Your Edge In Biotech.
12
Oct
2020

Looking at Cancer From a Different Angle: Pearl Huang on The Long Run

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12 Oct 2020

Today’s guest on The Long Run is Pearl Huang.

Pearl is the CEO of Cambridge, Mass.-based Cygnal Therapeutics.

Pearl Huang, CEO, Cygnal Therapeutics

Cygnal is a startup dedicated to developing cancer drugs based on some fairly new understanding of the Peripheral Nervous System.

For years, scientists assumed that the PNS was merely a conduit of the central nervous system. But what if the PNS is not a passive actor in disseminating messages from the brain, but an independent force capable of propagating its own neural signals that help facilitate the growth and spread of cancer? Cygnal represents a wager that exoneural biology may be one of the keys to understanding oncogenesis, and one that’s been long overlooked.

Pearl comes to this work with a wealth of experience. She’s a scientist by training, and has worked her way up through the ranks at the Big Pharma companies Merck, GSK and Roche. In between there, she got her first taste for entrepreneurship as the scientific founder of BeiGene.

Pearl grew up in a small college town of the Upper Midwest, a place much like where I grew up. She has some interesting observations about the remote Upper Peninsula of Michigan, moving on to MIT when there weren’t many women around, and then later in life finding herself comfortable with taking on senior leadership roles. It all sets the scene for what drew her to the unorthodox approach to cancer being explored at Cygnal.

Please join me and Pearl Huang on The Long Run.

8
Oct
2020

A Historic Nobel for CRISPR, Pfizer Sticks Up for FDA, & a CDC Legend Speaks

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08 Oct 2020

Luke Timmerman, founder & editor, Timmerman Report

What a time to be alive in biomedicine. Catch up on the main events in Frontpoints.

The Babe Ruth of Public Health Speaks Out

William Foege is in his mid-80s. There’s a genome sciences building at the University of Washington named after him because Bill Gates gave money to build it, and he wanted it named after a scientific hero. Foege has nothing to prove to anyone, and doesn’t seek attention. He’s belongs on the Mount Rushmore of global health for his strategically brilliant and relentless campaign to eradicate smallpox from Earth.

So I snapped straight up and read every word Foege wrote when USA Today discovered and published a private letter Foege wrote to current CDC director Robert Redfield, dated Sept. 23.

Foege empathizes with the embattled CDC director in the opening, but like an angry and baffled father, he chastised Redfield for this monumental failing of American leadership in public health. The only real alternative at this point, Foege wrote, is for Redfield to document the horrifying cascade of White House incompetence and mendacity, and resign to save the CDC, a once-proud and now humiliated agency.

Read the full, scathing letter here.

CDC, Finally, Updates Airborne Guidance

We’ve known since January that SARS-CoV-2 is transmitted through the air. There have been debates over the relative extent of droplets versus aerosols, and how far is far enough for social distancing, but still, but the science on tiny aerosol transmission has been clear for some time. And yet, the CDC, has been unable to effectively communicate this to the public. Remember when Dr. Redfield told a Congressional committee that a mask was an even more effective defense tool than a vaccine, and when the President slapped him down for that act of fact-based insubordination? The latest shameful episode in CDC history came when the agency briefly took down guidance from its website in September that emphasized the risk from airborne transmission of the virus. It took until Oct. 5 – yet another day with more than 40,000 new cases – before the CDC was able to update its guidance on its website about airborne transmission. Look at the terrible case of confusing whiplash this gives the public, neatly captured in WSJ editor Jonathan Rockoff’s tweets.

If citizens had been given the straight scoop, straight from the podium of the CDC starting in January and continuously updated from that point forward, I firmly believe this country would have looked more like Germany today. We would have been able to save tens of thousands of lives. But now, as things are, many thousands more are going to die – still 1,000 a day! This horse should never have gotten so far out of the barn. The body politic should never have been so thoroughly poisoned that we’d up in a cynical abyss where large numbers of citizens refuse to wear masks and engage in common sense social distancing.

All of the elected officials who are responsible, and those who continue to enable this daily rolling national train wreck, must be voted out of office.

Kudos

The Nobel Prizes came out, and were quite illustrative of the golden age of biomedicine. On Monday, the Nobel Prize in Physiology or Medicine went to Harvey Alter at the National Institutes of Health; Michael Houghton, now at the University of Alberta; and Charles Rice, now at Rockefeller University. Their work on the hepatitis C virus laid the groundwork for one of the biggest success stories in biotech history – cures for this chronic, liver-damaging infection. Houghton, by the way, did his pioneering work on HCV while at Chiron, one of the early biotech companies (now part of Novartis).  

Then, on Wednesday, came an even bigger award – the Nobel Prize for Chemistry went to Jennifer Doudna and Emmanuelle Charpentier for their discovery of CRISPR-Cas9 gene editing. This discovery of precise editing tools was revolutionary, and is now setting the stage for a new crop of gene-edited medicines with potential to cure diseases like sickle-cell disease, a new generation of drug discovery platforms to speed up precision medicine development, clever agricultural applications, cheap and fast diagnostics and so much more. The cheap, fast, easy nature of CRISPR editing makes it an accessible lab tool widely distributed in labs around the world. Doudna and Charpentier’s contribution not only changed biomedicine, but this dynamic duo is especially inspiring to women scientists and young girls. That was the bigger story than the long-running patent dispute between the University of California-Berkeley and the Broad Institute. George Church and Eric Lander, a couple of leading lions of science with competing claims to novelty in the early work on CRISPR, both made gracious public comments, rather than resort to the kind of occasionally ugly professional jealousy that often swirls around the Nobels. Church, when asked about Doudna and Charpentier’s prize, told STAT “they made the key discovery.”

Isaac Kohane, a professor of biomedical informatics at Harvard Medical School, was awarded the 2020 Morris F. Collen Award of Excellence from the American College of Medical Informatics.

Regulatory Action

The FDA released guidance for COVID-19 vaccine development, and what the standards are for an Emergency Use Authorization, in advance of the upcoming Oct. 22 advisory committee to review the latest safety and efficacy data on this historic effort. The big news in the document (full version here) was that the FDA is calling for at least two months of safety data (see Appendix II) from participants in trials after getting their second and final dose. That means there’s no way an EUA can be issued before the general election on Nov. 3. The White House had reportedly balked at the guidance document, and held it up with questions for FDA. The White House has done considerable damage to the FDA’s reputation for scientific independence this year, but as the President was ill with COVID-19, the White House ultimately backed off, dropping its objections to the balance the agency has been trying to strike between the need for speed, as well as the need for adequate safety data. Given the state of vaccine hesitancy in the public, which perceives a corner-cutting job in the works for electoral purposes, we can be thankful that cooler heads have prevailed.

Albert Bourla, the CEO of Pfizer, may have had a hand in the White House backing off from its aggressive stance, as he said unequivocally that his company wouldn’t try to undercut the independence of the FDA (even if it’s presumably financially advantageous for the company to get a jump on rivals and start selling its COVID vaccine as fast as possible). See his Tweet below.

One final point about COVID-19 vaccine timelines that has gotten less attention: waiting just a few weeks longer for the trials to play out could be the difference between making a momentous decision on a rather skimpy data set, or making it based on a fully mature dataset rich with information on key subgroups like the elderly, and racial and ethnic groups that have been reluctant to enroll in trials (and who especially need vaccines because of the higher-than-average risk minority groups face.) See this comment I tweeted in the moment from Larry Corey of Fred Hutch, one of the leaders of the Operation Warp Speed effort, who spoke at a Johns Hopkins University and University of Washington symposium on Oct. 6.

Tarrytown, NY-based Regeneron Pharmaceuticals submitted a request Oct. 7 to the FDA for Emergency Use Authorization for its REGN-COV2 two-antibody cocktail that’s designed to neutralize the SARS-CoV-2 virus. This comes after the company issued a press release Sept. 29 with the first meaningful slice of clinical data, showing the antibody could significantly reduce viral loads, especially among patients with high amounts of circulating virus. Data from that rolling clinical program haven’t yet been published in a peer-reviewed journal. The move to seek an EUA for wide distribution to patients came the same day the President extolled the virtues of the therapeutic neutralizing antibody from Regeneron, which he received on a Compassionate Use basis, and which he publicly credited with helping him recover from COVID-19. Whether that’s true, of course, we don’t know.

New York-based Mesoblast received a dreaded Complete Response Letter from the FDA, explaining why it wasn’t willing to approve the company’s application to market a new treatment for pediatric steroid-refractory graft-versus-host-disease in children. This was a surprise, given that the FDA’s Oncologic Drugs Advisory Committee voted 9-1 in favor, saying the available data support the drug’s efficacy. The FDA disagreed, saying the company should run at least one additional randomized study in adults or children.

New York-based Y-mAbs Therapeutics received a Refusal to File letter – meaning the FDA declined to review its application to start marketing omburtamab as a treatment of pediatric patients with CNS/leptomeningeal metastasis from neuroblastoma. The agency said the company needs to provide more detail in its Chemistry Manufacturing and Control (CMC) section, and the Clinical section of the Biologics License Application.

San Carlos, Calif.-based Iovance Biotherapeutics reported that its plans to file a Biologics License Application to the FDA have been delayed, based on a disagreement with the agency over “the required potency assays to fully define its TIL therapy.” The company is developing lifileucel as a Tumor-Infiltrating Lymphocyte therapy for metastatic melanoma.

Deals

Bristol-Myers Squibb agreed to pay $13.1 billion in cash, or $225 a share, to acquire Brisbane, Calif.-based Myokardia, the developer of targeted therapies for cardiovascular diseases. Through the deal, BMS obtains mavacamten, a first-in-class treatment for obstructive hypertrophic cardiomyopathy which has gone through Phase III development, and which is expected to go before the FDA with a New Drug Application in the first quarter of 2021. Third Rock Ventures bet $38 million on this company in a Series A financing in September 2012 (see my coverage at the time on Xconomy.)

Pleasanton, Calif.-based 10X Genomics acquired Boston-based ReadCoor for $350 million, a few weeks after its acquisition of Stockholm-based CartaNA. The two acquisitions represent a strategic move into In Situ analysis. (See TR coverage of ReadCoor in this June 2020 feature on “Complexity in Motion.”)

Vancouver, BC-and Seattle-based Chinook Therapeutics closed its merger with Aduro Biotech and completed a $115 million private placement that leaves it with $275 million in cash to develop precision medicine therapies for kidney diseases.

Palo Alto, Calif.-based BridgeBio Pharma agreed to pay $175 million to acquire the remainder of Eidos Therapeutics which it didn’t already own. Eidos is developing acoramidis, a TTR stabilizer for patients with ATTR cardiomyopathy and polyneuropathy.

Cambridge, Mass.-based AVROBio in-licensed a lentiviral gene therapy program from the University of Manchester, to treat patients with Hunter Syndrome. (See TR coverage of AVROBio, September 2020)

The Netherlands and Belgium-based argenx announced a series of partnerships with Chugai Pharmaceuticals, The Clayton Foundation, and Halozyme Therapeutics to expand its antibody engineering capabilities.

Takeda Pharmaceuticals and Arrowhead Pharmaceuticals agreed to work together on further developing ARO-AAT for Alpha-1 Antitrypsin-Associated Liver Disease. Arrowhead is getting $300 million upfront.

Data That Mattered

Eli Lilly had the best clinical data of the week, hands down. The Indianapolis-based pharma company reported that its neutralizing antibody program for COVID-19, developed in collaboration with AbCellera against the spike protein of SARS-CoV-2, nailed an interim analysis of the BLAZE-1 clinical trial that looked at mild-to-moderate COVID-19 patients. The combo therapy of two antibodies did especially well at taking down viral loads at Day 3, Day 7 and Day 11, and reduced COVID-related hospitalization and ER visits. The company said it will seek Emergency Use Authorization from the FDA based on the result. This is the kind of biological and clinical data alignment that we all want to see. Key slide below.

Amgen had a mixed bag of recent results. The company reported positive top-line results for its KRAS G12C directed small molecule drug candidate, sotorasib, in a Phase II study of 126 patients with KRAS G12C mutated forms of advanced non-small cell lung cancer. A few days later, Amgen reported on a failed Phase III result for omecamtiv mecarbil in patients with heart failure with reduced ejection fraction (HFrEF). Technically, the trial hit the primary composite endpoint, but the benefit on that score was miniscule, and the drug failed to demonstrate an improvement in cardiovascular death, a key secondary endpoint. Results from the GALACTIC-HF study, which enrolled, 8,256 patients in 35 countries, will be presented at the American Heart Association’s Scientific Sessions on Nov. 13.

Gilead Sciences and collaborators from the National Institute of Allergy and Infectious Disease published final results for remdesivir in the New England Journal of Medicine. The full analysis confirms the earlier reports that the antiviral can help patients recover more quickly, and get out of the hospital faster. The drug didn’t show a statistically significant benefit on mortality at Day 29, but a post-hoc analysis showed there was a 72 percent mortality benefit in a subgroup of patients who got low-flow oxygen upon hospital admission.

Science
  • Airborne Transmission of SARS-CoV-2. Science. Oct. 5. (Kimberly Prather et al)
  • Cross Reactive Memory T-cells and Herd Immunity to SARS-CoV-2. Nature Reviews Immunology. Oct. 6. (Marc Lipsitch et al)
  • Antigen-based Testing, But Not Real-Time PCR, Correlates With SARS-CoV-2 Virus Culture. MedRxiv. Oct. 5. (Andrew Pekosz et al)
  • Remdesivir for the Treatment of COVID-19. Final Report. New England Journal of Medicine. Oct. 8. (John Biegel et al)
  • Effect of Hydroxychloroquine in Hospitalized Patients With COVID-19. New England Journal of Medicine. Oct. 8. (The RECOVERY Collaborative Group)
  • Remdesivir Targets a Structurally Analogous Region of the Ebola and SARS-CoV-2 Polymerases. Proceedings of the National Academy of Sciences. Oct. 7. (Michael Lo et al)
Science Features
Public Health
  • Get Serious About the People Putting All of Us at Risk. Let’s Enforce Mask Wearing. NYT. Sept. 29. (Elisabeth Rosenthal)
  • Against COVID-19, Imperfect Measures Do the Most Good. NYT. Oct. 4. (Joshua Schiffer)
Strategy
  • Playing to Win: Scenario Planning for a Binary Readout in Biotech. LifeSciVC. Oct. 8. (Ankit Mahadevia)
Politics
  • Why Nature Needs to Cover Politics More Than Ever Now. Nature Editorial. Oct. 6. (The Editors)
  • Dying in a Leadership Vacuum. New England Journal of Medicine Editorial. Oct. 8. (The Editors)
  • Coronavirus Advisor Scott Atlas Hits Back at Fauci and Others Who Doubt His Advice. “I’m Here Because the Country’s Off the Rails.” Business Insider. Oct. 6. (Ashley Collman)
Worth a Listen
  • Moncef Slaoui, The Man Behind America’s Race for a Coronavirus Vaccine. Sway podcast. Oct. 5. (Kara Swisher)
Personnel File

Merck said that Roger Perlmutter, president of Merck Research Laboratories since 2013, is retiring on Jan. 1, 2021. He will be replaced by Dean Li, the company’s senior vice president of discovery sciences and translational medicine. Li is a former professor of medicine and cardiology at the University of Utah. Perlmutter, an immunologist by training, presided over the breakout success of the cancer immunotherapy pembrolizumab (Keytruda).

Brett Zbar joined General Atlantic as global head of life sciences, as the growth equity firm formally established life sciences as its fifth core investment sector. Zbar was previously a managing director with Foresite Capital. (I wrote about Zbar in 2018 as one of “Nine VCs Who Matter, But You Never Read About.”)

Paul Medeiros joined Cambridge, Mass.-based Q-State Biosciences as president and CEO. The company is developing drugs for diseases associated with electrically excitable cells.

San Rafael, Calif.-based BioMarin Pharmaceutical hired Kevin Eggan as Group Vice President, Head of Research and Early Development. He was formerly a tenured professor in the Department of Stem Cell and Regenerative Biology at Harvard University, the Director of Stem Cell Biology for the Stanley Center for Psychiatric Research at the Broad Institute, and an Institute Member of the Broad Institute of MIT and Harvard.

San Diego-based Expansion Therapeutics named Renato Skerlj as its new CEO. The company is developing small molecule drugs against RNA targets.

Sarah Noonberg was hired as chief medical officer of San Francisco-based Maze Therapeutics. (See TR coverage of the $191 million Series A in this company in February 2019, led by Third Rock Ventures and Arch Venture Partners.)

