiliated entities.

21
May
2020

A Glimmer of Hope, and a Premature Celebration

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21 May 2020

Luke Timmerman, founder and editor, Timmerman Report

We all woke up Monday morning and saw an encouraging headline.

Then things started to go downhill.

To recap, Moderna, the Cambridge, Mass.-based messenger RNA therapeutics and vaccines company, provided a snapshot of preliminary data from its Phase I trial of a SARS-CoV-2 vaccine candidate, being tested in collaboration with Tony Fauci’s crew at the National Institute of Allergy and Infectious Disease.

From the first 45 volunteers who got this vaccine candidate, data from eight patients at the low 25 microgram dose and others at the mid-level 100 microgram dose were evaluated with 43 days of follow-up from first shot. These eight patients have developed neutralizing antibodies that have “exceeded the levels seen in convalescent sera,” according to the company.

Not a bad way to start the day, I thought, over a morning cup of coffee.

Neutralizing antibodies are what we want to see. But eight patients out of 45? And what level of neutralizing antibodies compared with what level in convalescent sera? And these patients were followed up for how long?

Did we need to hear this interim report – a half-baked dataset prematurely press-released, let’s get real – or would we be better off waiting for a few weeks for the data to mature in a way that might stand up to scientific scrutiny in a public forum?

From the company statement, we don’t know how many neutralizing antibodies were counted, or what the baseline figure was that Moderna used for comparison from convalescent plasma in recovered patients. We don’t know, and can’t know at this point, how long-lasting the neutralizing antibodies are. Not enough time has passed. We don’t know if neutralizing antibodies are produced at consistent levels across age groups, or whether they are reaching sufficient concentrations for the elderly who need it most. We have no idea if these antibodies are enough to protect people from exposure to the virus.

We certainly don’t know the optimal dose – but we better pray it’s as low as possible in order to stretch out the limited supply to vaccinate as many people as possible if the thing works at all.

These questions can, and will, be answered. In time.

By jumping the gun, this press release raised more questions than it answered.

So what actually did happen after the Monday morning release?

Moderna stock boomed. For a normal product in a normal time, nothing would happen when a company released a half-baked Phase I interim snapshot like this. A few specialist biotech investors would roll their eyes and move on. But on May 18, with this all-important vaccine candidate, Moderna’s valuation rocketed to the stratosphere of $30 billion. It’s an unheard-of valuation for a biotech company with no products that have won FDA approval, no products that generate revenue.

The euphoria didn’t stop with Moderna. The entire US stock market was lifted – I repeat, the entire US stock market was boosted by a press release that couldn’t pass Medical Evidence 101 and that few people understood, but which offered a faint early whiff of success.

Moderna struck while the iron was hot, raising $1.25 billion in a public offering.

Yes, we are in bizarro-land. Within 24 hours, people started asking questions about what just happened.

The questions go on and on — and there are plenty that aren’t even being asked yet by enough people.

For starters, we don’t know the right dose. If it works, can we make enough lipid nanoparticles to deliver the mRNA constructs for the 4-5 billion people worldwide in need? How about the medical-grade sterile glass vials needed for the fill & finish steps? Who’s managing the whole supply chain? How will all of that supply-chain calculus shift if the 50 microgram dose is sufficient, or whether we have to go as high as 100 micrograms or 250 micrograms to get the necessary immunity? In a supply constrained situation, who will get the limited supplies of vaccine first? Who will decide that, and how will they do it?

To give Moderna the benefit of the doubt, they know all this. Maybe they know that every penny of the $1.25 billion they just raised is legitimately needed to manufacture this vaccine at global scale. Maybe they need the money RIGHT NOW to build up capacity, before we even know if it’s a winner. I’m willing to accept that. I want to see the company succeed.  

The problem is we are not operating in a normal environment. Biotech plays a dangerous game when raising hopes too early.

Look at what else happened this week. The Moderna “success” inspired imitators. Other companies looked at the rising indices and said it was time to cash in. Some were inspired to pump up their own programs, issue truly ridiculous press releases, then turn to gullible reporters and cynical provocateurs, pumping up what in all likelihood is vaporware.

This isn’t the time for the usual biotech BS. We have about 94,000 dead Americans as of this writing, and another 1,000-2,000 deaths adding up every day. We’re looking at the very real prospect of a big second wave as we re-open the country. About 38 million people have lost their jobs in the past nine weeks. Millions more are going hungry, uncertain about their income, and desperate to get their lives back on track.

We are all fatigued. We are desperate as a people for some good news. We are counting on the scientific enterprise – academia, government and industry together – to rise to the occasion.

Industry has a chance to show the world what it is all about.

At a time when average citizens are drowning in propaganda and don’t know what to believe, and when trust in biopharma is at an all-time low, biopharma must level with people and tell the world it has delivered the goods only when it truly has the goods.

Now, on to other news in biotech this week.

Science

Science Features

Testing

Roche said on May 19 that its serology test for antibodies against SARS-CoV-2 was installed and live at 20 commercial and hospital labs in the US and on pace to scale up another full order of magnitude in the next several weeks – creating capacity for millions of tests a week. This test has 99.8 percent specificity and 100 percent sensitivity for SARS-CoV-2, with no cross-reactivity to other coronaviruses.

Investigations

  • Jetblue Founder Helped Fund Study by Stanford’s Ioannidis That Said Coronavirus Wasn’t That Deadly. Buzzfeed News. May 15. (Stephanie Lee)

Mental Health

  • Anxiety as a Public Health Issue. HBR. May 11. (Sandro Galea)

Annals of Misinformation

California biopharmaceutical company claims coronavirus antibody breakthrough. FOX News. May 21. This story stirred false hope. It’s full of outrageous hype, mixed in with the occasional copy-and-pasted comment from a credible person to give it the appearance of credibility. Yet the report fails to say the study in was done only in a cell line in the lab, not even an in vivo preclinical model. The evidence is a million miles from a controlled clinical trial. The story also failed to point to the corporate stock promotion angle, and the absurd $1 billion market valuation. This is the kind of bad behavior that is too often rewarded, and which gives biopharma a bad name.

Doctors such as Bob Wachter of UCSF are doing their level best on social media, in defense of rational inquiry, and to try to make facts “go viral.” See WSJ coverage.

Data That Mattered

ViiV Healthcare, the HIV company majority owned by GSK, said researchers stopped a 4,600-patient global HIV prevention study early because of positive results. Subjects who got ViiV’s injectable cabotegravir once every two months appeared to have a lower chance of getting HIV than patients who got the current standard of care for HIV prevention — daily oral emtricitabine/tenofovir disoproxil fumarate. The trial technically hit its primary endpoint, powered to show non-inferiority, while approaching superiority, pending final analysis, the company said.

Gilead Sciences and its partner, Galapagos NV, said they passed a Phase 2b/3 study of the JAK1 inhibitor filgotinib in a randomized study of 1,348 patients with moderate to severe ulcerative colitis. The high dose of 200 milligrams met the primary endpoint of clinical remission at Week 10, and the effect held up for a full year. The lower dose, 100 milligrams, didn’t reach the goal of clinical remission at 10 weeks.

Business Model Disruption

Hospitals Knew How to Make Money. Then Coronavirus Happened. NYT. May 20. (Sarah Kliff)

Big Science

The CDC said it’s planning to run a set of big serology studies in as many as 325,000 people in 25 metro areas to see how many have developed antibodies to SARS-CoV-2. The agency’s failures to this point, and the invisibility of its leadership in a time of crisis, have shaken my confidence in this great public health agency to the core. But it’s never too late to turn things around and start the long, hard work of rebuilding trust. Let’s let the scientists gather the data, analyze it to the best of their abilities, and communicate it to the public without fear or favor.

Financings

  • Switzerland-based ADC Therapeutics raised $233 million for its antibody drugs for cancer, via an IPO at $19 a share.
  • Watertown, Mass.-based SQZ Biotech raised $65 million in a Series D financing to advance its work on cell therapies for cancer.
  • Cambridge, Mass.-based Bluebird Bio raised $500 million in a stock offering at $55 a share.
  • Boulder, Colo.-based Clovis Oncology, just after winning a new FDA clearance, raised $89 million in a stock offering at $8.05 a share.
  • New Haven, Conn.-based Rallybio raised $145 million in a Series B financing, and plans to advance its lead drug candidate for fetal and neonatal alloimmune thrombocytopenia into the clinic later in 2020.
  • Franklin Lakes, NJ-based BD raised $3 billion in an offering of stock and convertible debt.
  • San Diego-based Amplyx Pharmaceuticals tacked on $53 million to its Series C round, bringing the total to $90 million. The company is developing an antifungal.
  • Phlow Corp. picked up a $354 million federal contract to manufacture essential medicines during the pandemic.
  • South San Francisco-based Tricida secured $175 million in a convertible debt financing. The company is developing a polymer to treat metabolic acidosis in patients with chronic kidney disease.
  • San Carlos, Calif. and Seattle-based Nautilus Biotechnology raised $76 million in a Series B financing to do low-cost proteomic analysis. Vulcan Capital led.
  • San Diego-based Turning Point Therapeutics raised $325 million to develop cancer drugs.
  • Vancouver BC and New York-based ARTMS raised $19 million in a Series A financing led by Deerfield to produce isotopes for medical imaging.
  • Pittsburgh-based Krystal Biotech, a gene therapy company, raised $125 million in a stock offering at $55 a share.
  • Warren, NJ-based Bellorophon Therapeutics raised $40 million in a stock offering.
  • South San Francisco-based Day One Biopharmaceuticals raised $60 million in a Series A financing to develop drugs for kids with cancer. (See TR in-depth coverage, subscribers only).
  • Boston-based HotSpot Therapeutics raised $65 million in a Series B financing to advance its allosteric binding drugs. SR One led. (See TR in-depth coverage of the science and business strategy, July 2018. Subscribers only).

Regulatory Action

Waltham, Mass.-based Deciphera Pharmaceuticals won FDA clearance to market ripretinib (Qinlock), a kinase inhibitor for patients getting fourth-line therapy for gastrointestinal stromal tumors (GIST).

Bristol-Myers Squibb won FDA approval to market the combination of its anti-CTLA-4 and anti-PD-1 antibodies for patients whose tumors express at least a little PD-L1, who don’t have EGFR and ALK mutations, and who are getting their first round of treatment for non-small cell lung cancer that has spread.

Boulder, Colo.-based Clovis Oncology won FDA clearance to start selling rucaparib (Rubraca), a PARP inhibitor, as a treatment for men with BRCA1/2 gene mutations and have prostate cancer that has spread and no longer responds to hormone deprivation treatment, and androgen-receptor therapy, and taxane chemotherapy.

The FDA warned the Seattle Coronavirus Assessment Network, an academic collaborative group formerly known as the Seattle Flu Study, to stop its surveillance programs, which include at-home tests. (See NYT report).

Roche / Genentech won FDA clearance to market the PD-L1 inhibitor atezolizumab (Tecentriq) as a first-line treatment for patients metastatic non-small cell lung cancer, if they express PD-L1 and don’t have EGFR or ALK mutations.

