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

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.


How Lunch with Bill Gates, Sr. Changed My Life

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).


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

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.


Moderna and Pfizer’s Vaccine Transparency, Gilead’s Megadeal and a Tribute to Bill Sr.

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.


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 late 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 been 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.


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.)

  • 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)
  • 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)
  • 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).

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.


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.

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

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.

Industry and Academia Take a Stand for Science

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.


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.


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).

  • 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)

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.)


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.


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.

Becoming a Biotech VC: Otello Stampacchia on The Long Run

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.


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

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.



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)


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 Features


  • 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)


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.


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.


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.


Tech Impact Requires Deep Engagement With Biopharma Lead Users

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:


The Data Are Telling Us to Prepare for a Difficult Fall

PEARLS BEFORE SWINE © 2020 Stephan Pastis. Reprinted by permission of ANDREWS MCMEEL SYNDICATION. All rights reserved.

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

I could not resist using the above, peerless comic strip from Stephan Pastis. Indeed, the two “plagues” are not just co-existing, but they are mutually reinforcing each other and making things worse.

We should take the “great wise ass on the hill” seriously and invest in science and (investigative, high quality) journalism.

About two months ago, I wrote here about “How We Are Losing the Fight Against the Virus.” At that time, the US had 2.5 million confirmed cases of COVID-19 and reported 126,000 deaths. As of this writing, we now have tallied up more than 6 million confirmed cases, and 183,000 deaths.

Sadly, those numbers will continue to grow this fall, based on my latest look at the relevant work in epidemiology, virology and immunology (and the social-political vibes you get from watching too much cable news).

I am dividing today’s contribution in four parts:

  1. Where things stand (focusing mostly on the US)
  2. What have we learned since the beginning of the pandemic
  3. What we still do not know
  4. Some thoughts and forecasts for the fall season

If you are, like most people reading Timmerman Report, up to date with the zeitgeist, I suggest perhaps you skip parts 1) and 2) (though a refresher never hurts) and jump to part 3).  

Where things stand

The above picture is from the COVID Tracking Project (@COVID19Tracking): after a worrying summer that saw 7-days rolling averages of confirmed cases exceed 60,000/day for several weeks, and rolling averages of deaths exceed 1,000/ day, the situation appears to be stabilizing / mildly improving, though on a much higher plateau than in May. Rolling averages for hospitalizations and percentage of positive tests are also showing improvements, though, again, at levels that are far from reassuring (roughly around 40,000 positive cases / day and ~900 deaths / day).  

Now that summer is winding down and schools, universities and workplaces are moving back into the rhythms of fall, people want to know what to expect.

It’s going to be painful.

I’ve been following an open-source AI-driven model from Youyang Gu which has been relatively accurate to date and is followed by the well-known statistical modeler Nate Silver at FiveThirtyEight.

Sadly, the model forecasts roughly 220,000 deaths by November 1st, from a current (already very grim) body count of over 180,000 confirmed cases. Please note that the current confirmed toll is already DOUBLE the number of US servicemen who died in Vietnam, Afghanistan and Iraq combined, and with no signs of stopping. (The US death toll for World War II was about 400,000).

Add to this the (very roughly) 50,000 excess deaths that are very likely already attributable to COVID-19, and the toll is very heavy indeed. This is not “normal”, it is not even remotely close to (non-pandemic) seasonal flu, and we must resist the (all too human) tendency to become numb and fatalistic about this sorry state of affairs.

According to the same model, the current best estimate of cumulative American COVID-19 infections is (roughly) 14% (close to 47 million out of 330 million people). We are (obviously, but it needs to be stated clearly) nowhere near the >70% of the population needed to achieve “herd immunity”. Please remember also that the death toll does not take into account the (unclear, but significant) number of #LongCovid sufferers (patients who have recovered from the infection but suffer long term, serious health consequences). Even ignoring all that resulting chronic disease with COVID “long haulers,” and using some very, very rough math, “letting it rip” (letting the pandemic propagate without any attempt at mitigating its spread) can lead to ~800,000-900,000 total confirmed US fatalities (more if some hospital systems become overwhelmed; possibly *many* more if we try to input “excess deaths” in the calculation).

To put this into a broader context: in the 5 days prior to Sunday, Aug. 30, the largest European countries (with a population total of 340M, roughly equivalent to the US’ 330M), reported a combined 250 deaths. During that same period, the US reported 5,500+ deaths. When you look at the death toll, the pandemic at this point is about 20x worse in the US.

This is staggering, and will have implications for the upcoming autumn.