Rick Bright, the former head of the Biomedical Advanced Research and Development Authority who became a whistleblower on the political interference in the COVID-19 response effort, including the unwarranted push for hydroxychloroquine, resigned. In his amended whistleblower complaint, he said he had only been given one assignment since being transferred to the NIH.

Norwood, Mass.-based Corbus Pharmaceuticals cut its workforce by 54 percent.

Name Change

Seattle Genetics officially changed its name to SeaGen Inc. – which has been its informal name for years. The company is actually based in suburban Bothell, Wash. and isn’t exactly a genetics company, it’s a cancer drug developer. It’s never made a lot of buzz for itself, but it has long been the unquestioned bellwether of the Seattle biotech hub with a $35 billion market valuation.

Financings

San Mateo, Calif. and Cambridge, Mass.-based Kronos Bio, a cancer drug developer led by former Gilead CSO Norbert Bischofberger, raised $250 million in an IPO at $19 a share.

Watertown, Mass.-based C4 Therapeutics, the developer of targeted protein degrading drugs, raised $210 million in an IPO at $19 a share.

Silver Spring, Maryland-based Aziyo Biologics raised $50 million in an IPO at $17 a share.

Durham, NC and Austin, Tex.-based Shattuck Labs, a cancer drug developer, raised $202 million in an IPO at $17 a share.

Exton, Penn.-based Immunome, a company working on memory B-cells to develop antibody therapies, raised $39 million in an IPO at $12 a share.

Cambridge, Mass.-based Oncorus, a viral immunotherapy developer for cancer, raised $87 million in an IPO at $15 a share.

Alameda, Calif.-based Scribe Therapeutics raised $20 million in a Series A financing to develop in vivo CRISPR gene editing medicines. Andreesen Horowitz led. It spun out of the Doudna Lab, Oakes Lab, and the Innovative Genomics Institute. Scribe also announced a Biogen partnership to work on neurodegeneration.

South San Francisco-based Federation Bio got started with a $50 million Series A to develop microbiome therapies. Horizons Ventures led, and was joined by existing investors Venrock and Altitude. Emily Drabant Conley, formerly of 23andMe, was named CEO.

Stamford, Conn.-based Springworks Therapeutics, a cancer drug developer, raised $250 million in a stock offering at $51 a share.

7
Oct
2020

Learning From COVID-19: The Lessons For Real World Data

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07 Oct 2020

David Shaywitz

The COVID-19 crisis created an urgent need for healthcare data.

For starters, it was necessary to characterize the spread of the pandemic. Quickly, reports were needed on the capacity of healthcare facilities responsible for care of the severely afflicted. Then there was the urgent need to assess the trajectory, and outcomes, of patients admitted to hospitals. 

The profound difficulty our healthcare system has had responding to each of these needs – despite the often heroic efforts of so many dedicated individuals – has revealed critical gaps in the way healthcare data are gathered, shared, and analyzed.

The challenges of defining the spread of COVID-19 relates in part to existing deficiencies – “We don’t really have a public health infrastructure,” Walmart Health’s Senior Vice President Marcus Osborne explains. 

The Centers for Disease Control and Prevention also made some high-profile blunders early on – perhaps most prominently, the distribution of a flawed initial test for the virus, which forced the country into catch-up mode from the start, as the New York Times and others have discussed. Also a key factor: the Trump’s Administration’s apparent distrust of, and disdain for, the established experts in the public health community; a representative headline, from Axios: “Trump’s war on public health experts.”

The failure experienced by hospitals in assessing capacity has been persuasively documented by Wall Street Journal reporters Melanie Evans and Alexandra Berzon.

The challenge of understanding collectively what happens to patients once they’ve been admitted to a hospital may be less visible, but remains equally problematic.  We are far better at, or at least more diligent at, determining what a patient should be billed for than determining at the most basic level how they actually fared, both individually and for most categories of patients.

This represents the “feedback gap” I recently described, in the context of a July conference on “Establishing a High-Quality Real-World Data Ecosystem” organized by the Duke-Margolis Center.

Recently, the Margolis Center convened another meeting, focused specifically on “Applying Lessons Learned from RWE [real world evidence] in the Time of COVID-19 to the Future.”  While the individual presenters were uniformly hopeful and optimistic, I emerged from the proceedings with the strong sense that the pandemic has thrown into sharp relief a number of persistent and long-standing challenges.

Those who are interested can watch the conference video on YouTube. 

Several topics caught my attention.

First, related directly to the origin of the feedback gap I previously described, is the idea emphasized by UCSF’s Dr. Laura Esserman. In typical care, “we don’t get outcomes on everybody – that’s a problem with medicine.”  She added, “We should track outcomes on everyone, and isn’t that just real-world data?” 

She continued,

“Our current electronic health records are not organized for quality improvement and you shouldn’t have to go to the IRB to get permission to collect the data that allows you to do your job.“

In other words: how can we improve the care we routinely provide if we’re not routinely, and systematically, determining and analyzing how the patients we’re currently taking care of are doing?

Dr. Robert Califf – legendary cardiology clinical trialist, former Commissioner of the FDA, and now Head of Clinical Policy and Strategy at Verily – highlighted a consequence of this failure: the vast amount of clinical practice is not informed by high-quality evidence. He cited a recent study that reported how few of the cardiology guidelines (just 8.5% of the recommendations in the American College of Cardiology/American Heart Association guidelines) are based on the highest level of evidence (supported by multiple randomized controlled trials – RCTs). Unfortunately, this pattern that doesn’t seem to have changed in the last decade.  

While we have a robust clinical trial enterprise, Califf explained, it isn’t meeting a number of critical needs. In particular, he says, “We are not generating the evidence we need to support the healthcare decisions that patients and their doctors have to make every day.”

Fixing this, he says, will require us to “deal with the fragmentation and misaligned incentives in our system.”  

As I’ve argued, a key “reason the information isn’t tracked is, essentially, no one (besides the patient!) really cares, in the sense of being personally invested in (and accountable for) the outcome.”

The consequence of our failure to collect – and the lack of adequate motivation to routinely collect – the information we need to improve care, even at the level of most individual hospitals, much less the regional and national level, has been felt especially acutely by FDA Deputy Commissioner Dr. Amy Abernathy.  An expert in real-world evidence from her Duke and Flatiron Health days, Abernathy has been seeking to organize the incoming COVID-19 data and analyze it through collaborative efforts such as the COVID-19 Evidence Accelerator (in which I’m a participant).

Reflecting on what she’s learned, Abernethy highlighted what struck me as the observational research version of Mike Tyson’s memorable epigram, “Everyone has a plan until they get punched in the mouth.”

In the case of learning from COVID-19 RWE, there was important methodological lesson to be learned from the challenges of even the seemingly most basic elements, such as defining “time zero,” determining what constitutes a hospital admission, and discerning whether a patient was receiving intensive or critical care. 

Many of these issues were surfaced, Abernethy noted, at the Evidence Accelerator, when participants were encouraged to show their work, and get into the critical “nitty-gritty.”  Some of these challenges were also highlighted by conference participants, including Harvard’s Griffin Weber.

Abernethy also pointed out that we’ve become relatively proficient at understanding at a glance what to look for in a high quality RCT, assessing attributes like adequate statistical power and how the blinding was managed.  Now, she said, we need to develop this intuitive understanding for observational studies as well. 

Abernethy also emphasized the need to refine our conception of RWE.  We often tend to view RWE-driven studies as a “replacement product” for RCTs – but this framing may be misleading and distracting.  Everyone would like to have robust RCTs to answer every question, she said, but that’s not possible, and we need RWE “to fill in the gaps.”  

RWE, she emphasized, can be used for a range of purposes, such as understanding patterns of care, or deciding which RCTs should be conducted.

This is a critically important idea: the value of RWE is not as a substitute for RCTs, but rather to more effectively capture the totality of data in the healthcare system, and to provide information about healthcare as it’s actually practiced, within the acknowledged messiness of routine care, as I’ve discussed.

I was also struck by Abernethy’s focus on the importance of high-quality datasets, which would seem to be the cornerstone of meaningful analytics. Abernethy highlighted the problem of data gaps, and the need to link data sets and fill in missing data using different data sources, in effort to approach a level of “completeness” that would enable meaningful study. She noted that technology might be helpful here, in the form of “synthetic controls” (statistically generated comparators based existing data; a nice explainer from Jen Goldsack here) and the use of tokenization (an approach to de-identification of data permitting it to be shared; a useful white paper from Datavant, a leading startup in this space, here).

Abernethy also offered what I thought was spot-on advice regarding the development and application of technology, and some important advice about how healthcare could more effectively engage with technologists and tech companies.

There’s a pervasive problem, she said, with “vendor-think” – the idea that the healthcare stakeholder (hospital, payor, biopharmaceutical company, health services researcher) specifies what a vendor needs to provide, and then the vendor “builds against that list.” 

She described with perfect clarity not just how many large healthcare organizations typically approach large projects, but also the mindset within healthcare organizations that I’ve witnessed and described, where data experts and statisticians are often treated as second-class citizens.

What’s needed, she persuasively argued, is for authentic collaboration, where you have at the same table not just the manager or executive, say, who’s sponsoring the project, but also healthcare domain experts, who understand the subtleties and context of how the data were generated, as well as the technologists – the data scientists and engineers who can build and refine the solution. 

Such ongoing collaboration not only ensures a better mutual understanding of needs, but also enables the work to proceed iteratively, and to evolve as the participants refine their understanding of both the problem to be solved and the solutions that can be envisioned.

Achieving this balance is notoriously difficult, and vanishingly rare to see in practice.  This barrier – a hurdle in organizational dynamics as much as technological expertise – also represents an exceptional opportunity for an integrative and empathetic leader who can not only bring the right people to the table, but (and this is the hard part) ensure their talents are fully elicited and authentically embraced.

7
Oct
2020

Seeing COVID-19 in Context: Applying Spatial Biology to the Lungs

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07 Oct 2020

Sarah Warren, senior director, translational science, NanoString Technologies

It’s worth looking back on what is known about the SARS-CoV-2 virus, which was first detected in the US in mid-January, when a man traveled from Wuhan, China to Seattle.

Nearly 10 months later, a tremendous amount of knowledge has been gathered about the virus, how it is transmitted, and the disease symptoms it causes.

We know, for instance, the risk factors that are associated with severity of infection, such as being elderly, or having certain pre-existing conditions like Type 2 diabetes. We are beginning to understand all the ways the virus can be transmitted, particularly through the air. And yet, much remains unknown about the virus, particularly its impact on the body at the molecular level.

Jason Reeves, senior scientist, NanoString Technologies

In our quest to gain a deeper understanding of the molecular and cellular pathology of the disease, investigators have been leveraging every tool and platform available. Applying spatial biology – a strategy for profiling the distribution of cells and molecular pathways within tissues – to samples collected from patients who died from the disease, represents a powerful way to understand at a local level how the virus is reshaping infected tissue and the subsequent immune response.

Our company, Seattle-based NanoString Technologies, recently hosted a virtual Advancing Spatial Biology Conference to feature the work of investigators who are using the company’s GeoMx Digital Spatial Profiler to address a variety of research questions. One of the tracks was dedicated to studies that addressed the impacts of COVID-19 in the lungs. Although the data are still early, the collective results presented by these investigators reveal insights into the underlying biology of the virus and will guide development of therapeutics, supportive care, and vaccines.

Some of the major findings from these studies are summarized below.     

Infected Tissues Are Heterogeneous

The GeoMx technology enables simultaneous profiling of 60-90 proteins, and up to 1800 RNA transcripts (today), from multiple regions of up to half a millimeter in diameter within a tissue section with a profiling area of 14×36 mm.

Capturing this much data, in spatial context from a tissue sample, enables the use of data analysis methodologies suitable for high-plex data to create a deep understanding of how the infection manifests in different patients.

What we see again and again is that the disease varies greatly between individuals. Several investigators during the track pointed out that lung tissue sections from COVID-19 patients were more variable than lung tissue sections from patients that died from other causes. Chris Mason and colleagues at Weill Cornell Medicine in New York were able to compare COVID-19 lung tissues to flu-infected lung tissues, to underscore the wider range of possibilities.

What might be driving this? Partly, the diversity is driven by different courses of the disease that are observed for each patient. Some people succumb rapidly to infection and pass away shortly after diagnosis and presentation in a hospital. These people tend to have evidence of active viral replication and strong interferon response.

Other people have a longer course of disease. They may survive the initial diagnosis but then die from secondary effects of the infection such as inflammatory cytokine storms or other dysregulated immune responses. The lung tissue from these patients tends to be characterized by more tissue repair signaling pathways, perhaps as the lungs attempt to heal themselves.

However, this dichotomization is not universal, so there must be other as yet unidentified causes of the diversity. Viral load may be one contributing factor. Intriguing data presented by Gordon Jiang from Beth Israel Deaconess presented showed that the levels of 5-lipoxygenase, an enzyme involved in the production of inflammatory leukotrienes, is expressed in proportion to viral load.

Despite this inter-patient variability, there were some common patterns of expression, especially in the immune response. Certain innate immune cells, such as macrophages and neutrophils, are activated by the virus and robustly recruited to the sites of viral infection early in the course of disease. The type I interferon response, part of the body’s first line of defense against viral infection, is consistently one of the strongest upregulated pathways.

This suggests that therapeutics targeting these pathways and currently in clinical trials, such as baricitinib, the JAK1/2 inhibitor developed by Lilly that blocks production of interferons, may be effective at tamping down runaway inflammation early in infection, if given in combination with antivirals to control viral load, such as remdesivir, or therapeutic neutralizing antibodies in development. Intriguingly, data presented by the keynote speaker, Dr. Peter Sorger from Harvard Medical School, suggested that similar pathways may also be upregulated in non-human primates infected with COVID-19.

The Virus Affects Tissue Architecture and Immune Response

It is also abundantly evident that the virus is impacting both the immune response and altering the underlying tissue architecture. Regions of the lung with high viral load are characterized by hyaline membranes, sheets of dead cells, surfactant, and proteins that are associated with acute respiratory distress.

These hyaline membranes can be visualized on tissue sections and are accompanied by hyperplasia (excessive growth) of type II alveolar cells. This is a key cell population in the lung that is a progenitor for the gas-exchanging type I alveolar cells. These cells maintain the lubricating surfactants, and recruit immune cells following injury, which are necessary to maintaining normal breathing ability.

Type II alveolar cells are recognized as a reservoir of COVID-19, where the virus hides out, allowing the infection to progress into the lower lungs. These type II alveolar cells provide a fertile breeding ground for the virus, as they express the ACE2 protein that acts as a viral receptor. Spatial profiling of the lungs revealed enrichment of collagen synthesis pathways and extracellular remodeling pathways in the Cornell cohort. Building on that finding, Asa Segerstolpe of the Broad Institute presented evidence of increased keratin expression in infected regions of the lung.  

As previously mentioned, the immune response is dominated by interferon signaling and associated chemokine expression. This was accompanied by robust recruitment of myeloid cells, including monocytes, macrophages, and dendritic cells, to infected regions of the lung, whereas T cells and NK cells were more abundant in patients with high viral load but displayed less specificity for highly infected regions of the lung. In these studies, cell population abundance was inferred through gene expression deconvolution strategies to enable profiling of 14 different immune cell populations. Patients with high viral load also had expression of some immune checkpoints, including PD-L1 and IDO1, but mixed expression of other checkpoints including CTLA4, LAG3, and VISTA.

Impact of Spatial Profiling

One of the most interesting observations from the COVID-19 studies has been the diversity of the localization of immune responses to infection. David Ting, from Massachusetts General Hospital, demonstrated that in addition to variation between patients who have high and low viral titers, there is also variation between regions of interest with high viral load and those without, but only for some signaling pathways.

For example, chemokines CXCL9, CXCL10, and IDO1, which recruit and regulate immune cells, are expressed at higher levels only in areas of the lung with detectable viral transcripts from patients with high viral load. In contrast, antiviral proteins IFITM1, IFIT3, and IFI6, are expressed at approximately equal levels in virus-high vs virus-low areas of the lung. Antigen presenting genes are displayed uniformly throughout the lung regardless of viral load. These observations are only possible with spatial biology tools that enable simultaneous profiling of a large number of targets in parallel.

As these studies and other mature, we are starting to better understand some of the mechanisms at play in COVID-19 infection. However, given the rarity of these samples and the not insignificant risk physicians must undertake to collect them, we must try to learn as much as possible from each sample we have.

