Your Edge In Biotech.
22
Dec
2020

Listening Through The Noise and Talking to Those Who Will Listen

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22 Dec 2020

Sam Blackman, MD, PhD; co-founder and chief medical officer, Day One Biopharmaceuticals

Pediatric oncologists like me tend to know their cancer chemotherapy combinations, chapter and verse.

But for me and many of my colleagues, vaccines have always loomed large, integral to the “pediatric” part of our medical training.

As a medical student in the late 1990s and a resident in pediatrics during the early 2000s, vaccination was a constant source of discussion.

We were watching the clinical and regulatory community debate the risks of using thimerosol  – an organomercury preservative – in multi-dose vials of various vaccines because of a convergence of factors. Autism diagnoses were on the rise, prompting some to raise concerns about an epidemic.

Much attention was focused on the now-retracted, fraudulent 1998 publication from Andrew Wakefield. New Jersey Congressman Frank Pallone raised concerns about the effects of environmental mercury poisoning. Despite no evidence of harm from its use, thimerosol was removed from all vaccines routinely given to children 6 years of age and under, manufactured for the US market.

The flurry of competing conspiracies, fears, statements, and studies turned the once-routine discussion with parents around childhood vaccinations into increasingly complex conversations on the nature of risk and evidence.

The fears stoked by the growing anti-vaccination movement were hard to counter. These fears frequently collided with the natural reticence of physicians and scientists to use words like “impossible” and “never” – words loaded with the hubris of total certainty.

At the same time, the early 2000s were also notable for major disruptions in the supply of vaccines against the major childhood illnesses, including diphtheria, influenza, measles, mumps, pertussis, tetanus, and varicella. Our community primary care clinic at Cincinnati Children’s would have a dry-erase board that would remind the residents what vaccines we had in stock, and more concerningly, what vaccines we didn’t have in any fridge or freezer. And woe unto the resident who spent their 15 or 20-minute clinic visit convincing a parent to vaccinate their child only to find out that we lacked supply – oftentimes that was sufficient for yet another child to fall between the cracks.

As if these first two challenges weren’t enough, the mid-2000s also saw a significant expansion of the childhood vaccine schedule with the approval and introduction of the first meningococcal vaccine (Menactra), a new rotavirus vaccine (RotaTeq, which had to overcome concerns about the first generation rotavirus vaccine and its association with small bowel obstruction due to intussception), and most notably, the introduction of a vaccine against HPV (Gardasil) which prevented both genital warts and pre-cancerous genital lesions. The latter again led to an uncomfortable overlap between public health policy and politics when then-Governor Rick Perry of Texas mandated all girls to be immunized as a condition of entry into 6th grade.

Religious conservatives cried foul against the mandate, that it would encourage sexual promiscuity. Liberals later howled in outrage when reports surfaced that Merck had lobbied for the mandate as a good way to increase sales of a new patented vaccine.

What was the result of this extreme noise? As a pediatric residents, my colleagues and I found ourselves spending a disproportionate amount of time working hard to overcome intense vaccine skepticism and vaccine hesitancy, particularly in the inner-city neighborhood served by my program’s primary care clinic. There were (and still are) pediatricians who were so frustrated by parents who they couldn’t convince to vaccinate that they considered discharging them from their practices – something that I personally considered.

Then I became a parent. And while that didn’t cause a moment’s hesitation for me or my wife in terms of whether or not to vaccinate our daughter, it did give me a chance to sit in the “patient” seat for the first time in a long time. Coincident with being a parent is that your siblings and friends have kids, and as a pediatrician, I got a number of calls – some of which took me by surprise because they came from friends who were also physicians – asking basic questions about vaccine safety. This gave me the opportunity to relive the conversations I had as a younger, childless resident physician, and refine my technique.

So, how can these experiences and lessons inform the moment we are living in now, when the noise – from the anti-vaccination groups, conspiracy theorists, foreign and domestic political opportunists, and even malignant elements within our own government – is deafening?

Here are some suggestions, and I think they apply equally to physicians and nurses and other health care professionals as well as those of us in the biopharmaceutical industry:

  • Keep the message simple and unambiguous: Science, especially new science, can be intimidating. While those of us in biotech have fully internalized the central dogma of molecular biology, not everyone appreciates the fact that the road from a synthetic mRNA to an immunogenic protein is a one-way street. A Schoolhouse Rock approach to explaining how vaccines work, and their importance, is always going to find a broad audience. And we must remember that not only are we looking to influence adults, but also their children.
  • Describe risk in easily understandable terms. With the infection fatality rate and crude mortality rate in the US increasing, the risk of dying from COVID-19 for certain age groups is comparable to other known risks, including some where we reflexively take preventive measures such as wearing seatbelts, bicycle helmets, or lifejackets, some of which are government-mandated. Similarly, the risks from vaccines is infinitesimally small compared with risks we take in day-to-day life. Giving people a frame of reference and using a gentle, questioning manner  (“Why did you wear your seatbelt when driving today?”) can be a great conversation-starter on relative risk.
  • It’s important that we set a good example. I am insanely jealous of my friends in clinical practice who are posting their immunization selfies – a condition now referred to on #BioTwitter as #VaccineEnvy – partly because they have access to the vaccine, but partly because I know they are at the leading edge of setting a good example for their peers and patients. Health care professionals must practice what we preach. We must talk to our vaccine-hesitant peers to address their concerns and fill knowledge gaps.
  • We must be empathic. It goes without saying that a sanctimonious stance when it comes to vaccines will not only fail to be convincing, but will likely close the door to future opportunities to influence people to get vaccinated. Bullying patients into compliance does not work. At the same time ….
  • We shouldn’t waste time trying to convince the unconvincible, but we must not give up. In a fast-moving pandemic, it is essential that the uptake rate for the vaccine be as brisk as possible. Spending time trying to convince the hard-core conspiracy theorists (Watch this only after a taking a few deep preparatory breaths) to get vaccinated rapidly reaches the point of diminishing returns. We need to move on to the next patient, talk to those who will listen, and remember that the Pareto principle is a very useful tool during times of crisis. We will achieve herd immunity more efficiently by finding the 80% who will willingly vaccinate with little additional convincing.
  • Institutions must take a stance. We are experiencing a pandemic, so the mandatory vaccination rules we use for measles and tetanus and HPV aren’t sufficient. However, rules set by governments and large private institutions can be a forcing function. We should debate the consequences – both intended and unintended – of private employers mandating vaccination (especially in health care settings), private health insurance requiring immunizations as a condition of coverage, and international travel restrictions for those who electively choose to go unvaccinated.

People may bristle at being forced to do something they don’t want to do, but for this, and future pandemics, we need to continue to explore ways to effectively combat science denialism and protect our citizens and our economy.

Samuel C. Blackman, MD, PhD lives on Orcas Island, WA and trained as a pharmacologist, pediatric hematologist-oncologist, and neuro-oncologist. He is currently the co-founder and Chief Medical Officer of Day One Biopharmaceuticals. His views reflect his personal opinions, and not those of Day One Biopharmaceuticals.