What have we learned since the beginning of the pandemic

I will attempt to summarize some of the knowledge / facts accumulated on the virus and its properties / means of propagation (and implications thereof) since the beginning of the pandemic.

a) Deaths lag hospitalizations; hospitalizations lag confirmed cases increases: the steep increase in number of cases in the US observed in the early summer led, predictably, after several weeks, to an increase in hospitalizations and then in subsequent deaths. There is an obvious lag between these events, caused by several factors: i) as the infection spreads first in the younger, less vulnerable (but not *invulnerable*) strata of the population; ii) as (unconscionable) delays in test results do not give us an accurate and timely picture of the infections spreading, and, finally (and even more unconscionably) iii) as it might take several *weeks* to report COVID-related deaths (a particular dishonorable mention to the Sunshine State, Florida, for the egregious delays, if not outright obstructionism, in reporting deaths). Remember that we are all actually living in the future versus what we normally perceive to be the present (meaning, what we could perceive the current status of the pandemic spread to be: human beings are particularly prone to recency biases). It is of particular concern when, in areas where tests are performed at scale and some speed, positive rates increase quickly. In such situations, measures such as localized / temporary lock-downs / further enforcing of social distancing / obligatory mask wearing in public are likely warranted (the latter should be enforced nation-wide ASAP).

b) This is a very infective virus: It is not as bad as measles, but it is very transmissible, especially in indoor, crowded, poorly ventilated environments. You have heard (am sure) about the dreaded R0 (R “naught”) number. Crucially, R0 is not a fixed number, but it is influenced by many factors, including human behavior (masks…) and context in which a potential transmission could occur (shouting / singing in an small / contained indoor space). The virus is spread by droplets / aerosol particles generated by breathing / talking loudly from an infected person. Worryingly enough, there is now emerging evidence that such droplets can also propagate the infection by connecting with unprotected ocular surfaces (your eyes).

By now, you should also be familiar with the importance of “super-spreading events” in transmitting / propagating the virus. As little as 10% of infected individuals could be the source of ~80% of overall infections, again especially in specific environments / context (indoor, poorly ventilated, talking loudly / singing, no masks): for example, a wedding in rural Maine, an area as yet untouched by the pandemic, led to a large outbreak in the state.

Another extremely well-researched example, very close to home for me and for many readers of Timmerman Report, was the meeting of Biogen’s executive management in Boston towards the end of February (the meeting ended on Feb 27th): the event was attended by ~175 people, from different regions in the US as well as from other countries (including Italy). Scientists have estimated that over 20,000 individual infections were originated from that single conference and then spread all across the globe.

Which leads us to:

c) Non-Pharmaceutical Interventions (NPIs) are very effective in preventing viral spread: social distancing and, especially, wearing masks / face shields in indoor areas have been proven (by a whole body of scientific literature, on this pandemic and others before it) as being very effective in preventing transmission. The graph below is a great summary of the transmission risk in various circumstances and could act as a very rough guideline (always wear a mask anyway). Please note that everything is relative and highly context-dependent: if you are in an area of high prevalence of infections (Miami-Dade County in Florida, for example, or NYC during the peak of the pandemic there in March), even low-risk endeavors, if repeated many times and by a highly susceptible individual can lead to infection. Remember the probabilities here are additive. I am not going to go into which type of masks are most effective but they are an essential component. In addition, face masks also help in reducing the amount of virus that you are infected by (viral inoculum, sometimes confused with viral load), which leads to this one essential point below:  

d) Viral inoculum size is very important (and may be the factor making the difference between you ending up in the hospital or just walking it off): forgive me for perhaps stating the obvious here, but I feel this topic, of paramount importance, has not been discussed much (if at all) in the general discourse surrounding the pandemic. People seem to only assume binary outcomes from encountering the virus: you either get infected or not, and then, if you get infected, you either die or survive. This is *OBVIOUSLY* not the case (not sure if you can picture me rolling my eyes right now, but, I assure you, it is happening). How much virus you are exposed to at the beginning of your infection (viral “inoculum”) has a strong correlation with the subsequent severity of your symptoms. We have known this for a while, and yet, we are still having these inane / insane and sometime unhinged discussions / fights (including at various stores across the country) about how the obligations to wear masks infringe on people’s civic liberties. Masks do, at the very least, SUBSTANTIALLY reduce the viral inoculum you are exposed to in an infective situation, and therefore *will* either i) prevent the (non-infectious) wearer from catching a potentially lethal dose of the virus or ii) prevent the (infectious) wearer from spreading a potentially lethal dose of the virus in his/her surroundings. I honestly cannot believe we are still debating this stuff 6 months into a pandemic, but there you have it.

