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Jeremy Levin, CEO, Ovid Therapeutics; chairman, BIO
Democracy is fragile.
Its stability depends on the acceptance of its principles by the population as a whole, the resilience of the institutions that support it, an independent judiciary, a free press, free and open elections and, in the United States, the foundation laid by the Constitution.
The struggle to balance those critical pillars has been waged across the globe in modern times. Despite the terrible lessons of the last century, we see the basic principles supporting democracy under attack, and the ascendency of authoritarian and dictatorial governments around the world.
Few Americans have believed, until perhaps Jan. 6, that the fabric of our democracy could be stretched in a similar fashion and that we might follow a similar path.
And yet here in the greatest democracy that the world has ever seen, we saw a violent attempt to interfere with the peaceful transfer of power determined by the voters in a national election.
The stress on our democracy has been building for some time. A president who knew he would lose the election, proceeded to undermine its legitimacy before a single vote was cast. Then when he lost, he lied about the results and proceeded to try and undermine the electoral process.
This sustained attack on democracy culminated with a physical assault on the core of our government, our Congress. This assault was deliberate and deadly. It was planned and executed with the intent not only to overturn a legitimate electoral process and deprive the nation of its right to choose its President but also to destroy the foundation of that process and our democratic constitution.
Americans are used to assuming that checks and balances will allow for a robust political dialogue while ensuring a smooth, peaceful political transition in keeping with the Constitution. On this occasion we are witnessing — in real-time — an attempt by a sitting president to formulate an insurrection and impose on the nation a form of dictatorship seen elsewhere in the world.
These attempts will fail. But they will fail not only because of the bravery of those overseeing the elections in battleground states, or the barriers put up in courts around the nation where facts matter, but because the attempt was so blatant and obvious that suddenly the real intent of a President who had been supported by so many for so long, was revealed in stark relief.
The want-to-be emperor has no clothes. Stripped naked, the lies, the malign intent and complete lack of compassion were laid bare. Instead of a leader who had been given the mandate to lead the nation in 2016, and who could have built so much, we saw what has been seen in so many other lessor nations. We saw the raging of someone who never cared for the nation, surrounded by sycophants and glory seekers, attempting to overthrow democracy.
Elected leaders, who should know better, did not take action to stop the insurrection. Indeed, while the mob attack was ongoing, a few leaders in the Senate and many members of the House continued to fan the flames – spreading the myths and lies of an illegitimate election.
It was a brutal and disgraceful display of cynicism, craven political cronyism and unthinking fealty.
Instead it was left to brave, outnumbered and ill-equipped individual police officers to protect the Capital. It is they who mitigated what could be one of the greatest terror attacks in our history.
Have egged the mob on to attack Congress and then throughout this terrible episode as mayhem unfolded, as with the horror and devastation by COVID-19, the president remained silent. When, hours later, he released a video telling the mob to “go home,” he continued to repeat his lies about a stolen election and called members of the crowd “very special people.”
Not a word of care was spoken by the President about the Vice President and his family, who may well have ended up on a gallows erected in the Mall, exactly as the crowd who stormed Congress made clear was its intent.
This was a display worthy of the worst excesses of nations ruled by despots.
But despite this, there is hope. Our nation has reacted in horror. Business leaders have reacted by cutting off donations to those who persist in politically supporting the president’s lies and insisting that the election was “stolen”. Importantly, Twitter, Facebook, Google, Amazon and others have finally stepped forward. They are preventing some, but not all, of the lies and propaganda that are being spread as insidious as a cancer across the psyche of the American population.
It’s a start.
What we witnessed leading up to and including this last week was not a dispute between Republicans or Democrats. It was a clash between democracy and demagoguery. Dictatorship and freedom.
We need legal consequences for those who incited, and participated in, this dangerous attack on America.
It will be painful, and some will make political arguments against accountability. But it’s a necessary first step toward protecting and strengthening our cavalierly maligned democracy.
Once the insurrection has been put down, we will need to heal the fractured relationship between the parties and those who know that together, as a country, we are stronger. If we do not do so, many abroad will take advantage to diminish and / or harm our nation. Some have started to take advantage of the perceived turmoil — including Russia, North Korea, Iran and China.
In the face of this, our allies in Europe, Asia and elsewhere need to feel confident of our support. We will have much work to do to stabilize the erosion of global confidence in America and rebuild its credibility, economic strength and political standing around the world.
More importantly, we have rebuilding to do here at home. We need to ensure that the domestic terrorists who, encouraged and egged on by the delusions of a president who refuses to except facts and persists in lying, are not able to continue to incite violence, and that they are no longer able to undermine institutions of democracy which we all count on.
The strongest way to do this is for our leaders to acknowledge the pain and anguish the nation is experiencing economically, politically and medically. Each is a huge challenge. All pillars need to be strengthened at all levels and across all social and racial groups. We know we are stronger together.
The healing that needs to take place now will need to happen against the backdrop of the miasma and horror of the COVID-19 pandemic. But there is hope at the end of this tunnel. The biopharmaceutical industry united to tackle the onslaught of the virus, delivering in record time vaccines which will stop the pandemic in its tracks. That example of pivoting, uniting, and focusing on solving an existential threat is one that our political leadership can, and hopefully will, emulate.
I believe we should hope and expect of our leaders come together to forge a stronger, more robust democracy out of the chaos and mayhem.
But let us make no mistake, if our leaders cannot find common ground, then what we saw on Jan. 6 is not an instance of horror and despicable behavior but the beginning of what has been seen in so many other nations — the dissolution of a dream. To prevent that, there can be no compromising at all with the behaviors that led up to the insurrection. There must be an absolute guarantee that those who involved themselves in this despicable act of insurrection are prosecuted fully.
At the end of the day, I believe the American dream is stronger than anything we have witnessed over the last four years and in the immediate last six days. Ours is a nation built to stand tall and strong: because of the fundamental good nature and values of the vast majority of our citizens we have the capacity to be even stronger. And we will be.
Jeremy M. Levin is the chairman and CEO of Ovid Therapeutics, and chairman of the Biotechnology Innovation Organization.
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Luke Timmerman, founder & editor, Timmerman Report
The virus, at the start of a New Year, has arrived on all seven continents. Even Antarctica.
An estimated 2 million people have died worldwide from the SARS-CoV-2 virus, and that’s surely an undercount. About 4,000 people are dying per day in the US. About 255,000 new people are being diagnosed with this dangerous and mysterious invader every day in the US.
We see a few new variants circulating. We are seeking to understand what that means.
The pandemic is causing Biblical levels of suffering. Hospital staff are exhausted, reduced in many instances to operating in battleground triage mode.
Millions of people are jobless. Many are homeless or living on the brink of eviction. Millions are starving.
A violent mob, incited by a twisted individual still in place as President of the United States, attacked the heart of the nation’s capital. The mob attempted to overturn an election. They took selfies, gleefully thumbing their noses at democracy. Police were either unable or unwilling to stop the mayhem.
It’s the logical result that follows from years of mass radicalization by cynical political leaders and entertainment / media personalities.
These are sad, cold truths. I get angry and frustrated sometimes.
But we won’t get anywhere by wallowing in the horror, averting our gaze, hoping it will all just go away, or lashing out at the “Others.” We must get swift justice for those responsible for the domestic insurrection. Then we have to do a lot of long, hard work in rebuilding our communities.
Ugly as this week has been, there is beauty out there. We can allow ourselves to open our eyes and see it.
Biopharma is one of the bright spots. This industry, in partnership with government and academic researchers, has produced two remarkably effective vaccines. We knew they would be supply-constrained from the start, and we’d have to be patient. Yet the rollout is more painful than it had to be. Too many of the vaccines we have – 95 percent effective vaccines, remember! — are sitting around on freezer shelves instead of getting injected into arms.
Only 5.9 million first doses have been administered out of the 21.9 million doses delivered to states, according to the CDC on Jan. 7. Systemic failure on multiple levels explains this situation. There’s vaccine hesitancy, aided by firehoses of misinformation. There’s no serious federal plan, never has been. The state agencies are chronically underfunded and understaffed.
Local stay-at-home orders and social distancing requirements remain intact. People are struggling without the social contact we all need. No surprise, we are seeing waves of depression, apathy, suicide, homicide.
Much of what’s described above is beyond our control. But look around in biopharma, especially at the list of financings and deals this week. The capacity for good — the industrial horsepower that can be channeled into progress that will end this pandemic — it’s palpable. This community has tremendous capacity for good work. The beating heart is on display for anyone who cares to look.
We should be thankful to be alive in this biotech renaissance. What we are witnessing, and participating in, isn’t an accident or a lucky break. The foundation has been laid for decades with government and industrial investments in enabling technologies, better understanding of basic biology, vibrant capital markets with an appetite for high-risk / high-reward propositions, a growing pool of experienced executives, savvy and independent regulators, and a talented, committed, increasingly diverse workforce.
People of ability and good will, over decades, cultivated the biopharma community we live in today.
You can’t take the pulse this January at San Francisco’s Union Square, but everything I see and hear says the industry is adapting and improving in the pandemic. Some old bad habits and craft attitudes are being shed. The industry is moving faster. It’s rediscovered the power of single-minded, intense focus — rather than trying to sometimes be everything to everyone. It’s getting more productive. It’s getting more inclusive. More empathetic. More understanding of industry’s role in the wider world.
We have a chance, if we finally decide to deliver universal healthcare to US citizens, to enter a truly great age of progress in improving the health of individuals and society.
It would be easy to snicker at the above paragraph, and say this has been tried before. But now that the world has seen a once-in-a-century mobilization of the scientific enterprise pay off in spades, why not think universal healthcare is possible? Why not imagine a tripling of the NIH budget over the next 10 years? Why not build an entirely new NIH campus west of the Mississippi, in a place with some strong biomedical assets already in place, like Missouri, Nebraska, or Utah? Why not dream of a world in which the most talented young people are drawn like moths to careers in science, instead of investment banking or management consulting?
What might be possible if that were to happen?
I’ve been covering biotech for 20 years. I’m confident that what I’ve been fortunate to witness thus far will pale in comparison to what I’ll get to see in the next 20 years.