21
Dec
2020

More Than Words. Taking Steps Together Towards Greater Health Equity

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21 Dec 2020

Nina Kjellson, general partner, Canaan Partners

Healthcare leaders have made many commitments this year on racial equity.

The question now is how we turn words into action.

Over the past couple years, I’ve become a believer in the power of small groups that share an immersive, cultivated experience.

In September, I convened one such group on a two-day virtual journey to Montgomery, Alabama. This virtual conference grew out of my work on Impact Experience//Health Equity. It’s a partnership born of an Aspen Health Innovators’ fellowship in collaboration with longtime equity educators, Impact Experience.

The trip to Montgomery was inspired in part by the experience a few of us biotechies had in climbing Mt. Kilimanjaro for cancer research at Fred Hutch. On that trip in summer 2019, all 14 men and all 13 women made it to the summit of the highest peak in Africa (elevation 19,340 feet). It wasn’t always easy. But coming down, we realized we had forged a cohesive family committed to each other’s well-being and success. Our email threads and Zoom reunions ever since have been a vibrant reflection of community born of sweat and struggle and revelations shared step by step.

My recent tour of Montgomery, with a couple friends from the Kilimanjaro climb, was the start of a new journey. We sought to trace the roots of structural racism in health care and what can be done about it.

This conference was unlike anything we had attended before. Our collective horror at the murder of George Floyd and Brianna Taylor, on top of the mounting evidence of the unequal toll of the COVID pandemic — both economic and health-wise — turned discomfort into moral outrage. We started to see inaction as complicity.

Consider some data:

Data analyzed by APM Research Lab.

  • If death rates from COVID were equal by race, 20,000 Black and 9,000 Latinx Americans would still be alive right now.
  • Many more young BIPOC people are being hospitalized and dying of COVID-19 as compared to white populations, despite younger people having much less risk of severe symptoms or mortality. (Source: APM Research Lab)
  • Over 70% of Black and 60% of Latinx households report serious financial problems during the pandemic compared to just over a third of white households (36%) and 40% of Black and 60% Latinx households report job loss, furloughs or wage cuts during this time. (Robert Wood Johnson Foundation)
  • Black and Latinx households have been statistically more likely to experience food insufficiency throughout the pandemic with shortages increasing over time. (Urban Institute)

As scientists and biotechnologists, we know well that these disparities are not rooted in biology. Melanin and a few continental alleles can’t explain the drastic differences in predisposition, access, experience and outcome with respect to health care and the many other institutions that determine health and social status.

Neither does income or education explain the disparities. We know, for instance, that fetal and maternal health outcomes for Black women are still well below those for white women when normalized for earning and academic achievement. Pregnancy related mortality for Black women with a college degree is 5 times that for their white counterparts. FIVE times. (Centers for Disease Control and Prevention)

Some disparity may be explained by a distrust and voluntary avoidance of the health care system leading to the delayed diagnosis and treatment of serious diseases such as cancer. Blacks have higher death rates from most cancers than all other racial/ethnic groups. Despite similar rates of breast cancer, Black women are much more likely than White women to die of the disease, according to the National Cancer Institute.

If this is because of a reluctance to seek care, might this be the legacy of James Marion Sims, the Tuskegee trials or the Flexner Report’s elimination of Black medical colleges (here and here)?

Like any journey, it has to start somewhere. This one begins with education and awareness. The Impact Experience//Health Equity program is comprised of pre-curriculum, a guided (virtual) tour, community-member engagement, moderated seminars with expert faculty and group and individual exercises. But it wasn’t all about content. The two days were interspersed with unstructured time for music, art and conversation. We crafted the program to cover history, current events, social and emotional learning.

Our vision is to catalyze both a committed peer cohort and firm action plans for implementing change.

We had an initial group of 29 participants on our virtual journey to Montgomery. These people were leaders from biopharma, pharma, diagnostics, academic medicine, health insurance, public health, venture and public investing and management consulting.

To a person, the reviews on the experience were exceedingly positive – for the depth of exploration, space for personal introspection and group activities imagining – and charting – a future free of implicit and structural bias.

In follow-up conversations over the past three months, we have seen a great deal of camaraderie, including local e-meet-ups and projects. We are seeking to hold ourselves accountable to the goals we’ve set for our companies and ourselves. We’ve had deep debriefs of the experience, in order to spread what we’ve learned throughout our organizations.

We’re insisting on concrete actions like implementing new ways of hiring and training, tools for recruiting diverse participants in clinical trials, criteria for selecting minority-owned vendors and new approaches to talking about race and equity.

Everyone, of course, is busy. Two days might seem like a lot to commit to a seminar or continuing education program. But the time allowed for immersion not just in the curriculum, but also for building relationships among peers.

There’s something special about getting to know professional peers on a personal level. The level of intimacy that emerged was striking. Participants shared personal experiences of bias, racism, and hard-fought assimilation into power hierarchies. This was essential to breaking down barriers and confronting one’s own implicit biases.

These are the kind of raw, deeply felt conversations that rarely surface in the corporate environment.

These meaningful conversations translated into clear actions. New internship programs were established. Some of us redirected, or increased, our personal and corporate giving.

The structural barriers that exist in our sector runs deep – from the way we train, teach, architect and even structure information. Medicine, historically, hasn’t anticipated including women or people of color in leadership.

Health care emerged as a sector within a historical, societal, and cultural context. It will take many years and much effort to undo bias and reinvent the field. The journey we took as a group to Alabama started with the 250-year history of enslavement, the next 100 years of the Jim Crow era, followed by the Civil Rights era of the 1960s to the present. We can’t begin to understand the health disparities of today, and the potential solutions, unless we understand this arc of American history.  

The distance we traveled together, from our heads and deep into our hearts, gives me great hope that we as leaders can accelerate change. There are things we can all do, from grass roots solutions all the way through helping advance legislation at the state and federal levels.

And if the moral calling isn’t the motivation, then the markets and business needs will compel us.

Over the next 10-20 years, more than half the US population will be self-described as other than white, according to the US Census Bureau. This means the demographics of our studies, employees, patients, payers, regulators, investors will be shifting. Study after study has shown financial and compliance outperformance by companies with greater gender, racial/ethnic and immigration diversity. A McKinsey report from 2017 found a 33% likelihood of EBIT outperformance by companies with ethnic and cultural diversity and 21% higher profitability from companies with above average gender representation on executive teams.  

As we reflect on 2020 – and the ways in which we have been moved by this difficult year – I hope we can take the moments of awakening and make them into movements towards a more equal, equitable and healthy world. (Whether out of love, righteousness or business-interest).

You can join networks like this, to spark movement in your spheres. You can create this kind of momentum.

I’m getting ready for another Impact Experience//Health Equity. The next journey is in March. We are seeking to turn the words of 2020 into the actions of 2021.