Spatial biology represents a powerful tool to directly examine the infected tissue of COVID-19 patients and characterize its inherent complexity, rather than risk getting overly focused on a single variable that’s just one of many factors at work. By applying tools such as GeoMx and methods such as spatial profiling, we can deepen our understanding of the disease and accelerate the development of treatments and vaccines to mitigate the growing burden of this pandemic.

1
Oct
2020

FDA Commissioners Speak Out, An Antibiotic Incentive Proposal and a Drug Price Grilling

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01 Oct 2020

Luke Timmerman, founder & editor, Timmerman Report

Rummaging around in the garage can be about more than just tossing out junk.

Going through old files lately, I found a printout from the Carnegie-Knight Task Force in 1997. That was the year I graduated from college and went to work as a local newspaper reporter.

The task force, convened by the Project for Excellence in Journalism, was wrestling with the advent of 24-hour cable news. Internet news was just getting started. Many journalism old-timers worried about an erosion of traditional standards across platforms, and unholy merger of news and entertainment. The O.J. Simpson trial was fresh in people’s minds.

A group of prominent journalists attempted to hash out what they called a Statement of Shared Purpose.

The first bullet point in a 9-point theory of journalism said:

Journalism’s first obligation is to the truth

Democracy depends on citizens having reliable, accurate facts put in a meaningful context. Journalism does not pursue truth in an absolute or philosophical sense, but it can — and must — pursue it in a practical sense. This “journalistic truth” is a process that begins with the professional discipline of assembling and verifying facts. Then journalists try to convey a fair and reliable account of their meaning, valid for now, subject to further investigation. Journalists should be as transparent as possible about sources and methods so audiences can make their own assessment of the information. Even in a world of expanding voices, accuracy is the foundation upon which everything else is built — context, interpretation, comment, criticism, analysis and debate. The truth, over time, emerges from this forum. As citizens encounter an ever greater flow of data, they have more need — not less — for identifiable sources dedicated to verifying that information and putting it in context.

Re-reading this statement now, I think it’s possible to swap in the word “science” where you see “journalism.” These are very different professions, but both are important means people have used to navigate the world since the Enlightenment.  

Science has held up much better than journalism in the past 20 years. In many ways, we are living in a biology Renaissance brimming with new possibility for the treatment and prevention of disease.

Science, of course, can’t give us all the answers with crystal clarity. It isn’t perfect, and neither are the people who work in the scientific enterprise. But science is the best available means we have for asking and answering some of the most vital questions of the day.

There’s a whole lot more heat than light being emitted into our information commons at the moment, but science is the way back onto a clear path. All of us should defend it.

Now, make sure you didn’t miss anything big in biotech this week. Read Frontpoints.

Trust

When seven former FDA commissioners get together to write an op-ed in the Washington Post under the headline “The Trump Administration is Undermining the Credibility of the FDA” — you know you are in uncharted territory. The authors of this piece span 30 years of leadership at the FDA, and they served in Democratic and Republican administrations. They have battle scars from political interests who tried to tip scientific decision-making one way or another. If you read one thing this week, I’d suggest it be this piece by Robert Califf, Scott Gottlieb, Margaret Hamburg, Jane Henney, David Kessler, Mark McClellan and Andy von Eschenbach.

Problem-Solving

Antibiotic development has languished for way too long. How can we get ahead of the curve, and incentivize more antibiotic development now so that we’re better prepared for the next infectious disease calamity? This is not a new issue. It’s a bipartisan issue. It is appropriately being treated as such by US Sens. Michael Bennet of Colorado and Todd Young of Indiana. Bennet is a Democrat and Young is a Republican. These guys will not get cable TV news air time for confronting this serious issue. But they introduced a creative bill this week to set up a subscription model to provide predictable revenue streams for antibiotic developers, along with some provisions for appropriate use of the drugs they develop. It’s just a bill at this point and needs debate. But this is the kind of thing an intelligent, forward-thinking country populated by active citizens ought to debate. See the full bill language here, and a one-page summary here.

Data That Mattered

Tarrytown, NY-based Regeneron Pharmaceuticals released an interim cut of data from 275 patients who enrolled in a rolling clinical trial its therapeutic neutralizing double-antibody combo treatment for COVID-19. REGN-COV2 reduced viral loads and cut down on the time it took to recover from symptoms in non-hospitalized patients. Cutting down viral loads is a good early sign, especially with a clean safety profile. (For background, see Q&A With Regeneron SVP of global clinical development, David Weinreich, TR, June 29, 2020).

Cambridge, Mass.-based Ironwood Pharmaceuticals said it failed in a Phase III clinical trial with IW-3718, an experimental drug for gastroesophageal reflux disease (GERD). The company shut down further clinical development of the drug, and said it plans to cut 100 jobs, or about 35 percent of its workforce.

Cambridge, Mass.-based Alnylam Pharmaceuticals, the RNA interference drug developer, said its experimental treatment lumasiran passed the 18-patient, Phase III Illuminate-B study for primary hyperoxaluria Type 1 in children under the age of six. The results were consistent with the Illuminate-A study that looked at patients ages 6 and older. Alnylam said full results will be presented at a virtual meeting Oct. 22.

Vaccines

Moderna CEO Stephane Bancel said at a Financial Times conference that the company’s mRNA vaccine candidate for COVID-19 won’t be ready for widespread distribution until spring 2021. That should be no surprise to anyone paying close attention to the biotech sector, but it does contradict recent statements by the President.

AstraZeneca’s COVID-19 vaccine candidate has been on clinical hold in the US since Sept. 6, and the FDA has now widened its inquiry into the safety data to date, according to Reuters. The trial was paused after a report of a vaccine subject coming down with transverse myelitis, an immune disorder.

Pfizer CEO Albert Bourla has attracted a ton of scrutiny, rightfully, since he has made repeated claims that the company — in a best-case scenario — might have data as soon as October that says its Phase III COVID-19 vaccine study is a success, and worthy of an Emergency Use Authorization application to the FDA. The caveats and qualifiers have largely been stripped away in our red-hot election season. When the President said at this week’s debate that we are only “weeks away from a vaccine,” Bourla felt compelled to write to Pfizer employees that he was “disappointed” in how vaccines were discussed in political terms. In the memo, posted on LinkedIn Thursday afternoon after reporting by Politico and others, Bourla wrote “we are approaching our goal and despite not having any political considerations with our pre-announced date, we find ourselves in the crucible of the U.S. Presidential election.” He added: “We would never succumb to political pressure.”

Testing
  • Trump Announces Plan To Ship 150 Million Rapid Antigen Tests for COVID-19 for States, Tribes and Territories. NYT. Sept. 28. (Katherine Wu)
  • Rethinking COVID-19 Test Sensitivity. A Strategy for Containment. NEJM. Sept. 30. (Michael Mina et al)
Science Features
  • Cycle Threshold Could Help Reveal How Infectious a COVID-19 Patient Is. Should Test Results Include It? Science. Sept. 29. (Robert Service)
  • Alexa, Do I Have COVID-19? Nature. Sept. 30. (Emily Anthes)
  • Why We Need to Keep Using the Term Long COVID. Oct. 1. (The BMJ Opinion)
  • Science and Scientists Highly Regarded Across the Globe, Pew Survey Says. Oct. 1. (Agence France Presse)
  • HHMI Is the Second Major Funder to Mandate The Research It Pays For Be Published Openly. Nature. Oct. 1. (Holly Else)
Public Health
  • Public Health, Pandemic Response and the 2020 Election. The Lancet Public Health. Oct. 1. (Esther Choo and Aaron Carroll)
  • This Overlooked Variable is Key to the Pandemic. It’s Not R. The Atlantic. Sept. 30. (Zeynep Tufekci)
  • Trump Allies Say the Virus Has Nearly Run Its Course. ‘Nonsense,’ Experts Say. NYT. Sept. 29. (Donald G. McNeil Jr.)
Our Shared Humanity
  • Timothy Ray Brown, First Person Cured of HIV, Dies of Cancer. Associated Press. Sept. 30. (Marilynn Marchione)
Financings

Pfizer agreed to make a $200 million equity investment in Suzhou, China-based CStone Pharmaceuticals. The companies are working together on a PD-L1 antibody for use in mainland China.

China-based InventisBio, a cancer drug developer, raised $147 million in a Series B financing led by Hillhouse affiliate GL Ventures.

Berkeley, Calif.-based Carmot Therapeutics raised $47 million in a Series C financing to advance its incretin receptor modulators through Phase II studies. Amgen joined The Column Group and other existing investors.

Switzerland-based Sophia Genetics raised $110 million in a Series F financing to scale up to meet global demand from clinical and biopharma customers for its “data-driven medicine” offerings. aMoon and Hitachi Ventures led.

New York-based Koneksa raised $16 million in a Series B financing to scale up its work on digital biomarkers for drug development. Spring Mountain Capital led, and was joined by new investors McKesson Ventures, Novartis Pharma and MBX Capital.

Miami Beach-based Vesper Healthcare Acquisition raised $400 million in an IPO. It’s a blank check company intended for M&A. Brent Saunders, the former CEO of Allergan, is the CEO.

Sarissa Capital Management is forming a Specialty Acquisition Company (SPAC) or “blank check” company, seeking to raise $200 million. Sarissa CEO Alex Denner and others at the firm will “ target businesses with valuations of $500 million to $1 billion that have the potential to be substantially greater over time due to their underlying business characteristics and growth opportunities as a public company,” according to the S-1.

New Haven, Conn.-based Biohaven Pharmaceuticals raised $60 million to set up an Asia-Pacific subsidiary.

XtalPi, an AI for drug discovery company, raised $319 million in a Series C deal led by Softbank Vision Fund.

South San Francisco and Seattle-based Sonoma Biotherapeutics expanded its Series A financing to $70 million. The company is working on T-reg cell therapies for autoimmune diseases. Investors included Lyell Immunopharma, Arch Venture Partners, 8VC, LifeForce Capital, and Lilly Asia Ventures Biosciences. (See TR coverage, including interview with CEO Jeff Bluestone, Feb. 6. 2020)

Cambridge, Mass.-based Vedanta Biosciences secured $7.4 million upfront, and potentially another $69.5 million, from BARDA to further develop its experimental defined bacterial consortium therapy for C. difficile infections.

Kudos

Frank Bennett, the longtime chief scientific officer of Carlsbad, Calif.-based Ionis Pharmaceuticals, the antisense drug developer, won the Lifetime Achievement Award from the Oligonucleotide Therapeutics Society.

Personnel File
  • Germany-based Merck KGaA said Belen Garijo will be its new CEO, taking over from Stefan Oschmann. She will start in the top job in May 2021.
  • South San Francisco-based insitro, a company using machine learning to facilitate drug discovery, added Roger Perlmutter, president of Merck Research Laboratories, to its board of directors.
  • Lexington, Mass.-based Kaleido Biosciences named Daniel Manichella its new CEO, replacing Alison Lawton.
  • Boston-based Akouos, a gene therapy for ear diseases company, hired Sachiyo Minegishi as chief financial officer, and promoted Jennifer Wellman from SVP of regulatory and quality to COO.
  • Research Triangle Park, NC-based G1 Therapeutics, a cancer drug developer, named Jack Bailey as its new CEO. He will replace Mark Velleca.
  • Cambridge, Mass.-based Rubius Therapeutics hired Jose “Pepe” Carmona as chief financial officer.
  • Cambridge, Mass.-based Nimbus Therapeutics promoted Abbas Kazimi to chief business officer. He previously had the title of VP of business development.
  • Cambridge, Mass. and New York-based Black Diamond Therapeutics named Robert Ingram its new chairman of the board. Brad Bolzon of Versant Ventures will give up that seat, but remain on the board.
  • Toronto-based Deep Genomics hired Ferdinand Massari as chief medical officer.
  • Cambridge, Mass.-based Thrive Earlier Detection added three new executives. Sam Asgarian was hired as chief medical officer, Frank Diehl is the new executive vice president of product solutions, and Dina Ciarimboli is the full-time chief legal officer.
  • Watertown, Mass.-based Tarveda Therapeutics, a cancer drug developer, promoted Brian Roberts to CEO from CFO.
  • Waltham, Mass.-based Xilio Therapeutics, the developer of tumor-selective immunotherapies for cancer, named Rachel Humphrey to its board of directors.
  • France-based Genfit, the NASH drug developer, cut 40 percent of its workforce.
Regulatory Action

Plymouth Meeting, Penn.-based Inovio said its pivotal clinical trial of a COVID-19 vaccine has been placed on partial clinical hold by the FDA. The agency put the hold in place because of questions about the company’s planned delivery device for the trial. The Cellectra2000 device, the company says, “provides a brief electrical pulse to reversibly open small pores in the local skin area cells resulting in more than a hundred-fold increase in product delivery providing dose sparing and consistency.” Inovio shares fell 28 percent on the setback.

GSK won FDA approval to market mepolizumab (Nucala) as a treatment for Hypereosinophilic Syndrome (HES), a disease in which patients produce too many eosinophils, a type of white blood cell. The drug is an antibody directed against IL-5.

Japan-based Shionogi won FDA clearance to market cefiderocol (Fetroja) for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by gram-negative bugs like acinetobacter.

CSL Behring won FDA clearance to market Haegarda, (C1 esterase inhibitor Subcutaneous [Human]) to prevent attacks of hereditary angioedema in patients age 6 and older.

Cambridge, Mass.-based Solid Biosciences said the FDA lifted the clinical hold on its gene therapy for Duchenne Muscular Dystrophy. The company said it answered questions that the agency submitted in July, about manufacturing, updated safety and efficacy data, and “direction on total viral load to be administered per patient.”

Brea, Calif.-based Beckman Coulter secured Emergency Use Authorization from the FDA for a fully automated test to detect IL-6 in blood or plasma of COVID-19 patients – a sign of a potentially dangerous cytokine storm in severely ill patients.

Franklin Lakes, NJ-based BD said it received a CE Mark in Europe to market a rapid point-of-care antigen test for COVID-19 that can deliver a result in 15 minutes. The test has been available in the US since July.

Sunnyvale, Calif.-based Cepheid won Emergency Use Authorization from the FDA for its Xpert Xpress that can test simultaneously for SARS-CoV-2, Flu A, Flu B, and RSV infections – which all can present with some similar symptoms. The 4-in-1 test is designed to run on Cepheid’s installed base of 26,000 machines worldwide, and can deliver a result in 36 minutes.

Deals

Norway-based Vaccibody, a neoantigen cancer vaccine developer, formed a partnership with Genentech. The little company stands to collect $200 million in upfront and near-term milestones.

Belgium-based Celyad Oncology said it formed a clinical collaboration with Merck to test Celyad’s non gene-edited allogeneic CAR-T cell therapy candidate in tandem with the PD-1 inhibitor pembrolizumab (Keytruda).

Stamford, Conn.-based Sema4 formed a collaboration with Janssen Pharmaceuticals to use genomic data and data analysis to stratify patients most likely to benefit in its cancer clinical trials.

Switzerland-based Covis Group agreed to acquire Waltham, Mass.-based AMAG Pharmaceuticals for $13.75 a share, or about $647 million.

Tweetworthy

At a U.S. House of Representatives committee hearing on Wednesday, Rep. Katie Porter grilled former Celgene CEO Mark Alles for the years of unjustified price increases for the cancer drug lenalidomide (Revlimid). This public flogging was sharp and succinct. She hit on the classic, and unresolved, core issue in biopharma – how are companies supposed to fairly balance the responsibility to shareholders with the responsibility to patients? (Porter didn’t even get to the part where Alles did a lousy job for shareholders, as he ran Celgene into the ground, sold it to Bristol-Myers Squibb, and then personally walked away with even more money in his pocket). (Video clip, 5:04)

Rep. Porter had more to say about greed on the second day of hearings. This whiteboard drawing from Rep. Porter is worth keeping in mind the next time you hear a pharma CEO pat himself on the back for his company’s heroics.

30
Sep
2020

COVID-19 Diagnostic Testing Needs To Be Open, Not Closed

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30 Sep 2020

Alex Dickinson, co-founder and executive chairman, ChromaCode

The U.S. already has the real-time PCR infrastructure to run tens of millions of tests per day. Why don’t we use that capacity?

Our consumer electronics companies are constantly marketing the newest one-touch, automatic machine. They make it sound so simple, so alluring, so irresistible. Think of our smartphones and watches.

That might partly explain the administration’s instant embrace of the Abbott ID NOW point-of-care machine for COVID-19 testing. FDA commissioner Dr. Stephen Hahn touted the box’s features and benefits – a 6.6-pound box, the size of a toaster, that could deliver accurate yes-no test results in 15 minutes — at a Rose Garden news conference back in March. President Trump even seemed to cradle it briefly.