AstraZeneca won FDA clearance to market its PARP inhibitor olaparib (Lynparza) for patients with metastatic prostate cancer who have homologous recombination repair mutations. An estimated 20-30 percent of men with prostate cancer that resists chemical castration therapy have this form. On the same timeline, Foundation Medicine won approval for a companion diagnostic test to identify those patients.

Chiesi Global Rare Diseases, a Boston-based unit of the Italian company, won FDA clearance to sell deferiprone (Ferriprox) to treat iron overload disorders in thalassemia patients.

Deals

San Diego-based Vividion Therapeutics collected a $135 million upfront payment from Roche, as part of a partnership that allows the big company access to its proteomics screening platform and library of small molecules aimed at E3 ligases, as well as a range of oncology and immunology targets.

New York-based Aetion formed a research collaboration with the FDA to analyze real-world data for the coronavirus pandemic.

Cambridge, Mass.-based Surface Oncology formed a partnership with Merck to test its CD39 directed drug candidate in combo with Merck’s pembrolizumab (Keytruda) for solid tumors. Surface also raised $30 million via an at-the-market financing.

Cambridge, Mass.-based Synlogic said its partnership with AbbVie has ended.

San Francisco-based Atomwise, the company developing AI for small molecule drug discovery, said it’s participating in 15 research collaborations against COVID19.

Personnel File

  • The Atlantic, the magazine which has done consistent and excellent reporting on the pandemic, said it’s laying off 68 workers, or 17 percent of its staff. Like many media companies, The Atlantic is suffering from the collapse of its advertising and conference revenues. It’s another example of quality journalism that isn’t being rewarded in the marketplace as it’s currently constructed.
  • Moncef Slaoui was named the new head of the White House’s Operation Warp Speed, overseeing efforts to develop a SARS-CoV-2 vaccine. He’s the former head of vaccines at GSK, and a partner at Medicxi. He stepped down from the board of Moderna to avoid a conflict of interest with the company developing an mRNA vaccine candidate in collaboration with the National Institute of Allergy and Infectious Disease.
  • Seer, a proteomics company in Redwood City, Calif., named David Horn, a former Morgan Stanley executive, as its chief financial officer.
  • Iya Khalil was hired as the global head of the AI Innovation Center at Novartis in the Boston area. She was a co-founder and chief commercial officer at GNS Healthcare.
  • Ken Rhodes joined Wave Life Sciences as senior vice president of therapeutics discovery.
  • Mike Zaranek joined Science 37 as chief financial officer.
  • John Sundy joined Pandion Therapeutics as chief medical officer.
  • Tim Trost joined AskBio as chief financial officer.
  • Joseph Leveque joined Mirati Therapeutics as chief medical officer.
21
May
2020

Creating Leaner and Meaner Clinical Trials for the Long Run

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21 May 2020

Pamela Tenaerts, MD, MBA, executive director of the Clinical Trials Transformation Initiative, co-founded by Duke University and the U.S. Food and Drug Administration.

The clinical trial enterprise has been due for a reckoning for a long time. The good news is that a fundamental re-thinking of how clinical trials are done – one that could bring lasting positive changes – has started to happen. 

I believe there is good reason to be optimistic that some long-overdue changes will be made permanent after the pandemic.

Consider the unprecedented mobilization of academia, industry, and government. As of May 11, there are more than 144 active trials of therapeutic agents with another 457 development programs for therapeutic agents in the planning stages for COVID-19 treatments, according to the U.S. Food and Drug Administration (FDA). Guidance by FDA and others to help improve COVID treatment trials are crafted and made publicly available in weeks rather than the usual process that can take years.

The sense of urgency is palpable. It’s visible how quickly sponsors, investigators and regulators are moving through every step of the process – including development of protocols, drafting of informed consent forms, IRB approvals, training at clinical sites, all the way through enrollment of subjects.

We’ve seen regulators providing detailed feedback on proposed clinical trial designs in days rather than weeks. IRB approvals, which can notoriously sometimes take weeks or months for the most minor modifications to study protocols, are now sometimes coming in as little as 24 to 72 hours. 

One of the most inspirational examples I’ve seen, has been with the RECOVERY master protocol. That study, intended to evaluate a handful of different therapeutics for COVID-19, went from draft protocol to first patient enrolled in a lightning-fast nine days in the UK. 

In the US, similar stories are emerging, COVID-19 hospital-based studies are moving from initial conception to first dose in patients within a week or two rather than the average 3+ months needed to get through ethics review and contract processes at most academic, VA and hospital-based sites. 

A new sense of urgency

This rapid pace of research in times of COVID-19 is new, for obvious reasons. The FDA was charged, via the Kefauver-Harris Amendment of 1962, with the responsibility to ensure that each treatment approved for medical use in the US, be shown to be both safe and effective.

Randomized clinical trials are the best form of study for understanding benefits and risks of medical products, in light of that legislation. But they aren’t perfect. Randomized controlled trials have become prohibitively complex, expensive and slow to start and finish. The US, in particular, is a highly litigious environment, and institutions are quite mindful of that when signing on to study protocol contracts and informed consent forms. Those costs, and risks, act like sand in the gears of researchers and patients seeking answers to important scientific questions.

So what was the typical process for starting a clinical trial, pre-pandemic? An investigator or team of investigators would draft a written protocol (and supporting documents) which formed the basis (like a recipe book) for a clinical trial. Once written, several committees were consulted, and several levels of approvals to start the trial had to be obtained: for example, hospital committees and institutional review boards (ethics committees), who are tasked with protecting the welfare, rights, and privacy of participants in clinical trials.

All of this is done in collaboration with the sponsoring entity — a company, a government agency, a foundation, or some combination of all three. There are also regulatory bodies — sometimes multiple regulatory bodies — that weigh in on whether the study design is valid, or could use some revisions.

Before you know it, a series of well-intended steps turned into a straitjacket of red tape that reined in creative thought and slowed down the enterprise to the point where it could actually undermine the mission of the trial — which is supposed to seek a valid answer to an important medical question. 

Luckily, for COVID-19 treatment trials, some of these processes have gone at unseen speed. Sadly, for most other trials in the pre-COVID-19 era, this sense of urgency — and resulting rapid advancement — was lacking. That meant patients with cancer or genetic diseases or other deadly or disabling illnesses simply had to wait much longer than they should have because of a dysfunctional process.

This requires high quality clinical trials

Now that we have speed, it is even more critical to do the right trials, the ones that can get us to reliable answers for treatment options.  Speeding up the process only to do “small uninformative trials” — those that are not designed to get us to reliable answers while keeping participants safe — is not progress.

At the Clinical Trials Transformation Initiative (CTTI), where we live and breathe improving clinical trials, we’ve created resources specifically for COVID-19 treatment trials. Previously, we also developed recommendations to design high quality protocols. You can accomplish this by engaging everyone including patients as equal partners in clinical trial design, and gathering feedback on symptoms that are important to their quality of life, but which don’t always get factored into a study’s primary or secondary endpoints.

We recommend incorporating digital health technologies for endpoint capture into trials, and conducting more decentralized clinical trials where the participants can stay at home, so they can enter a study without having to worry about the risk of entering a building that could be a COVID-19 hot zone. Sometimes, information can be simply gathered from home; other times a telemedicine visit can serve as a substitute for an in-person visit, while keeping the study on track.

Before COVID-19, barriers to change were mostly cultural (“This is how we’ve always done it.”) and risk aversion (“What bad thing might happen if we change anything?”) 

The status quo is generally considered the default “safe” option.

No more excuses, trials can and need to be done differently

COVID-19 has shown us we cannot run trials in this way, and consider that the “safe” option. An FDA guidance, created for trials in progress during COVID-19 was released only weeks into the pandemic.  Everyone recognized they must rise to the challenge, and that means discarding a lot of time and process that wasn’t actually all that necessary. Because of shelter in place regulations, active trials had to be stripped of non-critical elements and slimmed down to what matters that what could be captured in alternate ways answering the most important research question at hand, minimizing burden on participants and research sites. Other ongoing trials were halted.  

With 1,000 to 2,000 people in the US dying every day and the very real prospect of a second wave in the fall, we need to keep moving at this breathtaking speed to match the medical need for treatments and vaccines. Simultaneously, we need to adapt medical practice in real-time. New treatment guidelines should be based not on anecdotes or a case series of similar anecdotes, but on methodical and rigorous medical evidence that is the gold standard.

We need to design large, well-powered and streamlined randomized, controlled trials that are feasible and simple for health care workers to conduct, now for COVID-19 trials as well as future trials in other disease areas. We need to identify multiple sites rapidly, and we need to test multiple potential treatments at once rather than one at a time. How one can go from single therapy to cocktail therapies will also need to be considered, as was the case with HIV in the 1980s.

Focus on what matters

Fortunately, a framework exists to aid in designing high-quality clinical trials. It’s best known in the industry as quality by design or QbD. The key principles of QbD are to focus on things that matter. Quality does not have to slow things down. By focusing on quality in trial design, urgently needed efficiencies are created. Those efficiencies can help to rapidly launch protocols so trials can begin accruing patients and minimize extra steps and contact between people.

Specific to COVID-19 treatment trials, a recent FDA guidance document outlined what efficacy endpoints could be considered, what matters, and how they vary depending on the severity of the disease. We should focus on getting the answer to those data points — and those data points alone — unless there is a very good reason. The endpoints are objectively measurable and meaningful — reduction of hospitalization rate for an out-patient participants with mild to moderate symptoms of COVID-19, or time on a ventilator or all-cause mortality for trials of more severe patients. Trials should be powered to answer those questions — no more, no less.

Drugs in earlier development may need to be tested in smaller-than-usual proof of concept trials. It really is a question of matching the design of your trial with the purpose of your trial. This is not the time to overload clinicians or burden participants with excessive procedures and requirements that are not directly tied to the endpoints. Doctors and nurses now have their hands full, and simply cannot deal with excess data collection.

A single center trial, no matter how good the idea, will not get us reliable data that can be applied more broadly. This is the time to collaborate to not do trials the way we have always done them because it is comfortable, and because change is hard.

Uncommon circumstances require a new way of thinking. 

We can create additional efficiencies by rethinking ways to collect informed consent electronically and run trial data embedded in e-health records. Randomization of treatments to a standard of care is the only way to determine benefit of the studied treatment over the standard of care.

There is power in collaboration

We also need to create a site identification system in a nimble, systemic approach that leverages existing networks such as hospital systems, physician groups and NIH trial networks, rather than identifying one site at the time. Currently, sponsors of COVID-19 treatments and vaccines are seeking trial sites in hotspots, which can often be moving targets. We must be positioned to respond to the pandemic in real time and not wait for it to come to a site near you.

When considering the urgent need for therapies and the number of drugs that could be tested, there has been great interest in using master protocols to simultaneously test multiple products to get answers as quickly as possible and not have to worry about picking a “winner” in your single treatment one-off trial. Master protocols have been used to speed the development of products for diseases such as cancer, and trial experts believe they can be useful for pandemics, including this one.