e) The virus is not becoming less lethal over time / the virus has not mutated into a (measurably) milder version: the (very much welcome) reduction in the mortality rates that you are seeing across countries (most of them developed: emerging countries are still seeing very high case fatality rates: see Mexico, Peru, India) is because of a variety of cumulative factors: hospitals / caregivers are no longer overwhelmed; a larger percentage of the population now being infected is younger / with less co-morbidities and risk factors; practitioners have learned / shared more information on how to deal with severely ill patients (for example, by not putting them on ventilators immediately; for those of you with an interest, I suggest joining the slack channels used to exchange know-how and tips by healthcare practitioners); more people are wearing masks / being more careful in their behaviors and therefore are being exposed to lower viral inocula when infected; finally, a few pharmaceutical interventions have since become available and are making an impact (especially dexamethasone), and with more to come: People have been focusing a lot (for good reason) on vaccines, but there is a whole bunch of other stuff that might show its effectiveness before they become widely available. As any rational person would (should?) tell you, in a(ny) pandemic you do not want to get sick early. If you’re going to get sick, it’s better that it happen later, when healthcare professionals know more about the virus and its effects.

f) There is no pre-existing, foolproof, 100% protective “immunity” to this virus. I have seen over the last few weeks the spreading of this fascinating, completely unproven “theory” that there is a large amount of existing immunity to COVID-19 in the population due to the fact that, supposedly, up to 50% of people have T cells with cross-reactivity (in Petri dishes, in a lab) to this virus because of previous exposure to other (seasonal) coronaviruses. This reminds me of the late ‘90s, when curing cancer in mice was enough to make stock prices for certain (mildly overpromoting) biotech companies skyrocket… (yes, I know this statement ages me quite a bit, thanks very much). Even given this (completely unproven) “theory” (I think “opinion” might be closer to the mark) the benefit of the doubt, again we come back to the *fact* that a smaller viral inoculum (and subsequent viral load in your bloodstream) is probably more important in determining your progression towards the worst symptoms. Even some mild degree of cross-reactivity and therefore (possibly, not surely) protection will not help you if you are inhaling infectious particles by the millions without masks at an (indoor, poorly ventilated) bar. In the words of Ricky Gervais (if you do not watch his comedy stand-ups, you should): “You can have your own opinions, but you cannot have your own facts”. 

g) Children (especially very young children) are not, by and large, severely affected by the virus: what I mean by saying “by and large”, is that they are not as affected as adults, probability-wise. There is, also in children, a continuum in the risk probability, again increasing with age, and with other pre-conditions predisposing to severe symptoms (obesity etc.). That said, the risk is not exactly zero even for very young children. To provide some quantification of the probabilities here, Dr. Stephanie Graff (@DrSGraff), described a recent State of Florida pediatric report (using data since March)… OK, HOLD ON. I know what you are thinking. So let me address the elephant in the room here first: far be it from me to rely upon, let alone celebrate, “Florida statistics” on the pandemic, which is as close to an oxymoron as I can think of, but this is all I got so far. At any rate, according to said (possibly very flawed) Florida statistics, 48,928 children statewide have tested positive; of these, 600 have been hospitalized (~1.2%), with most of them recovering, and 8 have tragically died (~0.01%). 50 children <18 have been diagnosed with MIS-C, which is a severe inflammatory disorder caused by the virus (~0.1%, or 1/1000 for those of you who suck at math). I have not been blessed with children, so will leave to parents their own risk-reward calculations analysis. At any rate, it is also abundantly clear that children are infected by the virus and can transmit it, sometimes very efficiently: young, college-age adults effectively seem to transmit as well as older adults. This has severe implications for community transmission as soon as schools reopen (see below), and particularly for inter-generational households with grandparents or people with other pre-existing conditions.

What we still do not know

Most of the unknowns that still plague us are related to this incredibly complex organ of the human body, the immune system. This is a new virus for the human species, and, notwithstanding the incredible progress made to date, there are still lots of things we do not know, some of which are (unfortunately) essential before being able to plan a return to some semblance of normal life.