In late March, when horrific images from overwhelmed New York hospitals were dominating television, this seemed like good news that people wanted to hear. The call for the fast and simple answer was on display again this week, as the Trump Administration announced plans to distribute 150 million rapid antigen tests.

If there is a consistent pattern to this Administration’s response, it has been to put faith in quick fixes instead of strategic long-range plans that play out over a period of months. We’ve seen the unfortunate results of this excessive faith in the latest shiny technology object.

Like many things about the COVID-19 pandemic, the truth about point-of-care testing machines is more complicated than their coolly modern façades indicate. Whether these rapid testing instruments are molecular tests that look for the SARS-CoV-2 virus’ signature genetic material, or antigen tests that detect specific proteins on the virus’ surface, there are accuracy trade-offs with the rapid point-of-care tests, when compared with traditional real-time PCR platforms. Multiple academic studies have shown higher false-negative rates than what Abbott has reported on its ID NOW platform.

The issue of test inaccuracy hasn’t received much attention, but it has gotten some notice. Recently, the Governor of Ohio, Republican Mike DeWine, received a positive result from a point-of-care machine that detects antigens. Subsequent RT-PCR testing thankfully showed that the previous point-of-care test was a false positive.

The reliability of these sleek point-of-care machines is not the only thing that should concern us. These are highly automated, closed systems. That sounds good at first glance to most people, because it implies simplicity, speed and consistency. The term “sample to answer” is the diagnostic industry equivalent of “plug and play.” What’s not to like?

Besides the problems with accuracy, these closed systems create capacity constraints.

Our increasing reliance on these closed systems is hampering our ability to ramp up national testing effort to the scale it needs to be. Recent reporting from Reuters assigns blame for the U.S. testing shortfall on these closed testing systems.

These companies operate on the razor and razor blade model. They sell the machine first, and then supply the proprietary consumable supplies such as chemical kits and plastic sample plates and pipettes needed to make it run. It’s similar in concept to the branded printer cartridges in use on your HP or Epson home printer.

The rapid point-of-care COVID-19 diagnostic testing companies – four major manufacturers – simply can’t manufacture enough consumable chemicals, sample plates and pipettes in their special kits to keep their instruments running at full capacity nationwide. This is the primary cause of testing backlogs. And it’s not just the “printer cartridges” that are in shortage – many of these companies can’t make enough of the “printers” themselves to meet demand.

These closed systems can be useful and convenient under normal circumstances. During a typical flu season, hospitals can quickly determine whether a few patients are suffering from the flu or a different respiratory illness and treat accordingly.

But a pandemic is not a normal circumstance. And while some experts have recently called for an increase of less accurate antigen tests to more quickly track and contain the virus — essentially throwing “everything but the kitchen sink” at the problem because the U.S. has struggled to generate a comprehensive national testing plan — there’s no evidence that these manufacturers can produce the instruments and consumables at the necessary scale.

For our country to reasonably manage this pandemic, we need much more than just the test results for a few dozen patients at a time delivered by a quick, easy-to-use black box.

These point-of-care machines do have a role to play, however. They can be invaluable tools for COVID-19 testing in specific environments, such as daily testing of caregivers at assisted living facilities. But as a nation, experts say we need to be doing millions of tests per day — the latest estimate by Harvard’s Global Health Institute is 4 million per day. The network of discrete closed systems cannot handle that kind of volume, nor is it flexible enough to scale up and down as testing needs change.

Fortunately, we already have an open-system network that we can harness to produce the amount of testing needed to safely reopen our economy: an installed base of “old-fashioned” real-time PCR machines.

Every big central lab, government lab, hospital lab and research lab in the country has at least one open-platform real-time PCR instrument. Different manufacturers make these instruments, but they all run in basically the same way, using the same chemical supplies.

These systems aren’t as quick to deliver results and require trained technicians to operate. But they can handle tremendous volumes of tests. These traditional RT-PCR machines can handle 10-100 times higher throughput than the point-of-care tests, and are able to generate >1,000 results per day per machine. In contrast to ID NOW, they are the gold standard of accuracy.

Certainly, open-platform PCR instruments are currently handling a significant portion of the testing. But right now, only labs that are CLIA certified by the federal government are allowed to handle diagnostic testing. That leaves out most academic labs and many, many commercial research labs that are run to exacting specifications, but are not technically CLIA certified. Add to that a large number of PCR instruments that run diagnostics for our pets. We love our pets, but I think most people would agree to delay those diagnoses to free up capacity for the urgent COVID-19 demand.

The federal government could, and should, use its influence to requisition these instruments for use in COVID-19 testing. The capacity exists – it just needs to be properly directed and mobilized. It’s not too late to swing into action.

At a low estimate, the U.S. has 30,000 open-platform PCR instruments. If each instrument is leveraged to run the 1,000 tests per day it can run, that would give us 30 million tests per day. Capacity could be stretched further through the use of robots, pooled testing or the application of data science.

This is a robust infrastructure that will better meet the testing demands this pandemic calls for. Testing at high volume will help us find our way back to something closer to normal until we have a widely distributed vaccine. 

The role for open systems is clear.

As Gary Kobinger, a Canadian researcher best known for his work on Ebola, argues in that same Reuters report that all diagnostics should be done on open platforms. “At one point there will be a new pathogen, and the company that makes the cassette that is controlling everything is not going to be able to supply you,” Kobinger said. “And this is where we are now, right?”

Right.

 

Alex Dickinson, PhD is the co-founder and executive chairman of ChromaCode. He is a life sciences executive with over 25 years of experience leading strategic initiatives that have transformed small companies and enabled large companies to penetrate new markets. Most recently, he was the Senior Vice President of Strategic Initiatives at Illumina, where his responsibilities included working with national governments and large institutions to develop precision medicine programs for healthcare systems.

28
Sep
2020

Small Molecules Against RNA Targets: Jennifer Petter on The Long Run

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28 Sep 2020

Today’s guest on The Long Run is Jennifer Petter.

She is the founder and chief scientific officer of Waltham, Massachusetts-based Arrakis Therapeutics.

Jennifer is a medicinal chemist who has spent her career thinking about how to make small molecules with all the classic Lipinski “Rule of 5” characteristics against protein targets.

Jennifer Petter, founder and chief scientific officer, Arrakis Therapeutics

Five years ago, when she was looking for a new entrepreneurial challenge, she attended a Gordon conference. She saw a couple scientific presentations from Matt Disney at Scripps and Kevin Weeks at UNC Chapel Hill that gave her an idea. Might it now be possible to make small molecules against RNA targets?

She was inspired to get going on building a new drug discovery platform at what we now call Arrakis Therapeutics.

Arrakis took this work up several notches this spring, through a new partnership with Roche. The big drugmaker, seeing the possibility for creating multiple small molecules against RNA targets, agreed to pay $190 million upfront to Arrakis to work together on making it happen. Arrakis also recently described its work in detail in its first peer-reviewed publication in ACS Chemical Biology.

Jennifer also used to identify as a man, and was known as Russ Petter. She came out publicly as transgendered in June 2018. CEO Mike Gilman wrote about it on the company blog.

In this conversation, we spent the first part talking about Jennifer’s early life and key steps in her career leading up to her current work at Arrakis. At the end, we talked about her gender transition and how she handled that in the workplace. I think my questions are a little awkward, but it’s OK because the situation was awkward for a lot of people. It’s old news, but I think Jennifer has some timeless thoughts on handling the situation with grace.

Now, please join me and Jennifer Petter on The Long Run.

23
Sep
2020

How Lunch with Bill Gates, Sr. Changed My Life

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23 Sep 2020

Thong Le, CEO, Accelerator Life Science Partners

“I’m gonna have the halibut and chips. And a medium vanilla milkshake. What about you, Thong?”

I looked up at my towering companion as he peered down at me with a gentle smile. I’m about 5-foot-8, and he was about 6-foot-7. I quickly scanned the menu board, then made my choice.

“You know, Mr. Gates, I think I’m going to have the exact same thing that you’re having.”

“Please, Thong, call me Bill. And lunch is on me.”  Unbeknownst to Mr. Gates (or to me for that matter), that first lunch meeting more than 20 years ago at Daly’s Drive-In, a burger joint in Seattle’s Eastlake neighborhood, would inspire me and alter the trajectory of my career.

Photo from Gates Notes.

As many know, Mr. Gates was a giant among giants. A tall and imposing figure, he made many lasting contributions to the communities that he so graciously served. He served our country during World War II, he established a prominent law firm (now known as K&L Gates), and he has given generously of his time and resources to help countless community organizations focused on global health, education, and the arts. His leadership at the Bill & Melinda Gates Foundation propelled the Foundation to tackle some of the world’s most pressing issues in global health and education, and to create better opportunities for the poor and vulnerable around the world.

Mr. Gates was also very forward-thinking when it came to the relationship between university research and its potential to catalyze progress. Shortly after the passage of the Bayh-Dole Act in 1980, he saw potential for the University of Washington to translate some of its research for the wider world. Not surprisingly, given his position in the community and his legal acumen, he played a seminal role in developing policies, initiatives, and a successful foundation dedicated to promoting and advancing technology commercialization in the region.

These accomplishments are substantial for any single individual, but they represent only a portion of the impact that Mr. Gates had on folks like me who were fortunate to cross his path. Beyond the highly visible ways he made an impact – like serving on Boards or leading fundraising campaigns – Mr. Gates also took a lot of time to meet with individuals like my younger self.

As generous as he was with his philanthropy, he was even more generous with his wisdom and counsel. He took an interest in hearing the stories behind an individual, and he went out of his way to open doors and inspire a spirit of selfless giving.

My story was one of the ones that seemed to have resonated with Mr. Gates. You see, I had no direct connection to him or to the many organizations that he was affiliated with. At the time, I was a young kid who had found the beginnings of a path to a better life. My parents had immigrated to this country from Vietnam at the end of the war while my mother was still pregnant with me. Upon arriving, my father was unable to find work to support the family, especially given his (then) limited grasp of the English language. He took jobs as a janitor and then as a television repairman in order to make ends meet. 

As time went on, my father continued to strengthen his English, and began taking courses at a local community college. That helped him to land a job as a social worker, where he worked for more than 30 years to support our family of six. While we had little materially, because of my father’s example, we possessed a commitment to hard work, perseverance, and education.

Those family commitments led me to excelling in school, and eventually attending Harvard where I developed an interest in science and business. Those interests led me to join a biotech-focused management consulting firm after college that gave me the tools to solve difficult business problems. I also threw my energies behind a start-up company that I co-founded, which taught me what it meant to sacrifice everything to build something new.

Unfortunately, not all sacrifices pay off, and I had to extract myself from that startup before I could see it develop as I hoped it might. I moved back to the West Coast from New England, pondering where the next season of my career might lie. I wanted to know where there might be opportunities to combine my passion for science and my experience for business. I wanted to know where I might be able to grow as a business leader while also impacting those around me. I wanted to know where my future might be.

With the help of a business colleague whom I met through my management consulting work, I was able to obtain the contact information for Mr. Gates. I reached out to him, hoping he’d be interested in helping someone like me.

At that lunch meeting, Mr. Gates listened carefully, and wisely counseled me to look past the hardships of my past and to look ahead to the future. He encouraged me to focus on the positive, and to not dwell on those that took advantage of me. He advised me to surround myself with people that were mission-driven and full of integrity. And he inspired me to consider possibilities that I might not have otherwise considered, especially local ones in a growing Seattle sector. Seeing that my mind was full of questions about “where” and “when”, Mr. Gates was able to provide a lens to focus my passions and experiences to the “here” and “now.”

Were it not for Mr. Gates, I never would have made the connections that ultimately led me to join the team at Washington Research Foundation (WRF), a non-profit organization that Mr. Gates co-founded to translate university research into the business world, and which plowed back its proceeds into supporting scholarship and more research in Washington-based research institutions.

I joined WRF’s investment team (known as WRF Capital) in June 2000 — a few months after our lunch at Daly’s. Over the next 14+ years, I was fortunate to work alongside a team of talented professionals at WRF to identify and invest in breakthrough technologies. By the time I decided to leave WRF to lead Accelerator Life Science Partners, WRF’s collective efforts — through intellectual property licensing, returns from successful start-up investments, and philanthropy — had returned more than $500 million to the University of Washington alone. WRF’s impact in the region continues to this day, and I’m proud to have contributed to WRF’s successes as an organization.

My father died about 10 years ago. Before he passed away, he shared with my brothers and sister the story of his life leading up to his decision to risk everything at the end of the Vietnam War to immigrate to this country. And he shared with us a Vietnamese proverb that essentially says it is our duty and privilege to do everything we can to ensure that the lives of those we care about are better than the ones we have. 

In the time that I knew him, Mr. Gates lived this philosophy out fully. Mr. Gates allowed me to stand upon his shoulders at a time when I needed it the most. He did so selflessly, without any expectation that doing so would benefit him in any way. It was only 90 minutes of his day in the spring of 2000. It didn’t cost him much. Yet that effort to inspire me and support his community in the Pacific Northwest made a very real impact.

And I know there are countless others whose stories are the same – stories about a giant of a man who did everything he could so that future generations are better off than the ones that came before.

 

Thong Q. Le is the President & CEO of Accelerator Life Science Partners, a venture firm that catalyzes the development and commercialization of breakthrough biotechnology innovations (for more information, please visit www.acceleratorlsp.com).

21
Sep
2020

What We Know About COVID-19, and What We Don’t

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21 Sep 2020

Alex Harding, MD.

He or she will have had fever and chills for the past few days, severe fatigue, muscle aches, and cough. They have no interest in food. They will have felt short of breath when doing the mildest of tasks, such as walking upstairs in their house.

They might have had some lightheadedness and may say that they feel chest pain or tightness—they place their hand over their breastbone as they say it—when they take a deep breath.

Since my internal medicine clinic at Massachusetts General Hospital (MGH) converted into a respiratory illness clinic at the beginning of March, I have seen around 100 patients who came to the hospital with these symptoms and later tested positive for COVID-19. Some might call this the classic presentation for mild to moderate COVID-19. But I’ve learned that there is no classic presentation for COVID-19.

More than anything else, what stands out to me is that this disease causes a tremendous variety of symptoms, with a vast range of severity.

Even more befuddling, close to half of infected people have no symptoms at all, while a significant share become critically ill, leading to mechanical ventilation, heart-lung bypass, and death. While severe disease disproportionately strikes the elderly, there are young, healthy people who develop critical illness, as well as elderly people in poor health who have no symptoms or only mild symptoms. So, while the symptoms I described are common for patients with COVID-19, they do not represent a norm.

There is no norm.

Another lesson I’ve learned is to respect COVID-19. The first patient I ever saw with the disease was a healthy man in his late 20s who walked into our temporary surge clinic in the emergency department’s ambulance bay at MGH in early March.

Although he said he was doing “OK,” his blood pressure was a bit low and I sent him to the emergency department for intravenous fluids. The next day, his condition rapidly deteriorated.  He was one of the first patients with COVID-19 admitted to our intensive care units, where he had acute respiratory distress syndrome and severely low blood oxygen levels.

Since that day, I’ve seen many patients who appeared fine at one moment and yet developed severe, even deadly, symptoms mere hours later.

COVID-19 can do strange things. Although it’s primarily seen as a respiratory illness, and it is transmitted via respiratory droplets and aerosols, there’s no question that when people get the infection, the virus can take on protean manifestations.

Perhaps the most well-known symptom is anosmia—loss of sense of smell. While plenty of viral respiratory infections can cause loss of taste and smell, what stands out about the anosmia seen in COVID-19 is that it often precedes other symptoms like nasal congestion that normally cause lost sense of smell in other infections. I have not yet read a convincing explanation for this phenomenon, but it can be a useful diagnostic finding and does not present a life-threatening danger to patients, so it is an odd symptom I am actually grateful for, because it can be helpful as part of a clinical diagnosis.

Unfortunately, not all of COVID-19’s oddities are so benign. Another feature of COVID-19 that has gotten a lot of attention is the risk of blood clots. Any severe infection will predispose patients to blood clots, but the frequency of clots in COVID-19 is striking, with over 25% of hospitalized patients experiencing a venous clot.

The cause of clots in COVID-19 is not fully understood, although it probably involves excessive inflammatory signaling that stimulates blood to clot. Treatment is controversial, with some doctors advocating for high doses of blood thinners in hospitalized patients to prevent clots from forming, although such an aggressive approach has not been studied scientifically to assess for safety and efficacy.