Sponsors should consider master protocols that enable multiple drugs to be tested against a control arm. One international preparedness trial in pneumonia that existed prior to the pandemic, REMAP-CAP, is using a novel “learning while doing” approach. The trial, developed by researchers worldwide including at the University of Pittsburgh School of Medicine, was able to offer an elegant solution by adding a COVID-19 arm to the protocol to determine whether to quickly adopt new “off-label” therapies during a pandemic, such as the anti-malarial drug hydroxychloroquine, or wait until they are tested in longer clinical trials. In addition, it uses an efficient machine-learning model and is embedded in the electronic health record.

While there are many promising trials underway for COVID-19, they are not all high-quality and expected to provide reliable results. There are many small trials of just a few patients, enrolled at a single site, that aren’t randomized with a control group. These trials are cheap and relatively easy for a lone wolf investigator to start up, but they are ultimately a waste of everyone’s time and effort. They will not provide the steadfast scientific answers we need to help a large percentage of the population.

On the other hand, there are many worthy master protocol trials that are testing potential COVID-19 therapies. What we need is coordination between these master protocols. They should do the following:

  • Enable alignment of endpoints. Are we looking for COVID-19 treatments to provide a mortality benefit, to reduce hospitalization time, or something else? We should have a consensus.
  • Ensure treatments for all types of COVID-19 patients – exposed, mild, moderate and severe disease – are being tested.
  • Share process and data. Hoarding raw patient data at individual sites, in proprietary EHR systems that don’t interoperate, has got to go. Not sharing protocols, consent forms and other critical documents will stymie progress.
  • Compare and, if needed, combine results across trials, as in meta-analysis.
We cannot go back and lose this progress

We have the opportunity to reconsider and optimize our whole evidence generation system and we should. Some of these changes ought to become the new standard procedures of the future.

Our challenge now is to transfer some of that same speed, that same critical thinking, we have been forced to do in this emergency, to the next set of non-COVID-19 trials. 

Once these fundamental changes make trials leaner and meaner, we should then be better poised after this pandemic to tackle some of the most pressing global public health challenges.

If we’re smart, history will look back and see the beginnings of a meaningful scientific revolution.

Pamela Tenaerts, MD, MBA, is the executive director of the Clinical Trials Transformation Initiative, a public-private partnership involving all the parties as equal partners in clinical research (patients, academia, government, investigators, sponsors, technology, IRBs, etc), co-founded by Duke University and the U.S. Food and Drug Administration to develop and drive adoption of practices that will increase the quality and efficiency of clinical trials.

Views expressed in this publication do not necessarily reflect the views of CTTI nor do they represent the views or policies of FDA or HHS.

20
May
2020

Pharma’s Digital Champions Should Focus On Solving One Problem Well

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20 May 2020

David Shaywitz

Come for the tech, stay for the culture. 

That seems to be the hope of most digital champions inside large pharma companies. These executives hope to instill in their organizations not only important new capabilities, but also a “Silicon Valley” mindset, an innovative spirit characteristically associated with tech entrepreneurs.

The reality, of course, is more complicated; pharma executives – and to some degree, all of us, perhaps – tend to imagine ourselves as more audacious, more creative, more risk-embracing than in the end we actually are. 

It’s not just a big pharma phenomenon; when I was in venture capital, I saw the same tendency emerge whenever a startup on whose board I served conducted a search for a new executive. Typically, the headhunter would be asked to think expansively, and identify a broad range of talent, including less traditional candidates. Yet in the end, the consensus generally landed on someone who felt comfortable and familiar, a leader who was perhaps less interesting than some candidates, but also viewed as less risky, and more of a known quantity. Flirt with risk, marry stability.

The challenge facing innovators who want to bring change to pharma was captured nicely by Craig Lipset, a digital health pioneer at Pfizer. On a recent Tech Tonics episode, Lipset told Lisa Suennen and me that the three unofficial rules for anyone pitching digital health inside the company was that it needed to be safe for patients (of course); not threaten anyone’s job; and not threaten to land the company in court.

Venture capitalist Josh Kopelman of First Round Capital (early investors in Uber, Square, Flatiron Health) captured this tendency perfectly on an April episode of Patrick O’Shaugnessy’s always excellent podcast, noting that one of the best opportunities for startups is to leverage (arbitrage) the intrinsic risk aversion of large corporations. 

Kopelman described an experience he had early in his career, after he sold a company he started to eBay, and he got to know the big online marketplace. eBay, he said, noticed that payments on its platform were being consummated by the startup, PayPal, and eBay wanted to handle those transactions itself, so that PayPal wouldn’t be able to take a cut.  

So eBay set up a joint venture with Wells Fargo called Billpoint, in theory a formidable partnership between a top bank and the top online market. But the reality, Kopelman said, was that at the initial product meetings there were nearly as many lawyers in the room as there were product managers. Digital payments were a fairly new space. There was a lot of grey area. Wells Fargo in particular couldn’t afford to jeopardize its business by skating too close to the regulatory line. 

PayPal, on the other hand, embraced the risk; when PayPal filed its S-1 form as it prepared to go public, Kopelman says, the company disclosed it was under investigation by a slew of state attorneys general. PayPal’s willingness to take on this risk – and do so successfully – were key to its ultimate success (including its post-IPO acquisition by eBay for $1.5 billion).

Kopelman also cites the example of Uber, specifically calling out controversial founder Travis Kalanick for his fearless approach to regulatory grey areas. 

It’s amusing to contemplate how innovators like Kalanick and the PayPal leaders would fare within big pharma, an industry that is highly regulated to begin with, and then has arguably exacerbated these challenges through a culture that reflexively resists innovation through a deep, shared belief that “regulators will object.” 

Moreover, these concerns are not unfounded; as much as FDA leaders such as former Commissioner Scott Gottlieb, current Principal Deputy Commissioner Amy Abernethy, and the head of the Oncology Center of Excellence Richard Pazdur have passionately championed innovation and flexibility, this attitude is still not universally embraced (to say the least) by the reviewers responsible for most of the heavy lifting inside the agency. 

Other qualities of startup founders described by Kopelman might also struggle in the context of a large pharma. For example, Kopelman highlights the value of betting on people rather than a specific idea – he views a founder’s initial product proposal as more of lens to understand how the founder makes decisions and processes signals than it is a detailed plan describing what’s actually going to happen. Similarly, Kopelman says his firm tends not to be “thematic” investors, contending that by the time something bubbles up as a discrete theme, it is effectively too obvious, and something everyone is doing. (I entirely agree; however, most VCs, and virtually all corporate VCs, are explicitly thematic.)

Again, anyone who’s tried to get buy-in to anything in a large pharma appreciates immediately the contrast; extensive and excruciatingly deliberative processes generate themes and areas of focus (leading invariably to oncology, immunology, and rare disease these days), and even individual early-stage projects that hope to be resourced must be described and mapped out in exaggerated, if not comical, precision. (Then again, I’ve heard the same said from academic researchers applying for NIH research grants.)

Several attributes of successful founders cited by Kopelman can and — I’ve often insisted — should be adopted by pharmas. For example, Kopelman emphasizes that you can’t build a great platform without first having a killer app; while he was making an even deeper point, one simplistic way to think about this is that pharmas contemplating data science would do well to consider what very specific and concrete problems they hope to solve, and then focus on developing a pragmatic solution that clearly works. 

Instead, there’s an unfortunate tendency to spend huge amounts of time and resources investing in and developing a massive data and analytics platform in hopes that it will someday prove useful – despite considerable experience to the contrary. Startups are often critiqued for creating an elegant solution in search of a problem. The related mistake large companies tend to make is architecting a vague, expansive solution they hope will solve every problem, presumably reflecting the promises required to secure funding in complex, matrixed organizations.

Kopelman also emphasizes the importance of getting product feedback early and often – an idea long-advocated by “Lean Startup” guru Steve Blank. If instead, you decide you know from the outset exactly what’s needed and work head-down until you’ve perfected your product, the product you emerge with may be elegant but totally off base.

Bottom line: A large, legacy pharma is never going to have the agility of a startup, and compelling new ideas will always struggle for traction given the intrinsic risk-aversion of massive multinational corporations. Many (I assume most) new health technology concepts will have to be developed and proven out in a less constrained environment first. The innate skepticism towards tech solutions by most people in the trenches at big pharmas remains exceptionally high, and the meticulously-structured, rigidly-articulated way most work is done in pharmas (and other large companies) tends to be poorly aligned with the agility and improvisation new tech product development often requires. The most exciting and most innovative opportunities at the interface of health and tech almost certainly remain in the startup space.

Yet pharmas desperately need better technology, and promising technologies can benefit from the scale, experiences, and established relationships of a large pharma. 

To succeed, pharmas need to scope projects in a fashion that’s relentlessly focused on tangible outcomes that matter, results that are palpably experienced by users. Uber was adopted because you press a button and a ride shows up; Google was adopted because you type a query and the answer shows up; Amazon was adopted because you place an order and your purchase shows up. Simple. And effective.

A successful technology in pharma doesn’t need to be all things to all people. Paradoxically, it’s this very need to gain the approval of multiple stakeholders that often results in poorly-scoped, ill-fated projects. Instead, at least initially, the tech solution should brilliantly meet the substantive needs of an individual stakeholder, and accelerate an important process. In actually delivering on this promise – in delivering tangible delight and utility for somebody in the organization — a technology champion in pharma can do more to change a company’s culture and attitude than all the Successories posters, inspirational corporate messaging, and aspirationally hip (tucka-tucka) corporate hackathons combined.

19
May
2020

Getting the COVID-19 Numbers Wrong

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19 May 2020

Ruth Etzioni, Full Member, Division of Public Health Sciences, Fred Hutch Cancer Center

When I was in college, everyone wanted to major in psychology. I signed up, but switched out after only a few weeks.

Why? Well, the more I read, the less I seemed to know. Psychology, after all, is an inexact science.

I sought refuge in the exact worlds of computer science and mathematics. Those courses led me to build a career in statistics, the science of uncertainty.

For the past 20 years, I have partnered with colleagues in the Surveillance Program at the National Cancer Institute to explain why cancer rates go up and down from one year to the next. We can do this work because we know how many cancers cases – and deaths – there are every year. Our analysis is grounded in hard data that is reliably and consistently collected.

For years, an information infrastructure has existed to funnel data from pathology laboratories to local cancer registry offices, who interface with hospitals and doctors’ offices to catalog each cancer case.

I always appreciated the NCI’s Surveillance Program for its tireless work to bring us the numbers and double-check to make sure they are right. Reliable data is the bedrock of our analysis.

I appreciate the fundamental, unglamorous data-checking and cleaning work even more as I look at the state of COVID-19 surveillance. I wonder about the data we are relying on to track cases and deaths, to prepare for the future, and to make critical policy decisions.

It seems to be a house of cards.