a) How long does immunity last? In early July, a British study pre-print showed declines in neutralizing antibody titers (antibody amounts / volume of blood) observed during a ~3 months follow up period post-infection. Cue (predictably) apocalyptic commentaries. However, there are reasons (I know, this is unlike me, but bear with it for a bit) to be a bit less pessimistic: as eloquently described by Derek Thompson in The Atlantic in this very thoughtful piece as well as by his (very witty) colleague Ed Yong in many great articles (this one in particular is worth a read) the immune system is extremely complex and has many components. First, even a lower antibody titer later on might still be sufficient to forestall a severe re-infection (see below) DEPENDING ON THE VIRAL INOCULUM (see? Keep wearing a mask please). Also, the authors of the British study only looked at B cell antibody responses, and did not measure T cell responses (to be fair, that is a much harder measurement to make): there are reasons to believe that T cell responses might provide the strongest / longest-lasting immunity to COVID-19 (read here if you want to geek out). Perhaps some very rough calculations might also provide some guidance: we know that existing, seasonal coronaviruses (responsible for ~25% of seasonal common colds) are capable of re-infecting people every year or so which means immunity might last for a few months; on the other hand, SARS and MERS (the other recent coronavirus epidemics) *seem* to provide some degree of immunity for ~24 months. That said, both SARS and MERS only infected (luckily: their fatality rate was very high) a few individuals, so we do not have a deep data set to use here. If I were a betting man, I would work under the operating assumption that exposure to infection (and subsequent recovery) might confer some protection for anywhere between 12 and 24 months. The uncertainty is due to myriad factors (how much virus were you exposed to; the infected individual’s sex and the overall state of his / her immune system; the amount of virus exposed to in a subsequent re-infection; etc.). Which brings us to the latest developments:

b) People can get re-infected: note, this should technically be in section 2), but it is a very new development and there is still a lot of uncertainty / debate on the possible consequences. As described by more and more reports in the last few days, there have been (some more, other less “properly” confirmed) cases of COVID-19 re-infection (in Hong Kong, Belgium, Netherlands, and now Nevada): in these cases, the virus genetic sequence in the second infection was sufficiently different from the one from the earlier infection to rule out artifacts of detection and other explanations. Before I go on, I would like to highlight the sheer “amazingness” of this: we are testing and sequencing viruses of many infected individuals, globally. This is leading us to important learnings on the virus (the above is a not-so-snide retort to people / organizations who would like to reduce testing volumes or only test symptomatic people; apparently one such organization included, until recently, the US CDC). I’d start with the (important) premise that such cases, at the population level, are in my opinion quite rare and likely to remain so and be restricted to individuals who have decided to have the questionable bad luck of i) living in areas of very high pandemic prevalence, ii) being particularly susceptible to infection, and / or iii) engage in very risky behaviors. That said, the Nevada case is of particularly concern, since the individual had much more serious / severe disease symptoms the second time around than during the first infection: normally, even if the immune response generated after the first infection is unable to prevent a second one, it should, however, conceivably, at least forestall more severe symptoms. However, as brilliantly put by Dr. Sarah Cobey (epidemiologist / evolutionary biologist from U. Chicago, quoted in the article above), “Infection is not some binary event”, and with a reinfection, “… the question is how much is the immune system getting engaged?” Which, again, takes us back to viral inoculum size and its interaction with any individual’s immune system. As a corollary of this (extremely important) topic and the consequences on testing, I would strongly suggest you follow Prof. Michael Mina on Twitter (@michaelmina_lab): in particular, this thread (on the consequences of using PCR testing alone in guiding public health decisions) is very important.

c) Implications for vaccines: the above questions have huge implications for vaccines’ development / testing / distribution logistics: if immunity generated by the virus is indeed short-lived, then we might have to become accustomed to annual booster shots, for example. Add to this huge uncertainty some other important complexities, such as i) the mRNA vaccines currently under development are likely to require -70 Celsius or -20 Celsius cold chains; ii) that as much as 30% of the US population does not believe in vaccines and, finally, and perhaps very importantly, iii) that the recent public communication blunders by the FDA and the CDC are very likely to further increase the suspicion that any vaccines approved in a hurry just ahead of a close, contested election might be more motivated by politics than science, and you have all the ingredients for a very messy situation in which not enough people get vaccinated. [Clarification: 9:34 am ET, Sept. 1. The cold chain conditions can vary depending on the mRNA vaccine candidate. A previous version of this article grouped them together.]

Some thoughts and forecasts for the fall

First of all, thanks for sticking with me so far. Obviously what follows is speculation. That said, I am quite concerned about the upcoming autumn / winter season. As mentioned above, the virus spreads readily and easily indoor, virus inoculum sizes become probably much bigger, and as we transition to indoor classes / living in general, in a much more generally dry environment, this is very dangerous, especially as the baseline of people already infected in the US is extremely high, driving a steady rate of community transmission (compared to most other countries). As a data point that further corroborates this, we should look at Australia: as well discussed by Silvia Merler (@SMerler), and as shown below, Australia is now truly undergoing a “second wave”, with much higher mortality rates than the first. For those of you who have not been to Australia (and who are not familiar with the fact that our planet has opposite seasons in the two hemispheres: yes, am talking to you, flat-earthers…), Australia underwent its first wave around the end of their summer and is now undergoing their second wave in their winter. With the usual lag, the second wave appears to be having a disproportionately high fatality rate vs the first. At the same time, we cannot say Australia is governed by a “negationist” government or was not warned about the virus ahead of its second wave.