It is also clear that COVID-19 can affect the heart in multiple ways. Although many patients do mention chest pain or tightness early in the disease course, I do not think that most of those patients have a problem with their heart. Nevertheless, there is a minority of patients with COVID-19 that do develop true heart problems, including heart attacks and inflammation of the heart muscle (myocarditis). Unfortunately (recurring theme here), the mechanism of heart injury is still uncertain but probably is related to severe systemic inflammation and perhaps direct infection of heart tissue.

There is a long list of other organs that can be affected in COVID-19. The kidney, liver, and central nervous system have gotten a lot of attention. A colleague of mine saw a patient with thyroid inflammation leading to severely low thyroid function, which was probably caused by a COVID-19 infection. It’s still unclear whether these diverse effects are caused by direct infection by COVID-19, but my suspicion is that generalized inflammation in response to the virus, rather than local infection, is the primary driver of these effects.

Other effects of COVID-19 have been overhyped or exaggerated.

Remember COVID toes? Back in April and May, it was all the rage for people to call their doctors because they had noticed spots or bumps on their toes. And it is possible that COVID-19 does rarely cause lesions on the toes, perhaps from the deposition of antibodies and other immune products in small blood vessels. But among patients who actually have COVID-19 who have come to my clinic, very, very few have had any toe lesions that could be attributed to the infection.

Instead, it’s likely that with the chilly weather here in the Northeast in April and early May, while people were staying home and more likely to be barefoot, they developed sores on their toes related to a condition called chilblains or pernio that causes sores on cold toes—completely unrelated to COVID-19 except in the sense that during the lockdown people were less likely to be wearing shoes and socks. As the weather warmed up, questions about COVID toes have gone down.

Another topic that has been exaggerated is the risk of long-term lung fibrosis after COVID-19 infection. In my role as a venture capitalist, I have seen several companies pitching new treatments to block fibrosis in patients who had recovered from COVID-19 infections. While it is too early to say anything about the long-term effects of COVID-19 with certainty, lung fibrosis does not yet appear to be a major issue. In general, it is quite unusual for acute lung infections to result in long-term lung fibrosis of any consequence for patients. Some COVID-19 patients do have some scarring in their lungs that can be seen on CT scans, but it is unlikely that this amount of scarring will significantly impair lung function.

There has also been a lot of commentary about “silent hypoxia,” where people with COVID-19 are awake and alert and yet have very low oxygen levels in their blood. This is a very real phenomenon, one that I have seen with my own eyes several times. But it is not a mysterious or magical effect specific to COVID-19. It’s basic physiology.

The sensation of shortness of breath is mainly driven by having too much carbon dioxide in the blood, not by too little oxygen. When our ancestors chased after wooly mammoths looking for a bite to eat, a fall in blood oxygen was always accompanied by a rise in carbon dioxide, so this signaling system worked out. But when there is an infection in the lungs, the oxygen level drops without a proportional rise in carbon dioxide. So, it is no surprise that some people with COVID-19 can “look OK” even when their oxygen level is dangerously low. Doctors need to be aware of this phenomenon and warn our patients to watch their symptoms very closely.

Lastly, I want to comment on patients who have symptoms for months after their initial infection with COVID-19. Some of these patients have labeled themselves ‘long-haulers.’ Very little is known about these long-term effects, but I have seen several patients with months of symptoms. The most common symptoms include severe, fluctuating fatigue, muscle aches, persistent fevers, and effects on the autonomic nervous system, which controls basic bodily functions like heart rate and blood pressure. I have seen patients with a heart rate over 110 beats per minute for weeks straight.

These symptoms may be similar to another poorly-understood condition called chronic fatigue syndrome, which can occur after other viral illnesses. There is a long-standing medical debate about whether chronic fatigue syndrome is “real.” Having seen COVID long-haulers myself, I can tell you the symptoms are very real. We need to understand what’s causing them so that we can make people better.

Over the past six months, we have all gotten way too familiar with COVID-19. Armchair experts have sprouted up all over. Hopefully, my first-hand perspective is useful, albeit anecdotal. If there is one message I would like you to take away, it’s how much we still do not know about COVID-19, especially its long-term effects.

As with so much else, more high-quality research is needed.

 

Alex Harding is an internal medicine physician at Massachusetts General Hospital who sees patients in an urgent care clinic. He is also senior director of business development at two Atlas Venture-backed startup companies. Alex was previously a senior associate at Atlas Venture.

17
Sep
2020

A Tribute to Bill Sr.

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17 Sep 2020

Luke Timmerman, founder & editor, Timmerman Report

Before diving into a big week in biotech, let’s pause to think about the life of a tremendous human being we can learn from.

RIP

Bill Gates Sr. died at age 94. He had Alzheimer’s.

The father of one of the world’s richest men was a prominent lawyer, and deeply engaged civic-minded figure in my hometown of Seattle.

The older Bill loomed large over young Bill. (In more ways than one — Bill Sr. was tall).

I didn’t personally get to know Bill Sr. But as a kid reporter at The Seattle Times, I covered some of his public activities. One memory is of Bill Sr.’s determined, but quixotic, effort to fix the regressive and unstable Washington state tax system. We have no income tax, and rely heavily on sales tax, which tends to drop in recessions.

During the early 2000s, Bill Sr. chaired a citizen commission that investigated alternatives. The committee concluded the state needed more stable financing mechanisms, like an income tax, to support things like K-12 and university education and social services. He was for it, even though that meant increasing taxes on wealthy people like him and his son.

That was news. But what I didn’t fully appreciate was that the position reflected Bill Sr.’s appreciation for the balance between individuals and communities.

To test people’s assumptions about wealth, he liked to ask a rhetorical question.

“What if my son had been born in Bangladesh?”

The answer, for those willing to stop and think, is that William H. Gates III never would have had a chance to start anything like Microsoft, usher in the computer age, or create the world’s richest philanthropy to advance global health, development and education.

Bill Sr. knew that his determined and brilliant son achieved such things because of a constellation of factors way beyond any individual.

For starters, young Bill grew up in Seattle. It was, and still is, a safe and beautiful community filled with smart, imaginative and entrepreneurial people. Young Bill had the advantage of growing up in a loving family, with accomplished parents that expected a lot. For a while, the family sent him to an excellent public school (View Ridge Elementary). The family later sent the boy to an excellent private school, Lakeside.

All around young Bill there were dedicated and caring teachers. All around, there were smart and caring parents of other kids watching out for everyone.

During adolescence, there was the fateful opportunity to meet a bright and nerdy young classmate named Paul Allen. And crucially, in a part of the story many people forget or never hear at all, there was a treasure of a public university down the street – the University of Washington.

This outstanding public university had the resources to acquire some of the early mainframe computers long before teenage Bill’s imagination started firing about what to do with such things. The rebellious youngster and his friend Paul snuck in there and cadged some computer time when the grad students and professors weren’t paying much attention. The plucky youngsters were thrilled with possibilities.  

The point is this. The environment we choose to create for each other, and for future generations, is crucial to our success. Bill Gates Sr. understood this, and reminded his son of this unavoidable fact, especially when the son may have leaned toward self-centered arrogance. William H. Gates III became unimaginably wealthy, through a combination of talent, good timing, and luck.

But above all, it was because this kind of success was possible in the United States.

We would be better off as a country if we could set aside the popular myth of the rugged individual and self-made man. With a little more humility and empathy, we could begin again to unify and do more to uplift everyone else around us.

That would be a fine way to honor the legacy of William Gates Sr.

Vaccine Transparency

Moderna and Pfizer – the two front-runners in the COVID-19 mRNA vaccine quest – responded to the pressure from academia and industry observers by opening up their Phase III clinical trial protocol. Moderna went first with its 135-page protocol, putting pressure on everyone else. Within hours, it was followed by Pfizer. Here we can see some of the best-case scenarios for early stopping of trials that could lead to the fastest answer, in more context.

Eric Topol, a cardiologist at The Scripps Research Institute who has pushed for greater clinical trial transparency, applauded the move. Then he highlighted some key aspects of their design.

In sum, even though these are large randomized trials, the absolute numbers of infections in each arm of the study could be quite small. We knew that already, but now we can see the actual numbers. As biotech investor Brad Loncar said, referring to the first interim analysis on the Pfizer protocol, which allows for early stopping based on compelling efficacy based on 32 infections (6 in the vaccine group, and 26 in the placebo group):

    

A reasonable person might say ‘Hey, maybe we should enroll some more people and gather just a little more longer-term safety data.’ That’s open to debate.

While we wait for clarity, it helps to be as open as possible.

AstraZeneca, by contrast, has fumbled its chance to build trust at this crucial moment. First, CEO Pascal Soriot divulged key details about the adverse event that halted its trial to a private audience of investors convened by JP Morgan, as reported by STAT. That was a terrible mistake, feeding the most critical perceptions of the pharma industry. Then, when pressed by reporters to elaborate on the adverse event and whether it might be vaccine-related or not, the answer remained elusive.

When CNN reported on an internal AZ safety report, AZ responded by saying the report “contains inaccuracies,” and is “based on preliminary findings” but didn’t point to any specific inaccuracies, and then declined further comment. That’s weak.

Is it fair for outsiders to jump to quick conclusions about the fate of a vaccine and entire trial based on a single patient? No. But crawling into a business-as-usual “trust us” defensive crouch won’t cut it in this environment.

While we’re at it, why has your trial resumed enrollment in the UK, but not in the US?

AZ, do better.

Crisis at the CDC

The director of the CDC, Robert Redfield, has failed to rise to the occasion in this pandemic, as STAT’s Helen Branswell reported the morning of Sept. 16. But that day, Redfield told the truth in front of a Congressional committee. Redfield said that a mask is a more valuable tool against the pandemic than a vaccine at the moment. He also had to be the bearer of bad news, saying it will take until later in 2021 to widely distribute COVID-19 vaccines across America.

Quickly, Redfield got a scolding phone call from the President.

The President corrected his own CDC director, saying that Redfield was spreading “incorrect information.”

No, he wasn’t. Redfield said something true about masks to Congress, under oath. Then he was forced to walk it back and apologize because it contradicted what the boss is saying on the campaign trail.

A day later, we find out, thanks to the New York Times, that the terribly irresponsible guidance from CDC last month, which said asymptomatic people who have been exposed to COVID-19 don’t need to bother getting tested posted on the CDC website, but written by higher-ups at the White House coronavirus task force and Health and Human Services. Scientists at the CDC strongly objected, but were overruled.

This revelation comes after we learned that political operators have been interfering with the CDC’s ability to communicate to scientists through its trusted Morbidity and Mortality Weekly Report (MMWR).

Meanwhile, what are schools and universities and businesses supposed to do?

Why can’t we get unvarnished science-based advice from the CDC?

We have to do better.

Therapeutics

Eli Lilly reported some good news from a randomized, placebo-controlled, 452-patient Phase II study of its therapeutic neutralizing antibody for COVID-19. The drug was developed in collaboration with Abcellera and with testing help from the National Institute for Allergy and Infectious Diseases Vaccine Research Center. Newly diagnosed patients ended up in the hospital 1.7 percent of the time after getting the antibody drug, compared with 6 percent in the placebo group – a 72 percent reduction in relative risk. No serious adverse events were reported on the drug. The drug was tested at three dose levels, and only the middle dose – a whopping 2,800 milligrams – met the pre-specified primary endpoint of reduction in viral load from baseline to Day 11. The dose is very high, so that creates an extra manufacturing burden to serve large numbers of patients, but still, this is a demonstration of what can be achieved clinically by hitting the spike protein with a neutralizing antibody. (These Lilly results, by the way, were much better than with its JAK inhibitor baricitinib for reducing cytokine storms, which shaved off a median of 1 day off recovery time.)

Science
  • Slight Reduction in SARS-CoV-2 Viral Load Due to Masking Results in Significant Reduction in Transmission With Widespread Implementation. MedRxiv. Sept. 14. (Ashish Goyal et al)
  • Molecular Architecture of the SARS-CoV-2 Virus. Cell. Sept. 14. (Hangping Yao et al)
  • SARS-CoV-2 in the Kidney. Bystander or Culprit? Nature Reviews Nephrology. Sept. 14. (Anitha Vijayan et al)
  • Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. Cell. Sept. 15. (Leonid Yurkovetskiy et al)
  • Artificial Intelligence, Drug Repurposing and Peer Review. Nature Biotechnology. Sept. 14. (Jeremy Levin et al)
Epidemiology
  • Clustering and Superspreading Potential of SARS-CoV-2 in Hong Kong. Nature Medicine. Sept. 17. (Dillon Adam et al)
  • Children in Utah got COVID-19 in child-care facilities, and transmitted it to others, resulting in one parent being hospitalized. CDC Morbidity and Mortality Weekly Report. Sept. 11. (Adriana Lopez et al)
  • Characteristics of COVID-19 in Homeless Shelters. Annals of Internal Medicine. Sept. 15. (Julia Rogers et al)
Perspectives
  • Stop Expecting Life to Go Back to Normal Next Year. NYT. Sept. 15. (Aaron Carroll)
Building Trust
  • A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older. Full 135-page protocol. (Moderna Inc.)
  • Moderna Shares the Blueprint for its Coronavirus Vaccine Trial. NYT. Sept. 17. (Denise Grady and Katie Thomas)
  • Emergency Use Authorization of Medical Products During the COVID-19 Pandemic, Including a Look Ahead a Possible EUA of a COVID-19 Vaccine. (Preventing Epidemics).
  • Heidi Larson: Shifting the Conversation About Vaccine Confidence. The Lancet. Sept. 10. (Pamela Das)
  • Zeke Emanuel: US Government Must Rebuild Trust in the FDA. Yahoo. Sept. 15. (Brian Sozzi)
Eroding Trust
Drug Pricing
  • Executive Order on Lowering Drug Prices by Putting America First. Sept. 13. (gov)
  • Trump Unveils Plan to Slash Drug Costs Tied to What’s Paid Abroad. Politico. Sept. 13. (Sarah Owermohle)
  • America, the Engine of Biomedical Discovery, Should Be Trump’s ‘Most Favored Nation.’ Timmerman Report. Sept. 15. (Tom Culman)
Confronting Racial Inequities
An Exceptional Country, But With Failed Leadership
  • Suboptimal US Response to COVID-19 Despite Robust Capabilities and Resources. JAMA. Sept. 16. (Jennifer Nuzzo et al)
  • Bill Gates Slams ‘Shocking’ US Response to the COVID-19 Pandemic. STAT. Sept. 14. (Helen Branswell)
  • Scientific American, for first time in 175 years, Endorses a Candidate for President. Joe Biden. October issue. (Scientific American Editors).
Deals

Gilead Sciences agreed to pay $21 billion, or $88 a share, to acquire Immunomedics, the developer of a recently FDA approved antibody drug conjugate against Trop-2, and indicated for triple-negative breast cancer. The price was more than double what Immunomedics was trading at prior to the proposed acquisition.

Elsewhere in the world of antibody-drug conjugates, Merck and Seattle Genetics agreed to a big deal. Merck agreed to co-develop SeaGen’s ladiratuzumab vedotin, an ADC targeting LIV-1, currently in Phase II clinical trials for breast cancer and other solid tumors. Merck is paying $600 million upfront in cash and is making a $1 billion equity investment by buying 5 million SeaGen shares at $200 apiece. In a separate deal, SeaGen provided Merck a license to sell the HER-2 directed small molecule drug tucatinib (Tukysa) in Asia, the Middle East, Latin America and other regions outside the US, Canada and Europe. SeaGen pocketed $125 million upfront for that license.

Moderna and Vertex agreed to work together on using mRNA and lipid nanoparticle delivery technologies to make gene-edited therapies in lung cells for cystic fibrosis. Moderna is getting $75 million upfront.

San Diego-based Illumina spun out Grail to use next-gen sequencing for early cancer detection, and apparently is now looking into acquiring the company, which has filed paperwork to go public. Bloomberg News reported on the rumored transaction. Valuation for Grail could reportedly exceed the $6 billion – which prompted a selloff of Illumina shares.

Germany-based Boehringer Ingelheim and New York-based Click Therapeutics agreed to work on a prescription digital therapeutic for schizophrenia. The upfront to Click wasn’t disclosed, but total deal value with milestones is $500 million.

Irvine, Calif.-based Novus Therapeutics completed a reverse merger, acquiring privately held Anelixis Therapeutics, the developer of an anti-CD40L directed antibody to tamp down excessive immune reactions in organ transplant settings, autoimmunity, and for neurodegeneration. In connection with the merger, investors led by BVF Partners, and including Cormorant Asset Management, Ecor1 Capital, Logos Capital, Fidelity Management and Research Company, put in $108 million. DA Gros will be the CEO of the newly combined company.