We know that the reported daily tally of cases is hopelessly wrong. Cases can only be confirmed if they are tested by one of the reliable RT-PCR diagnostic tests that uses samples from nasal swabs. From the beginning, the US has struggled with a shortage of these tests. So the number of cases reported on any given day is determined not only by the spread of the virus itself, but also by the availability of tests. Many people don’t know that they have the virus, and of those that exhibit symptoms, many who want a test can’t get one. Access to reliable diagnostic testing varies widely over time and across locations. So the meaning of “number of confirmed cases” differs depending on the date and where you are.

The number of cases simply can’t be interpreted without understanding the state of testing. But, even if we knew how many tests were being done each day, this would not be enough. Just figuring out how many symptomatic cases there are would require how many of these people actually present themselves to a healthcare provider, asking for a test. We don’t have the data to understand this, but it surely varies depending on the date and where you are. And this doesn’t even get at how to account for asymptomatic cases.

New antibody studies can provide us valuable snapshots in time, if conducted with a reliable blood test, and with a rigorous random sample of the population – not just people who volunteer because they think they might have COVID-19. These studies may help us to reconstruct how many surviving individuals had the virus, whether they know it or not, and this could potentially help correct our daily tally of cases, retroactively. But, results of these studies are subject to debate and cannot be taken at face value.

As an example, an antibody study conducted in Santa Clara county was roundly criticized, because the underlying test produced false positive results that could have accounted for many of those told they had antibodies. Still, as these studies accumulate, we will likely gain a better idea of the foothold the virus has established in the population.

Given that we are in a pickle when it comes to counting cases, we might turn to harder data, like the numbers of hospitalizations or deaths. Hospitalizations are limited by system factors that have nothing to do with disease burden. But deaths? Surely deaths are more reliable. You are either alive or not, there’s no squishy subjective judgment at work, and no faulty test to wonder about. Right?

It’s not quite that simple. Until recently, it seemed that most people trusted the counts of COVID-19 deaths reported around the world. Even as China kept changing its definition of what constituted a coronavirus case, its death tally was not questioned. On Mar. 19, breathless headlines declared a “grim milestone” – Italy’s COVID-19 death toll of 3,405 had exceeded China’s reported death toll of 3,249. Reported deaths from China and Europe became the basis for models that predicted the scale of the epidemic in the US and informed social distancing policies across the country. I have written in these pages about the models and warned about how they are being miscommunicated, but I never mentioned my concerns about the death data which drives them.

I can’t remember when I first became skeptical about the deaths. But it was definitely before Mar. 19 because I recall reading the grim milestone headlines on that day and wondering why everybody believed the official number from China. Maybe it was after I personally asked a Chinese statistician colleague now living the US who said that in her opinion the numbers from China were made up so as to imply a fatality rate that was between one and two percent.

Still, I told myself, our surveillance systems in the US would never allow this to happen here.

Recently, important data has emerged that strongly suggests that we are undercounting COVID-19 deaths in this county – by tens of thousands. The basis for this is in the numbers; the official count of deaths due to the virus is far below the excess in the overall number of deaths compared to what would be expected at this time of the years based on data from the last few years. On May 13, Nicholas Kristof of The New York Times reviewed the numbers and concluded the COVID-19 death toll had already exceeded 100,000.

The counting of excess deaths to shed light on cause-specific mortality is not new. We do it to assess our progress against cancer all the time. Sometimes it is hard to know whether a person with a history of cancer died of, or with, their disease.

Suppose a breast cancer patient dies of a heart attack. Was that death due to cardiovascular disease or to the chemotherapy drug she was given and that is known to weaken the heart? Death certificates can only do so much to tell us, and generally focus on what we call the proximal cause of death, which in this case would be cardiac arrest and not cancer. To avoid undercounting deaths among patients with a specific cancer, we can tally the excess deaths among individuals with a history of that cancer and stack the result against the deaths among comparable individuals (e.g. same age and race) in the population. This technique, developed in the 1950s, is called relative survival. It has been shown to work really quite well for many cancers.

In the case of COVID-19, which can cause death via a diverse array of awful disease symptoms, this makes a lot of sense. Death certificates list first the proximal cause of death – what actually caused you to die.

We know COVID-19 can kill you by suffocating you, giving you a stroke, causing your heart to stop beating or your kidneys to fail. This is what gets listed first. If COVID-19 is known or suspected, this is recorded as a second, third or even fourth cause.

My cousin, an all-knowing MD and research scientist, who directs a critical care unit in Denver, tells me that even when patients die of respiratory failure, the best known COVID-19 cause of death, the proximal cause is listed as Acute Hypoxemic Respiratory Failure (AHRF) and the next cause is the condition, Acute Respiratory Distress Syndrome (ARDS). COVID-19 infection only appears third – so long as the patient is known to have the virus.

Patients not tested, who don’t make it to the hospital, or whose deaths masquerade as being from strokes or heart attacks may not even have COVID-19 listed as an underlying cause in the death certificate.

So it makes sense to look beyond the cause-specific tally to the overall mortality data.

I think we can trust the overall number of deaths. It is possible that heart attack or stroke deaths may have gone up a bit this year even in the absence of COVID-19. And we certainly don’t want to count deaths that were truly due to these causes as COVID-19 deaths just because a person had a confirmed diagnosis and then had a fatal heart attack or stroke.

But, on balance, if we look at overall all-cause mortality rather than cause-specific deaths, we are left with the inescapable conclusion that the official tally of COVID-19 deaths in the US is way low. When you look at all-cause mortality, and make a direct comparison of March 2020 to March 2019, or April 2020 to April 2019, you will see an unmistakable increase in death rates. This is despite various conspiracy theories to the contrary to which I won’t devote any airtime. Let their proponents debate our National Center for Health Statistics.

At this point I hope we are all on the same page about the need to look beyond the official COVID-19 death toll to the cases who don’t get to have the virus listed on their death certificate. But what is happening in some states now is worse; they are changing their definition of a COVID-19 death to only count those for whom the virus is coded as a proximal cause.

I know that this is happening in Colorado because my cousin shared his frustrations about his patients’ causes of death being wrongly recorded by the state. Colorado coroners are objecting, according to a piece run by CBS4 in Denver. A new Scientific American article out this morning cites the Colorado issue.

In Florida, the state forced medical examiners to stop releasing their counts of COVID-19 deaths which were at odds with official state figures, and fired the creator of the state’s COVID-19 data portal, who claims she was terminated for refusing to manipulate the numbers. And in states like Georgia, where COVID-19 can only be listed in as a cause of death in confirmed cases, reducing the number of tests performed will automatically trigger a decline in deaths. Of note: Georgia is no longer releasing data on testing numbers.

We tend to think of numbers as facts and data as absolute; it feels safer that way. Unfortunately, when it comes to COVID-19, it seems that there is no safety in the numbers. When we wake up each morning and check the dashboards of cases and deaths in our local papers or cable TV news, we need to bring a healthy dose of curiosity – and perhaps skepticism – to the table.

If we don’t, we may jeopardize our understanding of the true burden of COVID-19 and compromise our ability to navigate our way out of it.  

19
May
2020

COVID Doctors Navigate Tension Between Individual Autonomy and Systematized Care

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19 May 2020

David Shaywitz

I was recently speaking with a friend of mine, a pulmonologist at a large academic medical center in the Midwest, about his COVID-19 experience. I was especially interested, in the context of iterative experimentation, to learn how his hospital was working on improving the care of COVID-19 patients, especially those in the ICU, which he oversees. 

It’s real problem, he said. On the one hand, there are specific initiatives he’s trying to evaluate, in a classic, controlled fashion, so he can figure out if the intervention is effective and should become part of the standard of care.

That’s the goal.

In reality, however, here’s what he says is actually happening: most of the front-line doctors are hearing about the very latest approaches, generally from social media (such as Twitter or medical podcasts), and are trying to immediately apply these methods to their patients. As a result, the care patients receive depends (to some degree) on the specific physician involved, as well as the extent to which that physician has been influenced by other opinionated doctors.

At a recent Boston innovation conference (discussed here), Dr. Paul Biddinger, an emergency medicine physician who leads emergency preparedness at the Massachusetts General Hospital, made a remarkably similar observation. He praised the “unprecedented information sharing” associated with the COVID crisis. But he also expressed concern about the “practicing by anecdote,” and more generally the “temptation to fall off what have been the time-proven methodologies of science.”

The tension here captures an especially distinctive aspect of American medicine, a characteristic beloved by some and lamented by others. 

Intrinsically, doctors value their independence, and the opportunity and obligation to be masters of their own domain. This is how U.S. medicine generally works: once doctors are trained and licensed, they more or less can treat patients as they see fit, within a fairly wide band of professional expectations. Care generally isn’t cookie-cutter, and doctors are typically free to offer a range of potential approaches, constrained mostly by what the patient’s insurance is likely to accommodate or reject (and by the hassle of navigating that process). 

To be sure, physicians are supposed to stay up to date, and not commit blatant malpractice like treat a strep infection with a blood thinner, say, but there’s a lot of room for individual interpretation and improvisation, which many doctors have embraced, believing it acknowledges the individualized nature of each patient/doctor encounter. Call this the “libertarian” view of medicine.

Contrast this approach with what might be called the “systemic” or “operations” view of healthcare, described eloquently nearly a decade ago by Dr. Atul Gawande in his classic “Cheesecake Factory” New Yorker essay.  In this view, while doctors are the ones actually laying on hands, the expectation as well as the mindset is that these providers should be more focused on consistency than individuality; care should adhere clearly to “best practice” guidelines, and while modest customization is permitted, significant deviations should be evaluated deliberately and programmatically, not ad-hoc. 

In this view, much of what’s wrong with American medicine is precisely the individual physician’s insistence on acting, well, individually, leading to dramatic variances in care, and often, it is said, the suboptimal treatment of patients.  Medicine practiced in this way tends to view physicians as providing the “customer service,” but adhering to master pathways and algorithms.  Not surprisingly, many (but not all) doctors in systems like this tend to view themselves as interchangeable cogs and data entry clerks, rather than empowered inquisitive physicians in the Judah Folkman tradition. 

The uncomfortable question raised by advocates of a systems approach is whether it promises better care of patients but lacks traction because it challenges the self-esteem of doctors.

The COVID-19 crisis highlights the dilemma. In the unlucky event you were hospitalized with COVID-19, would you want your care driven by a standardized algorithm, rigorously followed, or would you want your doctor to improvise, and potentially apply the latest and greatest – although it might not be so great, and perhaps may reflect little data and instead just the strongly-held opinion of a persuasive, social-media-savvy clinician? Or, it might incorporate a valuable emerging insight, the sort of adjustment that could take a relatively long time to incorporate into a standardized protocol.

On the one hand, most physicians wouldn’t want to practice, and don’t like practicing, in a climate of rigid pathways and defined approaches – that’s not why most doctors went into medicine. Moreover, the physicians who self-select for environments with great autonomy may be more likely to have the imagination or creative insight that the clinicians in more rigid systems lack.