We are a dynamic, flexible country. We have been gifted with a system of democratic self-governance, quite intentionally the opposite of a monarchy or authoritarian regime. It’s our job to maintain it as active participating citizens. If we accept that challenge, then we can be confident we will continue to live in a system that is sometimes volatile, but rebalances and recalibrates every so often. Our representative democracy has its flaws, but it has proven durable in its ability to unleash human flourishing while generally resisting the various idea viruses circulated by factions and mobs.
We still have it within us to strive for greatness.
I grew up poor on a small family farm in Grant County, Wisconsin. I got to attend the flagship state university about 90 minutes away, in Madison. I now own and operate a successful small business, where I get to interview the smartest scientific entrepreneurs in the world on a daily basis. Many of the people I interact with are brilliant immigrants who have overcome all sorts of obstacles to come here and do amazing things.
This kind of thing can, and does, happen so often that we sometimes take it for granted. We shouldn’t.
We will find our North Star again as a country as we correct the catastrophic errors of the past and present.
I look forward to hearing your ideas on what you’re doing, however small it may seem, to make a positive contribution. We all have a part to play.
Let’s think big. I’m listening. luke@timmermanreport.com.
Financings
Venrock raised its ninth fund, worth $450 million, to invest in early stage tech and healthcare companies.
Boston-based Scorpion Therapeutics raised $162 million in a Series B financing co-led by Boxer Capital of Tavistock Group, EcoR1 Capital, Omega Funds and Vida Ventures. It’s a precision oncology company led by Gary Glick, the star serial entrepreneur. (Read my interview with Glick when he stepped down from the CEO role at his last startup, December 2019.)
Cambridge, Mass.-based LifeMine Therapeutics raised $50 million in a Series B led by Rick Klausner and Milky Way Investments. The company is working on a fungi-based drug discovery platform. (See TR coverage of LifeMine, including my interview with CEO and CSO Greg Verdine.)
Cambridge, Mass.-based Werewolf Therapeutics raised $72 million in a Series B financing. Its lead product candidates are engineered IL-2 and IL-12 protein therapies for cancer. RA Capital led.
South San Francisco-based Senti Bioscience raised a $105 million Series B financing to develop programmable cell therapies for cancer. Leaps by Bayer led. (See TR coverage of Senti, including interview with co-founder and CEO Tim Lu.)
Cambridge, Mass.-based Myeloid Therapeutics said it raised “over $50 million” in startup funding to develop engineered myeloid cells for cancer. NewPath Partners led. (See TR coverage of Myeloid, including interview with co-founder Siddhartha Mukherjee).
Newton, Mass.-based Abcuro raised $42 million in a Series A-1 deal co-led by co-led by Mass General Brigham Ventures and Sanofi Ventures. The company is engineering cytotoxic T and NK cells.
Boston-based Ikena Oncology raised $120 million in a Series B financing led by Omega Funds. The company is working on biomarker-directed cancer drugs. Otello Stampacchia, a TR contributing writer par excellence, is joining the board.
Cambridge, Mass.-based Immuneering raised a $62 million Series B financing, led by Cormorant Asset Management. The company is focusing on drugs that target the RAS/MAPK pathway.
San Diego-based Iconovir raised $77 million in a Series A financing co-led by Nextech and Vida Ventures. It’s developing oncolytic virus therapies for cancer. Mark McCamish was named the CEO.
Philadelphia-based Aro Biotherapeutics, the developer of what it calls “precise receptor-mediated delivery of RNA drugs to address intracellular gene targets,” said it raised $88 million in a Series A financing. Northpond Ventures and Cowen Healthcare Investments co-led the round.
San Francisco-based Color, a genomic testing company, raised $167 million in a Series D financing led by General Catalyst and T. Rowe Price Associates.
Deals
Durham, NC-based Ribometrix received a $25 million upfront from Genentech as part of a deal to work on small molecules directed against RNA targets.
Cambridge, Mass.-based Dewpoint Therapeutics, a company working on a biomolecular condensate-based platform for drug discovery, formed a deal with Pfizer to work on drugs for myotonic dystrophy type 1, DM1. Dewpoint is getting an undisclosed upfront payment and milestones worth as much as $239 million. (TR startup profile of Dewpoint, Apr. 2019).
Netherlands-based argenx, an immunology-based drug developer, formed a deal with Shanghai-based Zai Lab to develop and commercialize efgartigimod in China, Taiwan, Hong Kong and Macau. Argenx is getting $75 million upfront in Zai Lab equity. The drug is designed to tamp down excessive production of disease-causing IgG antibodies.
Switzerland and California-based Myovant Sciences forged a deal with Pfizer to work on relugolix – a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist – for cancer and women’s health indications in the U.S. and Canada. Myovant is collecting $650 million upfront.
Waltham, Mass.-based Morphic Therapeutic, the company developing small molecules against integrin targets, said its partnership with Janssen Pharmaceuticals has expanded to include a third integrin target. The deal was struck in Feb. 2019. (See TR coverage of Morphic, Oct. 2018, and listen to scientific founder Tim Springer on The Long Run podcast, Nov. 2019).
Tokyo-based Sosei Heptares said it regained worldwide rights to its muscarinic agonist programs, after getting them handed back from its partner, Allergan (now part of AbbVie.) The programs are being studied against Alzheimer’s disease and schizophrenia. (Listen to Karuna Therapeutics CEO Steve Paul on The Long Run podcast for more on muscarinic receptor modulation for schizophrenia.)
Vaccine Rollout. Not. Good.
Vaccines
Treatments
Testing
Science – COVID-19
Science (Non-COVID)
The Business of Biotech
Science Features
Managing in a Pandemic
Our Shared Humanity
Personnel File
Boston-based Jnana Therapeutics, a company working on metabolite transporter therapies, added Annie C. Chen, the chief medical officer of Cambridge, Mass.-based Nimbus Therapeutics, to its board of directors.
Seattle-based TwinStrand Biosciences, a next-generation DNA sequencing company, added Gary Gilliland to its board of directors. He’s the former president of the Fred Hutchinson Cancer Research Center, and former head of cancer research at Merck. (TR coverage of TwinStrand and other next-gen sequencing startups, June 2020).
Seattle-based Sana Biotechnology, the cell therapy company, hired Ke Liu as head of regulatory affairs and strategy. He’s a 17-year veteran of the FDA, and former associate director of the cell and gene therapy unit within the Center for Biologics Evaluation and Research.
Boston-based Entrada Therapeutics added Peter Kim, the Stanford biochemistry professor and former head of Merck Research Laboratories, to its board of directors.
Waltham, Mass.-based TScan Therapeutics, the developer of T-cell therapies, added Brian Silver to its board of directors.
Newton, Mass.-based Abcuro, a T-cell and NK-cell engineering company, named John B. Edwards as the Executive Chair of the board and David de Graaf as CEO.
Watertown, Mass.-based Forma Therapeutics named Selwyn Vickers to its board of directors. He’s the senior vice president of medicine and dean of the School of Medicine at The University of Alabama at Birmingham (UAB). He’s a pancreatic cancer researcher and leader in health disparities research.
Cambridge, Mass.-based Aura Biosciences, the developer of conjugated biologic therapies for cancer, named David Johnson to its board. He’s the CEO of VelosBio.
Boston-based Karuna Therapeutics, the developer therapies for neuropsychiatric disorders, named Denise Torres to its board.
A Scientific Nation That Can Do Better
While the world grapples with the rise of the B117 and E484K variants of SARS-CoV-2, and the implications for the pandemic response, the US – the world leader in DNA sequencing – is behaving like a corrupt, impoverished country.
Somehow, we are unable to leverage the strengths we have in genomic surveillance to provide better early warnings for our citizens in a pandemic that’s killing almost 4,000 people a day.
See the tweets below from Pavitra Roychoudhury and Trevor Bedford, genomic surveillance experts, which sparked a somewhat incredulous and angry tweet from me.
With a strong leader and probably less than $50 million – a drop in the bucket – we could take this bull by the horns. It’s no panacea, but it is an important aspect of the pandemic response we need now and in the future. It would not only protect our citizens in the immediate here and now, but would radiate world leadership of the sort we used to take for granted.
This is just one of many, many aspects of the pandemic response that must be improved as we turn the page on this nightmare chapter in American history and begin to re-imagine what we can do when we attempt to mobilize to achieve a shared objective.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
David Shaywitz
The mRNA vaccines for COVID-19, developed by Moderna and BioNTech/Pfizer, were a conspicuous bright spot in a generally devastating year. Besides giving us a chance to bring the pandemic to an end, they remind us more generally of the profoundly transformative potential of emerging technologies.
Audacious scientific and entrepreneurial ambitions can take years of grinding persistence, often sounding unrealistic or absurd to outsiders along the way, before suddenly they become generally accepted wisdom.
Moderna’s stock, which IPO’d at $23 a share in December 2018 and struggled to maintain this level in 2019, now sits at north of $100. The company was valued at $7.5 billion at the time of its IPO. Many considered the valuation staggering at the time. As MarketWatch reported, “no mRNA-based drug has ever been approved by the FDA nor any other regulatory agency, so it will be years before Moderna will be able to bring anything to market.”
Three years later, the company is now valued at over $40 billion.
It took a solid decade of sweat and capital before Moderna could truly take flight. As Crunchbase notes, 10 years earlier, “it was just a concept-stage company in the earliest stages of formation at Boston area biotech venture firm Flagship Pioneering.”
Stephane Bancel, CEO, Moderna.
While success always requires a prodigious amount of luck, it’s also clear – especially from this fascinating January 2018 Long Run interview with Moderna CEO Stephane Bancel – how much intentionality and deliberate choice were involved as well.
There was a compelling vision that thoroughly captivated founding VC Noubar Afeyan, subsequently shared by Bancel, who Afeyan recruited from Bancel’s previous role as CEO of French diagnostics company bioMérieux. (Fun fact: Bancel actually started his career as a sales rep for bioMérieux in Asia.)
Of course, not everyone bought into this vision, especially after repeated disappointments, nicely chronicled by STAT here. Many wondered if the perennially-hyped promise of mRNA therapeutics would ever been meaningfully realized. (To be fair, outside of vaccines, which conveniently don’t require chronic dosing, many still worry.)
But it’s not only mRNA vaccines that delivered; as I wrote in the context of JPM2018 (remember JPM?), we’re living through a remarkable moment in biotech, where the promises made decades ago (effective gene therapy, increasingly customized cell therapy, ever more elegant molecular editing) are at last being realized.