Cambridge, Mass.-based Obsidian Therapeutics said its partner, Bristol-Myers Squibb, opted in to develop a cell therapy designed to provide controlled expression of CD40L. It’s the first opt-in since the partnership was announced in 2019.

Financings

Waltham, Mass.-based Dyne Therapeutics, the developer of treatments for muscle diseases, raised $233 million in an IPO priced at $19 a share.

Seattle-based Athira Pharma, an Alzheimer’s drug developer, raised $204 million in an IPO at $17 a share.

Menlo Park, Calif.-based Synthekine raised $82 million in a Series A financing co-led by Canaan Partners, Samsara BioCapital and The Column Group. The company is seeking to fine-tune cytokine therapies for cancer and autoimmunity.

Somerville, Mass.-based Finch Therapeutics, the developer of oral microbiome-based therapies, raised $90 million in a Series D financing.  

Questa Capital Management, a venture growth equity firm, closed on a $348 million fund to invest in healthcare services, technology and medical devices.

San Francisco-based Graphite Bio raised $45 million in a Series A financing from Versant Ventures and Samsara BioCapital. The company is seeking to develop a more efficient gene editing platform, starting with sickle cell disease. (See TR coverage, Sept. 16).

San Diego-based Escient Pharmaceuticals raised $77.5 million in a Series B financing to develop Mas-related G-Protein Coupled Receptor targeting drugs. Sanofi Ventures and Cowen Healthcare Investments co-led.

Germany-based BioNTech received a 375 million Euro grant from the German government to develop vaccines against SARS-CoV-2.

South San Francisco-based Attralus raised a $25 million Series A round led by venBio. The company is developing technology to better diagnose and treat various forms of amyloidosis. (See TR coverage)

New York and Amsterdam-based Neogene Therapeutics raised $110 million in a Series A financing to develop neoantigen-based cell therapies against solid tumors. EcoR1 Capital, Jeito Capital and Syncona led the financing.

Biogen said it plans to invest $250 million over the next 20 years to eliminate its use of fossil fuels, and to support research at Harvard and MIT on reducing air pollution. As a guy who’s been literally cooped up in the house nonstop since Sept. 10 because of Seattle’s horrific smoky air – AQI scores consistently between 200-300 – I’m hoping other companies follow this lead. For the sake of the planet.  

Data That Mattered

Pasadena, Calif.-based Arrowhead Pharmaceuticals reported positive interim results from a Phase II study that showed its RNAi treatment for liver disease associated with alpha-1 antitrypsin deficiency (AATD). Patients on the treatment saw significant reductions in a mutant protein, and reduced circulating enzymes that are a sign of liver damage.

Radnor, Penn.-based Marinus Pharmaceuticals said it passed a Phase III clinical trial for CDKL5 deficiency, a rare genetic form of epilepsy. Patients who got the company’s experimental drug, ganaxolone, showed a significant 32.2 percent median reduction in 28-day major motor seizure frequency, compared to a 4.0 percent reduction for those receiving the placebo. The company said it plans to seek FDA approval in mid-2021. Separately, Marinus announced it won a $21 million BARDA contract to develop IV ganaxolone for Status Epilepticus caused by nerve agent exposure.

Cambridge, Mass.-based Voyager Therapeutics and San Diego-based Neurocrine Biosciences presented three-year follow-up data on a single-shot gene therapy for Parkinson’s that showed sustained benefits in motor function. The treatment showed improvement for 14 of 15 patients at the 3-year analysis.

Regulatory Action

Roche won FDA approval for a more sensitive cytology test to detect high-risk forms of human papillomavirus. This will help prevent cervical cancer.

Manufacturing in the 21st Century

Takeda Pharmaceuticals opened a 24,000 square foot cell therapy manufacturing center at its R&D headquarters in Boston.

Personnel File
  • Third Rock Ventures named three new venture partners. They are Lorence Kim, the former CFO of Moderna; David Kaufman, the former chief medical officer of the Bill & Melinda Gates Medical Research Institute; and Andrea van Elsas, the former chief scientific officer of Aduro Biotech.
  • Matthew Roden joined MPM Capital as an executive partner. He comes from Bristol Myers Squibb.
  • San Francisco-based Unity Biotechnology cut its workforce by 30 percent to extend its cash runway into mid-2022.
  • South San Francisco-based Tizona Therapeutics, a cancer drug developer, promoted Christine O’Brien to be its new CEO. She was previously COO.
  • Philadelphia-based Century Therapeutics hired Michael Diem as chief business officer.
  • Cambridge, Mass.-based Obsidian Therapeutics, a company developing controllable cell and gene therapies, hired Jan ter Meulen as chief scientific officer.
  • Chicago-based AbbVie is preparing to bring employees back to in-person work. This is happening even though Illinois has recorded the sixth-highest number of cases among states in the US, and the number of new cases reported each day has remained steady at around 2,000 per day in September. Several employees told CNBC they are feeling pressured to come back, and unsafe about doing so. What could possibly go wrong?
  • Barbara Ryan and Matthew Szot joined the board of Sarasota, Florida-based INVO Bioscience, a fertility company.
  • Julie Carretero was hired as chief people officer at Cambridge, Mass.-based Evelo Biosciences.
  • South San Francisco-based Veracyte, the molecular diagnostics company, said it promoted Richard Kloos to executive medical director.
  • San Diego-based Viracta Therapeutics named Roger Pomerantz, the former CEO of Seres Therapeutics, as its chairman of the board.
  • Cambridge, Mass.-based EQRx hired 4 new executives. Rona Anhalt is the new chief people officer; Christian Antoni is chief development officer; Eric Hedrick, chief physician executive; and Daniel Hoey is the new chief of technical operations. (See TR coverage of the company’s founding strategy, January 2020).
  • Cambridge, Mass.-based Voyager Therapeutics named Michelle Quinn Smith chief human resources officer.
  • Watertown, Mass.-based Forma Therapeutics hired Fitzroy Dawkins as vice president, clinical development and Ruth du Moulin as vice president, medical affairs.
15
Sep
2020

America, the Engine of Biomedical Discovery, Should Be Trump’s ‘Most Favored Nation’

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15 Sep 2020

Tom Culman, senior research assistant, RA Capital

Imagine if John F. Kennedy had stepped to the podium at Rice University on Sept. 12, 1962 and said:

“We choose to go to the moon. We don’t know how to do it, but we’ll pay what seems like a fair price for one rocket — something like what the Soviets are paying their people.” 

That wouldn’t inspire anyone. It certainly wouldn’t have motivated the NASA contractors charged with delivering on the audacious vision of putting a man on the moon and returning him home safely. 

Winning the Space Race took a miraculous combination of science, ingenuity, and will. Victorious, our engineers were deemed worthy of substantial reward. 

As JFK actually said that day in Houston in 1962: “We must pay what needs to be paid.”

President John F. Kennedy views a mock-up of an Apollo command module during a tour of spacecraft displays at a NASA facility in Houston, Sept. 12, 1962. Public domain photo by Cecil Stoughton. White House Photographs. John F. Kennedy Presidential Library and Museum, Boston

President Trump’s “Most Favored Nations” drug pricing executive order, signed over the weekend and announced on Twitter, reflects a very different mindset in how America rewards innovation. 

The executive order would limit what Medicare would pay for drugs to the prices paid by other developed nations. Instead of “paying what needs to be paid,” to spur the entrepreneurial spirit necessary to create new drugs that help people, the President’s order seeks to put a lid on the rewards for this kind of life-saving innovation. This order undermines what should be a source of national pride and unity: the American innovation that drives the engine of biomedical progress around the world. 

While it’s true that out-of-pocket costs to individuals must be reduced (or eliminated), these patient-level costs should not be confused with our society’s investment in curing cancer, ameliorating chronic conditions like diabetes, or tackling COVID-19 and future pandemics — collective efforts just as grand as reaching the moon. 

At the beginning of the Space Race, NASA hardly knew how to make a multi-stage rocket, let alone what it would take to put a person inside it and send it into space. In the end it took not one, but six Saturn V rockets as well as dozens of prototypes, about $283 billion in today’s money, and the lives of three astronauts for us to reach the moon in July 1969. 

Contractors, like Boeing and Velcro, made healthy profits in the short and long term, and their discoveries led to the development of countless technologies. If we had asked our scientists and industries to launch such ambitious initiatives without providing the necessary incentives for them to do so, the U.S. may never have reached orbit and we‘d be living in a different world. 

Joe Biden calls the quest to cure cancer a “moonshot.” Why do some of us think making groundbreaking medical discoveries will be easier than landing on the moon — or worth any less?

The Apollo program was not always a point of national pride. Polling from the time indicates that Americans felt the U.S. was overspending on the Space Race, with NASA as the top choice for budget cuts (ahead of funding for the Vietnam War). Even into the 1990s, when NASA budgets had already shrunk as a percentage of the federal budget, critics on Capitol Hill fired off sound bites like “Taxpayer dollars are being flushed into a dark hole in space!” It took decades for sour feelings on space exploration to shift in a positive direction.

More recently, a 2019 Gallup report — 50 years after the Apollo moon landing — suggests that technological advancement was enough to sway public opinion on whether NASA’s budget was “worth it.” 

Just after Apollo, things like personal computers and satellite communication felt unobtainable outside the context of NASA and other cutting-edge institutions. The value of society’s investment didn’t become clear until these products became available to the public and prices dropped.

In a similar way, drugs become more available when their patents expire and competition renders them affordable for the rest of time. But instead of the romantic gratitude that surrounds NASA, a few well publicized incidents of price fixing and patent abuse leading to higher costs paint the biotech industry — specifically “Big Pharma” — as greedy bad guys, making it the least-liked industry in America. In truth, pharmaceutical companies only make about a 10-20% profit margin because, like rockets, many drugs are going to fail before a company finds one that works.

The difference between investing in space exploration and investing in the biotech industry is about who bears the cost: society as a whole or people as individuals. Nobody went bankrupt when our country went to the moon. Nobody fell into “moon debt.” That’s because citizens didn’t pay a penny out of pocket for the Apollo program; instead, the funds came from a conscientious allocation of tax dollars. Same goes for the only industry to rival healthcare in federal spending today: the military. 

The average American — especially the financially unstable, uninsured or underinsured — doesn’t care much about the list prices of most drugs, just like we don’t care much about what a Saturn V rocket or a Sherman tank costs. As individuals, we care most about how much gets drained out of our checking account.

Most proposals to control drug prices — like The Most Favored Nations Order — would either stymie innovation or fail to deliver the lower prices being promised. Instead of linking US drug prices to those set by other countries, current and future drug costs can be managed by ensuring that all patents expire without undue delay and drugs go generic immediately following a reasonable period of profit.

The key to preserving biotech innovation while protecting individuals from unfair costs lies in making sure every American is adequately insured with reasonable (or zero) out-of-pocket costs. Doing so would eliminate the possibility of medical debt — a failure of the system that devastates individuals and costs all of society when it drives people to avoid appropriate care until they are too far gone.

We as a nation can get to a place where people don’t have to resort to such desperate measures. And when people get the appropriate care, without the fear of going broke, maybe then we’ll be able to take pride in the achievements of our pharmaceutical companies instead of shaming an entire community of scientists and innovators for efforts that save lives.

Disclosure: RA Capital is a registered investment adviser. This material is not intended, and should not be construed as, investment advice or recommendation to invest in any security. Likewise, this material is not intended as a solicitation to invest in any RA Capital product or service.
10
Sep
2020

Industry and Academia Take a Stand for Science

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10 Sep 2020

Luke Timmerman, founder & editor, Timmerman Report

Science is under attack. The FDA and the CDC have seen their credibility tarnished, largely because of the relentless pressure, and lies, of certain political leaders.

The pharmaceutical industry, built on a bedrock of science, knows darn well that the whole business will come crumbling down if the world continues indulging in this bottomless cynicism and nihilism that says everything is bullshit and lies or some conspiracy concocted by evildoers on the Other Team.

It’s one thing to ignore the political sturm und drang in election season if you think it’s just a passing thunderstorm, and everything will revert to normal. But that’s not happening in an environment this poisonous.

A vaccine that people don’t believe in, and refuse to take, is a nightmare scenario we can’t allow to happen. Polls are showing serious slippage in public confidence in the vaccine effort.

If the President can run over an honest scientific review like a Mack truck, and the public were to see such a catastrophe with their own eyes, then the pharmaceutical industry itself could slide back in public perception to where it was 100 years ago – nothing but a snake oil business. The entire scientific enterprise – government, academia and industry – could be viewed as little more than tools of gutter politics.

Seeing the potential danger ahead, nine leading vaccine companies banded together and issued a statement saying they won’t submit any applications to regulators seeking approval for a COVID-19 vaccine candidate until they are confident they have the delivered the goods on safety and efficacy. No cutting corners.

That means no cutting corners, even if the President of the United States demands the FDA wave through a half-baked investigational data set to score some political points at the last minute before Election Day.

The whole industry should be proud to see the CEOs of these nine companies — AstraZeneca, BioNTech, GSK, Johnson & Johnson, Merck, Moderna, Novavax, Pfizer, and Sanofi — take this stand. (Full statement).

The test will be following through on the pledge. Everyone who evaluates clinical trials knows there are shades of gray involved and plenty of room for debate on what counts as “enough data” or “convincing data.” The urgency is as real as it gets, and there’s no time for nitpicky academic debates. We need to get a point where the evidence is truly convincing to people who know what they’re talking about – experts in virology, immunology and epidemiology – before we roll out the vaccine at scale.  

Academia has a role to play here, too, in defense of scientific thinking and science-based policy.

The good news is we saw people with good faith standing up for what’s right. More than 100 members of the Stanford faculty – including people who know what they’re talking about in microbiology, immunology and infectious disease research – signed an open letter chastising their former Stanford colleague and current Hoover Institution senior fellow Scott Atlas.

Atlas, a radiologist by training with no qualifications in infectious disease, has apparently gained the President’s ear by undercutting some of the best science-based recommendations we have in this pandemic.

This is a full letter worth reading. See it posted on the NYT.

Lastly, for those looking for a timely multi-disciplinary synthesis of where things are with the science of SARS-CoV-2, the extent of the outbreak, and updates on the response, I encourage you to take at least 30 minutes, and preferably the entire hour, to listen to Anthony Fauci’s appearance this week at Harvard Medical School’s Grand Rounds lecture.

Anthony Fauci, director, National Institute of Allergy and Infectious Diseases

In a world filled with sound bytes and tweets, which often degrades, muddies, and warps the things that people try to say, it’s refreshing to turn off the distractions and just listen for a solid hour to a real infectious disease expert speaking humbly, and in plain English, about where things stand.

(Watch Dr. Fauci’s slide presentation here).

Now synthesize some of the other main happenings of the week in biotech.

Vaccines

AstraZeneca paused the Phase III clinical development of its COVID-19 vaccine candidate after a volunteer in a study, a woman in the UK, came down with transverse myelitis, a rare spinal inflammatory disorder. The Data Safety Monitoring Board is looking at the data to see whether it’s safe to continue the study. There was an extraordinary burst of energy and commentary online about this single adverse event, which may or may not be an important story at all. It’s all of a piece with the shoot-first-ask-questions-later modus operandi of the social web in 2020.

Epidemiology

The death rate among African Americans with COVID-19 increased in August, while the death rate for white population slightly declined, according to data analyzed by the Color of Coronavirus project. Translation: the disparity was bad before, and it’s getting worse. (The Guardian).

Science
  • Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. The Lancet. Sept. 4. (Denis Logunov et al)
  • A Closer Look at the Bradykinin Hypothesis. Medium. Aug. 31. (Thomas Smith)
  • Coronavirus Infections. More than Just the Common Cold. JAMA. Jan. 23. (Catherine Paules, Hilary Marston & Anthony Fauci).
  • Emerging Pandemic Diseases: How We Got to COVID-19. Cell. Aug. 15. (David Morens and Anthony Fauci)
  • The Dynamic Changes in Cytokine Responses in COVID-19: A Snapshot of the Current State of Knowledge. Nature Immunology. Aug. 27. (Maja Buszko et al)
Our Fragile Political Moment
  • Public Trust in the CDC, Fauci, and Other Top Health Officials is Evaporating, Poll Finds. STAT. Sept. 10. (Nicholas Florko) Poll from the Kaiser Family Foundation, conducted Aug. 28-Sept. 3, 2020.
  • Even Big Pharma is Turning on Trump. NYT. Sept. 10. (Michelle Cottle)
  • Once Again, US at Pandemic Crossroads. Politico. Sept. 7. (Joanne Kenen)
Science Features
  • Profile of Young Epidemiologist Caitlin Rivers, Bridging the Gap of Science and Politics. Science. Sept. 10. (Kelly Servick)
  • Actual Expert Too Boring for TV. The Onion. May 4, 2005.
  • For Long-Haulers, COVID-19 Takes a Toll on the Mind as Well as Body. NYT. Sept. 7. (Emma Goldberg)
  • It Will Take More Than a Vaccine To Beat COVID-19. The New Yorker. Sept. 8. (Dhruv Khullar)
Financings

Salt Lake City-based Recursion raised $239 million in a Series D financing to advance its work on technology-enabled drug discovery (with AI). See my coverage of the financing, and a strategic collaboration to develop drugs for fibrotic diseases with Bayer.