But it’s also possible – especially as more care becomes templated and algorithmic – that the consistency and transparency provided by these systems offers not only a higher average level of care, but also enables a degree of continuous, iterative improvement in care that is far more difficult to achieve in less structured environments. 

One worry is that in such a command-and-control framework, you’re potentially relying on centralized planning – on detached, “enlightened” supervisors to suggest modifications, rather than benefiting from the experience and insights of front-line providers, doctors whose imagination and creativity could well be crushed in a system that valorizes provider conformity, and expects providers to perform their job consistently and empathetically, but looks elsewhere for insight and originality.

Historically, the physicians so many of us have looked up to are the brilliant, iconoclastic individuals who figured out on their own a new way to do something.  It will be interesting to see if there are future heroes who distinguish themselves by their ability to apply deliberate, iterative experimentation to raise the standards of a system. 

19
May
2020

Stepping Up One’s Game, Pandemic Style

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19 May 2020

Lisa Suennen

Luke Timmerman calls me his humor columnist. That’s become a laugh line of its own in our house.

My adult daughter, staying with us during the pandemic, said this to me just last week:

“If you’re going to need frequent comedic validation, you’re going to have to step up your game.” 

Giggles have been hard to come by these past two months, I must admit. My own sense of humor, usually my most used sense, has been erratic, to say the least. Some days I’m finding the humor in the situation (at least according to me, if not my daughter). Other days I’m seriously considering faking my own death and running off into the woods.

This pandemic period has been so weird for everyone. The universal sentiment I keep hearing is, “What day is it again?” And that’s funny in its own right, given how close we are to living in the zeitgeist of Groundhog Day. The bigger question isn’t really the day of the week, it’s “what year is this again?” I haven’t seen gas down in the $2 a gallon range since whatever year it was when I didn’t have to worry if people noticed that my gray roots have grown out. 

Like most people I know, my days are a constant stream of Zoom meetings. It’s starting to make me realize how little I actually miss people. Everyone is starting to look like Max Headroom. The things you are guaranteed to say and hear are captured beautifully in this conference call bingo Zoom background. It has become my favorite for meetings after I brazenly copied it from one of my team members.

I’ve also started yelling out, “Can everyone go on mute?!” even when just talking to my current housemates. What I wouldn’t give for a moment of quiet that does not take place in my car!

The Zoom phenomenon has one great advantage. You get to see everyone’s real life persona. I love seeing people’s homes. Their awkward backgrounds. Their un-hip book selections. Their goofy lighting set-ups. Their kids making guest appearances. Their pets walking through the scene. I have come to recognize when people have their cameras pushed upward just enough so they can hold their pet in their lap, Dr. Evil style, while discussing the latest method of monetizing murder hornets.

Seriously? Murder hornets? What kind of fresh hell is this?  

By the way, the Murder Hornets would be an excellent band name.

Sometimes the pet situation can be a little daunting. My new puppy, a chihuahua named Olive, has learned to bark in exact concordance with the most important sentence of the meeting. 

My cat, a Bengal who goes by Luna, is struggling. She wonders why we are always home sitting on her couch, and she despises the puppy’s very existence. Luna seems to think that sitting on my computer keyboard is definitely the way to get back at me.

Maybe we need another square on the bingo board for “Hey cat, get the F off the keyboard!” 

Here’s how I know I am a) not alone with my cat woes; and, b) still somewhat sane: I was not the subject of this news story where a Vallejo, CA planning commissioner had to resign for slinging his cat into a wall during a Zoom meeting. Dude, we’re all stressed, but get a grip.  

Zoom life (vs. real life) also seems to work despite the fact that many of us have just given up on grooming. It’s become a badge of honor to have your gray roots showing, your bangs covering your eyes and an anti-gravity hair styling reminiscent of Motley Crue circa 1980. (Luke tells me he’s channeling his inner Lynyrd Skynyrd “Simple Man” from 1974).

Motley Crue

Many women who would never leave their own bedroom without makeup, much less go outside, have gone totally cold-turkey and now show up for their Zoom close-ups au natural. One study suggested that makeup use has declined over 50% since the Shelter-in-Place began, which I think might be understated by about half. I do have one or two friends who insist on looking good and wearing lipstick to their Zoom meetings; they are just making the rest of us look bad, if you ask me. 

I had a big (Zoom) presentation to a large pharma company CEO a few weeks ago and, after a 6-week-long make-up hiatus, I actually went to the effort to put mascara on. I nearly forgot how to do it and managed to poke myself in the eye. I have been applying my own mascara since gas was down in the $1 range, so that was a real wake-up call. Not only am I losing actual muscle by sitting around, but actual mascara muscle memory.   

Dear God, what have we wrought?

And in the most inconvenient way possible, I also managed to somehow get myself an ear infection while sitting around. I ventured out to see an actual doctor in person. He was looking into my ear with such gusto that I thought he may have found the holy grail. 

I noticed that next to the examination table there was a large bottle of Clorox. I suggested he save me a trip to the pharmacy by just pouring that in my ear, given that we now know it is the drug of choice for science-deniers who want virus-free insides. I think we both laughed, but it was hard to tell through the face masks.  

It’s not that weird to see a doctor in a mask, but it must be pretty weird for the doctors to see their patients sporting them, too. I had a sudden flash to this great Chevy Chase movie moment as I walked out into the hallway, seeing everyone in their PPE and not being able to tell which were doctors and which were people who somehow managed to get ear infections while sitting around their house. 

Back in the work milieu, all of the venture investor stories have been about whether or not people would/should back entrepreneurs whom they have never met in person. It’s tough to really get a read on people through a computer screen. I mean, seriously, what if they launch their cat after signing off? But it struck me as incredibly ironic that if the place where everyone wants to put their money right now is in telemedicine companies, wouldn’t it be weird to insist on meeting the team in person?  The whole point is…oh never mind! I have listened to a few start-up pitches these last few weeks and I admit to my own ambivalence on this issue.

But my favorite new business stories these days are the ones about the ingenuity that people are applying to the relaxation of the shelter-in-place rules. Every major sports team has its own line of face masks now. I can imagine that when stadiums and arenas open again, which I hope does happen in my lifetime (Go San Francisco Giants!), the big winner will be whomever invents a face mask that can hold two cans of beer connected by a straw. Those giant No.1! fingers will have to grow to six feet long to enforce appropriate social distancing. 

Actually, there is a cafe in Germany, and I am not making this up, that has created a hat with an attached 6-foot long pool noodle to enable patrons to dine safely. Are you the one giving the side-eye to fellow diners who might be only five feet away? Pull out the pool noodle hat to enforce your boundaries!

Can you imagine what the aliens would think if they touched down outside that café right about now?

I have also recently seen not one, not two, but multiple articles about the many uses of plexiglass to help keep people separated and thus healthy. For those of you with a long pop culture memory, these articles reminded me of the movie, The Graduate, starring Dustin Hoffman (Millenials and Gen Zers: go look it up on IMDB). The movie was released in 1967 when gas was around $.32 per gallon and was perhaps the most prescient story ever told. If you have seen the movie, you know that one of its most classic lines is “I just want to say one word to you…are you listening? Plastics.”  

It was excellent advice. Who knew it would stand the test of time oh-so-well.

As I think about the brave new world of consumer products, post-pandemic, it occurs to me we are going to have to ditch the phrase “go viral.” I heard someone say it last week in reference to a new product launch and I couldn’t help but say, “too soon.” People use that phrase and don’t really understand what it means. Now they should get it in the starkest of ways. If you are going to launch a new product and use social media as a method to scale your brand, you are going to have to come up with a new word. 

Anything will be better than hearing “go viral” in the context of the rapid spread of pool noodle hats. How about this, “It will fly off the shelves like murder hornets!”

Stay safe, stay sane, definitely do what you can to get some laughs. If you need me, I’ll be home trying to step up my pandemic humor game.

14
May
2020

Meet My Friend Who Supported Trump in 2016

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14 May 2020

Luke Timmerman, founder & editor, Timmerman Report

[This week, I’m re-publishing this column written Nov. 9, 2016. It’s probably more important to read now.—Luke]

I’ve been dreading this moment since June. That’s when I started telling people: Trump was going to win. I could feel it in my bones, because of where I’m from.

We’ve heard enough by now that the elites have let us down. The elites in politics, business, and the media couldn’t see what Donald Trump was tapping into. Most of these successful people (including you) live in islands of prosperity, coastal cities full of highly educated folks doing interesting work. The economy is improving in those places. The future looks bright, right?

The electoral map tells us a different story. Vast geographic stretches of people voted red, for a guy who ran as an authoritarian candidate, not a traditional Republican. It’s a powerful statement against the establishment.

I know these voters well. I spent the first 18 years of my life growing up on an 80-acre family farm in Grant County, southwestern Wisconsin. I grew up driving tractors, shoveling pig shit, and spreading it as fertilizer on corn fields.

All around me were people who owned guns, went deer hunting, did manual labor, and told off-color jokes. Most of these people were interested in family and traditional values. They weren’t that interested in advancing the causes of historically disadvantaged groups—women, minorities, gays. While I was fortunate to grow up in a stable, loving, two-parent family, I recognize the environment painted by J.D. Vance in his excellent memoir “Hillbilly Elegy.”

When I went to college in the liberal haven of Madison, Wisconsin, and pursued a career in journalism, I left most of that world behind. I stayed in touch with my family and a small group of high-school friends. But, essentially, I emigrated from working class, blue collar, rural America to wealthy, elite America.

It’s VERY rare for someone from my socioeconomic background to travel the journey I’ve traveled. Almost nobody I know in journalism or biotech grew up on a farm, qualified for reduced-price lunches at school, or came from a blue-collar family like me. They came mainly from the suburbs, from more privileged backgrounds.

These days, I spend my time in a very privileged zone. Running this newsletter, writing for Forbes, and hosting the Signal podcast means interacting with people who graduated from Ivy League schools, CEOs of companies, and high-level government officials. After a while, it gets comfortable. Normal. It’s easy to forget where you come from.

Even for me, living in urban, liberal Seattle, it’s easy to quickly become blind to vast swaths of America.

Until this past summer, when I had a deep, two-hour conversation with a friend I’ve known since middle school in Platteville, Wisconsin. I’ll call him J.

He is in his early 40s, with two teenage kids, living in a western state. He’s a skilled tradesman who installs sports equipment for schools and churches. He makes a decent middle-class living, and he travels the country on jobs. He also does a little driving on the side for Uber. He’s alone a lot while traveling, and he listens to a lot of conservative talk radio.

J sat in my living room and talked at length, in matter-of-fact tones, about why he was supporting Trump. I told him I strongly disagreed, but I didn’t try to talk him out of it. I decided this was a time for me to listen, and for him to talk.

“The system is broken. Corrupt.”

“We need to blow the whole thing up. Push the reset button.”

“It can’t get any worse.”

“Trump’s not perfect, but he’s not beholden to anyone.”