Interested? nina@canaan.com

If you are making your year-end charitable giving list, please consider Life Science Cares. We are channeling funding and volunteerism from the life science community to close the needs gaps in Boston, Philly and the San Francisco Bay Area. Our focus is on homelessness, hunger, STEM education and internship and workforce opportunity with an emphasis on diversity. Please make a note designating geography of interest. https://lifesciencecares.org/donate/

20
Dec
2020

Science in the Face of Fear: Vaccine Hesitancy and Public Trust

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20 Dec 2020

Larry Corey, MD

This month has been a media whipsaw.

News of the Pfizer and Moderna mRNA vaccines’ compelling efficacy and the U.S. Food and Drug Administration’s rapid response and issuance of an Emergency Use Authorization for both vaccines have been met with equal parts jubilation and fear from a divided public.

For me, as a medical virologist and researcher, this remarkable achievement is a clear demonstration of the power of science and its potential impact to save lives. To see these curves below that show the difference in disease course between those vaccinated and those receiving the saltwater placebo are about as big a spread as I’ve ever seen in any study.

We call these Kaplan-Meier curves, and if you’ve worked in cancer or most diseases, you just never get to see curves like these. Even when a study is considered a success, rarely do you see evidence this overwhelming in favor of a new drug or vaccine. And this is one reason I have embedded the curves of both studies into this blog. If you are used to seeing these curves, they just make you smile and think, “How did that happen?”

A scientific success such as this one just feels good. With it comes a sense of community pride, particularly when you see the incredible adulation from impassioned medical care workers who are grateful to receive the vaccines. It’s wonderful to see videos of them dancing outside of the hospitals. We as scientists have to smile when we see images of front-line workers with their heads bent, overcome with relief and gratitude for a vaccine that seems powerful enough to relieve them of the stress of dying on the job.

And yet, we can’t quite fully celebrate now. How does one measure a successful outcome in its entirety when recent polls show that approximately 40% of Americans would be unlikely to get a vaccine even when it becomes available to them? Or when one reads about town hall meetings populated by fellow Americans who are clearly mistrustful, images with hesitant faces. The fear is plain.

These images and data force one to pause—to take a step back and view the difference in perspectives—because the two visions side by side are difficult to balance.

True, maybe many Americans haven’t seen a Kaplan-Meier curve before. Maybe they don’t understand the nuances of the clinical studies and their protocols. But they understand what 95% protection from disease means—a clear indication the vaccine means it helps; it helps a lot.

Even so, I see the fear firsthand. An acquaintance of mine recently told me his mother refuses to take the vaccine. She is over the age of 70, and has multiple risk factors for severe COVID-19. This woman has sought my advice for other medical concerns, so she clearly has some measure of trust and respect in my opinion. But in this situation, the fear overrides her knowledge of what science can (and does) accomplish.  

My first reaction was to talk to my acquaintance in an authoritative way, wearing my medical science hat, so to speak. Then it occurred to me that I wasn’t going to change her worldview simply because I was “the medical authority” sharing the information.

So, then I tried to step back and ask myself a few questions. How can I do this respectfully? Or how much energy should I put into this? How do we set our expectations? What’s the goal here? I’m reminded of one of those statements learned by most of us early on—probably while arguing with an authority figure who was trying to offer reason: you can lead a horse to water, but you can’t make it drink.

So, I think there are lessons to be learned on both sides—that we all need to be respectful of differing viewpoints while we move toward greater understanding, compassion, and trust. And we all need to understand that there is context—for each person.

There are some situations—and the COVID-19 pandemic might be one of them—where the tincture of time is needed to heal the wounds. And there are wounds that have bred mistrust: wounds caused by self-serving narratives of national leadership that were unrelated to the scientific process at hand. And although the outgoing administration did a wonderful thing by providing an enormous amount of funding, “Operation Warp Speed” isn’t a name that inspires trust.

In most other contexts, and certainly outside of a public health emergency, when we think of the rigors of science, speed is not something we associate with positive outcomes. As one old proverb goes “haste makes waste.” Even those who don’t subscribe to that folk wisdom might naturally wonder, “were corners cut along the way to get a result this good, this fast?”

As someone on the inside I can say unequivocally – no, corners weren’t cut. Rigor was maintained. Yet I can see why people might still be suspicious. Throughout the vaccine trials, anytime something good happened, credit was narcissistically claimed by the President rather than letting the real inventors own it. By personalizing it, the vaccines became politicized. It created an odd discord, as if science—and what is in a vial—had something to do with whether you’re a Republican or Democrat.

Of course, we didn’t put Democrats in the vial; we didn’t put Republicans in the vial. It’s true: we had a lot of political leaders take control in an unscientific way and try to dictate the human behavior they wanted to see. But the scientific goal has always been: how do we alter and stop the disease that was rapidly attacking our nation and its people? How do we use pharmaceutical and nonpharmaceutical interventions alike to control the spread and keep Americans safe?

Scientifically, the goal has always been the same. How different political leaders communicate varies. And the vial gets caught up in the middle.

I don’t know how to unwind this except for time. I don’t know how to unwind this except for understanding.

My brother-in-law, a role model who inspired me to become a physician, passed on a wise saying when I was young. He died far too early, at age 37, from Candida sepsis that struck him while getting treatment for Hodgkin’s disease. Before he died, he said to me, “Larry, the educated man is the tolerant man.”

It will take work by all of us—in the scientific community and in the broader public. It will take hard work to convey the importance of vaccination. It will take time to rebuild trust across the divide. And it will take a public open to healing discourse; a public which remains curious and eager to know more as we learn more. Because we will.

If this pandemic has taught us anything, it has taught us that scientific successes beyond imagining are possible with resources, urgent focus, and the kind of global scientific collaboration we’ve seen over the past ten months. And as a scientist and physician, I will take solace in knowing that those who want the vaccine and can benefit from it, will be able to get access to it.

I pray that all who want, not just in our country but globally, will be able to receive this gift of science. All the people of the world deserve to be vaccinated. It is a great feat to say, with clear conviction, “COVID-19 is a vaccine-preventable disease.” 

 

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN ) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.

19
Dec
2020

There Is Light at the End of the Tunnel, Yes. But it’s a Long Tunnel

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19 Dec 2020

Otello Stampacchia, founder, Omega Funds

I will start with the good news.

The good news

As of this writing, on Dec. 19, the FDA has just granted ModeRNA an Emergency Use Authorization (EUA) for a coronavirus vaccine. We now have two vaccines available, based on essentially the same mRNA-based technology, including the one from Pfizer/BioNTech that received an EUA earlier this month.

It’s worth stating that both ModeRNA and BioNTech (the company that originated the vaccine developed by Pfizer) are led by immigrants. Think about that when you want to close borders and stop immigration, perhaps?

Before I move on to more depressing topics, it is important to reflect and rejoice on just how *amazing* this feat of science is. The coronavirus genetic sequence was made available in January. In less than 11 months, we have now two vaccines passing muster with regulators and being widely distributed.