Which raises the question: what’s next? Who are the Moderna’s of today? What are the nascent concepts or embryonic startups of today, that will revolutionize medicine tomorrow?
If I was certain of the answer, of course, I would have already founded the company. But I know a few things.
First, there is exceptional and largely unrealized promise that will emerge from the intersection of biopharma and digital/data. Yes, there’s also extraordinary hype and extravagant expectation; in his always-essential year-end review, life science VC Bruce Booth calls out (not unfairly) “AI and machine learning in drug discovery” as the “most prominent” area that’s “over-hyped relative to [its] practical application.”
Yet from all this heat, I’m confident some real light will emerge. Three of the “V’s” associated with big data are plainly abundant in healthcare: volume, velocity, variety. Two others – veracity, value – would seem to be more of a work in progress.
There’s also ever-more powerful computers, and smarter (and perhaps even more ethical) algorithms. Misaligned incentives remain a pervasive problem, especially in healthcare delivery, but the essential opportunities to deliver better medicines more rapidly to the right patients, and to help healthy people remain healthy so they don’t require medicines — remain fundamentally compelling, even if aligning these objectives with durable business models represents an underappreciated, pervasive challenge.
And as for the breathless promises – I’m less worried about them. After all, mRNA vaccines were dismissed as ludicrously overhyped until about, oh, two minutes ago.
A second reason for optimism reflects the lessons we’ve learned about the implementation of emerging technology from successful leaders of innovative biotech companies. In many ways, Bancel may represent the very model of modern integrative CEO, combining the attributes of authentic intellectual curiosity about emerging technology with deep domain expertise in developing approvable drugs.
Bancel, after completing his MBA at Harvard, joined Lilly and deliberately chose to focus on understanding manufacturing (a famously unglamorous, yet, as Bancel had learned at Harvard, absolutely vital function), then worked on resolving a range of regulatory-related corporate challenges, first at Lilly, then [as CEO] at bioMierieux.
All told, Bancel spent years (Long Run listeners will recall) learning the fundamentals of biotech, a grounding ended up positioning him well for what came later.
The point is that Bancel’s success wasn’t driven by a lifelong passion for mRNA technology, but rather by the ability to recognize the potential of the technology, and then to have the wherewithal — operational sophistication plus situational awareness — to gainfully apply it to a relevant problem.
While the successful application of digital and data advances to drug development will similarly require both an appreciation for and a facility with emerging technologies, I would bet on – and invest in – the thesis that success is far more likely to be driven by savvy implementation driven by a deep understanding of the critical business problems to be solved, rather than by whether a particular algorithm is powerful enough to go to 11.
It’s a difficult time to be optimistic, but I couldn’t feel more encouraged by the promising future I see at the intersection of biopharma and digital technology. This vision is inspired by patients, powered by data, and enabled by computation, yet will be realized only by pragmatic implementation, by investors and executives who value but are not distracted by dazzling technology, and maintain a relentless focus on the critical problems constraining the core business.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Alex Harding, MD. Entrepreneur in Residence, Atlas Venture
When I received the COVID vaccine on Dec 24, it was the end of a tense, frustrating two-week period.
Thousands of healthcare workers like me — doctors, nurses, physician assistants and more — at the Mass General Brigham health system were eager to get vaccinated, and antsy about whether we’d get the shot as soon as it was available.
The rollout at Mass General Brigham had problems from the beginning. There was a delayed start in announcing the process for scheduling vaccine appointments. Then came confusion about who was prioritized for the vaccine. Technological flaws caused the scheduling system to crash multiple times. One night, we experienced a tense free-for-all where thousands of staff raced each other to see who could click through a complicated online scheduling site to grab one of the coveted vaccine slots before they were all taken.
I was lucky, and thankful, to get my first dose of vaccine on Christmas Eve. Many of my colleagues, people who have also treated their share of COVID patients this year, had to wait longer.
This tale, for the time being, has a happy ending. All of the top-priority staff in our health system—those who care for known COVID patients—have had the opportunity to receive the first of two doses of the vaccine. But the sluggish and confusing vaccine rollout at Mass General Brigham isn’t unusual. We saw other hospitals around the country struggle with running an efficient and fair vaccination program (Stanford’s debacle is a more extreme example).
As we look beyond the current rollout to healthcare workers and nursing home residents to much larger swaths of the population, such as essential workers and the elderly, I worry my experience is a microcosm for what is to come.
The consequence on that larger scale is not just confusion and frustration. People could be waiting for months longer than necessary to receive their vaccine. When thousands of people are dying every day from COVID, delays in the vaccine campaign come with an enormous toll of suffering and death.
The COVID vaccination campaign, the largest ever attempted, is off to an alarmingly slow start across the country. As of Tuesday, the CDC said that over 17 million doses of the vaccine had been distributed but only 4.8 million doses had actually been administered. These doses are primarily being used for hospitals and clinics to vaccinate their own staff.
When the rollout shifts gears and larger groups of people become eligible, the complexity of administering the vaccine will only increase. It will be more difficult to allocate the right number of doses to specific sites. It will also be more tricky to determine patient eligibility, schedule patients, and make sure everyone is getting their second dose of vaccine on time.
The Unites States is likely to struggle with the vaccination logistics more than other developed countries. First, there has been minimal coordination at the federal level, aside from determining how many doses each state would receive and the CDC making high-level vaccine prioritization recommendations. Instead of taking responsibility for overseeing the rollout, the federal government has passed that task to the 50 state departments of health. These are chronically underfunded institutions that need far more resources to effectively carry out such an important responsibility.
Most problematic for the vaccine rollout is the decentralized manner in which care is provided to patients in this country. Patients in the US receive care through an archipelago of hospitals and clinics that compete with one another instead of collaborating. While most countries in the world have healthcare funded and administered by the government, the US has long favored a decentralized, privately-run model.
The US approach to healthcare can work wonderfully for individual patients in need of acute care. If I needed a heart transplant, knee replacement, or intensive care for a COVID infection, and I had access to good insurance, there is no place on Earth I’d rather be than the US. But when it comes to primary, preventive, and population healthcare, America’s approach does not deliver good results.
The failure of the US healthcare system for primary, preventive, and population healthcare is not news. Although the US spends far more on healthcare as a share of our GDP than any other country, we have one of the lowest life expectancies of any of the 36 countries in the OECD. According to the Commonwealth Fund, compared to 10 peer countries, the US had the highest number of hospitalizations from preventable causes and the highest rate of avoidable deaths.
These failures disproportionately affect the poor and vulnerable members of our society who cannot afford health insurance and struggle to navigate the enormously complex maze of entities that administers and pays for care in this country.
What’s new is that, suddenly, a population health measure has captured the entire nation’s attention. As thousands of people die each day, lack of coordination will lead to chaotic and slow vaccination efforts. Delays of weeks or months could end up costing tens of thousands lives in a pandemic that is killing more than 2,000 people every day.
It is no coincidence that Israel and the UK are two of the countries furthest ahead in the race to vaccinate. In Israel, healthcare is universal and every citizen must join one of four integrated healthcare organizations. In the UK, healthcare is even more consolidated through the National Health Service, which guarantees care to every UK citizen through a single public entity.
Similarly, I anticipate that integrated care organizations like Kaiser Permanente and Geisinger Health, because they handle both paying for and providing care at a very large scale, will be more successful than most clinics and hospitals in the US at vaccinating their patients.
Could the emerging crisis of the delayed vaccination rollout in the US be the catalyst to prompt real reform in our health system? Dysfunction in Washington may make any major legislative effort appear improbable. But we have already demonstrated the ability to achieve highly improbable goals during this pandemic. Creating and developing vaccines with 95 percent efficacy against a novel infectious disease, in less than 12 months, is nothing short of breathtaking. This country’s scientific and biopharma sectors (with the help of German collaborators at BioNTech) have delivered the two most effective COVID vaccines so far. There could be more to come, thanks to our scientific and industrial efforts.
We discovered and developed the vaccines that have the power to end this plague. Now, we are faced with an equally difficult task. Will we be able to efficiently deliver the vaccine to protect people from infection?
Our health system, as currently configured, is not able to execute well on this crucial job.
We can use this moment as an opportunity to catalyze reforms that will deliver the vaccine more quickly by fostering integrated care models and ensuring universal coverage through a public insurance option—reforms that will leave us with a health system that provides better, more equitable health outcomes for all Americans during this pandemic and beyond.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Today’s guest on The Long Run is Steve Paul.
Steve is the chairman, president and CEO of Boston-based Karuna Therapeutics.
Karuna is developing new treatments for neuropsychiatric disorders. By the time you listen to this conversation, Karuna will either be very close to starting a Phase III clinical trial of its lead drug candidate, or it will already have begun.
Steven Paul, CEO, Karuna Therapeutics
The drug candidate, called KarXT, is an attempt to break new ground in the treatment of schizophrenia. The drug is a formulation of xanomeline and trospium chloride. It’s designed to get into the brain and selectively activate a couple of muscarinic receptors. An earlier form of xanomeline was tested for Alzheimer’s.
It didn’t work for that memory-robbing disorder. But as Steve describes in the later part of the show, the drug had a curious secondary effect in Alzheimer’s patients. That gave scientists an idea for another group of patients. Timmerman Report subscribers can read an in-depth piece on the company from July 2020.
Steve is one of the rare individuals who has truly seen it all in science. He did world-class research at the National Institutes of Health early in his career. He oversaw teams at Eli Lilly that developed important new medicines for mental health. Then, in this most recent chapter of his career, he has gone to work at startups that have sought to blaze new trails in neuroscience drug development. Sage Therapeutics, Voyager Therapeutics and Karuna Therapeutics are companies that bear his fingerprints – and they are worth a collective sum of $7.2 billion as of this recording.
In this conversation, Steve talks about his humble upbringing which didn’t exactly preordain him to become a scientific entrepreneur. We also talk about the nature of the scientific enterprise itself, based on his unusual set of experiences across all three major branches of science – industry, academia, and government.
Steve is a thoughtful guy on the nature of innovation, and some of the pressing challenges we face with mental health in our society.
Please join me and Steve Paul on The Long Run.
Sam Blackman, MD, PhD; co-founder and chief medical officer, Day One Biopharmaceuticals
Pediatric oncologists like me tend to know their cancer chemotherapy combinations, chapter and verse.