This kind of apocalyptic view didn’t seem to square with his economic experience. J doesn’t have a college degree, but he’s done well financially for himself and his family. We’ve both flown to Pasadena to watch our beloved Wisconsin Badgers play in the Rose Bowl more than once. J’s experience tells me Trump’s appeal is cultural more than economic.

Despite J’s economic success, he has some serious anxiety and resentment beneath the surface. He rails against the popular notion that “everybody must get a college education” to get ahead, that the economy should be only knowledge-based. This has been an uplifting message of both political parties for a long time. That cultural value system, and programs to advance that policy objective, have created a lot of opportunity for people who previously had limited educational opportunity.

It also has created a downside: People like my friend J feel like second-class citizens because of a lack of college education. He feels condescended to in the media, and laughed at in sit-coms and movies. Conservative talk radio fans the flames. Think about how many people who work in construction, at the post office, in the trash hauling business, feel the same way. They want a president who takes them seriously.

It would be easy to write off my friend J as narrow-minded and simple. That’s where too many elites go wrong. He may not be formally educated, but he’s one of the most curious people I know – much more curious about biotech than most college-educated people. J always wants to hear about the exciting advances I’m writing about in biotech. He pulls out his iPhone and avidly listens to the Signal podcast.

After one show on the rise of superbugs, he wrote:

I really wish that kind of topic would make more news.  People really have no clue how much damage can be done to themselves and others.  It’s good that the medical community is getting on top of it, but the public really needs to be educated. My biggest complaint with your podcast is there is not enough of them.

These are the words of someone who cares about his country, cares about issues, just like I do. He’s not a wingnut.

There certainly are angry people out there, and many of them have reason to be angry at the establishment. When I drove my family hundreds of miles across the American West this summer to vacation in Yellowstone National Park, I saw some troubling things. There were destitute run-down buildings in Montana, where heroin and oxycodone was easy to spot.

In eastern Idaho, I saw a giant Confederate flag hoisted above the American flag. Further down that same junk-strewn highway, when I stopped for lunch with my African-American wife and daughter, a man driving a sport-utility vehicle gave me a 30-second, intimidating staredown.

Message: Your kind isn’t welcome here.

These people are being left behind, and that’s not right.

Today, after the Trump victory, my friend J was cautiously optimistic. “At the very least, it is a massive shake up to our political system, that definitely needs the shaking,” he wrote.

The pharmaceutical industry may be breathing easy today, knowing that Clinton’s drive to corral drug prices has been squashed. Thoughtful people in this industry are working on solutions focused on people in red America, but there aren’t enough.

This industry would be wise to remember that it serves the whole country, the whole world. It’s easy to get comfortable with the tiny slice of elite investors, elite media, elite physicians, and elite scientists we know personally. It’s easy to forget everyone else.

As people re-assess the pharma industry’s social contract, it’s important to remember just how big a place the world is.

Now on to the highlights of the week in biotech

Story of the Week

  • An Outbreak of Severe Kawasaki-like Disease at the Epicenter of the SARS-CoV-2 Epidemic in Italy. Observational Cohort Study. The Lancet. May 13. (Lucio Verdoni et al).

This, in my view, was the single most disturbing scientific report of the week. Turns out kids aren’t bulletproof to COVID19, after all. This new cohort study from Italy reinforces a similarly mysterious case series of massive inflammation and multi-organ failure in kids in New York City, which was closely followed by corroborating reports from doctors in France.

This toxic shock syndrome in kids is deeply worrying to parents. It could also be an eye-opener for the large and vocal faction in the US that has been arguing that we should shrug off the pandemic partly because “oh, it’s just old people dying.” We can’t shrug off the virus and turn the clock back to 2019. That’s not going to happen. People are dying. Many more will die because of our inaction and incompetent federal leadership. As a result, we have to come to terms with a new way of life.

It’s up to us how we reinvent the world.

The Wild West

  • “After Wisconsin court ruling, crowds liberated and thirsty descend on bars. ‘We’re the Wild West,’ Gov. Tony Evers says.” (See Washington Post coverage with infuriating pictures).

Compare that with the NYT caseload chart for Wisconsin. The rate of new cases in Wisconsin is slowing. Good. But the bear hasn’t yet been wrestled to the ground. The virus is nowhere close to contained.

It’s way too early to declare victory and hit the bars. Based on what we know about the epidemiology, you can set your calendar for an increase in cases in Wisconsin in 2-3 weeks. Part of me wants to scream at the people who are jamming themselves in, elbow-to-elbow into the bars without masks. Many probably don’t know anyone with COVID19. Many probably think the media elites are manufacturing fear and controversy. Many want to “own the libs.” Many take delight in thumbing their noses at Gov. Tony Evers, a Democrat who had extended the state’s stay-home order, until it was struck down by the conservative majority on the Wisconsin Supreme Court.

Many of these protesting citizens also know 85,000 are dead, the death toll grows every day, and that’s terrible.

But people do seem to forget many relevant facts. Such as:

  • As of mid-May, we are still way behind on testing, with about 320,000 nationwide performed per day (compared to the target of 5 million a day a Harvard team has said we need to be doing by early June).
  • Based on serology testing to date in hotspots, most epidemiologists believe we probably have 10 times as many cases in the US than the 1.4 million currently confirmed.
  • People also seem to forget that asymptomatic people spread the disease – i.e. we likely have millions of people who have no idea they are sick who are out and about infecting others.
  • Many people probably don’t realize the emerging risk for kids. It might take a few weeks for the reports about toxic-shock syndrome in children in New York, Italy, and France to sink in.

It’s a lot to ask members of a free society to stay up-to-the-minute on all the fast-moving science news. Especially when so many have been coached to distrust everyone and everything. But now that quite a few people seem to think they’ve “sacrificed enough” and it’s time to hit the bars, we have to brace ourselves for a lot more sacrifice.

Science

  • Should COVID19 Take Advice from Rheumatologists? The Lancet. May 7. (Kate Kernan and Scott Canna)
  • Performance of the rapid Abbott ID NOW, the 5-minute Test for SARS-CoV-2 Infection in nasopharyngeal swabs and dry nasal swabs (It was basically useless). BioRxiv. May 12. (Atreyee Basu et al at NYU Langone Health). Abbott questioned the study methods.
  • Seroprevalence Study Shows 5% of Spaniards Have Antibodies to Coronavirus, and 90% of Infections Were Undetected by Healthcare System. El Pais. May 14. (Borja Andrino et al)

Science Features

  • Legendary Virologist Peter Piot, Who Fought HIV and Ebola, on His Near-Death Experience with COVID-19. Interview with Science. May 8. (Dirk Draulans)
  • One Benefit. The Expansion of Telemedicine. NYT. May 11. (Jane Brody)
  • This Supernova in Human History Will Need Many Perspectives to Understand. STAT. May 14. (Vinay Prasad and Jeffrey Flier)
  • Everything You Need to Know About Herd Immunity. Elemental. May 13. (Tara Haelle)
  • How Gilead Prepared for the Big Moment with Remdesivir. Bloomberg News. May 14. (Robert Langreth)
  • COVID19 Brings Health Disparities Research to the Forefront. NIH Director Blog. May 14. (Francis Collins)

Testing

  • The Testing Strategy We Need to Reopen Safely. Time. May 13. (Scott Gottlieb)

Treatments

  • Monoclonal Antibodies. Why Are You Optimistic? In the Pipeline. May 14. (Derek Lowe)
  • Hydroxychloroquine in 150 Hospitalized Patients in China. A Failed Randomized Study. BMJ. (Wei Tang et al)

Investigations

Policy & Politics

  • Official CDC Reopening Guidelines for States, Silenced by the White House. (Full document)
  • Highlights of Tony Fauci Congressional Testimony. STAT. May 12. (Lev Facher)
  • To Restart Business, Protect Workers. Bloomberg Opinion. May 11. (Michael R. Bloomberg)
  • We’re Retreating. Let’s Call the New COVID19 Strategy What It Is. Washington Post. May 13. (Leana Wen)
  • We Need to Enter the Fifth Stage of Coronavirus Grief: Acceptance. The Sooner We Accept the New Normal, the Sooner and Safer Reopening Will Be. Washington Post. May 14. (Tom Frieden)
  • Rick Bright Warns The Crisis Will Worsen Without Fast Federal Action. Politico. May 14. (Sarah Owermohle and Dan Diamond)

Strategy

  • Long Range Planning Reframed as “Leaders Require Purpose.” LifeSciVC. May 8. (Rene Russo)
  • Why Big Investors Aren’t Betting It All on a Coronavirus Cure. WSJ. May 14. (Gregory Zuckerman)

Vaccines

The Dysfunctional US Health Care System

  • Why 1.4 million US Healthcare Jobs Have Been Lost During a Huge Health Crisis. NYT Upshot. May 8. (Margot Sanger-Katz)
  • America’s True COVID19 Death Toll Already Exceeds 100,000. NYT. May 13. (Nicholas Kristof)

Manufacturing and Access

  • Gilead Signs Deals with 5 Generic Manufacturers in India and Pakistan to Boost Remdesivir Production. (Gilead statement)
  • HHS Announces US Distribution of Remdesivir to Certain States. May 9. (HHS statement)
  • France Says It Would Be ‘Unacceptable’ if Sanofi Provides a COVID19 Vaccine to the US Market First. May 14. Agence France-Presse.

Thinking Big

Illumina and Genomics England are teaming up on a study across the UK’s National Health Service. They’re doing whole genome sequencing on 20,000 people currently or previously in an intensive care unit with SARS-CoV-2, plus another 15,000 people with mild or moderate symptoms.

Personnel File

Dr. Michelle McMurry-Heath was named the new president and CEO of the Biotechnology Innovation Organization. She replaces Jim Greenwood on June 1. Dr. McMurry-Heath represents quite a turn in direction at the industry trade group. She has outstanding credentials as a physician-scientist. She has experience at the FDA and in regulatory affairs at Johnson & Johnson. She’s African-American. She speaks about social justice. All of this makes for a strikingly different background than her predecessor, who came to BIO primarily because of his political relationships and knowledge from the years when he was a Republican member of Congress from Pennsylvania. I don’t know Dr. McMurry-Heath. But I am happy to see a black person get the top job at BIO, and am eager to see what she does in this role. See STAT’s coverage of the new BIO leader.

Moncef Slaoui was tapped to head up the vaccine effort for Operation Warp Speed, the US federal government response. He’s a partner with Medicxi Capital, and a former head of GSK’s vaccines division.

Mike Varney is stepping down from one of biopharma’s most scientifically influential jobs as head of Genentech Research and Early Development (gRED). He’s leaving at the end of July. He’s being replaced by Aviv Regev, a faculty star at the Broad Institute, and a leader of the Human Cell Atlas. (See Dr. Regev’s comments for a December 2019 TR article on the emergence of single-cell sequencing).  

Atul Gawande, the celebrated surgeon and author, stepped down from his role as CEO of Haven, the Amazon-JPMorgan-Berkshire Hathaway backed company. He said he plans to focus more on COVID-19.