To conclude, some suggestions:

a) I am extremely glad that a number of jurisdictions, including some universities, seem to be starting to administer the current season’s flu vaccine early, to prevent a flooding / overrun of their healthcare systems. I suggest this should become mandatory across the country, as soon as possible.

b) I understand the economic imperative for universities and schools to reopen (also, which parent would want their teenage children brooding at home for another year???). However, we need to be extremely mindful for the potential to further increase spread due to disorderly behavior usually associated with young adults (who are not usually showing the most compliant and obedient behavior at the best of times). It is truly amazing to observe the wave of innovative solutions being tested by various universities / colleges. Some examples of such innovation are shown here: I believe more colleges should follow the University of Arizona and University of North Carolina approach and implement wastewater virus testing from college dorms to have an early warning signal which allows them to implement contact tracing and isolation of infected / asymptomatic individuals very early in the process. Amongst many reasons to use this testing is that i) there is evidence that the virus shows in stools before or at least concomitantly with the early infectiousness period and ii) the method does not require asking teenagers to be compliant with various testing / masking / social distancing guidelines.  

c) The recent launch of a fast, cheap and easy to perform antigen test format (from Abbott Laboratories) could also finally introduce a much-needed game changer on the playing field: again as discussed by Michael Mina this test format could really be useful to break transmission chains, therefore limiting / containing local outbreaks early on in their spread (which is not the case, still, with the current test types available in the US, due to their lack of reliability and the incredible, mind-boggling delays in obtaining results). This test, and hopefully soon others like it, should be deployed at scale across the country ASAP. What do I mean by “at scale”? Looking at the scope of the pandemic in the US, we should test tens of millions of people A WEEK to have a chance of contain local outbreaks / superspreading events.

d) Wear a mask.

Follow Otello Stampacchia on Twitter: @OtelloVC

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


A Swing and a Miss from the CDC

Mike Pellini, managing partner, Section32

Please help me understand the value of OUR Centers for Disease Control and Prevention in 2020.

It’s baseball season — sort of. We have been waiting and waiting for the CDC to step up to home plate. The bases have been loaded for 7 months, and their fans have been waiting. The CDC is supposed to be our national cleanup hitter.

Yet, instead of trying to hit the ball out of the park for the grand slam, they have either struck out each time or tried for the occasional bunt single. This week, they decided to not even leave the on-deck circle.

Here’s the situation. Millions of kids and parents are seeking solid, science-based recommendations on what to do about school this fall during the pandemic. The CDC responded to this challenge by issuing revised guidance on Aug. 26 that said asymptomatic people who have been exposed to an infected person don’t necessarily need to get tested.

That revised guidance — to do less, not more testing — reportedly came from the White House and top levels of the Department of Health and Human Services. Maybe it did; maybe it didn’t. What matters is that the CDC issued the information.

Scientists were baffled, as the new guidance makes no sense. Within hours, CDC director Robert Redfield backpedaled, telling reporters that “testing may be considered” for anyone who has been exposed to the virus.

In a statement, Redfield said:

“Everyone who needs a COVID-19 test, can get a test. Everyone who wants a test does not necessarily need a test; the key is to engage the needed public health community in the decision with the appropriate follow-up action.”

The public needs firm guidance. This statement is so wishy-washy, it is meaningless.

Is there any real value left for this aging, high-priced player? 

Stats in baseball don’t lie. Stats in healthcare generally don’t lie either. Roughly 40% of the spread of COVID-19 virus is from asymptomatic people. In a country with 5.9 million confirmed cases of COVID-19, and many more unconfirmed cases, it’s safe to say we have several million people capable of spreading this disease without even knowing they are sick. That’s undebatable at this point (though I know even the most basic facts are seemingly up for debate these days.)

Let’s recap some of the most visible and critical missteps by the CDC since the start of the pandemic, and let’s consider the consequences.