But for me and many of my colleagues, vaccines have always loomed large, integral to the “pediatric” part of our medical training.
As a medical student in the late 1990s and a resident in pediatrics during the early 2000s, vaccination was a constant source of discussion.
We were watching the clinical and regulatory community debate the risks of using thimerosol – an organomercury preservative – in multi-dose vials of various vaccines because of a convergence of factors. Autism diagnoses were on the rise, prompting some to raise concerns about an epidemic.
Much attention was focused on the now-retracted, fraudulent 1998 publication from Andrew Wakefield. New Jersey Congressman Frank Pallone raised concerns about the effects of environmental mercury poisoning. Despite no evidence of harm from its use, thimerosol was removed from all vaccines routinely given to children 6 years of age and under, manufactured for the US market.
The flurry of competing conspiracies, fears, statements, and studies turned the once-routine discussion with parents around childhood vaccinations into increasingly complex conversations on the nature of risk and evidence.
The fears stoked by the growing anti-vaccination movement were hard to counter. These fears frequently collided with the natural reticence of physicians and scientists to use words like “impossible” and “never” – words loaded with the hubris of total certainty.
At the same time, the early 2000s were also notable for major disruptions in the supply of vaccines against the major childhood illnesses, including diphtheria, influenza, measles, mumps, pertussis, tetanus, and varicella. Our community primary care clinic at Cincinnati Children’s would have a dry-erase board that would remind the residents what vaccines we had in stock, and more concerningly, what vaccines we didn’t have in any fridge or freezer. And woe unto the resident who spent their 15 or 20-minute clinic visit convincing a parent to vaccinate their child only to find out that we lacked supply – oftentimes that was sufficient for yet another child to fall between the cracks.
As if these first two challenges weren’t enough, the mid-2000s also saw a significant expansion of the childhood vaccine schedule with the approval and introduction of the first meningococcal vaccine (Menactra), a new rotavirus vaccine (RotaTeq, which had to overcome concerns about the first generation rotavirus vaccine and its association with small bowel obstruction due to intussception), and most notably, the introduction of a vaccine against HPV (Gardasil) which prevented both genital warts and pre-cancerous genital lesions. The latter again led to an uncomfortable overlap between public health policy and politics when then-Governor Rick Perry of Texas mandated all girls to be immunized as a condition of entry into 6th grade.
Religious conservatives cried foul against the mandate, that it would encourage sexual promiscuity. Liberals later howled in outrage when reports surfaced that Merck had lobbied for the mandate as a good way to increase sales of a new patented vaccine.
What was the result of this extreme noise? As a pediatric residents, my colleagues and I found ourselves spending a disproportionate amount of time working hard to overcome intense vaccine skepticism and vaccine hesitancy, particularly in the inner-city neighborhood served by my program’s primary care clinic. There were (and still are) pediatricians who were so frustrated by parents who they couldn’t convince to vaccinate that they considered discharging them from their practices – something that I personally considered.
Then I became a parent. And while that didn’t cause a moment’s hesitation for me or my wife in terms of whether or not to vaccinate our daughter, it did give me a chance to sit in the “patient” seat for the first time in a long time. Coincident with being a parent is that your siblings and friends have kids, and as a pediatrician, I got a number of calls – some of which took me by surprise because they came from friends who were also physicians – asking basic questions about vaccine safety. This gave me the opportunity to relive the conversations I had as a younger, childless resident physician, and refine my technique.
So, how can these experiences and lessons inform the moment we are living in now, when the noise – from the anti-vaccination groups, conspiracy theorists, foreign and domestic political opportunists, and even malignant elements within our own government – is deafening?
Here are some suggestions, and I think they apply equally to physicians and nurses and other health care professionals as well as those of us in the biopharmaceutical industry:
People may bristle at being forced to do something they don’t want to do, but for this, and future pandemics, we need to continue to explore ways to effectively combat science denialism and protect our citizens and our economy.
Samuel C. Blackman, MD, PhD lives on Orcas Island, WA and trained as a pharmacologist, pediatric hematologist-oncologist, and neuro-oncologist. He is currently the co-founder and Chief Medical Officer of Day One Biopharmaceuticals. His views reflect his personal opinions, and not those of Day One Biopharmaceuticals.
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Nina Kjellson, general partner, Canaan Partners
Healthcare leaders have made many commitments this year on racial equity.
The question now is how we turn words into action.
Over the past couple years, I’ve become a believer in the power of small groups that share an immersive, cultivated experience.
In September, I convened one such group on a two-day virtual journey to Montgomery, Alabama. This virtual conference grew out of my work on Impact Experience//Health Equity. It’s a partnership born of an Aspen Health Innovators’ fellowship in collaboration with longtime equity educators, Impact Experience.
The trip to Montgomery was inspired in part by the experience a few of us biotechies had in climbing Mt. Kilimanjaro for cancer research at Fred Hutch. On that trip in summer 2019, all 14 men and all 13 women made it to the summit of the highest peak in Africa (elevation 19,340 feet). It wasn’t always easy. But coming down, we realized we had forged a cohesive family committed to each other’s well-being and success. Our email threads and Zoom reunions ever since have been a vibrant reflection of community born of sweat and struggle and revelations shared step by step.
My recent tour of Montgomery, with a couple friends from the Kilimanjaro climb, was the start of a new journey. We sought to trace the roots of structural racism in health care and what can be done about it.
This conference was unlike anything we had attended before. Our collective horror at the murder of George Floyd and Brianna Taylor, on top of the mounting evidence of the unequal toll of the COVID pandemic — both economic and health-wise — turned discomfort into moral outrage. We started to see inaction as complicity.
Consider some data:
Data analyzed by APM Research Lab.
As scientists and biotechnologists, we know well that these disparities are not rooted in biology. Melanin and a few continental alleles can’t explain the drastic differences in predisposition, access, experience and outcome with respect to health care and the many other institutions that determine health and social status.
Neither does income or education explain the disparities. We know, for instance, that fetal and maternal health outcomes for Black women are still well below those for white women when normalized for earning and academic achievement. Pregnancy related mortality for Black women with a college degree is 5 times that for their white counterparts. FIVE times. (Centers for Disease Control and Prevention)
Some disparity may be explained by a distrust and voluntary avoidance of the health care system leading to the delayed diagnosis and treatment of serious diseases such as cancer. Blacks have higher death rates from most cancers than all other racial/ethnic groups. Despite similar rates of breast cancer, Black women are much more likely than White women to die of the disease, according to the National Cancer Institute.
If this is because of a reluctance to seek care, might this be the legacy of James Marion Sims, the Tuskegee trials or the Flexner Report’s elimination of Black medical colleges (here and here)?
Like any journey, it has to start somewhere. This one begins with education and awareness. The Impact Experience//Health Equity program is comprised of pre-curriculum, a guided (virtual) tour, community-member engagement, moderated seminars with expert faculty and group and individual exercises. But it wasn’t all about content. The two days were interspersed with unstructured time for music, art and conversation. We crafted the program to cover history, current events, social and emotional learning.
Our vision is to catalyze both a committed peer cohort and firm action plans for implementing change.
We had an initial group of 29 participants on our virtual journey to Montgomery. These people were leaders from biopharma, pharma, diagnostics, academic medicine, health insurance, public health, venture and public investing and management consulting.
To a person, the reviews on the experience were exceedingly positive – for the depth of exploration, space for personal introspection and group activities imagining – and charting – a future free of implicit and structural bias.
In follow-up conversations over the past three months, we have seen a great deal of camaraderie, including local e-meet-ups and projects. We are seeking to hold ourselves accountable to the goals we’ve set for our companies and ourselves. We’ve had deep debriefs of the experience, in order to spread what we’ve learned throughout our organizations.
We’re insisting on concrete actions like implementing new ways of hiring and training, tools for recruiting diverse participants in clinical trials, criteria for selecting minority-owned vendors and new approaches to talking about race and equity.
Everyone, of course, is busy. Two days might seem like a lot to commit to a seminar or continuing education program. But the time allowed for immersion not just in the curriculum, but also for building relationships among peers.
There’s something special about getting to know professional peers on a personal level. The level of intimacy that emerged was striking. Participants shared personal experiences of bias, racism, and hard-fought assimilation into power hierarchies. This was essential to breaking down barriers and confronting one’s own implicit biases.
These are the kind of raw, deeply felt conversations that rarely surface in the corporate environment.
These meaningful conversations translated into clear actions. New internship programs were established. Some of us redirected, or increased, our personal and corporate giving.
The structural barriers that exist in our sector runs deep – from the way we train, teach, architect and even structure information. Medicine, historically, hasn’t anticipated including women or people of color in leadership.
Health care emerged as a sector within a historical, societal, and cultural context. It will take many years and much effort to undo bias and reinvent the field. The journey we took as a group to Alabama started with the 250-year history of enslavement, the next 100 years of the Jim Crow era, followed by the Civil Rights era of the 1960s to the present. We can’t begin to understand the health disparities of today, and the potential solutions, unless we understand this arc of American history.
The distance we traveled together, from our heads and deep into our hearts, gives me great hope that we as leaders can accelerate change. There are things we can all do, from grass roots solutions all the way through helping advance legislation at the state and federal levels.
And if the moral calling isn’t the motivation, then the markets and business needs will compel us.
Over the next 10-20 years, more than half the US population will be self-described as other than white, according to the US Census Bureau. This means the demographics of our studies, employees, patients, payers, regulators, investors will be shifting. Study after study has shown financial and compliance outperformance by companies with greater gender, racial/ethnic and immigration diversity. A McKinsey report from 2017 found a 33% likelihood of EBIT outperformance by companies with ethnic and cultural diversity and 21% higher profitability from companies with above average gender representation on executive teams.
As we reflect on 2020 – and the ways in which we have been moved by this difficult year – I hope we can take the moments of awakening and make them into movements towards a more equal, equitable and healthy world. (Whether out of love, righteousness or business-interest).
You can join networks like this, to spark movement in your spheres. You can create this kind of momentum.
I’m getting ready for another Impact Experience//Health Equity. The next journey is in March. We are seeking to turn the words of 2020 into the actions of 2021.