Cambridge, Mass.-based Celsius Therapeutics, a company leveraging single-cell sequencing techniques for the treatment of cancer and autoimmunity, hired Jeanne Magram as chief scientific officer. She replaces Christoph Lengauer, a partner at Third Rock Ventures who co-founded the company, and who will remain as an advisor and board member to the startup. Rene Russo, CEO of Xilio Therapeutics, also agreed to join the Celsius board.

Waltham, Mass.-based AMAG Pharmaceuticals cut 30 percent of its workforce, or 140 workers.

Financings

  • Cambridge, Mass.-based QurAlis raised $42 million in a Series A financing to advance R&D against amyotrophic lateral sclerosis and other neurodegenerative diseases.
  • Cambridge, Mass.-based Dyno Therapeutics came out of stealth mode, generally describing its work on novel capsids that are supposed to improve AAV viral vectors, especially for delivery in ophthalmic, muscle, central nervous system, and liver disease. The company raised $9 million from Polaris Partners and CRV in 2018.
  • Palo Alto, Calif.-based Kriya Therapeutics raised $80.5 million in a Series A financing to develop gene therapies.
  • South San Francisco-based Sutro Biopharma, the developer of protein drugs in a cell-free manufacturing system, raised $98 million in a stock offering of 12.6 million shares at $7.75 apiece.
  • San Rafael, Calif.-based BioMarin Pharmaceutical raised $550 million in a convertible debt offering.
  • Newark, Calif.-based Protagonist Therapeutics raised $98 million in a stock offering of 7 million shares at $14 apiece.
  • Quest Diagnostics raised $550 million in a debt offering.
  • Cambridge, Mass.-based Axcella raised $52.3 million in a stock offering.
  • Cambridge, Mass.-based Akebia Therapeutics, a developer of drugs for kidney disease, raised $132 million in a stock offering of 11 million shares at $12 apiece.
  • Gaithersburg, Maryland-based Novavax said it stands to collect as much as $388 million from CEPI to develop its COVID19 vaccine candidate.
  • Menlo Park, Calif.-based Frazier Healthcare Partners said it put $15 million into a Series A financing for Lengo Therapeutics, a precision oncology company. Mike Gallatin, Roger Ulrich, Jim Bristol and Bruce Roth are all involved, working with partners in India.
  • New York-based Stellar Health, a health tech company, raised $10 million in a Series A led by Point72 Ventures.

Deals

Cambridge, Mass.-based Bluebird Bio and its partner, Bristol-Myers Squibb, were dealt a whopper of a setback at the FDA. The regulatory action said it can’t yet begin to review the application submitted to review ide-cel (bb2121), a BCMA-directed CAR-T immunotherapy for patients with multiple myeloma. The agency said more detail is required in the chemistry, manufacturing and control section of the application – and it can’t begin a formal review of the application until that work is done.

That’s a screw-up. The same day it announced this unforced error, Bluebird announced that it had renegotiated its partnership. BMS agreed to pay $200 million now so it doesn’t have to pay Bluebird milestones and royalties in the future on sales generated outside the US for both ide-cel and a second-generation BCMA-directed cell therapy. The companies will continue to split sales equally in the US. Bluebird stock traded as high as $63.55 the day before the announcement, and closed May 14 at $54.06.

Boehringer Ingelheim agreed to acquire Northern Biologics, a developer of drugs aimed at the tumor microenvironment. Terms weren’t disclosed.

Kirkland, Wash.-based Prevencio agreed to work with Seattle Children’s Research Institute to repurpose the Prevencio blood testing platform to detect signs of Kawasaki syndrome, a rare and very dangerous inflammatory reaction similar to the kind of inflammation seen in children with SARS-CoV-2 infections.

Data That Mattered

Brisbane, Calif.-based Myokardia said it hit all primary and secondary endpoints in a Phase III study of its mavacamten treatment for hypertrophic cardiomyopathy. The company issued a standard top-line press release with statistically significant p-values, showing the favorable result was not the result of chance. Like many companies in this enviable spot, MyoKardia held back the more meaningful details on the magnitude of clinical benefit seen in patients on the drug compared with the placebo. That will come later at a medical meeting, the company said. Immediately after announcing success, MyoKardia cashed in on the momentum in its stock price. It raised $551 million by selling 5.25 million new shares at $105 apiece on May 12. Shareholders won’t mind the minor dilution, as shares rocketed from $61.09 prior to the announcement all the way to $118 on May 14.

Regulatory Action

AstraZeneca and Merck won FDA clearance to market the PARP inhibitor olaparib (Lynparza) as a maintenance therapy for patients with advanced ovarian cancer, in combination with Roche/Genentech’s VEGF inhibitor bevacizumab (Avastin). The approval is for patients with homologous recombination deficiency, an umbrella term that includes patients with a BRCA gene deletion, suspected BRCA gene mutation, or genomic instability. The drug was found to extend survival by a median of 20 months in combo with the VEGF inhibitor, compared with the VEGF inhibitor alone.

Eli Lilly won FDA approval for selpercatinib (Retevmo) for patients with lung and thyroid cancers driven by RET gene mutations or fusions. This is one of the drugs Lilly obtained through its $8 billion acquisition of Loxo Oncology.

Abbott Laboratories won an FDA Emergency Use Authorization of a new COVID19 antibody blood test that runs on its Alinity i System. It has 99.6 percent specificity and 100 percent sensitivity, the company said. The new test is part of Abbott’s plan to ship 30 million antibody tests worldwide in May.

RUCDR Infinite Biologics, a bioprocessing lab affiliated with Rutgers University, won FDA clearance for the first saliva-based at-home test to detect SARS-CoV-2 infections. The test was developed in collaboration with Spectrum Solutions and Accurate Diagnostic Labs.

Quidel won FDA Emergency Use Authorization for a SARS-CoV-2 antigen test that can be run in 15 minutes. It detects active infection in samples collected from nasopharyngeal swabs, like the existing PT-PCR tests. It’s not as accurate as RT-PCR tests, but can be performed in point-of-care settings that have Quidel’s benchtop Sofia 2 analyzer.

Tweetworthy

13
May
2020

Coronavirus Vaccine Strategy: Larry Corey on The Long Run

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13 May 2020

Today’s guest on The Long Run is Larry Corey.

Larry is one of the nation’s best-known virologists and vaccine developers. Much of his research over the years has been on HIV, herpes simplex viruses, and viruses associated with cancer.

Larry Corey, MD; President and Director Emeritus; Member,
Vaccine and Infectious Disease Division, Fred Hutch; Principal Investigator, HIV Vaccine Trials Network

He’s the founding director and principal investigator of the HIV Vaccine Trials Network – a collaborative group to study vaccine candidates at 30 sites around the world. He’s based in Seattle at the Fred Hutchinson Cancer Research Center. He served as president and director of that institution in the early 2010s, but now is back to running his own virology lab.

Larry has spent 50 years thinking hard about viruses and how to combat them, dating back to a stint at the CDC during the Vietnam War days. Early in his career at Burroughs-Wellcome, working with future Nobel laureate Dr. Gertrude Elion, he developed acyclovir as the first effective therapy for genital herpes. As director of the AIDS Clinical Trials Group, he led the organization that proved combination antiretroviral treatments could control HIV. The team later demonstrated that these drugs could reduce transmission of HIV from mothers to their infants.

This whole set of experiences has shown him what each major player in the scientific enterprise brings to the table – academia, government, and industry.

All of this makes him a great person to talk to now about vaccine strategy for COVID-19. Just before we recorded this episode May 12, he published a perspective piece in Science with Tony Fauci, John Mascola and Francis Collins of the NIH. They wrote about how to think about spinning up an unprecedented global vaccine effort against the pandemic. See that strategy paper here.

This is a timely and frank conversation about one of the most important aspects of the pandemic response.

Please join me and Larry Corey on The Long Run.

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13
May
2020

If Trikafta Isn’t Good Enough for ICER, What Drug Is?

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13 May 2020

JessicaSagers, PhD; head of engagement, RA Capital

Last week ICER released a report concluding that Vertex’s groundbreaking triple-combination cystic fibrosis (CF) drug, Trikafta, is too expensive for the value it provides to patients.

By all scientific and clinical standards—including ICER’s own—Trikafta, a novel combination of a CFTR potentiator and two correctors, is a transformative drug. It compensates for a mutation present in 90% of all CF patients, turning a disease that has long been a death sentence into a manageable chronic condition. Following stellar Phase 3 data, the FDA approved Trikafta five months ahead of schedule. The patient, physician, and research communities exploded in exuberance when it was approved. NIH director Francis Collins, who helped discover the CFTR gene in 1989, whipped out his guitar and sang on stage in celebration.

ICER awarded Trikafta an “A” – its highest grade – for “certainty that Trikafta provides a substantial net health benefit over standard of care.” However, the magnitude of this achievement did not translate to a favorable review on price. Trikafta is priced comparably to similar drugs for rare conditions, at just under $24,000 per month in the US. And that’s a list price – insurance plans and Medicaid pay a lower but undisclosed net price, so after typical discounts and rebates (~15%), Trikafta’s net price is likely closer to $20,000 per month.

Once a patient starts on the drug, they have to stay on it to manage their disease. That’s not unusual for small molecule drugs or injectable biologics. But Trikafta works better for CF than most drugs work for their respective rare diseases. Even so, in ICER’s words: “Despite [Vertex’s CF drugs] being transformative therapies, the prices set by the manufacturer – costing many millions of dollars over the lifetime of an average patient – are out of proportion to their substantial benefits.”

This assessment caused an outcry among patients and foundations. They argued that the drug is a life-changer, and that ICER’s analysis didn’t include important variables that matter to patients. In a sentence that shocked CF families, ICER argued that even if Trikafta were able to generate a total functional cure such that patients never experienced any complications related to their disease, the drug would still not be worth paying for at the price set by Vertex:

“As an extreme scenario analysis, we evaluated Trikafta as a curative therapy and found that the cost-effectiveness ratio of lifetime therapy with Trikafta continued to far exceed commonly used cost-effectiveness thresholds even under the assumption that it maintained individuals with CF in normal health such that they never experienced any symptoms or complications of CF.” (emphasis added)

The callousness of this response aside, it isn’t that a drug—or even a cure—can never be overpriced. That’s conceivable, especially in the absence of any competition. But ICER tries to make the point that Trikafta is overpriced while leaving a lot of math on the table that does not suit its argument.

It’s worth exploring those overlooked variables and the societal norms that underlie value-based pricing analyses, which CF patients have cited in their defense of this vital medicine. It’s especially important to take this broader view considering how those norms might change following the COVID-19 pandemic. Let’s explore more accurate ways to model cost-effectiveness so that we don’t risk talking ourselves out of inventing what we really need.

Drug costs are mortgages, not rents

Healthcare costs in the United States are on the rise and will continue to increase. This is because paying for the time and expertise of trained medical professionals, keeping hospitals and clinics clean and operational, and maintaining the huge administrative burden of our medical system is expensive and will remain so. These costs are like an ever-rising rent that we as a society will always have to pay.