  • Misstep 1: Failing to swiftly deliver an accurate diagnostic test. This failure, from January and February, has been well documented.
    • Result: At least a 6-week delay in the availability of the initial COVID-19 tests for the public. That delay allowed the disease to spread far and wide from its initial ports of entry, undetected. This resulted in a constant game of catch-up in efforts to implement a serious testing/tracing/isolation strategy, which still hasn’t been implemented at the national level.
  • Misstep 2: Months into the pandemic, the CDC recognized the data being reported was a combination of viral and serology testing.
    • Result: Public COVID-19 data on which supply allocation decisions were being made was inaccurate. As a reminder, viral diagnosis generally spots current infections with the virus, while serology diagnosis generally tells us about infections that occurred in the past, and which prompted the patient to develop antibodies to the virus.
  • Misstep 3: The CDC has been muzzled from the start, unable to communicate directly and forcefully to the American people. No one from the CDC has provided clear guidance to educate the public on the appropriate utilization of serology versus viral testing.
    • Result: Public confusion on how to use each testing type, as well as the value of each approach.
  • Misstep 4: The agency has failed to produce appropriate and adaptable testing guidelines for workplaces and community organizations, including schools.
    • Result: Our businesses and local schools are flying blind and on their own. Most are developing their own testing guidelines from scratch and with limited to no guidance from the federal agency with the world’s best expertise in epidemiology. Schools are facing financial risks from donors and others who wonder why their policies appear to be out of step with the CDC, regardless of how inconsistent the agency’s guidance may be.

Now we have to deal with this latest blunder —  actually discouraging testing for asymptomatic individuals who have been exposed to a known infected person. Clearly, these people are at high risk of infection to themselves, and they pose a risk of infecting others — potentially many, many others if they show up unmasked, at a large event, especially indoors.

Why not test these people to reduce the chance of them becoming spreaders, or even superspreaders? Instead of making this common-sense recommendation, the CDC just walked off the field and did not even demonstrate an effort to hit the ball.

Our nation is at a loss. On what scientific justification did they make this decision?  

We know “The key to con­taining the virus is how ef­fectively a coun­try builds up sys­tems for test­ing, trac­ing and iso­lat­ing po­ten­tial virus car­ri­ers, while es­tab­lish­ing clear safety rules as the econ­omy re­opens.” (WSJ)

Let’s face it; the CDC has clearly demonstrated it either doesn’t have its head in the game, or it is a cleanup hitter that has been forced onto the bench.


Convalescent Plasma: Look Before You Leap

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

In the last few days I have been wondering how Michael Joyner and Arturo Casadevall have been feeling.

Joyner and Casadevall are the first and senior authors, respectively, of the report, “Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three Month Experience,” posted on Medrxiv on August 12. The preprint server allows researchers to make their work public before peer review, and has become a popular source for producers and consumers of evolving research on the SARS-CoV-2 pandemic.

The report describes the experience of an Expanded Access Program, providing convalescent plasma from recovered COVID-19 patients to roughly 35,000 hospitalized patients over 3 months. All received plasma transfusions, so patients receiving the product could not be compared with those who did not get it.

Despite the lack of any comparison between patients who did and did not receive plasma transfusions, this report has formed the basis for the FDA’s Emergency Use Authorization for convalescent plasma to treat COVID-19 patients. It’s the report that was embarrassingly misinterpreted by the commissioner of the FDA, Stephen Hahn, and by administration officials. And it is the report that may well have spelled the death knell for controlled trials that were hoping to give us a convincing answer as to whether and how well the treatment actually works.

It is hard to imagine that the report’s authors actually intended for all of this to happen. Yet, by doing what medical researchers do all the time, they played into the hands of an administration hungry for anything that would show they were making progress against an intractable virus that has killed at least 200,000 Americans.

To understand how this unfolded and why it bodes so badly for the future, we need to examine the story that the report lays out. The report itself is mostly reasonably transparent, at least about the patients involved (roughly 35,000 over three months from April to July) and how sick they were (52% ICU and 27% on ventilators). The authors obviously recognized that they were reporting an experience rather than a randomized study, and that there was no comparison group since all included patients received at least one unit of plasma. But they still concluded that their findings provided “signatures of efficacy for convalescent plasma.”

What were these “signatures of efficacy”? According to the report and the FDA announcement, there were two: that patients given the product earlier in the course of their illness and those with high antibody levels in their donated plasma were less likely to die than those given plasma later or whose transfusions had low antibody levels.

More specifically, 8.7% of those given plasma within the first three days following their COVID-19 diagnosis died within a week, whereas 11.9% of those given plasma four days or later died. And, of the few patients (roughly one out of ten) for whom information on antibody titer could be retrieved, 8.9% of those in the top 20% and 13.7% of those in the bottom 20% died within a week. Notwithstanding the modest absolute numbers, the relative differences are clinically significant.

At first glance, these results might seem somewhat convincing.