The previous vaccine development record was for mumps, developed in roughly 4 years and approved in 1967. We are witnessing a scientific revolution unparalleled, in its breadth and depth and in my (very) biased opinion, since the end of the Renaissance.

This truly is biology’s century.

Amazement should not stop at the speed of these vaccines’ development. They are (both) incredibly effective, certainly beyond my (perhaps pessimistic) expectations of a 60-70% efficacy range. In clinical trials with tens of thousands of individuals, both vaccines achieved >94% efficacy rates in protecting against infection, and resulted in *no severe symptoms in people who became infected*.

Importantly, they were both effective for different races / genders, and for individuals in high-risk populations (including the elderly, and people with underlying medical conditions). Side effects reported from the clinical trials were generally mild and temporary (more on this later). In summary, these two vaccines were not only developed in record time – they rank among the very best of all vaccines in terms of efficacy. 

As highlighted by this graph (from @xkcd’s Randall Munroe: one of the best / funniest comic illustrators of scientific / statistical topics): the data are so clear and compelling that we don’t need to do statistics on it (fear not, I will bother you with statistics in a bit)…

You know the expression “don’t shoot the messenger”? I say shoot it (the messenger RNA!) straight into my arm as soon as it is feasible to administer it to the (relatively) lower risk population I belong to!

Did I manage to make you feel good (nay: great!) about science? Fabulous.

Now let me make you feel bad about human beings and our behavioral fallacies.

The Bad News: This Tunnel is a Lot Longer and Darker Than You Think

If you are up-to-date with the latest coronavirus pandemic news, I suggest you skip this part. That said, I highly recommend you read it if you are planning large family (or any type of) gatherings with people outside your immediate, close family “bubble” around the upcoming holidays.

As published in JAMA (Journal of the American Medical Association) on Dec. 17, COVID-19 is now the leading cause of death in the United States. As JAMA horrifyingly and clearly says, “The daily US mortality rate for COVID-19… is equivalent to the September 11, 2001, attacks, which claimed ~3,000 lives, occurring every 1.5 days, or 15 Airbus 320 jetliners, each carrying 150 passengers, crashing every day”.

Let me repeat that: *15 full planes crashing every day*.

This country has gone to (many) wars for a lot less:

(Graph above by Rob Rogers, award-winning, nationally syndicated editorial cartoonist formerly with the Pittsburgh Post-Gazette: follow him at @Rob_Rogers).

And there is no immediate end in sight to the carnage. The graph below, from The COVID Tracking Project (@COVID19Tracking) makes this abundantly clear. We have been breaking hospitalization records across the country, day after day, for close to two months.

The graph to the right should be horrifying indeed: as predicted in my Aug. 31 Timmerman Report article, we are exceeding, and will sadly continue to exceed, peaks in deaths reached during the April phase of the pandemic, when we were unprepared and scientists knew much less about the virus and how it’s transmitted.

What is our excuse now? Did we really think this virus was going to magically disappear? If so, shame on us (well, I am not sure that should be on me, TBH, but I wanted to “participate” in the collective shaming of our behavioral fallacies).

As a country, we are collectively failing the “marshmallow test”. For those of you who are not into behavioral theories, the “marshmallow test” was a study on *delayed gratification* led by Walter Mischel (from Stanford) in 1972.

In the test, a child is presented with the opportunity to receive an immediate reward or to wait to receive a better reward. A relationship was found between children’s ability to delay gratification during the test and their subsequent academic achievement. In follow-up studies, researchers were able to find a connection between ability to delay gratification with better life outcomes, as measured through quantifiable metrics such as SAT scores, educational attainment, and Body Mass Index (BMI).

These findings were made before the pandemic (unfortunately, like 71 million Americans, I have meaningfully increased my BMI this year. I blame the alcohol.)

So, again and again, with our collective shortsightedness, we traded short-term gains for what has truly been a painful fall / winter. We had summer at beaches and bars, then Thanksgiving gatherings, all while *knowing* this will result in many more people spending Christmas in the ICU.

US Thanksgiving travel broke pandemic era travel records, and resulted in the spike in cases, hospitalizations and deaths we are currently seeing (remember: reported cases lag hospitalizations by 2-4 weeks, and those lag fatalities by another 2-4 weeks). You can see those spikes in the graph above. The same will happen following Christmas gatherings.  

How to Think About Risk

Warning: the segment below contains some discussion of statistics (trust me I will try to keep it simple).

The ”Swiss cheese” approach to protection and risk mitigation (adapted to the pandemic from earlier “Swiss cheese” description of risk by Australian virologist Ian MacKay: @MackayIM) has recently been discussed (even by the New York Times.) In my opinion, it has merit insofar as it illustrates how you can protect yourself from infection by layering “slices” of Swiss cheese (the real one is called Emmental, by the way, if you like cheese).

Each of the “cheese slices” has holes, i.e. is not perfect. Overall, though, combining them (social distancing, masks, hand-washing, air ventilation + humidity) significantly reduces the overall risk. Vaccination, when available, will add one more, (very) important protective layer.

The graph’s latest version (Ian has been working on versions of this for months, may the fates always be in his favor) organizes / segments the slices into “personal” vs “shared” responsibilities, and encourages people to think in terms of *all the slices* rather than any individual single layer being the most important. There is virtually no “zero risk” situation (unless you are living, like me, on top of a mountain for the time being).

I would add the role of keeping indoor environments (whenever in contact with people who are not members of your household) not just adequately ventilated but also properly *humidified*: viral droplets appear to stay afloat much longer in dry, cold environments (I have spent a small fortune on humidifiers in the last months).

The graph is hopefully self-explanatory. However, those of you needing stronger glasses might not have noticed the cute, but incredibly dangerous “disinformation mouse” eating away at the protective layers. Just like the virus is “weaponized” and much more dangerous in indoor / wintry conditions, the sustained (coordinated??) misinformation campaigns running on social media are particularly dangerous when coupled to a lack of clear and consistent communication from public authorities.

You might remember some of these statements: “this is just like the flu”; “look at how well Sweden is doing and they are not crippling their economy”; “we are close to herd immunity”; “if we only let it rip, we will achieve herd immunity by the fall”; “this only kills old people, I want to go to the bar”.

Sadly, the list is quite a bit longer.

If you still believe in any of the bracketed statements above, please do me the courtesy to stop reading this silly piece of mine (and of never, ever speaking to me or any members of my family again, in case we used to be on speaking terms): you are entitled to your opinions, but you are not entitled to your own facts.  

The disinformation mouse (I personally think it should be a rat, but the graph was not my idea!) is already starting to eat away at the potential enormous beneficial effects that rapid, at scale vaccination should bring.

(In)famously, and admittedly humorously, Brazilian President Bolsonaro railed on Dec. 17 against potential side effects from Pfizer’s vaccines saying “if you become an alligator, that is your problem.”