Cambridge, Mass.-based Korro Bio raised $91.5 million in a Series A financing. The idea is to use single-base RNA editing to make new medicines. Wu Capital led, with participation from current investors, Atlas Venture and New Enterprise Associates.

Cambridge, Mass.-based Casma Therapeutics raised a $50 million Series B financing, led by The Column Group. The company is seeking to build on new learnings about autophagy. The money is supposed to advance the company’s TRPML1 agonist in muscular dystrophy.

Cambridge, Mass.-based Trillium Therapeutics raised $130 million in a public offering at $13 a share. The company is targeting CD47, the ‘don’t eat me’ signal that cancer cells emit to escape the immune system.

Austin, Tex.-based Triumvira Immunologics raised $55 million in a Series A financing to develop engineered T-cell therapies for cancer. Leaps by Bayer and Northpond Ventures co-led.

Cambridge, Mass.-based Codiak Biosciences filed a new S-1 prospectus to go public. The company, the developer of exosome therapeutics is seeking to raise as much as $100 million. I wrote about Codiak’s new partnership with Sarepta in June.

Menlo Park, Calif.-based Grail, the early cancer detection company, filed an S-1 prospectus to raise up to $100 million in an IPO. The private company had an accumulated deficit of $1.4 billion as of June 30, 2020, according to the S-1. (See my coverage of Grail’s founding investment in January 2016.)

Deals

Alameda, Calif.-based Exelixis agreed to pay $10 million upfront to Catalent’s Redwood Bioscience subsidiary to develop site-specific conjugated antibody drugs for a fixed number of targets in the Exelixis preclinical portfolio.

Seattle-based Presage Biosciences announced an expanded research collaboration with Takeda Pharmaceuticals to use Presage’s Comparative In Vivo Oncology (CIVO) intratumoral microdosing platform to gain mechanistic insights for its Phase 0 clinical trials.

Kudos

David Baker, a biochemistry professor at the University of Washington and director of the UW’s Institute for Protein Design, won the $3 million Breakthrough Prize in Life Sciences for his work in designing proteins from scratch. For background, listen to my interview with him on The Long Run podcast from December 2019.

Data That Mattered

Cambridge, Mass.-based Spero Therapeutics passed a Phase III clinical trial. The company said its oral antibiotic candidate, tebipenem HBr, for adults with complicated urinary tract infection (cUTI) and acute pyelonephritis. Topline data from the trial demonstrate that oral tebipenem HBr – a novel oral formulation of a carbapenem antibiotic marketed in Japan since 2009 — was statistically non-inferior to intravenous (IV) ertapenem in the treatment of patients with cUTI and patients with AP. The trial was clinically significant because it was a rigorous study of a new antibiotic against tough Gram-negative bugs in the age of increasing antibiotic resistance, and because it’s a convenient oral formulation being tested head-to-head with an IV form. (See CEO Ankit Mahadevia’s recent writings on antibiotic resistance on Timmerman Report, and listen to him on The Long Run podcast from Aug. 2018).

Germany-based Merck KGaA announced positive Phase II results for its IL-17A and IL-17F directed nanobody for moderate to severe chronic psoriasis. Data are being prepared for a scientific publication.

South San Francisco-based Genentech said that satralizumab-mwge (Enspryng), an IL-6 receptor directed antibody, lowered the risk of relapse for Neuromyelitis Optica Spectrum Disorder in a pooled analysis of Phase III studies.

Kenilworth, NJ-based Merck & Co. said gefapixant, an oral, selective P2X3 receptor antagonist, passed a Phase III clinical trial for the treatment of refractory or unexplained chronic cough. The drug beat a placebo at the higher dose of 45 mg, twice-daily, at the 12 and 24-week analyses. Merck also said its experimental 15-valent pneumococcal vaccine candidate passed a Phase III clinical trial, demonstrating non-inferiority to the currently available 13-valent vaccine (Prevnar 13 from Pfizer). Merck said it plans to seek FDA approval for the new vaccine candidate by year-end.

Takeda said it missed the primary endpoint of a Phase III clinical trial of ixazomib (Ninlaro) in patients with multiple myeloma.

Regulatory Action

Cambridge, Mass.-based Sarepta Therapeutics said the FDA has asked in writing for “an additional potency assay” before it can release its gene therapy for clinical study, and that “additional dialogue with the Agency is required to determine the acceptability of the potency assay approach.” Translation: the gene therapy for Duchenne Muscular Dystrophy is delayed.

Action in the Community Outside the Lab

How engaged is your company in your community, in terms of philanthropic giving and volunteering? Life Science Cares (an organization supported by Timmerman Report), recently surveyed small, medium and large companies on this issue and created an initial Community Engagement Benchmark Report. The findings were discussed here.

Personnel File
  • Cambridge, Mass.-based C4 Therapeutics named Andrew Hirsch as CEO. He was CFO at Agios Pharmaceuticals.
  • Cambridge, Mass. and New York-based Black Diamond Therapeutics hired Rachel Humphrey as chief medical officer. She comes from CytomX Therapeutics.
  • Cambridge, Mass.-based Sherlock Biosciences, the company developing CRISPR-based diagnostics, hired Martin Madaus as chief operations officer.
  • Seattle-based Accelerator Life Science Partners hired Kevin Chow and Melissa Yeager as operating partners.
  • Seattle-based Lumen Bioscience hired Mike Spigarelli as chief medical officer.
  • Seattle-based Neoleukin Therapeutics named Martin Babler to its board of directors. He’s the CEO of Principia Biopharma.
  • Cambridge, Mass.-based Syros Pharmaceuticals added Gail Eckhardt to its board of directors.
8
Sep
2020

Becoming a Biotech VC: Otello Stampacchia on The Long Run

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08 Sep 2020

Today’s guest on The Long Run is Otello Stampacchia.

He’s the founder and managing director of Omega Funds.

Otello Stampacchia, founder, Omega Funds (illustration by Praveen Tipirneni)

Otello started Omega in 2004, and it’s now on Fund VI. Based in Boston, Omega has $1 billion under management, and invests in a wide variety of biotech companies – early stage, later stage, American, European, oncology, immunology, rare disease. There’s a lot going on here, in terms of different fields of science, and different kinds of business challenges at different stages in a company life cycle.

Otello, as you’ll pick up immediately from his accent, was born and raised in Italy. He got his PhD in molecular biology, then figured out what he really wanted to do – apply his scientific curiosity in the world of investments.

Readers of Timmerman Report will have seen Otello’s series of articles on the COVID-19 pandemic. He’s been consistently ahead of the curve. His writing has been a pleasure to edit and publish.

In this conversation, we talk about Otello’s early life influences, the beginning of Omega Funds, and the trends that make this the best time ever to do what he does. At the end, he and I ruminate a bit on luck – how important it is, how much is truly blind luck, and what kinds of fortuitous happenings are more the result of consciously preparing oneself to be in position to receive a lucky break.

Now, before we get started…a word from the sponsor — BIO-Europe.

Today, it’s more important than ever to CONNECT…to work together to discover new vaccines and advance drug development.

The biotech community makes connections at partnering conferences. Now, I don’t travel to many international events in an ordinary year, and I’m definitely not traveling internationally this year. But I’m excited to join BIO-Europe as it’s delivered digitally.

On October 26, I’m moderating a panel on “Innovating the Partnering Future” with Marianne De Backer from Bayer, Paul Stoffels from J&J, and Melanie Saville from CEPI.

Join us by registering at BIOEUROPE.com — use VIP code “LongRun” for $100 Off.

Now, please join me and Otello Stampacchia on The Long Run.

3
Sep
2020

FDA and CDC Credibility Tarnished; Pfizer Sprints Ahead With COVID19 Vaccine

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03 Sep 2020

Luke Timmerman, founder & editor, Timmerman Report

Credibility takes years to build. It can crumble in seconds. Repairs can take a lifetime.

The FDA and the CDC are two of the American public health agencies that became global models of excellence after World War II. We should remember that, and perhaps the FDA and CDC should plaster it up on their walls as a reminder.

Both agencies have tarnished their credibility in this crisis. The FDA was slow at first with clearing RT-PCR diagnostic tests, then too fast with serology tests that had little or no actual data. Again, with no real evidence, it granted an Emergency Use Authorization for hydroxychloroquine against COVID-19, then had to withdraw it, tail between legs, when the hotly promoted drug flunked rigorous clinical trials.

Worse, FDA commissioner Stephen Hahn exaggerated the evidence for convalescent plasma in late August, on nothing but a single uncontrolled observational study. He utterly failed to explain the difference between absolute and relative risk, leaving the public with the false impression that convalescent plasma was some kind of panacea.

The CDC has done even worse. For a quick review, see Mike Pellini’s latest article in TR. Incomprehensibly, we still have no national testing/tracing/isolation program to contain community transmission. Schools are flying blind this fall, without clear guidance from the agency best equipped to deliver the epidemiological goods.

This is seven months into a pandemic that has killed 190,000 Americans and continues to kill 1,000 per day.

The agency, with no credible public leader who can step to the mic, can’t get people to wear masks, can’t get people to believe in vaccines, and can’t defend itself from an Up-is-Down disinformation campaign seeking to make Americans believe our national leaders have done a fine job. Move along now, nothing to see here.

Former NIH director and Nobel laureate Harold Varmus, a man who knows many talented public servants, surely was pained to write: “It Has Come to This. Ignore the CDC.”

None of this would have happened if the scientists on the national level were in position to guide policy.

The climax of this story is coming with COVID-19 vaccines. We could get several. An FDA advisory committee is scheduled to review the data on safety and efficacy, Oct. 22. This will be the most high-profile adcomm in FDA history. The pressure to approve something for wide-scale distribution – anything, really – will be of the diamond-crushing variety.

The CDC is appropriately seeking to prepare state and local health authorities in case of success with one or two vaccines by Nov. 1. But even in a best-case scenario, care will have to be taken with equitable distribution of the first doses. The decisions will need to be communicated with transparency by trustworthy voices. (Governors, please?)

The FDA and the CDC have done many things to build up public trust. We have a thriving biopharma sector in the US today. We take it for granted, but one of the main reasons for that is our strong, independent, scientifically rigorous FDA. It gives investors the confidence to invest, and doctors the confidence to prescribe.

Our country led the way on eradicating smallpox from the planet, in large part because of our CDC.

These are just a couple of the achievements of our public sector agencies. They deserve our acclaim and gratitude.

Of course, government agencies are populated by humans, and humans make mistakes. All organizations do – public and private. What’s important is what the organization does to make things right when it screws up.

There’s a bargain in here for us. Those public agencies are accountable to us as citizens, as taxpayers. We need to be active, participating citizens to keep our taxpayer-funded agencies on their toes, to keep them focused on the mission. The media has a role to play here, and so do you.

Scrutiny is healthy. Battery acid is corrosive. The cynical attitude that says, “the government can do nothing right,” is a big part of our problem.  

It’s natural to feel exhausted. It’s understandable to throw up our hands in despair. I feel it sometimes, too.

But previous generations invested the time and talent and treasure to build these institutions for the public interest. Giving in to apathy about the cultural decay around us isn’t going to fix anything.

We have to defend science when it’s under attack.

We have to press our scientific institutions to do better.

We have to follow the science so we can rebuild.

It will require hard work.

It will take time.

It won’t get fixed in a Tweet.

 

Epidemiology

Tony Fauci warned that seven Midwestern states are at particular risk of seeing a surge in COVID-19 cases, heading into the Labor Day holiday weekend. Cases increased the last two times we had holiday weekends this summer – Memorial Day and Fourth of July. Come on, people. America is racking up 20x more deaths on a weekly basis than a comparable section of the European Union, as Otello Stampacchia pointed out in these pages this week.

How many more deaths are we willing to tolerate?

What will it take for us to start doing what works (social distancing, avoiding crowds, wearing masks). What we are doing now clearly isn’t working. (See chart from Worldometers)

Vaccines

Pfizer appears to be in the lead, having enrolled 23,000 subjects on its BioNTech-developed mRNA vaccine candidate since late July. The trial is designed to evaluate safety and efficacy in 30,000 people. Some are now getting their second of two planned doses. Based on the lightning-quick enrollment pattern, CEO Albert Bourla is projecting an initial readout on efficacy by “the end of October.” Long-term safety data, by definition, will not be available until long-term follow-up can be completed. Later yesterday, Moncef Slaoui of the federal government’s Operation Warp Speed said there is a “very, very low chance” that the existing trials could yield data by the end of October. But he did also say we could have 20-25 million doses ready by year-end — a serious testament to the urgency of this mission.

Moderna has said it expects to complete enrollment of its 30,000-person Phase III mRNA vaccine trial in September. These are the two candidates furthest along in development. The CDC has told state and local authorities that limited doses of vaccine could be available by late October or November. Others, with different mechanisms for stimulating immunity to SARS-CoV-2, are queuing up fast. AstraZeneca, on Aug. 31, said it began enrolling the first of 30,000 subjects in the US expansion cohort of its Phase III clinical trial for the COVID-19 vaccine candidate developed with the University of Oxford. Sanofi and GSK are a bit behind, announcing Sept. 3 they’re initiating a Phase I/II trial with 400 subjects on their recombinant protein & adjuvant vaccine candidate.

Science

Science Features

Policy

  • Reopening Schools During COVID-19. Science. Sept. 3. (Ronan Lordan et al)
  • Leader of US Vaccine Effort, Moncef Slaoui, Says He’ll Quit if Politics Trump Science. Science. Sept. 3. (Jon Cohen)

Credibility

Our Shared Humanity

Manufacturing and Access

Regeneron and Roche agreed to work together to scale up to meet global demand for REGN-COV2, the two-antibody cocktail developed by Regeneron to treat COVID-19 infections, and provide short-term prophylaxis. Regeneron said the arrangement will boost manufacturing capacity by 3.5x. Regeneron will distribute in the US; Roche will distribute to the rest of the world, and each company will bear its own expenses in its territories. Regeneron is getting Roche to help foot the bills for an ongoing Phase III prevention study, and a Phase I healthy volunteer study, plus more studies to come.

Financings

Watertown, Mass.-based Kymera Therapeutics raised $199.8 million in an IPO priced at $20 a share on Aug. 25. The company, the developer of targeted protein degrading drugs, has traded between $27 and $37 a share in the early days since the IPO.

Plymouth Meeting, Penn.-based Harmony Biosciences raised $147.6 million in an IPO priced at $24 a share on Aug. 21. The company is developing drugs for rare neurological diseases. The stock has climbed as high as $43 a share.

San Diego-based Inhibrx, the developer of biologic drugs for cancer and rare diseases, pulled in $136.9 million in an IPO at $17 a share on Aug. 21.

Germany-based CureVac, the developer of mRNA based therapies and vaccines, raised $245 million in an IPO at $16 a share on Aug. 18. The stock tripled on Aug. 20 after CureVac reported it is in “advanced discussions” with the European Commission to supply more than 400 million doses of an mRNA vaccine candidate for COVID-19. Elon Musk also bestowed some praise on the company, driving action in the stock. CureVac traded over $56 a share yesterday.

CM Life Sciences, sponsored by affiliates of Casdin Capital Management and Corvex Management, pulled in $385 million in an IPO. The company, led by CEO Eli Casdin and chairman Keith Meister, said it will seek business combinations that bring together “three separate areas of the life sciences industry that are often fragmented – life sciences tools, synthetic biology and diagnostics.”

Seattle-based Lumen Bioscience raised $16 million in a Series B financing to advance clinical programs for C. difficile infections, norovirus and traveler’s diarrhea.

Redwood City, Calif.-based Synthego, a genome engineering company, raised $100 million in a Series D financing led by Wellington Management.

South San Francisco-based Freenome raised $270 million in a Series C financing to advance the company’s blood test for colorectal cancer. Bain Capital Life Sciences, a new investor, co-led with existing investor Perceptive Advisors.

San Mateo, Calif.-based Kronos Bio raised $155 million in a private financing to advance its cancer drug development. Perceptive Advisors led.