Interested? nina@canaan.com
If you are making your year-end charitable giving list, please consider Life Science Cares. We are channeling funding and volunteerism from the life science community to close the needs gaps in Boston, Philly and the San Francisco Bay Area. Our focus is on homelessness, hunger, STEM education and internship and workforce opportunity with an emphasis on diversity. Please make a note designating geography of interest. https://lifesciencecares.org/donate/
Larry Corey, MD
This month has been a media whipsaw.
News of the Pfizer and Moderna mRNA vaccines’ compelling efficacy and the U.S. Food and Drug Administration’s rapid response and issuance of an Emergency Use Authorization for both vaccines have been met with equal parts jubilation and fear from a divided public.
For me, as a medical virologist and researcher, this remarkable achievement is a clear demonstration of the power of science and its potential impact to save lives. To see these curves below that show the difference in disease course between those vaccinated and those receiving the saltwater placebo are about as big a spread as I’ve ever seen in any study.
We call these Kaplan-Meier curves, and if you’ve worked in cancer or most diseases, you just never get to see curves like these. Even when a study is considered a success, rarely do you see evidence this overwhelming in favor of a new drug or vaccine. And this is one reason I have embedded the curves of both studies into this blog. If you are used to seeing these curves, they just make you smile and think, “How did that happen?”
A scientific success such as this one just feels good. With it comes a sense of community pride, particularly when you see the incredible adulation from impassioned medical care workers who are grateful to receive the vaccines. It’s wonderful to see videos of them dancing outside of the hospitals. We as scientists have to smile when we see images of front-line workers with their heads bent, overcome with relief and gratitude for a vaccine that seems powerful enough to relieve them of the stress of dying on the job.
And yet, we can’t quite fully celebrate now. How does one measure a successful outcome in its entirety when recent polls show that approximately 40% of Americans would be unlikely to get a vaccine even when it becomes available to them? Or when one reads about town hall meetings populated by fellow Americans who are clearly mistrustful, images with hesitant faces. The fear is plain.
These images and data force one to pause—to take a step back and view the difference in perspectives—because the two visions side by side are difficult to balance.
True, maybe many Americans haven’t seen a Kaplan-Meier curve before. Maybe they don’t understand the nuances of the clinical studies and their protocols. But they understand what 95% protection from disease means—a clear indication the vaccine means it helps; it helps a lot.
Even so, I see the fear firsthand. An acquaintance of mine recently told me his mother refuses to take the vaccine. She is over the age of 70, and has multiple risk factors for severe COVID-19. This woman has sought my advice for other medical concerns, so she clearly has some measure of trust and respect in my opinion. But in this situation, the fear overrides her knowledge of what science can (and does) accomplish.
My first reaction was to talk to my acquaintance in an authoritative way, wearing my medical science hat, so to speak. Then it occurred to me that I wasn’t going to change her worldview simply because I was “the medical authority” sharing the information.
So, then I tried to step back and ask myself a few questions. How can I do this respectfully? Or how much energy should I put into this? How do we set our expectations? What’s the goal here? I’m reminded of one of those statements learned by most of us early on—probably while arguing with an authority figure who was trying to offer reason: you can lead a horse to water, but you can’t make it drink.
So, I think there are lessons to be learned on both sides—that we all need to be respectful of differing viewpoints while we move toward greater understanding, compassion, and trust. And we all need to understand that there is context—for each person.
There are some situations—and the COVID-19 pandemic might be one of them—where the tincture of time is needed to heal the wounds. And there are wounds that have bred mistrust: wounds caused by self-serving narratives of national leadership that were unrelated to the scientific process at hand. And although the outgoing administration did a wonderful thing by providing an enormous amount of funding, “Operation Warp Speed” isn’t a name that inspires trust.
In most other contexts, and certainly outside of a public health emergency, when we think of the rigors of science, speed is not something we associate with positive outcomes. As one old proverb goes “haste makes waste.” Even those who don’t subscribe to that folk wisdom might naturally wonder, “were corners cut along the way to get a result this good, this fast?”
As someone on the inside I can say unequivocally – no, corners weren’t cut. Rigor was maintained. Yet I can see why people might still be suspicious. Throughout the vaccine trials, anytime something good happened, credit was narcissistically claimed by the President rather than letting the real inventors own it. By personalizing it, the vaccines became politicized. It created an odd discord, as if science—and what is in a vial—had something to do with whether you’re a Republican or Democrat.
Of course, we didn’t put Democrats in the vial; we didn’t put Republicans in the vial. It’s true: we had a lot of political leaders take control in an unscientific way and try to dictate the human behavior they wanted to see. But the scientific goal has always been: how do we alter and stop the disease that was rapidly attacking our nation and its people? How do we use pharmaceutical and nonpharmaceutical interventions alike to control the spread and keep Americans safe?
Scientifically, the goal has always been the same. How different political leaders communicate varies. And the vial gets caught up in the middle.
I don’t know how to unwind this except for time. I don’t know how to unwind this except for understanding.
My brother-in-law, a role model who inspired me to become a physician, passed on a wise saying when I was young. He died far too early, at age 37, from Candida sepsis that struck him while getting treatment for Hodgkin’s disease. Before he died, he said to me, “Larry, the educated man is the tolerant man.”
It will take work by all of us—in the scientific community and in the broader public. It will take hard work to convey the importance of vaccination. It will take time to rebuild trust across the divide. And it will take a public open to healing discourse; a public which remains curious and eager to know more as we learn more. Because we will.
If this pandemic has taught us anything, it has taught us that scientific successes beyond imagining are possible with resources, urgent focus, and the kind of global scientific collaboration we’ve seen over the past ten months. And as a scientist and physician, I will take solace in knowing that those who want the vaccine and can benefit from it, will be able to get access to it.
I pray that all who want, not just in our country but globally, will be able to receive this gift of science. All the people of the world deserve to be vaccinated. It is a great feat to say, with clear conviction, “COVID-19 is a vaccine-preventable disease.”
Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN ) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.
Otello Stampacchia, founder, Omega Funds
I will start with the good news.
As of this writing, on Dec. 19, the FDA has just granted ModeRNA an Emergency Use Authorization (EUA) for a coronavirus vaccine. We now have two vaccines available, based on essentially the same mRNA-based technology, including the one from Pfizer/BioNTech that received an EUA earlier this month.
It’s worth stating that both ModeRNA and BioNTech (the company that originated the vaccine developed by Pfizer) are led by immigrants. Think about that when you want to close borders and stop immigration, perhaps?
Before I move on to more depressing topics, it is important to reflect and rejoice on just how *amazing* this feat of science is. The coronavirus genetic sequence was made available in January. In less than 11 months, we have now two vaccines passing muster with regulators and being widely distributed.
The previous vaccine development record was for mumps, developed in roughly 4 years and approved in 1967. We are witnessing a scientific revolution unparalleled, in its breadth and depth and in my (very) biased opinion, since the end of the Renaissance.
This truly is biology’s century.
Amazement should not stop at the speed of these vaccines’ development. They are (both) incredibly effective, certainly beyond my (perhaps pessimistic) expectations of a 60-70% efficacy range. In clinical trials with tens of thousands of individuals, both vaccines achieved >94% efficacy rates in protecting against infection, and resulted in *no severe symptoms in people who became infected*.
Importantly, they were both effective for different races / genders, and for individuals in high-risk populations (including the elderly, and people with underlying medical conditions). Side effects reported from the clinical trials were generally mild and temporary (more on this later). In summary, these two vaccines were not only developed in record time – they rank among the very best of all vaccines in terms of efficacy.
As highlighted by this graph (from @xkcd’s Randall Munroe: one of the best / funniest comic illustrators of scientific / statistical topics): the data are so clear and compelling that we don’t need to do statistics on it (fear not, I will bother you with statistics in a bit)…
You know the expression “don’t shoot the messenger”? I say shoot it (the messenger RNA!) straight into my arm as soon as it is feasible to administer it to the (relatively) lower risk population I belong to!
Did I manage to make you feel good (nay: great!) about science? Fabulous.
Now let me make you feel bad about human beings and our behavioral fallacies.
If you are up-to-date with the latest coronavirus pandemic news, I suggest you skip this part. That said, I highly recommend you read it if you are planning large family (or any type of) gatherings with people outside your immediate, close family “bubble” around the upcoming holidays.
As published in JAMA (Journal of the American Medical Association) on Dec. 17, COVID-19 is now the leading cause of death in the United States. As JAMA horrifyingly and clearly says, “The daily US mortality rate for COVID-19… is equivalent to the September 11, 2001, attacks, which claimed ~3,000 lives, occurring every 1.5 days, or 15 Airbus 320 jetliners, each carrying 150 passengers, crashing every day”.
Let me repeat that: *15 full planes crashing every day*.
This country has gone to (many) wars for a lot less:
(Graph above by Rob Rogers, award-winning, nationally syndicated editorial cartoonist formerly with the Pittsburgh Post-Gazette: follow him at @Rob_Rogers).
And there is no immediate end in sight to the carnage. The graph below, from The COVID Tracking Project (@COVID19Tracking) makes this abundantly clear. We have been breaking hospitalization records across the country, day after day, for close to two months.
The graph to the right should be horrifying indeed: as predicted in my Aug. 31 Timmerman Report article, we are exceeding, and will sadly continue to exceed, peaks in deaths reached during the April phase of the pandemic, when we were unprepared and scientists knew much less about the virus and how it’s transmitted.
What is our excuse now? Did we really think this virus was going to magically disappear? If so, shame on us (well, I am not sure that should be on me, TBH, but I wanted to “participate” in the collective shaming of our behavioral fallacies).
As a country, we are collectively failing the “marshmallow test”. For those of you who are not into behavioral theories, the “marshmallow test” was a study on *delayed gratification* led by Walter Mischel (from Stanford) in 1972.
In the test, a child is presented with the opportunity to receive an immediate reward or to wait to receive a better reward. A relationship was found between children’s ability to delay gratification during the test and their subsequent academic achievement. In follow-up studies, researchers were able to find a connection between ability to delay gratification with better life outcomes, as measured through quantifiable metrics such as SAT scores, educational attainment, and Body Mass Index (BMI).
These findings were made before the pandemic (unfortunately, like 71 million Americans, I have meaningfully increased my BMI this year. I blame the alcohol.)
So, again and again, with our collective shortsightedness, we traded short-term gains for what has truly been a painful fall / winter. We had summer at beaches and bars, then Thanksgiving gatherings, all while *knowing* this will result in many more people spending Christmas in the ICU.