Intriguingly, as seen below in a portion of the FDA report on one of the vaccine trials, there can be serious events indeed happening after administration of the vaccine: a trial participant was struck by lightning 28 days after vaccination!

Talk about incredible side effects!

I hope you are not taking the above *too* seriously: serious events happening to clinical trial participants *are not necessarily side effects caused by the vaccine*! (I certainly hope lightning strikes are not…).

Just to give you a better sense of the fundamental difference between correlation and causation, I invite you to read one of Derek Lowe’s articles that dwells on the math here (the tile is, in itself, masterful: “Get Ready for False Side Effects”.

Quoting Bob Wachter’s great Twitter thread and Derek’s great article, “if you take 10 million people and just wave your hand back and forth over their upper arms, in the next two months you would expect to see about 4,000 heart attacks. About 4,000 strokes. Over 9,000 new diagnoses of cancer. And about 14,000 of that 10 million will die, out of usual all-cause mortality. No one would notice. That’s how many people die and get sick anyway.

But if you took those 10 million people and gave them a new vaccine instead, there’s a real danger that those heart attacks, cancer diagnoses, and deaths will be attributed to the vaccine. I mean, if you reach a large enough population, you are literally going to have cases where someone gets the vaccine and drops dead the next day (just as they would have if they *didn’t* get the vaccine).

In Conclusion

I would like to end with some (dark, obviously) attempt at humor. I watched, laughing and almost crying, the latest Saturday Night Live’s Weekend Update skit, with Dr. Wenowdis (the incomparable Kate McKinnon) on the COVID-19 vaccine.

“We didn’t do good. It could have been better. But it actually could not have been worse… we blow dys”. “It’s just like the light at the end of the tunnel has shown us how stinky and bad the tunnel is.”

Even the New York Times used the analogy (used by Colin Jost at the end of the same SNL skit above) that it is “always darkest before the dawn”. The quote is attributed to English theologian and historian Thomas Fuller (1608 – 1661).

I wish I had different news, but you should know that it will get quite dark indeed over the course of the next 3-4 months (for a glimpse of how dark, I have put some statistics in the Appendix below). But, you should stay hopeful: there is indeed light up ahead, and quite possibly a government who will efficiently administer the vaccine in the shortest possible time.

In the meantime, please avoid gathering over the upcoming holidays if any member of your household is at risk. I look forward to seeing as many of you as I can in the coming year and to celebrate together (why, yes, with Italian wine!) the end of an annus truly horribilis.  

Attachments area


 

Appendix

On Nov. 30, since I did not have anything else to do, I was reading some interesting comments from Dr. Ashish Jha (@ashishkjha), Dean of the School of Public Health at Brown University (and a fellow data geek): Full Thread. Here is a short summary that does not fills me with hope for the coming 2-3 months.

In short, as the number of people diagnosed with COVID has skyrocketed over the last several months (see graph above: we are now at over 212,000 patients diagnosed a day, using a 7-day rolling average, and I expect that number to hit 250,000 and more soon), the proportion of patients hospitalized is rapidly falling.

Over much of September and October, based on the data, you could make the accurate assumption that (roughly) 3.5% of the number of newly diagnosed positive individuals would be hospitalized 7 days later.

But in November, that ~3.5% number started to fall: initially to ~3.2% by Nov. 8, to 3.0% by Nov. 15, 2.5% by Nov. 22 and 2.1% by Nov. 29. What does this mean?

The good doctor’s theory, which I find myself in strong agreement with, is: as hospitals start to fill up, they are raising the bar for admissions, resulting in admissions for only the sickest patients (ICU resources and, perhaps even more importantly, medical professionals time and capacity of caring for patients cannot be scaled up ad infinitum). Basically, roughly 1 in 3 people who would have been admitted to a hospital on October 1 aren’t being admitted by November 22 (and given the large increase in percentages in positive tests, likely much higher proportion).

This is bad enough. Another consequence: when hospitals fill up, thresholds for hospital admissions for *everything* go up: this is likely to increase mortality for normally non-threatening conditions as well.

Winter is coming, and I pray it will not last long. But it will be dark indeed for many.

17
Dec
2020

A Triumph of the Scientific Enterprise – Industry, Academia, and Government

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17 Dec 2020

Luke Timmerman, founder & editor, Timmerman Report

Vaccines for COVID-19 are here.

Some are looking for a fly in the ointment. But there’s no mistaking these vaccines protect 95 percent of people from getting sick from a virus that has killed 1.6 million people worldwide this year and threatens millions more.

The one-two punch of messenger RNA vaccines for COVID-19 from Pfizer / BioNTech and Moderna in December 2020 will go down, unequivocally, as one of the great triumphs in the history of science.  

What fewer people may see is what it really took to get here.

This wasn’t the lone act of a tenacious billionaire genius. It wasn’t the result of a Herculean group of entrepreneurs and investors demonstrating the power of unfettered free enterprise. It didn’t happen because a tousled-headed weird scientist at Harvard or MIT. No God-like government leader snapped his fingers.

Some people have starring roles and deserve our admiration, but there’s no lone hero. Not Stephane Bancel. Not Noubar Afeyan. Not Tony Fauci.

These mRNA vaccines represent a shared triumph of this beautiful thing we call the scientific enterprise. That term, as I think of it, encompasses people working in government, academia, and industry. People from all those domains are dedicated to seeking the truth. They worked together with monomaniacal intensity to make this happen.

Whether most of us realize it or not, the scientific enterprise, broadly defined, has always been there. It’s our big idea. For 20 years, the essential R&D groundwork was being laid for precisely a moment like this. It culminated yesterday in Moderna winning a 20-0 recommendation from an FDA advisory committee for an Emergency Use Authorization.

The common enemy, the new coronavirus, was more important than whatever petty differences, professional rivalries and jealousies may exist between these people. These people have always had the capacity to work together. Always had the capacity to play to each other’s strengths. Always had the motivation to work together, under the right leadership and right circumstances.

As I wrote on Twitter yesterday:

This triumph of scientific enterprise is worth celebrating today, when so much of the world is in a dark place.

The vaccine, of course, needs to get injected in as many arms as possible, as fast as possible. We’re losing 3,000 lives per day. We have to run the most ambitious vaccination campaign in world history, while simultaneously figuring out how to put the pieces of our society back together again.

This is a project we will be investing in for the rest of our lives.

That might seem overly daunting, but I don’t think so. Seemingly impossible things — like developing a new pandemic vaccine in less than a year — are possible.

I’ll close with one tangible reason for hope.

We’re seeing the beginning of a “Fauci effect” in action. Applications to medical schools have surged by 18 percent, as young people see not just an expert communicator, but a brilliant physician-scientist who dedicated his life to public service.

These bright young people could have chased the big bucks in management consulting or investment banking. They could choose to worship billionaires on the covers of magazines. They could dedicate their lives trying to become one. Some surely will.

But I believe we are going to see a surge of young talent in the 2020s turn its creative energy toward public service, like Tony Fauci did 50 years ago. The state – in this case, the National Institute of Allergy and Infectious Disease – has demonstrated its catalytic power for entrepreneurs and investors who create valuable things.