Lyra Health raised $110 million in a Series D financing to advance its digital tools to support mental health.

Newark, Calif.-based Rain Therapeutics, a developer of targeted cancer drugs, closed a $63 million Series B round. Boxer Capital led, and was joined by Cormorant Asset Management, Samsara Capital and others. The company licensed a small molecule, oral MDM2 inhibitor from Daiichi Sankyo.

New York-based Immunovant, a developer of treatments for autoimmunity, raised $173.9 million in a public offering at $33 a share.

San Diego-based Erasca extended its Series B financing to $236 million. Partner Fund Management and OrbiMed joined the syndicate.

Vancouver, BC-based Chinook Therapeutics, a developer of drugs for kidney diseases, raised $106 million in a private placement. EcoR1 Capital and OrbiMed were among the new investors. Chinook is merging with publicly-traded Aduro Biotech.

Regulatory Action

Abbott Laboratories won FDA clearance for its $5 antigen test to detect COVID-19. The test can be run in 15 minutes by qualified labs. It’s not as accurate as the RT-PCR tests, but it does deliver a reported sensitivity of 97.1% and specificity of 98.5%, which is pretty good for a $5 test that can be run in minutes.

The FDA cleared Roche’s HIV-1/HIV-2 test for the cobas 6800/8800 platforms. The test is PCR based, automated, and able to distinguish between the two types of HIV.

The FDA cleared Novartis to start selling ofatumumab (Kesimpta) for patients with relapsing multiple sclerosis. The drug is an anti-CD20 antibody, designed to deplete B-cells, and has been approved since 2009 for chronic lymphocytic leukemia. The new drug is made into a self-injectable, once-monthly form that’s more convenient for patients with relapsing MS, and that doesn’t require the added expense of going to the hospital to get a typical infusion-based antibody.

The FDA issued a pair of notable Complete Response Letters in August. One was for Biomarin’s gene therapy for hemophilia A, saying it needs to see long-term follow-up data to be assured that the treatment effect persists. The other was for Gilead Sciences’ filgotinib for moderate to severe rheumatoid arthritis.

Deals

Brisbane, Calif.-based Aimmune agreed to be acquired by Nestle Health Science for $2.6 billion. Aimmune developed an FDA-approved treatment for peanut allergies.

Sanofi agreed to acquire South San Francisco-based Principia Biopharma for $100 a share, or $3.68 billion. Sanofi emphasized how the deal will strengthen its work on BTK inhibitors.

Carlsbad, Calif.-based Ionis Pharmaceuticals agreed to acquire the remaining 24 percent of shares in Akcea Therapeutics that it didn’t already own. Ionis agreed to pay $18.15 a share, for a transaction worth about $500 million.

Cambridge, Mass.-based Jounce Therapeutics secured an $85 million upfront payment, plus a $35 million equity investment, from Gilead Sciences. In return, Gilead received an exclusive license to develop JTX-1811, an antibody aimed at CCR8, a target found on T-regulatory cells that infiltrate tumors and suppress the action of other immune cells that can attack the tumor.

Johnson & Johnson agreed to acquire Momenta Pharmaceuticals, the developer of nipocalimab for autoimmune disease, for $6.5 billion in cash.

Gilead Sciences agreed to expand its collaboration with Cambridge, Mass.-based Tango Therapeutics, the developer of synthetic lethal cancer drugs. Gilead is paying $125 million in upfront cash, making a $20 million equity investment, and agreeing to pay as much as $410 million in milestone payments for each program it chooses to opt-in to develop, on programs against up to 15 targets. (For background, listen to Tango CEO Barbara Weber on The Long Run podcast, from November 2018).

Data That Mattered

Cambridge, Mass.-based Amylyx Pharmaceuticals said it hit the primary endpoint of a 137-patient pivotal trial, called Centaur, for patients with amyotrophic lateral sclerosis (ALS), the neurodegenerative disease also known as Lou Gehrig’s disease. Patients on the drug for 24 weeks scored 2.32 points higher than those on placebo, when answering questions about activities of daily living on a 48-point questionnaire. The drug candidate is a combination of sodium phenylbutyrate and taurursodiol. Results were published in the New England Journal of Medicine.

Cambridge, Mass.-based Akebia Therapeutics said it missed the primary endpoint for safety in the second of two Phase III PRO2TECT trials. The drug, vadadustat, is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for anemia in chronic kidney disease patients. The Akebia drug fell short versus darbepoetin alfa in “time to first occurrence of major adverse cardiovascular events (MACE), which is the composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke across both PRO2TECT studies,” the company said. Akebia said it still plans to file a New Drug Application to the FDA based on the totality of data from its Phase III program.

UK-based AstraZeneca reported that dapagliflozin, its oral SGLT2 inhibitor approved for Type 2 diabetes, passed a Phase III clinical trial, DAPA-CKD, for patients with chronic kidney disease. The drug was shown to reduce the risk of renal function worsening or risk of death from cardiovascular or renal causes by 39 percent, compared with placebo. The company said the results were consistent in patients with and without Type 2 diabetes.

Legal Corner

Amarin lost its appeal to the US Court of Appeals for the Federal District, in which it sought to overturn a lower court ruling in favor of a couple generic companies that challenged the Amarin patent to its fish oil compound marketed as Vascepa.  

Personnel File

New York-based Intercept Pharmaceuticals said it is laying off 170 workers, or 25 percent of its workforce. The move comes after the FDA rejected its application to start marketing its drug candidate for non-alcoholic steatohepatitis.

Watertown, Mass.-based Kymera Therapeutics, the developer of targeted protein degrading drugs, hired Richard Chesworth as chief scientific officer. He was previously with Third Rock Ventures.

San Francisco-based VIR Biotechnology named Janet Napolitano to its board of directors. She is the former chancellor of the University of California system, former Secretary of Homeland Security under President Barack Obama, and former Governor of Arizona.

San Diego-based Erasca named Mike Varney as chairman of R&D, and a member of its Scientific Advisory Board. He formerly led Genentech Research and Early Development (gRED).

Cambridge, Mass.-based Nimbus Therapeutics hired Scott Edmondson as senior vice president and head of chemistry. He comes from AstraZeneca.

Cambridge, Mass.-based Blueprint Medicines hired Fouad Namouni as president of R&D. He comes from Bristol-Myers Squibb.

Cambridge, Mass.-based eGenesis hired Michael Curtis as president of R&D. The company is working on xenotransplantation, by engineering pigs that produce organs that can be transplanted effectively into humans.

Cambridge, Mass.-based Magenta Therapeutics hired Lisa Olson as chief scientific officer and Kevin Johnson as SVP, head of regulatory and quality. Jason Ryan is leaving his position as chief operating and financial officer.

Cambridge, Mass.-based ROME Therapeutics hired Dennis Zaller as chief scientific officer. He comes from Bristol-Myers Squibb.

Novato, Calif.-based Ultragenyx Pharmaceutical said Mardi Dier will start as chief financial officer on Nov. 2. She will replace Shalini Sharp.

Seattle-based Sana Biotechnology, the developer of allogeneic T-cell therapies, said it hired Ed Rebar as chief technology officer and Terry Fry as SVP, head of T-cell therapeutics.

Cambridge, Mass.-based Obsidian Therapeutics named Rob Ross to its board of directors. He’s the chief medical officer at Surface Oncology.

2
Sep
2020

Tech Impact Requires Deep Engagement With Biopharma Lead Users

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02 Sep 2020

David Shaywitz

In today’s Wall Street Journal, I review The Innovation Delusion, a new book arguing that innovation is overrated and maintenance is underrated; moreover, the authors assert, we have magical thinking around innovation, and often view it as fairy dust that can be imported from Silicon Valley then sprinkled on ossifying organizations to revive and rejuvenate them.

(Steve Blank discussed the all-too-familiar phenomenon of “innovation theater” in last October’s Harvard Business Review).

The Innovation Delusion offers a thought-provoking read, as I discussed for the WSJ’s broad business audience. But it may also be of particular relevance to biopharma readers, inspiring me to expand on three thoughts of particular interest to my hardcore life science colleagues who read Timmerman Report:

  1. Technological innovation has largely been a force for good;
  2. Maintenance and infrastructure matter;
  3. Innovation does not equal progress; implementation is critical, and requires the deep domain expertise of engaged front-line users (extra emphasis on this point).
Technology: Force For Good

Amid all the handwringing that reliably accompanies technology development, and has probably been with us since Og first rubbed two sticks together, there are compelling data that the world is actually getting (much) better, not worse.  

While naturally controversial (especially at a time of such social and political angst), a compelling case for technology leading toward meaningful economic and health progress has been made by Steven Pinker (Enlightenment Now), Hans Rosling (Factfulness), and Andrew McAfee (More From Less – my WSJ review here), among others. I’d also recommend the “Our World In Data” website.

Asserting the world is getting better does not negate the existing serious problems, including well-documented inequities. Rather, it highlights the many ways we’ve made human existence so much better over the years, and emphasizes our potential to drive still more positive change.

Maintenance and Infrastructure Matter

The authors of The Innovation Delusion are correct to point out our intrinsic bias for novelty – what Nassim Taleb has called “neomania.” 

There is a tendency to imbue new tools and technologies with an imaginary ability to fix what ails us, and a contrasting disinclination to attend to the often-tedious responsibilities of keeping what we already have going. Few of us like to clean air conditioner filters or repair roof tiles, though objectively we recognize the value of doing so. 

At the same time, we should recognize that the importance of stability is hardly lost on successful tech companies – even Facebook refined its mantra from “move fast and break things” to “move fast with stable infrastructure.” Twitter became a more serious player once it consigned the “Fail Whale” to the dustbin of history. 

As I write in the review:

“Leading technology companies may talk innovation, but they already compete (as the writers themselves acknowledge) on reliability and uptime—striving for standards like the ‘five nines,’ meaning that service is available 99.999% of the time and down no more than five minutes a year.”

Implementation Enables Progress

The most important and most underappreciated hurdle in leveraging powerful emerging technologies is figuring out how to use them. 

New technologies by themselves do not equate to progress, and won’t result in progress unless and until they are gainfully applied to solving a relevant problem. It’s also why there’s such a long gap between when a technology is first discovered, and when it is adapted into something commercially relevant. (This also ties into the much-discussed delay between the arrival of new technologies and the ability to discern significant productivity gains.)

In life sciences, we have, and largely continue to live this disconnect.  We hear extravagant promises from enthusiastic technology developers. We then try to relate it to our own lived experience in the trenches of biopharma, pursuing our daily mission of discovering, developing, and delivering impactful new medicines to improve human life. 

The view from many on front lines is that a lot of technology, despite the hype, despite the pleadings of biopharma executives intrigued by notion of “digital transformation,” continues to feel peripheral to the core mission, at best perhaps helpful around the operational edges, but hardly moving the needle on the core business of curing disease, and as likely to be a distraction as a contribution. This is the largely unspoken reality I continue to see on the ground.

This pattern is not, and should not be, surprising. 

We shouldn’t despair.

This is characteristic of the way emerging technologies evolve, and also why there tends to be such a gap between the original discovery of the new technology, and its effective incorporation at scale. 

This gap reflects — and defines — the implementation challenge, the need to actually figure out how to leverage a powerful, emerging technology to solve a relevant problem in a given domain. Moreover, the key advances tend to come from “lead users,” curious pragmatic front-line workers who are looking to solve a discrete problem and believe a particular technology could be useful if appropriately applied.

In short, what this means is that whether you’re an aspiring healthtech startup looking to disrupt/transform/reinvent/reimagine some aspect of biopharma, or a large technology company seeking to add a lucrative biopharma vertical, your ultimate success requires deep domain expertise.

For startups, we need leaders — and investors — who are not only attuned to the technology to be deployed but, critically, who also inhabit and are fluent in the relevant domain, and who have acquired with time and lived experience a nuanced understanding of the real-world problems to be solved.

Barbara McClintock in the lab, 1947.

These leaders and their companies would have what maize geneticist Barbara McClintock classically described as a “feel for the organism.” 

For larger companies, we need a strategy more substantive than hiring once-prominent healthcare and biopharma figures to facilitate customer outreach; we need products designed and developed in deep partnership with lead users, relationships focused on solving pressing customer problems, not jamming in largely-established solutions.

Why This Matters: Biopharma Needs Help

I recently reviewed the (always) fantastic year-end summary from 2019 (available here) presented by Bruce Booth of Atlas Ventures, a prominent early-stage life science venture firm. The discussion affords an invaluable 20-year historical perspective of the life science industry. Despite some profound advances, the persistence of several core problems in the industry was striking. 

In the last two decades, the timelines for discovery and development “haven’t budged,” Booth demonstrates, while “costs continue their steady climb,” and the rate of mid- and late-development failures — exceptionally costly — remains staggeringly high.

Bruce Booth, partner, Atlas Venture

“Failure,” Booth ruefully notes, remains “an inescapable reality of drug R&D.” 

The impact on burden of disease has been significant for some patients with some conditions), but in aggregate, perhaps not exactly transformative.  For example, one graph required a conspicuously attenuated X-axis going from 64% to 70% to reveal the improvement in relative survival rate for all invasive cancers from 1999 to 2016. The rate bumped up from 66.0% to 69.3% which is meaningful, especially if you’re in the new 3.3%, but likely not the transformative progress towards which we all aspire. Some cancers, like pancreatic cancer and brain cancer, remain a difficult struggle. And cancer is the therapeutic area attracting by far the greatest amount of industry investment and attention.

In short, despite the proliferation of promising biological modalities, the process of prosecuting new therapeutics remains astonishingly difficult and expensive, with success still the rare exception. Despite our best scientific efforts and extraordinary resource commitments we remain at the core a miracle-driven business.

The Opportunity For Tech?

Here’s the point: the job of life science companies remains as difficult as ever. Coming up with safe and effective new medicines is really, really hard, mostly because biology is complex and messy, and it’s almost unimaginably hard to come up with something you can safely introduce into the human body that will effectively attack only the disease. It’s a preposterously difficult problem — and it’s also what the R&D folks in biopharma courageously tackle every single day.

To the extent that emerging digital and data technologies can help — can authentically and meaningfully help — life scientists tackle these outsized problems more effectively: that would be fantastic. 

But it will also require a far deeper focus on implementation and lead user engagement than most of what we’ve seen from tech so far. It’s also why the impact of tech on life science has been so outrageously minimal and so elusive. 

Factories weren’t meaningfully helped by the replacement of steam power with electric generators; productivity improvements were driven when factories themselves were reimagined and reconfigured to optimize the flow of material. The big change came when these dense three-dimension structures designed around a single source of power were replaced by the long linear layout more familiar today. 

As I wrote last year in Clinical Pharmacology and Therapeutics,

“In areas ranging from the power loom where efficiency improved by a factor of twenty, to petroleum refinement, to the generation of energy from coal, remarkable improvements occurred during the often lengthy process of implementation, as motivated users figured out how to do things better, ‘learning by doing’ as Bessen describes it in his book of the same name.

Many of these improvements are driven by what Massachusetts Institute of Technology professor Eric von Hippel calls ‘field discovery,’ involving frontline innovators motivated by a specific, practical problem they’re trying to solve. Such innovative users—the sort of people who Judah Folkman had labeled ‘inquisitive physicians’—play a critical role in discovering and refining new products, including in medicine; a 2006 study led by von Hippel of new (off‐label) applications for approved new molecular entities revealed that nearly 60% were originally discovered by practicing clinicians.”

I conclude my recent Wall Street Journal book review by describing the opportunity before us:

“New technologies really can make the world better, though how they will deliver their benefits can be hard for the originator to perceive. (Thomas Edison expected that his phonograph player would be used for recording wills.) The hustle and hype around emerging technologies, so easy to ridicule, reflect the chaotic effort to identify something of real value. More often than not, it is pragmatic, curious frontline workers—‘lead users,’ in innovation-speak—who make the incremental advances that fulfill the promise and realize the potential.”

For biopharma, specifically this means that we should avoid our initial impulse to either ridicule emerging technologies or endow these technologies with extravagant expectations (and sometimes both). 

Rather, we should seek opportunities to leverage our deep expertise as lead users, and actively shape the implementation of emerging technologies to address the many challenges before us. 

Success will require not only thoughtful engagement from life scientists, but an evolution in the mindset of the technology developers — including, critically, their early champions and investors, who tend to grok technology but are often far more superficial in their knowledge of drug development. A deep understanding of drug development, and a deeper, more authentically collaborative relationship with creative, front-line drug developers will be essential if the technology’s promise is to find expression in the delivery of important new medicines that improve the lives of patients.

Further reading:

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