US Thanksgiving travel broke pandemic era travel records, and resulted in the spike in cases, hospitalizations and deaths we are currently seeing (remember: reported cases lag hospitalizations by 2-4 weeks, and those lag fatalities by another 2-4 weeks). You can see those spikes in the graph above. The same will happen following Christmas gatherings.
Warning: the segment below contains some discussion of statistics (trust me I will try to keep it simple).
The ”Swiss cheese” approach to protection and risk mitigation (adapted to the pandemic from earlier “Swiss cheese” description of risk by Australian virologist Ian MacKay: @MackayIM) has recently been discussed (even by the New York Times.) In my opinion, it has merit insofar as it illustrates how you can protect yourself from infection by layering “slices” of Swiss cheese (the real one is called Emmental, by the way, if you like cheese).
Each of the “cheese slices” has holes, i.e. is not perfect. Overall, though, combining them (social distancing, masks, hand-washing, air ventilation + humidity) significantly reduces the overall risk. Vaccination, when available, will add one more, (very) important protective layer.
The graph’s latest version (Ian has been working on versions of this for months, may the fates always be in his favor) organizes / segments the slices into “personal” vs “shared” responsibilities, and encourages people to think in terms of *all the slices* rather than any individual single layer being the most important. There is virtually no “zero risk” situation (unless you are living, like me, on top of a mountain for the time being).
I would add the role of keeping indoor environments (whenever in contact with people who are not members of your household) not just adequately ventilated but also properly *humidified*: viral droplets appear to stay afloat much longer in dry, cold environments (I have spent a small fortune on humidifiers in the last months).
The graph is hopefully self-explanatory. However, those of you needing stronger glasses might not have noticed the cute, but incredibly dangerous “disinformation mouse” eating away at the protective layers. Just like the virus is “weaponized” and much more dangerous in indoor / wintry conditions, the sustained (coordinated??) misinformation campaigns running on social media are particularly dangerous when coupled to a lack of clear and consistent communication from public authorities.
You might remember some of these statements: “this is just like the flu”; “look at how well Sweden is doing and they are not crippling their economy”; “we are close to herd immunity”; “if we only let it rip, we will achieve herd immunity by the fall”; “this only kills old people, I want to go to the bar”.
Sadly, the list is quite a bit longer.
If you still believe in any of the bracketed statements above, please do me the courtesy to stop reading this silly piece of mine (and of never, ever speaking to me or any members of my family again, in case we used to be on speaking terms): you are entitled to your opinions, but you are not entitled to your own facts.
The disinformation mouse (I personally think it should be a rat, but the graph was not my idea!) is already starting to eat away at the potential enormous beneficial effects that rapid, at scale vaccination should bring.
(In)famously, and admittedly humorously, Brazilian President Bolsonaro railed on Dec. 17 against potential side effects from Pfizer’s vaccines saying “if you become an alligator, that is your problem.”
Intriguingly, as seen below in a portion of the FDA report on one of the vaccine trials, there can be serious events indeed happening after administration of the vaccine: a trial participant was struck by lightning 28 days after vaccination!
Talk about incredible side effects!
I hope you are not taking the above *too* seriously: serious events happening to clinical trial participants *are not necessarily side effects caused by the vaccine*! (I certainly hope lightning strikes are not…).
Just to give you a better sense of the fundamental difference between correlation and causation, I invite you to read one of Derek Lowe’s articles that dwells on the math here (the tile is, in itself, masterful: “Get Ready for False Side Effects”.
Quoting Bob Wachter’s great Twitter thread and Derek’s great article, “if you take 10 million people and just wave your hand back and forth over their upper arms, in the next two months you would expect to see about 4,000 heart attacks. About 4,000 strokes. Over 9,000 new diagnoses of cancer. And about 14,000 of that 10 million will die, out of usual all-cause mortality. No one would notice. That’s how many people die and get sick anyway.
But if you took those 10 million people and gave them a new vaccine instead, there’s a real danger that those heart attacks, cancer diagnoses, and deaths will be attributed to the vaccine. I mean, if you reach a large enough population, you are literally going to have cases where someone gets the vaccine and drops dead the next day (just as they would have if they *didn’t* get the vaccine).
I would like to end with some (dark, obviously) attempt at humor. I watched, laughing and almost crying, the latest Saturday Night Live’s Weekend Update skit, with Dr. Wenowdis (the incomparable Kate McKinnon) on the COVID-19 vaccine.
“We didn’t do good. It could have been better. But it actually could not have been worse… we blow dys”. “It’s just like the light at the end of the tunnel has shown us how stinky and bad the tunnel is.”
Even the New York Times used the analogy (used by Colin Jost at the end of the same SNL skit above) that it is “always darkest before the dawn”. The quote is attributed to English theologian and historian Thomas Fuller (1608 – 1661).
I wish I had different news, but you should know that it will get quite dark indeed over the course of the next 3-4 months (for a glimpse of how dark, I have put some statistics in the Appendix below). But, you should stay hopeful: there is indeed light up ahead, and quite possibly a government who will efficiently administer the vaccine in the shortest possible time.
In the meantime, please avoid gathering over the upcoming holidays if any member of your household is at risk. I look forward to seeing as many of you as I can in the coming year and to celebrate together (why, yes, with Italian wine!) the end of an annus truly horribilis.
Attachments area
Appendix
On Nov. 30, since I did not have anything else to do, I was reading some interesting comments from Dr. Ashish Jha (@ashishkjha), Dean of the School of Public Health at Brown University (and a fellow data geek): Full Thread. Here is a short summary that does not fills me with hope for the coming 2-3 months.
In short, as the number of people diagnosed with COVID has skyrocketed over the last several months (see graph above: we are now at over 212,000 patients diagnosed a day, using a 7-day rolling average, and I expect that number to hit 250,000 and more soon), the proportion of patients hospitalized is rapidly falling.
Over much of September and October, based on the data, you could make the accurate assumption that (roughly) 3.5% of the number of newly diagnosed positive individuals would be hospitalized 7 days later.
But in November, that ~3.5% number started to fall: initially to ~3.2% by Nov. 8, to 3.0% by Nov. 15, 2.5% by Nov. 22 and 2.1% by Nov. 29. What does this mean?
The good doctor’s theory, which I find myself in strong agreement with, is: as hospitals start to fill up, they are raising the bar for admissions, resulting in admissions for only the sickest patients (ICU resources and, perhaps even more importantly, medical professionals time and capacity of caring for patients cannot be scaled up ad infinitum). Basically, roughly 1 in 3 people who would have been admitted to a hospital on October 1 aren’t being admitted by November 22 (and given the large increase in percentages in positive tests, likely much higher proportion).
This is bad enough. Another consequence: when hospitals fill up, thresholds for hospital admissions for *everything* go up: this is likely to increase mortality for normally non-threatening conditions as well.
Winter is coming, and I pray it will not last long. But it will be dark indeed for many.
Luke Timmerman, founder & editor, Timmerman Report
Vaccines for COVID-19 are here.
Some are looking for a fly in the ointment. But there’s no mistaking these vaccines protect 95 percent of people from getting sick from a virus that has killed 1.6 million people worldwide this year and threatens millions more.
The one-two punch of messenger RNA vaccines for COVID-19 from Pfizer / BioNTech and Moderna in December 2020 will go down, unequivocally, as one of the great triumphs in the history of science.
What fewer people may see is what it really took to get here.
This wasn’t the lone act of a tenacious billionaire genius. It wasn’t the result of a Herculean group of entrepreneurs and investors demonstrating the power of unfettered free enterprise. It didn’t happen because a tousled-headed weird scientist at Harvard or MIT. No God-like government leader snapped his fingers.
Some people have starring roles and deserve our admiration, but there’s no lone hero. Not Stephane Bancel. Not Noubar Afeyan. Not Tony Fauci.
These mRNA vaccines represent a shared triumph of this beautiful thing we call the scientific enterprise. That term, as I think of it, encompasses people working in government, academia, and industry. People from all those domains are dedicated to seeking the truth. They worked together with monomaniacal intensity to make this happen.
Whether most of us realize it or not, the scientific enterprise, broadly defined, has always been there. It’s our big idea. For 20 years, the essential R&D groundwork was being laid for precisely a moment like this. It culminated yesterday in Moderna winning a 20-0 recommendation from an FDA advisory committee for an Emergency Use Authorization.
The common enemy, the new coronavirus, was more important than whatever petty differences, professional rivalries and jealousies may exist between these people. These people have always had the capacity to work together. Always had the capacity to play to each other’s strengths. Always had the motivation to work together, under the right leadership and right circumstances.
As I wrote on Twitter yesterday:
This triumph of scientific enterprise is worth celebrating today, when so much of the world is in a dark place.
The vaccine, of course, needs to get injected in as many arms as possible, as fast as possible. We’re losing 3,000 lives per day. We have to run the most ambitious vaccination campaign in world history, while simultaneously figuring out how to put the pieces of our society back together again.
This is a project we will be investing in for the rest of our lives.
That might seem overly daunting, but I don’t think so. Seemingly impossible things — like developing a new pandemic vaccine in less than a year — are possible.
I’ll close with one tangible reason for hope.
We’re seeing the beginning of a “Fauci effect” in action. Applications to medical schools have surged by 18 percent, as young people see not just an expert communicator, but a brilliant physician-scientist who dedicated his life to public service.
These bright young people could have chased the big bucks in management consulting or investment banking. They could choose to worship billionaires on the covers of magazines. They could dedicate their lives trying to become one. Some surely will.
But I believe we are going to see a surge of young talent in the 2020s turn its creative energy toward public service, like Tony Fauci did 50 years ago. The state – in this case, the National Institute of Allergy and Infectious Disease – has demonstrated its catalytic power for entrepreneurs and investors who create valuable things.
The scientific enterprise is fragile. We could screw it up. Plenty of people have ideas that would suffocate it.
But if we figure out how to delicately nurture the right kind of incentives for each of the members of the scientific enterprise – government, academia, and industry (large and small companies) – we will be on our toes when the next pandemic comes. We’ll put a major dent in terrible diseases like cancer, Alzheimer’s, autoimmunity, rare diseases and more. We’ll create a healthier and wealthier world.
This isn’t pure doe-eyed speculation. The proof is right there in front of our eyes today. We can do it again. Let’s do it together in the years ahead.