The scientific enterprise is fragile. We could screw it up. Plenty of people have ideas that would suffocate it.

But if we figure out how to delicately nurture the right kind of incentives for each of the members of the scientific enterprise – government, academia, and industry (large and small companies) – we will be on our toes when the next pandemic comes. We’ll put a major dent in terrible diseases like cancer, Alzheimer’s, autoimmunity, rare diseases and more. We’ll create a healthier and wealthier world.

This isn’t pure doe-eyed speculation. The proof is right there in front of our eyes today. We can do it again. Let’s do it together in the years ahead.

Deals

AstraZeneca agreed to pay $39 billion to acquire Boston-based Alexion Therapeutics, the developer of treatments for rare diseases. It’s a steep price for a company that relies for the bulk of its $6 billion in annual revenue on a single product, eculizumab (Soliris).

Novartis agreed to acquire Cambridge, Mass.-based Cadent Therapeutics, a neuroscience drug developer focused on allosteric modulators. Novartis obtains full rights to a schizophrenia drug candidate, a drug for movement disorders, and another for treatment-resistant depression. Cadent shareholders are getting $210 million upfront, plus $560 million in potential milestones. Investors include Atlas Venture, Cowen Healthcare Investments, Qiming Venture Partners, Access Industries, Clal Biotechnology Industries, Novartis Corporate and Slater Technology Fund.

Eli Lilly agreed to acquire New York-based Prevail Therapeutics, a gene therapy company working on neurodegenerative diseases. Shareholders in Prevail are getting $22.50 a share upfront, plus a contingent value right of up to $4 a share, for a total deal value of between $880 million and $1.04 billion.

Cambridge, Mass.-based Relay Therapeutics, the computational drug discovery company that looks at protein targets in their dynamic states of movement, formed a collaboration with Genentech. The smaller company is pocketing a $75 million upfront payment. The collaboration pertains to RLY-1971, a candidate aimed at SHP2, and which could be tested in combination with Genentech’s KRAS G12C drug candidate. (For background, listen to Relay CEO Sanjiv Patel on The Long Run podcast, Jan. 2020.)

Cambridge, Mass.-based Surface Oncology nailed down an $85 million upfront payment from GSK as part of a collaboration to develop an antibody against PVRIG (aka CD112R), an inhibitory protein on Natural Killer cells and T cells.

Gilead Sciences, based on feedback from the FDA, pulled the plug on its plan to seek FDA approval of filgotinib (Jyseleca) for rheumatoid arthritis. Gilead will pay a 160 million Euro breakup fee to Galapagos, and the smaller company will take over full responsibility for the drug in Europe, as a treatment for rheumatoid arthritis.

South San Francisco-based Veracyte agreed to expand a collaboration with Johnson & Johnson, in which the companies will work together on a 9,000-patient study to advance early detection of lung cancer.

Financings

Vancouver, BC-based AbCellera raised $483 million in an IPO at $20 a share. The company uses AI technology to assist in antibody drug discovery, including one of the therapeutic neutralizing antibodies against SARS-CoV-2 now being made by Eli Lilly.

New Haven, Conn.-based Arvinas, the developer of targeted protein degraders, raised $400 million in a stock offering priced at $70 a share.

New York-based Neurogene, a developer of gene therapies for neurological diseases, raised $115 million in a Series B financing. EcoR1 led.

Watertown, Mass.-based Forma Therapeutics, the developer of treatments for cancer and blood diseases, pulled in $275.8 million in a stock offering priced at $45.25.

San Diego-based BioAtla raised $150 million in an IPO at $18 a share. It’s developing antibodies for solid tumors.

San Diego-based Oncternal Therapeutics raised $86.2 million in a stock offering at $4.50 a share.

South San Francisco-based Neuron23 said it raised $113.5 million in combined Series A and B financings. The company is working to treat genetically defined neurological and immunological diseases. Westlake Village Biopartners, Kleiner Perkins and Redmile Group provided key early capital.

France-based Nanobiotix, a cancer drug developer, raised $113 million in an IPO at $13.50 per American Depositary Share.

Burlingame, Calif.-based ALX Oncology raised $208 million in a stock offering.

Emeryville, Calif.-based 4D Molecular Therapeutics raised $222 million in an IPO at $23 a share. It’s a gene therapy developer.

Cambridge, Mass.-based Sherlock Biosciences secured $5 million from the Bill & Melinda Gates Foundation to develop a self-administered, instrument-free, COVID-19 molecular diagnostic test. See Gates Foundation Dec. 9 announcement of new $250 million commitment to tests, treatments and vaccines to end the pandemic. (See also TR coverage of Sherlock Biosciences, Dec. 1.)

San Mateo, Calif.-based Vivace Therapeutics raised $30 million in a Series C financing led by Boxer Capital. The company is preparing to go to the clinic with a drug that targets tumors dependent on activated YAP.

San Diego-based Locanabio raised $100 million in a Series B financing to advance its RNA-targeted gene therapies for neurodegenerative, neuromuscular and retinal diseases. Vida Ventures led.

Los Angeles-based Westlake Village BioPartners said it raised $500 million for two new biotech funds focused on therapeutics technologies.

Cambridge, Mass.-based Cullinan Oncology raised $131.2 million in a Series C financing led by Foresite Capital.

Boston-based Gamida Cell, a cell therapy company, raised $65 million in a stock offering at $8 a share.

Friendswood, Texas-based Castle Biosciences, a commercial dermatologic cancer drug company, raised $232 million in a stock offering at $58 a share.

Cambridge, Mass.-based Exo Therapeutics raised $25 million in a Series A financing, led by NewPath Partners. It’s working on small molecules against novel exosite targets. (See TR coverage).

Durham, NC-based Atsena Therapeutics raised $55 million in a Series A financing to advance gene therapies against rare, inherited eye diseases. Sofinnova Investments led. (See TR coverage).

Menlo Park, Calif.-based Octave Bioscience pulled in $32 million in a Series B financing to advance an integrated care platform for multiple sclerosis. Northpond Ventures led.

Regulatory Action

GSK won FDA approval for belimumab (Benlysta) as a treatment for active lupus nephritis (inflammatory disease of the kidneys). The drug has long been on the market for systemic lupus erythematosus. The new approval extends to both the IV and subcutaneous formulations, the company said. The drug, originally developed by Human Genome Sciences, targets blocks the biological activity of B-lymphocyte stimulator, or BLyS.

Amgen got the green light from the FDA to start marketing a biosimilar version of rituximab, the blockbuster antibody long marketed as Rituxan. The Amgen drug rituximab-arrx will be marketed as Riabni, and is cleared for four clinical indications.

Rockville, Maryland-based MacroGenics secured FDA approval for margetuximab-cmkb (Margenza), as a treatment for HER2-positive breast cancer in patients who have gotten two or more prior rounds of therapy.