I mean, if you wait to get plasma you do worse, and if your plasma is antibody rich you do better. Surely this must mean plasma works!

Not so fast.

There are major issues with these results that go beyond the (utterly justified) criticism that the data doesn’t come close to the established standard for evidence about novel treatments, the randomized trial. Indeed, the report’s authors lacked not only a randomized comparison between a treated and an untreated group, they were missing the untreated group entirely. So, they presented two alternative comparisons.

Each is problematic for its own reason.

The question of whether it is better to treat a patient earlier rather than later is universally challenging. In prostate cancer, a major controversy has raged for years about whether high-risk prostate cancer cases should be offered additional (adjuvant) radiation treatment right after primary surgery, or wait until their cancer relapses. A similar question occurs in breast cancer. But we can’t just compare patients given radiation in the adjuvant setting with patients given radiation for recurrent disease. They are simply not the same; indeed, some of the patients treated early would never have progressed to relapse even in the absence of radiation therapy.

In general, patients treated early in their disease course are a mix of those who would and would not be eligible for treatment later. In the case of COVID-19, patients at day 2 include those who would make it to day 5 or 10 without treatment and also those who would not! So, the analysis in the report that compares the patients treated within three days against those treated at four days or later is ill conceived. In the end, the results are basically useless.

Alright, you say, but what about the plasma titer comparison? The authors go to great pains to note that the titer was not known at the time of treatment and even use the term “pseudo-randomized” to describe this comparison.

I am going to leave aside the fact that the antibody titer analysis only included about 10% of the sample, and that it is therefore unclear how representative this group might have been, because there is a bigger issue here. This is the matter of how the high- (and low-) titer groups were defined.

There is no established threshold to define high- versus low-antibody titer for SARS-CoV-2. The authors chose the top 20% to be the high-titer, and the bottom 20% to be the low-titer group. This seems reasonable until you realize that they could have chosen the highest and lowest 25%. Or the highest and lowest 33%! Maybe they even tried these thresholds but presented just the results provided. We don’t know. Regardless however, the results show only that survival was improved in the high-titer group compared with the low-titer group. We don’t know if those who received low-titer samples did any better than if they had not been treated at all. In fact, there are real concerns about whether low-titer plasma might induce a harmful effect, referred to as antibody-dependent enhancement (ADE) of  coronavirus infection.

At best, we can only conclude from the titer comparison that high-titer plasma, amounting to approximately one-fifth of the plasma samples, might possibly constitute an effective treatment. There is absolutely no signal of efficacy for low-titer samples. But the FDA’s Emergency Use Authorization actually emphasizes that it covers all plasma samples, reflecting the report’s conclusions which also do not differentiate.

I don’t have a crystal ball and I can’t read the minds of the report’s authors in terms of what other comparisons they may have considered, or what they might be working on now to deliver more reliable answers. But their choices and their conclusions thus far are entirely consistent with an academic culture that rewards the finding of significant, positive effects associated with new treatments. It is a culture that encourages positive spin about novel medical interventions and overstatement of marginal clinical results.

In normal times, we might take the admittedly cautious but still overstated conclusion of benefit in this report with a grain of salt and modulate our expectations of effectiveness in practice accordingly. Doctors wouldn’t rush off and change prescribing habits instantly on this thin body of evidence – not until they could see a clear and convincing difference between patients who got convalescent plasma, and patients who didn’t.

Clearly, these are not normal times. Scientists need to do whatever they can to make sure that their science is not misinterpreted, exaggerated, or even hijacked to make a political point. I sure hope that Drs Joyner and Casadevall are alarmed that their research featured so prominently in what can only be considered a dress rehearsal for the vaccine study results that are expected later this fall. 


An Underappreciated Aspect of Power: Listening

David Shaywitz

As the summer draws to a close, I thought TR readers might enjoy a final August distraction. I’ve always been an avid reader, and lately, I’ve found myself increasingly drawn to the history and science of American politics. 

On the history front, and inspired by Stanford professor Jeffrey Pfeffer (an expert on power and leadership), I’ve started Robert Caro’s famously comprehensive multi-part biography of Lyndon Johnson. I’ve completed the first volume: The Path To Power (1982), which describes how the Johnson family first arrived in Texas, and takes us from Johnson’s rough childhood in the unforgiving hill country, through his election as a Congressperson in 1937, and concludes with his razor-thin loss in the special Senate election of 1948.

Johnson emerges as a striking if deeply flawed individual, with indomitable ambition, a relentless work ethic, a need to be in charge, and a drive to win at all costs. A student of human nature, he cajoles those whose support he craves and dominates those beneath him, tirelessly manipulating all who he encounters.