AstraZeneca agreed to pay $39 billion to acquire Boston-based Alexion Therapeutics, the developer of treatments for rare diseases. It’s a steep price for a company that relies for the bulk of its $6 billion in annual revenue on a single product, eculizumab (Soliris).
Novartis agreed to acquire Cambridge, Mass.-based Cadent Therapeutics, a neuroscience drug developer focused on allosteric modulators. Novartis obtains full rights to a schizophrenia drug candidate, a drug for movement disorders, and another for treatment-resistant depression. Cadent shareholders are getting $210 million upfront, plus $560 million in potential milestones. Investors include Atlas Venture, Cowen Healthcare Investments, Qiming Venture Partners, Access Industries, Clal Biotechnology Industries, Novartis Corporate and Slater Technology Fund.
Eli Lilly agreed to acquire New York-based Prevail Therapeutics, a gene therapy company working on neurodegenerative diseases. Shareholders in Prevail are getting $22.50 a share upfront, plus a contingent value right of up to $4 a share, for a total deal value of between $880 million and $1.04 billion.
Cambridge, Mass.-based Relay Therapeutics, the computational drug discovery company that looks at protein targets in their dynamic states of movement, formed a collaboration with Genentech. The smaller company is pocketing a $75 million upfront payment. The collaboration pertains to RLY-1971, a candidate aimed at SHP2, and which could be tested in combination with Genentech’s KRAS G12C drug candidate. (For background, listen to Relay CEO Sanjiv Patel on The Long Run podcast, Jan. 2020.)
Cambridge, Mass.-based Surface Oncology nailed down an $85 million upfront payment from GSK as part of a collaboration to develop an antibody against PVRIG (aka CD112R), an inhibitory protein on Natural Killer cells and T cells.
Gilead Sciences, based on feedback from the FDA, pulled the plug on its plan to seek FDA approval of filgotinib (Jyseleca) for rheumatoid arthritis. Gilead will pay a 160 million Euro breakup fee to Galapagos, and the smaller company will take over full responsibility for the drug in Europe, as a treatment for rheumatoid arthritis.
South San Francisco-based Veracyte agreed to expand a collaboration with Johnson & Johnson, in which the companies will work together on a 9,000-patient study to advance early detection of lung cancer.
Vancouver, BC-based AbCellera raised $483 million in an IPO at $20 a share. The company uses AI technology to assist in antibody drug discovery, including one of the therapeutic neutralizing antibodies against SARS-CoV-2 now being made by Eli Lilly.
New Haven, Conn.-based Arvinas, the developer of targeted protein degraders, raised $400 million in a stock offering priced at $70 a share.
New York-based Neurogene, a developer of gene therapies for neurological diseases, raised $115 million in a Series B financing. EcoR1 led.
Watertown, Mass.-based Forma Therapeutics, the developer of treatments for cancer and blood diseases, pulled in $275.8 million in a stock offering priced at $45.25.
San Diego-based BioAtla raised $150 million in an IPO at $18 a share. It’s developing antibodies for solid tumors.
San Diego-based Oncternal Therapeutics raised $86.2 million in a stock offering at $4.50 a share.
South San Francisco-based Neuron23 said it raised $113.5 million in combined Series A and B financings. The company is working to treat genetically defined neurological and immunological diseases. Westlake Village Biopartners, Kleiner Perkins and Redmile Group provided key early capital.
France-based Nanobiotix, a cancer drug developer, raised $113 million in an IPO at $13.50 per American Depositary Share.
Burlingame, Calif.-based ALX Oncology raised $208 million in a stock offering.
Emeryville, Calif.-based 4D Molecular Therapeutics raised $222 million in an IPO at $23 a share. It’s a gene therapy developer.
Cambridge, Mass.-based Sherlock Biosciences secured $5 million from the Bill & Melinda Gates Foundation to develop a self-administered, instrument-free, COVID-19 molecular diagnostic test. See Gates Foundation Dec. 9 announcement of new $250 million commitment to tests, treatments and vaccines to end the pandemic. (See also TR coverage of Sherlock Biosciences, Dec. 1.)
San Mateo, Calif.-based Vivace Therapeutics raised $30 million in a Series C financing led by Boxer Capital. The company is preparing to go to the clinic with a drug that targets tumors dependent on activated YAP.
San Diego-based Locanabio raised $100 million in a Series B financing to advance its RNA-targeted gene therapies for neurodegenerative, neuromuscular and retinal diseases. Vida Ventures led.
Los Angeles-based Westlake Village BioPartners said it raised $500 million for two new biotech funds focused on therapeutics technologies.
Cambridge, Mass.-based Cullinan Oncology raised $131.2 million in a Series C financing led by Foresite Capital.
Boston-based Gamida Cell, a cell therapy company, raised $65 million in a stock offering at $8 a share.
Friendswood, Texas-based Castle Biosciences, a commercial dermatologic cancer drug company, raised $232 million in a stock offering at $58 a share.
Cambridge, Mass.-based Exo Therapeutics raised $25 million in a Series A financing, led by NewPath Partners. It’s working on small molecules against novel exosite targets. (See TR coverage).
Durham, NC-based Atsena Therapeutics raised $55 million in a Series A financing to advance gene therapies against rare, inherited eye diseases. Sofinnova Investments led. (See TR coverage).
Menlo Park, Calif.-based Octave Bioscience pulled in $32 million in a Series B financing to advance an integrated care platform for multiple sclerosis. Northpond Ventures led.
GSK won FDA approval for belimumab (Benlysta) as a treatment for active lupus nephritis (inflammatory disease of the kidneys). The drug has long been on the market for systemic lupus erythematosus. The new approval extends to both the IV and subcutaneous formulations, the company said. The drug, originally developed by Human Genome Sciences, targets blocks the biological activity of B-lymphocyte stimulator, or BLyS.
Amgen got the green light from the FDA to start marketing a biosimilar version of rituximab, the blockbuster antibody long marketed as Rituxan. The Amgen drug rituximab-arrx will be marketed as Riabni, and is cleared for four clinical indications.
Rockville, Maryland-based MacroGenics secured FDA approval for margetuximab-cmkb (Margenza), as a treatment for HER2-positive breast cancer in patients who have gotten two or more prior rounds of therapy.
Australia-based Ellume received Emergency Use Authorization from the FDA for the first fully at-home COVID-19 test. “By authorizing a test for over-the-counter use, the FDA allows it to be sold in places like drug stores, where a patient can buy it, swab their nose, run the test and find out their results in as little as 20 minutes,” FDA commissioner Steve Hahn said in a statement. Ellume said it will ramp up production to 100,000 a day in January 2021.
The FDA placed a partial clinical hold on Regeneron’s odronextamab, a bispecific antibody directed at CD20 and CD3, as a treatment for B-cell non-Hodgkin’s lymphomas. The FDA asked the company to amend protocols to reduce the rate of moderate to severe (Grade 3 and higher) cytokine release syndrome.
New Haven, Conn.-based Arvinas, the developer of targeted protein degraders, released some intriguing early data for an estrogen-receptor directed drug candidate that is being tested in tandem with Pfizer’s Palbociclib (Ibrance), the CDK4/6 inhibitor, for HER2-negative breast cancer.
Cambridge, Mass.-based Synlogic said its engineered microbial therapy was able to activate the STING pathway to upregulate immune responses in the tumor microenvironment, in a Phase I trial.
Barry Greene joined Cambridge, Mass.-based Sage Therapeutics, the developer of treatments for major depressive disorder and postpartum depression, as CEO. Jeff Jonas is stepping out of the top job, but will stay as chief innovation officer. Greene was the longtime No. 2 executive at Alnylam Pharmaceuticals.
Robert Coughlin, the longtime CEO of MassBio and an advocate for industry and patients, is stepping down to take a new job at JLL, the real estate firm. (MassBio statement).
Watertown, Mass.-based Kymera Therapeutics, the developer of small molecule protein degraders, said it hired William Leong as vice president of chemistry, manufacturing and controls, and Paul Cox as vice president of investor relations and communications.
South Korea-based Samsung Biologics named John Rim as its new CEO.
Cambridge, Mass.-based Spero Therapeutics, an antibiotic developer, named Sath Shukla as its chief financial officer.
The Buck Institute for Research on Aging named Malene Hansen as its new chief scientific officer.
South San Francisco-based 3T Biosciences, an immunotherapy company, named John Connolly as interim CEO. He’s the chief scientific officer of the Parker Institute for Cancer Immunotherapy.
Amanda Banks Christini, MD; CEO, Blackfynn
Tonight, I will receive my first dose of vaccine against COVID-19.
I’m a hospitalist on the front lines, taking care of patients with COVID-19 in Philadelphia.
The progress of this year takes my breath away.
One year ago, in December 2019 in China, people starting falling seriously ill with pneumonia-like symptoms. By January 2020, a novel coronavirus, SARS-CoV-2, was identified as the cause of the disease we now call COVID-19. Scientists immediately sequenced its genome. That code provided key instructions for vaccine developers and drug developers around the world.
By mid-March 2020, around the same time I was taking care of my first patient with severe COVID-19 disease during an overnight shift at the Philadelphia VA, the first messenger RNA-based vaccine candidate, from Moderna, began Phase 1 clinical trials. Last Friday night – less than a year after this novel virus was identified — the Pfizer / BioNTech mRNA vaccine was given Emergency Use Authorization by the FDA. Moderna is likely just a day or so away from similar authorization.
This is a biopharmaceutical marvel.
We’ve seen other paradigm-shifting accomplishments the past few decades. HIV was transformed from a uniformly fatal infection to a manageable, chronic disease. As a medical resident, I went from caring for patients dying from hepatitis C cirrhosis / hepatocellular carcinoma while awaiting liver transplant, to participating as a junior faculty member as a co-PI in the initial sofosbuvir (Sovaldi) trials, to seeing these patients cured -not treated, but cured -s with a pill and HCV disappearing as the leading cause of liver transplant in the US.
Those triumphs were decades in the making.
Speed isn’t the only thing that sets this example apart; the scientific challenges to developing vaccines for SARS-CoV-2 were, and remain, far more tractable than those for HIV or HCV, infectious diseases for which, after decades of research, no vaccine exists. Aside from the science, which is beyond my expertise, a few differentiating principles stand out that are worth calling out:
I am in no way suggesting that the process to get to this point was perfect. It is also not nearly over; additional studies will be required for full BLA approval, and the operational lift to vaccinate the majority of the global population is enormous.