But drug costs are mortgages, not rents. Drugs are the only element of the healthcare system that not only pay for themselves but save our system money in the long run. How? They go generic. After a new drug enjoys a finite branded period, patents expire, competitors enter the market, prices drop by 85-90%, and that advancement belongs to society as a low-priced generic forever. By law, Trikafta will go this route one day, too, most likely within about 15 years from its launch, as nearly all small-molecule drugs do. Vertex’s monopoly is temporary, not permanent, by design.

But ICER’s methodology does not take into account the fact that any drug will go generic. Instead, they model the drug’s launch price as its price each year for the entire lifespan of each patient, wildly overestimating its total lifetime cost. 

For the sake of argument, let’s assume an average CF patient starts taking Trikafta at age 10 and gets the patented drug for 15 years. If the patient remains in steady health, as would reasonably be assumed based on the drug’s profile, that 25-year-old patient in the year 2035 can expect many more years of healthy living on this drug at a less expensive generic price, not today’s premium branded one. ICER isn’t unaware of this flaw; rather, they expressly refuse to address it.

When called out on this point multiple times by CF patients and foundations, ICER punts:

“As is consistent with best practices at international HTA agencies and with the great preponderance of academic work in health economics, ICER’s cost-effectiveness analyses do not routinely make estimates of price changes across comparator treatments linked to patent and exclusivity time horizons, especially given the unpredictability of these changes in the US health care market.”

Yet the fact that a small molecule drug like Trikafta will go generic is one of the few predictable things about healthcare. One can model the possibility that some patent gamesmanship may result in a few years’ delay of a generic launch (inappropriate though it may be), but when modeling value on the scale of decades, these uncertainties hardly alter the fact that Trikafta’s genericization is inevitable. ICER argues that uncertainty in the timing of genericization and whether the price will drop by 80%, 85%, or 90% precludes modeling it at all. This is a disingenuous strategy, to say the least, and ignores a simple modeling assumption that can and should be factored in.

Economists who have modeled the impact of genericization have pointed out that doing so reveals a drug to be two- to three-fold more cost-effective than misrepresenting its mortgage cost as rent. Payers, regulators, and the biotech community should spurn ICER’s analyses if they continue to neglect drugs’ core value proposition. At this point, continuing to refuse to account for genericization is tantamount to perpetuating disinformation.

COVID-19 expands our definition of value

What would it be worth to you to know that if you contracted COVID-19, there would be a safe, effective treatment to get you back on your feet?

What would that peace of mind do for you when deciding whether to allow family members to go back to work or school?

What would such reassurance do for the global economy?

The COVID-19 pandemic illustrates that another vital benefit that drugs provide (and value-based pricing analyses fail to capture) is peace of mind: the freedom to act, plan, and work without the threat of a disease hijacking your life.

The mother of a CF patient captures this intangible benefit in her exchange with ICER:

CF Mother: ICER’s report fundamentally fails to capture the monumental progress my son has achieved thanks to this triple-combination therapy. Increased pulmonary function is important, but it is the freedom to prepare for a fruitful future rather than to prepare for death that matters most. The larger point here is that the improvements that matter most to patients are not at the center of ICER’s cost-effectiveness analysis.

ICER: We modeled Trikafta as a cure and it still did not meet societal norms for cost relative to benefit.

What ICER dismisses is that “societal norms for cost relative to benefit” are ours to set. ICER’s “societal norms” reflect the norms of its own staff, and certainly the publicly stated sensibilities of its major backer, billionaire John Arnold. But they do not represent those of the majority of Americans, who view healthcare as a human right. America excels in nurturing the kind of innovation that advances its goals. It is within our country’s means and abilities to improve our health and that of the world.

With the capabilities of biomedical innovation now on display and the world calling for more COVID-19 investment from all of society’s pockets – government, insurance, non-profit, and private sector – the pockets that everyone acknowledges we must not reach into are those of patients. Patients need affordable drugs, and America can make that possible not just for most, as it does now, but for all with proper insurance reform. That means ensuring that all Americans are insured and minimizing barriers to access for essential medications (i.e. by reducing out-of-pocket costs). Then we can collectively incentivize and fuel innovation to solve our unmet needs. We can do that by paying branded prices that, while seemingly high per patient, are finite and, in the long run, represent better value than continuing to suffer from the diseases that plague us.

Right now in the US, because of Trikafta, about 30,000 patients have a new, hopeful outlook on life. Every one of them is surrounded by family members that can now worry less about managing the disease and start thinking more about pursuing their own dreams. There is substantial human potential that can be unleashed whenever a powerful new drug like Trikafta comes along. 

Until we achieve insurance reform for everyone, we can put some patches in place to pay for this advance. The COVID-19 pandemic has already shown us that this is doable: for example, by capping insulin copayments at $35 for everyone regardless of insurance status and offering many medicines for low fixed costs to tens of millions of the uninsured. If drugmakers and insurers can do this for patients now, they can do it in the future.

It’s time we recognize that value can’t be captured by a single organization’s formula – especially one with the gall to insist a launch price lasts forever and that disregards the value of curing a devastating disease for ourselves and future generations. It’s hard to think of a societal norm more American than investing towards an accomplishment as immense as conquering CF, taking pride as a nation in getting the job done, and celebrating the heroes who did it. 

RA Capital is a registered investment adviser. This material is not intended, and should not be construed as, investment advice or recommendation to invest in any security. Likewise, this material is not intended as a solicitation to invest in any RA Capital product or service.

11
May
2020

Science in Plain English for the Pandemic

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11 May 2020

Art Krieg is one of the leaders in the field of oligonucleotide drug discovery, going back to the 1980s. Today, he’s the founder and chief scientific officer of Cambridge, Mass.-based Checkmate Pharmaceuticals, a cancer immunotherapy company.

Art Krieg, founder and chief scientific officer, Checkmate Pharmaceuticals

It’s his job to explain scientific concepts to a variety of professional audiences. But he leveraged that skill recently to do an interesting thing — a plain English, yet highly sophisticated 14-minute webinar aimed at general non-scientific audiences. It’s for the Oligonucleotide Therapeutics Society, a group he co-founded and recently served as president.

In the video (below), Art distills some basics on RNA and DNA medicines and vaccines. He talks about why this is an exciting time, and how this new biology could be applied in the pandemic. He uses plain English, not jargon. His tone toward the audience is one of respect. He immediately answers the ‘why should I care?’ question in his first breath — these oligo drugs are saving lives. He’s optimistic, yet he doesn’t overhype.

Essentially, he’s doing what many scientific entrepreneurs are capable of — telling an interesting, balanced scientific story that people can understand and appreciate. I think this is something other entrepreneurs could do, so I asked Art a few questions below to provide some background color.

 

Timmerman Report: You’re a scientist, not a practicing clinician. Communicating technical material to lay audiences isn’t really part of your day job.

Art Krieg: True now, but before I went full-time into biotech, I had 19 years of patient care experience, and that has an indelible impact on the way you think. You learn the importance of patient education and communication: patients are far more likely to take a medication as directed if their doctor explains it in a way that they can understand, and so I tried to do that. During my NIH fellowship in rheumatology I became involved with patient education at the Lupus Foundation of America, which gave me a chance to try to explain new scientific advances to a larger population than I could reach as an individual clinician.

TR: If we think about it, each of us can leverage our skills in different ways to be helpful now. You’ve given lots of scientific presentations and have that skill. But had it been directed in this public-education way previously?

AK: When I was a young assistant professor at the University of Iowa, I enjoyed getting involved with the state Lupus Foundation, and giving talks on lupus research and therapy to local chapters. As time went on, I became more involved in professional organizations, co-founding the Oligonucleotide Therapeutics Society (OTS) as a way to try to help advance the development of this whole new class of drugs. 

TR: Was this public education webinar something you had been meaning to do for OTS for a while, but never got around to?

AK: At the OTS we actually had scheduled a meeting for just a few weeks ago with FDA, NIH academic centers, patients, patient organizations, and bioethicists around how to accelerate the development of oligonucleotide therapeutics for N-of-1 diseases, that are so rare that no company can afford to develop a drug, even though the existing technology can be used to potentially save some patients’ lives. Then the pandemic hit, and we decided to reschedule that meeting. My OTS colleagues suggested to me that instead, I should prepare a video for the public on how our technologies can be used against the coronavirus. The idea immediately appealed to me.

TR: How much time and effort did you put into this little labor of love?

AK: It ended up taking WAY more time than I expected – I think every night for a week or so and most of two weekends.  

TR: Did you get some help along the way?   

AK: I got a lot of helpful feedback from OTS colleagues, friends, and family on 4 different versions of the webinar, and it was quite painful because I had to really simplify the message enormously, and cut it down from more than half an hour in the first version to under 14 minutes in the final one.

TR: Why did you want to do this?

AK: These drug development technologies are incredible, and I really believe at least some of them are going to work in a time frame that matters – I really wanted to communicate that to people because I thought the lay public might be glad to know the great progress in developing drugs to stop the pandemic.

After I finished the webinar, I read that a quarter of all Americans would refuse to get a vaccine against SARS-CoV-2, even if it was FDA approved as safe and effective. That horrified me – people are going to die unnecessarily if they refuse these new vaccines, and some who refuse to be vaccinated will transmit the disease to others who will die. No vaccine is going to be 100% effective, and so we should expect that the elderly population who are most vulnerable will have a lower response rate to these new vaccines, just as they have with older ones.

I get it that many people are afraid of things that they don’t understand, and if that is what is driving this refusal to get a SARS vaccine, then I hope that by explaining how these new RNA and DNA vaccines work, perhaps some of those people will understand and change their minds. I hope to change people’s minds by explaining that these RNA and DNA vaccines are assembled from natural building blocks that are already present in our bodies, and that these vaccines harness the same natural immune pathways (through TLRs) that our immune system uses every year to fight off the many viruses around us.

I don’t think it’s enough for us in the biotech industry to “only” develop lifesaving technologies to create new drugs faster than ever before – if we want to realize the full impact that these drugs and vaccines can have in saving lives, then we also have to explain them to people in a way that they can understand, so that they can get comfortable with them. 

The aluminum salts (alum) in older generations of vaccines are safe, but the fact that alum is not a natural part of our bodies scares many people. Call me naïve, but in the case of these new vaccine technologies that use these natural pathways, I just cannot see how someone could understand how they work, and still decide to refuse them. If just a few people who would have refused the vaccine decide to accept it because of my video, then it will have been worthwhile. And maybe I can encourage other people to pick up this work, and to spread this message better than I can.

TR: What’s your biggest hope with this – maybe that the video gets circulated with high school science teachers?

AK: I would be delighted if high school teachers watch this, and spread it to their students! And I would be even more thrilled if some of those students somewhere in the world then get interested in science and oligonucleotide therapeutics, and come into this field and help us develop new generations of technologies for the future! 

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