Johnson steals a series of elections, starting in college. Ironically, his defeat in the Senate 1948 race apparently reflected not the propriety of the election, but rather the ability of his opposition to cheat more effectively. 

It becomes immediately apparent that ambition, narcissism, and the privileging of victory over ethics is not the sole provenance of a particular person, party, place, or time. I’m just beginning the next volume (Means of Ascent [1990]), and the author cautions in the preface that (somehow) it promises to be even darker than the first.

For those interested in a deeper understanding of the contemporary political state, the obvious must-read here is Tim Alberta’s American Carnage (2019), describing the transformation of the Republican party into the party of Trump. Alberta is now the Chief Political Correspondent at Politico, and previously wrote for  the conservative National Review.

Alberta brings unusually deep insight into his subject, and the sense that he’s reporting about the party’s current state more in sorrow than in triumph. You can get a feel for his style from his deeply perceptive recent essay about the state of the GOP, lamenting that no one really knows what the party believes in anymore.

Technology and the sophisticated use of data and social media is often said to have played a central role in Trump’s 2016 victory. We’re afforded an insider view of this in Targeted, Brittany Kaiser’s account of her involvement with the infamous data firm Cambridge Analytica (CA), and its close relationship with the Trump campaign. Aspects of this are also covered in the Netflix documentary, “The Great Hack.”

While Kaiser suggests Cambridge Analytica played a key role in Trump’s victory, many others are more doubtful. Writing in The Atlantic, Ian Borogos and Alexis Madrigal dismiss the contribution from Cambridge Analytica, and emphasize the role of the Facebook algorithm itself.   

Even here the impact isn’t clear; Hugo Mercier, a cognitive scientist immersed in this literature, tells me that “the effects of advertising [including online ads] for political campaigns in general elections are small at best.” 

He adds “the effects of online ads are small and noisy, indeed, so small and noisy (as a rule) that even researchers at Google admit that it’s impossible to know whether online ads bring positive ROI [return on investment].” I recently downloaded his new book, Not Born Yesterday, and look forward to his discussion of why persuasion is so difficult.

The challenge of voter persuasion in particular was highlighted by a high-profile 2017 study from two academic researchers: David Broockman, now at UC Berkeley and Joshua Kalla, at Yale. They examined data from 49 field trials, and concluded that political campaigns have essentially no detectable impact on candidate choice in general elections. Most people ultimately vote along familiar party lines, and it’s apparently much more effective to mobilize your own partisans compared to trying to get partisans on the other side to switch.

It also turns out that the fraction of persuadable voters is probably also a lot less than you might think. A key research finding is that while ever-more people self-identify as “independent, if you push them, most of these acknowledge they lean left or lean right. Data suggest these leaners are at least as partisan in their ultimate voting as the voters who affiliate from the outset as either Democrat or Republican. Thus the number of true independents is comparatively small.” 

There’s also the added challenge of how to think about this middle group, often referred to as “undecideds.” This can refer to likely voters who are actively weighing who to vote for, but could also encompass voters who feel alienated from politics (and the increasingly partisan nature of politics), and opt not to vote at all; such “low frequency” voters are notoriously challenging to draw to the polls. 

Two fascinating political scientists who’ve thoughtfully discussed aspects of these issues: Rachel Bitecofer (here) and David Shor (here).

The difficulty of changing votes meanwhile doesn’t mean persuasion is entirely useless.  Work from Todd Rogers applying psychology to election strategy through an iterative series of field trials has resulted in a series of ways to “nudge the vote,” as Sasha Issenberg of the New York Times put it in 2010. (Issenberg subsequently wrote a book on the topic, The Victory Lab (2012), examining the science behind Obama’s 2008 win).

One successful method: closing the intention/action gap by asking voters questions that force them to think through how they’ll actually go about voting; this approach has been shown to increase turnout in a statistically significant fashion.

Importantly, while it can be difficult to convince voters to change their minds, research suggests that some efforts to persuade people to change their opinion – particularly outside the partisan signaling associated with a general election – can be successful. For example, Broockman and Kalla published a study in 2016 that found a small but significant number of respondents (about 10%) could be persuaded to embrace a more sympathetic view of transgender rights, a change that endured for at least three months. 

The key, it turned out, was “deep canvassing,” meaning the field volunteers engaged in an extended, empathetic conversation with the respondents, listening intently and asking thoughtful follow-up questions.

In these fractious times, this is a hopeful message from which we all can learn. When everyone is so busy trying to talk, there can be remarkable power in attentive listening.

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