But, in the face of extreme adversity, our system adapted. We can use this opportunity to learn, and to change how drugs and vaccines are tested, developed, approved, manufactured, distributed and used.
I am enormously grateful for the opportunity to care for some of the most vulnerable patients during this pandemic. I am equally honored to be among the first to receive a vaccine against COVID-19.
We will all take different things away from our experiences throughout this pandemic, and more broadly from this year of turbulence on so many other levels, societal and political. I choose to focus on what is possible if we adapt, focus resources in the right places, and come together around a common goal.
Today that target is COVID. What could be next?
Alex Harding, MD. Entrepreneur in Residence, Atlas Venture
When one of my COVID patients called my cell phone a few weeks ago, my stomach dropped.
“I feel worse,” she stammered. “I’m having more trouble catching my breath.”
It was late morning on a Sunday. I was planning to take my son to the park, but after hearing those words, I knew this was not going to be a quick phone call.
I had seen the patient, a woman in her late 30s, the previous afternoon in the respiratory illness clinic at Massachusetts General Hospital (MGH), where I’ve worked since the Biogen outbreak slashed through Boston in early March.
She had typical COVID symptoms: fever, muscle aches, chest tightness, and mild shortness of breath when she walked around her house. She was obese and prediabetic, but otherwise healthy. When, sure enough, her COVID test returned positive the next day, I called her hoping that she would already be feeling better.
Instead, what ensued was a conversation that my colleagues and I have had far too often in the past several weeks.
“What can I do to get better?” she asked.
The fear in her voice was unmistakable, as she could feel herself losing strength. Stories of critically ill COVID patients suddenly seemed much more personal. I’ve seen more than 100 COVID patients this year, and the sheer variability of their responses has been befuddling. I had no obvious answer at my fingertips.
I rubbed my brow as I contemplated a response. What treatments could I offer her? Was there anything that might stop her illness from worsening?
Should I tell her to go to the emergency department now?
To a doctor on the front lines, the first surge felt like standing knee-deep in surf, looking out at a choppy sea and seeing a tidal wave on the horizon. It was approaching rapidly, but I couldn’t see to the top of it to know how hard it would hit or when it would end. There were people bobbing in the water, and somehow, I had been designated as a lifeguard. And I didn’t even know how to swim.
This, the second surge here in Massachusetts, feels different. It’s a similar tidal wave, but I have an idea how tall it is and how hard it will hit. I’ve learned how to swim. But I’m still swimming unassisted—no life preserver, no flares, no rescue boat. Today, we know what COVID looks like.
We’ve learned a lot about the management of severely ill patients in the hospital. Pronation can help hospitalized patients breathe better. Dexamethasone can help the most severely ill patients and there’s a place for remdesivir in severely ill hospitalized patients as well. But we are still staring up at tidal waves of the unknown, particularly for non-hospitalized patients.
We still don’t know which outpatients will do well and which ones won’t; we still don’t know the best management strategies for common clinical situations; and we still don’t have any meaningful therapies to offer our patients outside of the hospital.
Remdesivir and dexamethasone have received a lot of attention for their utility in treating COVID, but they are only useful for patients inside the hospital. Remdesivir is an intravenous therapy and has not demonstrated efficacy in outpatients. Dexamethasone is only authorized for hospitalized patients on supplemental oxygen, and may actually worsen disease in patients with less severe disease.
The multiple vaccines with outstanding data, of course, offer hope for limiting new cases of the virus starting this spring. But they do nothing for people who are already infected, people who are suffering now and expected to continue filling up hospital beds in days and weeks ahead.
The FDA has recently authorized two medications for patients outside the hospital, Eli Lilly’s bamlanivimab and Regeneron’s casirivimab/imdevimab. Neither of them appears to be a transformative treatment for outpatients with COVID.
Bamlanivimab is a monoclonal antibody developed by Eli Lilly that is running a clinical trial in 452 outpatients with mild or moderate COVID. My clinic at MGH is one of the sites on that clinical trial, and I have referred patients to participate. The drug was authorized by the FDA on the basis of an interim data analysis that showed a clinically modest, but statistically significant, reduction in viral load at the middle of three doses. At that mid-level dose, the average viral load was reduced by 99.99% by day 11 of the study.
Sounds great, right? The catch is that, across all groups, including placebo, the average viral load was reduced by more than 99.9% by Day 11. In fact, the high dose and the low dose were statistically no different than placebo. The high dose, puzzlingly, actually had a lower percent reduction than placebo, although it was not a statistically significant difference.
It’s important to know that a treatment designed to neutralize the virus actually does bring down viral loads. Then again, doctors and patients do not care about a difference in viral load of less than 0.1% in and of itself. ‘Harder’ clinical endpoints like hospitalization, intubation, and death are much more meaningful. The interim readout of the trial – the basis for the FDA’s Emergency Use Authorization (EUA) — did not include enough hospitalizations to make firm conclusions on this endpoint. There were five hospitalizations (1.6%) among all three treatment doses—including the doses that did not reduce viral load—and nine hospitalizations (6.3%) in the placebo group.
In summary, there was a reduction in viral load in the middle dose that you might be able to see if you squint, and insufficient evidence to draw any conclusions about hospitalizations. It is a weak body of evidence to support a drug authorization—a strain to justify, even during a pandemic.
But the authorization was not just a strain. It was bizarre. Instead of authorizing the middle dose—the only dose that actually showed a reduction in viral load—the FDA authorized the low dose, which showed no benefit in viral load. The FDA’s explanation was that there would be more drug to go around if each patient got the lower dose. Yet every doctor I know would prefer to treat one patient effectively than four patients ineffectively.
The other treatment that the FDA recently authorized for outpatients is casirivimab/imdevimab, Regeneron’s dual antibody cocktail. The data for this combination looks similar to the bamlanivimab data. The reduction in viral load was modest but statistically significant for both doses tested. There were fewer hospitalizations and emergency department visits in the treatment groups than the placebo group, although the number of events was again too low to draw any conclusions.
The good news with this treatment is that the FDA authorized a dose that appears to actually do something (since both doses showed viral load reduction). The bad news is that the complete data from the clinical trial has still not been published, over three weeks after the authorization went into effect. The FDA included snippets of data in its EUA, but Regeneron has still not published a complete dataset in a peer-reviewed journal, or even on a pre-print database. As such, it is impossible for me to have an informed opinion on the utility of this drug for my patients.
Further complicating the muddy data for bamlanivimab and casirivimab/imdevimab is the logistical complexity of administering these treatments. Both are intravenous (IV) infusions. For outpatients, IV infusions are usually administered in an infusion center, a dedicated clinical unit. However, since these patients are infected with COVID, they cannot mix with other patients, requiring the creation of entirely new infusion spaces specifically for this purpose.
At MGH, a hospital fortunate to have the resources to create such a space, a central team reviews every patient case and determines who would be eligible for treatment, then places them in a lottery to see who can get the treatment. I don’t even have control over the prescribing process for my own patients.
We lack more than just medicines to treat outpatients with COVID. Many of the basics of clinical management of these patients remain undefined. We know that most patients with COVID have only mild disease, but a significant minority of patients develop severe, life-threatening illness. One of my biggest challenges is identifying the patients who are at risk for rapid clinical worsening. Several research groups are investigating tools to risk stratify patients, but none seems to be a definitive solution so far.
My colleagues and I are running a prospective trial in our clinic to see if exertional oxygen saturation (a patient’s blood oxygen level during light exercise) can identify the patients who are at risk of getting worse. Other groups have used machine learning to pull clues from patients’ charts. Chest X-rays and blood tests might be helpful. This is a huge clinical problem and I hope that one of these approaches turns out to be a reliable predictor of outcomes, so we can act accordingly to help patients early in their course of disease.
Management of a plethora of other clinical situations in outpatients with COVID also remain uncertain. Here are a few examples:
These questions come up nearly every day I am in clinic, yet there are no clear guidelines for handling any of these situations. There is an enormous amount about this disease that we still don’t know.
On top of better guidance on those clinical questions, we are in dire need of better therapies for outpatients. I am grateful for the antibody therapies that are being developed, but what we really need are potent, oral antiviral therapies. These drugs are probably a year or more away, because medicinal chemistry efforts to discover novel compounds with desirable pharmaceutical properties are necessarily slow. Repurposing existing compounds, as was done with remdesivir, is unlikely to be the solution because these compounds rarely have the potency and desired properties to make for a truly transformative therapy.
Let’s return to my phone conversation with my patient with worsening COVID.
“What can I do to get better?”
What could I say? I seriously considered telling her to go to the emergency department right then, but because she was young and in satisfactory health at baseline, I decided against it. I encouraged her to sign up for the clinical trial of bamlanivimab—that way, she would at least have a chance of getting the dose that reduces viral load. And I told her that if she started to feel any worse at all, she should call an ambulance.
I kept a close eye on her chart over the next week. She did enroll in the bamlanivimab trial, although I’ll never know which dose she received, or if she got placebo. In any case, she did not need to be admitted to the hospital and has since recovered from her illness. Her case was a small victory in a season full of losses. While I take pleasure in her recovery, I probably can’t take credit for it.
Not without better tools at my disposal to manage patients like her.
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Today’s guest on The Long Run is David Lee.
David is the CEO of Boston-based Servier Pharmaceuticals. It’s the US subsidiary of France-based Servier Group.
Servier, for those unfamiliar, is a rare bird in the pharmaceutical world. It markets both branded drugs and generic drugs. It is a truly global company with 21,000 employees in 148 countries, but it has only recently entered the world’s biggest pharmaceutical market – the US.
David Lee, CEO, Servier Pharmaceuticals
There’s more. It’s governed by a nonprofit foundation. As part of its mission as a nonprofit dedicated to improving health, it invests 25 percent of its annual revenue in R&D – quite a bit higher than the industry standard.
David is an industry veteran, having been around the block as a consultant and at a variety of business roles at pharma companies – Novartis and Shire, prior to its acquisition by Takeda. He came over to Servier with some assets that were being divested. Those assets provided a foundation for Servier’s US expansion, which includes R&D operations in Boston. David oversees all of that.
Now, please join me and David Lee on The Long Run.