Australia-based Ellume received Emergency Use Authorization from the FDA for the first fully at-home COVID-19 test. “By authorizing a test for over-the-counter use, the FDA allows it to be sold in places like drug stores, where a patient can buy it, swab their nose, run the test and find out their results in as little as 20 minutes,” FDA commissioner Steve Hahn said in a statement. Ellume said it will ramp up production to 100,000 a day in January 2021.

The FDA placed a partial clinical hold on Regeneron’s odronextamab, a bispecific antibody directed at CD20 and CD3, as a treatment for B-cell non-Hodgkin’s lymphomas. The FDA asked the company to amend protocols to reduce the rate of moderate to severe (Grade 3 and higher) cytokine release syndrome.

Science of SARS-CoV-2
Vaccines
  • Pfizer / BioNTech FDA briefing document.
  • Moderna FDA briefing document.
  • Audio Interview: COVID-19 Vaccine Fundamentals. NEJM. Dec. 17. (Eric Rubin et al)
  • COVID-19 Vaccines and Herd Immunity. Harvard School of Public Health blog. Dec. 17. (Marc Lipsitch)
  • Sanofi and GSK fall short in Phase I/II clinical trial for protein / adjuvant COVID-19 vaccine combo. (Company statement)
Science Features
Opinions
Manufacturing and Equitable Access to Healthcare
  • As COVID-19 Vaccines Emerge, a Global Waiting Game Begins in Poor Countries. Science. Dec. 15. (Jon Cohen and Kai Kupferschmidt)
  • States Report Confusion, as Feds Reduce Vaccine Shipments, Even as Pfizer Says it Has ‘Millions’ of Unclaimed Doses. Washington Post. Dec. 17. (Isaac Stanley-Becker et al)
  • Health Startup for Low-Income Patients Hits $1B Valuation. Bloomberg News. Dec. 10. (John Tozzi)
  • Thermo Fisher Scientific Invests in 67,000 square foot DNA plasmid manufacturing facility in Carlsbad, Calif. (Statement)
Data That Mattered

New Haven, Conn.-based Arvinas, the developer of targeted protein degraders, released some intriguing early data for an estrogen-receptor directed drug candidate that is being tested in tandem with Pfizer’s Palbociclib (Ibrance), the CDK4/6 inhibitor, for HER2-negative breast cancer.

Cambridge, Mass.-based Synlogic said its engineered microbial therapy was able to activate the STING pathway to upregulate immune responses in the tumor microenvironment, in a Phase I trial.

Our Shared Humanity
  • The Mountain and the Meaning of Life. Brain Pickings. (Maria Popova)
  • A Vaccine Has Arrived and the US is Still Screwing Up. Magical Thinking Won’t Stop a Pandemic. Medium. (Megan Ranney)
Science
  • Long read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits. BioRxiv. Dec. 14. (DeCode Genetics team)
  • Journal Club: How to Win an Evolutionary Arms Race. Guest Harmit Malik. (A16Z Bio Eats World Podcast)
Personnel File

Barry Greene joined Cambridge, Mass.-based Sage Therapeutics, the developer of treatments for major depressive disorder and postpartum depression, as CEO. Jeff Jonas is stepping out of the top job, but will stay as chief innovation officer. Greene was the longtime No. 2 executive at Alnylam Pharmaceuticals.

Robert Coughlin, the longtime CEO of MassBio and an advocate for industry and patients, is stepping down to take a new job at JLL, the real estate firm. (MassBio statement).

Watertown, Mass.-based Kymera Therapeutics, the developer of small molecule protein degraders, said it hired William Leong as vice president of chemistry, manufacturing and controls, and Paul Cox as vice president of investor relations and communications.

South Korea-based Samsung Biologics named John Rim as its new CEO.

Cambridge, Mass.-based Spero Therapeutics, an antibiotic developer, named Sath Shukla as its chief financial officer.

The Buck Institute for Research on Aging named Malene Hansen as its new chief scientific officer.

South San Francisco-based 3T Biosciences, an immunotherapy company, named John Connolly as interim CEO. He’s the chief scientific officer of the Parker Institute for Cancer Immunotherapy.

17
Dec
2020

A Grateful Physician Reflects on Getting the COVID-19 Vaccine

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17 Dec 2020

Amanda Banks Christini, MD; CEO, Blackfynn

Tonight, I will receive my first dose of vaccine against COVID-19.

I’m a hospitalist on the front lines, taking care of patients with COVID-19 in Philadelphia.

The progress of this year takes my breath away.

One year ago, in December 2019 in China, people starting falling seriously ill with pneumonia-like symptoms. By January 2020, a novel coronavirus, SARS-CoV-2, was identified as the cause of the disease we now call COVID-19. Scientists immediately sequenced its genome. That code provided key instructions for vaccine developers and drug developers around the world.

By mid-March 2020, around the same time I was taking care of my first patient with severe COVID-19 disease during an overnight shift at the Philadelphia VA, the first messenger RNA-based vaccine candidate, from Moderna, began Phase 1 clinical trials. Last Friday night – less than a year after this novel virus was identified — the Pfizer / BioNTech mRNA vaccine was given Emergency Use Authorization by the FDA. Moderna is likely just a day or so away from similar authorization.

This is a biopharmaceutical marvel.

We’ve seen other paradigm-shifting accomplishments the past few decades. HIV was transformed from a uniformly fatal infection to a manageable, chronic disease. As a medical resident, I went from caring for patients dying from hepatitis C cirrhosis / hepatocellular carcinoma while awaiting liver transplant, to participating as a junior faculty member as a co-PI in the initial sofosbuvir (Sovaldi) trials, to seeing these patients cured -not treated, but cured -s with a pill and HCV disappearing as the leading cause of liver transplant in the US.

Those triumphs were decades in the making.

Speed isn’t the only thing that sets this example apart; the scientific challenges to developing vaccines for SARS-CoV-2 were, and remain, far more tractable than those for HIV or HCV, infectious diseases for which, after decades of research, no vaccine exists. Aside from the science, which is beyond my expertise, a few differentiating principles stand out that are worth calling out:

  1. Universal urgency – eliminating COVID is a priority for everyone in the world in one way or another; it has already killed at least 1.6 million people worldwide in less than a year. Because it is transmitted through the respiratory route, it has the potential to touch every one of us – anyone and everyone can theoretically get infected. That is not true of HIV or HCV, viral illnesses transmitted by sex, IV drug use and other close contact. Groups that were already marginalized were affected most; their “immoral behavior” was blamed. This wholly uninformed and prejudiced view was used by many as grounds to turn a blind eye, stigmatize those who were suffering and dying, and behave as if it was not their problem. In sharp contrast, as the global economy continues to struggle to reopen, and health systems strain under the burden of 72 million infected and 1.6 million dead worldwide, COVID is everyone’s problem.
  2. Operational and regulatory efficiency – the studies that lead to EUA designation, run by Pfizer and Moderna, collectively tested vaccine candidates in many tens of thousands of people. The sponsors worked with regulators on trial design early and often. Regulatory steps that were historically serialized were parallelized to ensure time was not lost to administrative delays. Large-batch manufacturing of vaccine candidates began months ago, long before safety and efficacy was demonstrated. These efforts were critical as nearly 3,000 people die every day in the US from COVID-19 disease.
  3. Massive investment – an unprecedented series of investments in the US exceeding $20B over the past nine months – from industry sponsors, Operation Warp Speed and others like the Gates Foundation – has accelerated critical steps in the process. This capital infusion dwarfs the paltry sums committed to HIV and HCV research in the first decade after their emergence.
  4. Improved recognition and inclusion of most affected groups in trials. While it was rapidly clear that the elderly and people with chronic health conditions like obesity, diabetes and cardiovascular disease were at high risk of severe disease, it took more time to fully appreciate, and then acknowledge, that Black, Latino and Native American communities were disproportionately affected by COVID-related illness and deaths. Once this was understood however, the Pfizer and Moderna trials were modified to increase enrollment of these historically underrepresented groups, to gather robust data across demographic groups in order to gain Emergency Use Authorization, and bolster confidence in the vaccine among populations that are in need.
  5. “Collaborative competition” and data transparency – the above factors culminated to create an environment where dozens of vaccine and therapeutic candidates are simultaneously in development globally. Where evolving knowledge is shared early and often through publications, case studies and other means. This creates an arsenal of strategies and shots on goal to fight this virus. It has allowed clinicians to refine and improve treatment strategies as data on therapeutics like remdesivir and dexamethasone was rapidly published and broadly disseminated. As I listened to the FDA advisory committee meeting last week and reviewed the data package for the Pfizer / BioNTech vaccine, I was struck by the unusually high degree of transparency from industry. This gives me confidence.

I am in no way suggesting that the process to get to this point was perfect. It is also not nearly over; additional studies will be required for full BLA approval, and the operational lift to vaccinate the majority of the global population is enormous.

But, in the face of extreme adversity, our system adapted. We can use this opportunity to learn, and to change how drugs and vaccines are tested, developed, approved, manufactured, distributed and used.

I am enormously grateful for the opportunity to care for some of the most vulnerable patients during this pandemic. I am equally honored to be among the first to receive a vaccine against COVID-19.

We will all take different things away from our experiences throughout this pandemic, and more broadly from this year of turbulence on so many other levels, societal and political.  I choose to focus on what is possible if we adapt, focus resources in the right places, and come together around a common goal.

Today that target is COVID. What could be next?

17
Dec
2020

Round 2: What’s Changed and What Hasn’t in Caring for Outpatients with COVID-19

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17 Dec 2020

Alex Harding, MD. Entrepreneur in Residence, Atlas Venture

When one of my COVID patients called my cell phone a few weeks ago, my stomach dropped.

“I feel worse,” she stammered. “I’m having more trouble catching my breath.”

It was late morning on a Sunday. I was planning to take my son to the park, but after hearing those words, I knew this was not going to be a quick phone call.

I had seen the patient, a woman in her late 30s, the previous afternoon in the respiratory illness clinic at Massachusetts General Hospital (MGH), where I’ve worked since the Biogen outbreak slashed through Boston in early March.

She had typical COVID symptoms: fever, muscle aches, chest tightness, and mild shortness of breath when she walked around her house. She was obese and prediabetic, but otherwise healthy. When, sure enough, her COVID test returned positive the next day, I called her hoping that she would already be feeling better.

Instead, what ensued was a conversation that my colleagues and I have had far too often in the past several weeks.

“What can I do to get better?” she asked.

The fear in her voice was unmistakable, as she could feel herself losing strength. Stories of critically ill COVID patients suddenly seemed much more personal. I’ve seen more than 100 COVID patients this year, and the sheer variability of their responses has been befuddling. I had no obvious answer at my fingertips.

I rubbed my brow as I contemplated a response. What treatments could I offer her? Was there anything that might stop her illness from worsening?

Should I tell her to go to the emergency department now?

 

To a doctor on the front lines, the first surge felt like standing knee-deep in surf, looking out at a choppy sea and seeing a tidal wave on the horizon. It was approaching rapidly, but I couldn’t see to the top of it to know how hard it would hit or when it would end. There were people bobbing in the water, and somehow, I had been designated as a lifeguard. And I didn’t even know how to swim.

This, the second surge here in Massachusetts, feels different. It’s a similar tidal wave, but I have an idea how tall it is and how hard it will hit. I’ve learned how to swim. But I’m still swimming unassisted—no life preserver, no flares, no rescue boat. Today, we know what COVID looks like.

We’ve learned a lot about the management of severely ill patients in the hospital. Pronation can help hospitalized patients breathe better. Dexamethasone can help the most severely ill patients and there’s a place for remdesivir in severely ill hospitalized patients as well. But we are still staring up at tidal waves of the unknown, particularly for non-hospitalized patients.

We still don’t know which outpatients will do well and which ones won’t; we still don’t know the best management strategies for common clinical situations; and we still don’t have any meaningful therapies to offer our patients outside of the hospital.

Remdesivir and dexamethasone have received a lot of attention for their utility in treating COVID, but they are only useful for patients inside the hospital. Remdesivir is an intravenous therapy and has not demonstrated efficacy in outpatients. Dexamethasone is only authorized for hospitalized patients on supplemental oxygen, and may actually worsen disease in patients with less severe disease.

The multiple vaccines with outstanding data, of course, offer hope for limiting new cases of the virus starting this spring. But they do nothing for people who are already infected, people who are suffering now and expected to continue filling up hospital beds in days and weeks ahead.

The FDA has recently authorized two medications for patients outside the hospital, Eli Lilly’s bamlanivimab and Regeneron’s casirivimab/imdevimab. Neither of them appears to be a transformative treatment for outpatients with COVID.

Bamlanivimab is a monoclonal antibody developed by Eli Lilly that is running a clinical trial in 452 outpatients with mild or moderate COVID. My clinic at MGH is one of the sites on that clinical trial, and I have referred patients to participate. The drug was authorized by the FDA on the basis of an interim data analysis that showed a clinically modest, but statistically significant, reduction in viral load at the middle of three doses. At that mid-level dose, the average viral load was reduced by 99.99% by day 11 of the study.

Sounds great, right? The catch is that, across all groups, including placebo, the average viral load was reduced by more than 99.9% by Day 11. In fact, the high dose and the low dose were statistically no different than placebo. The high dose, puzzlingly, actually had a lower percent reduction than placebo, although it was not a statistically significant difference.

It’s important to know that a treatment designed to neutralize the virus actually does bring down viral loads. Then again, doctors and patients do not care about a difference in viral load of less than 0.1% in and of itself. ‘Harder’ clinical endpoints like hospitalization, intubation, and death are much more meaningful. The interim readout of the trial – the basis for the FDA’s Emergency Use Authorization (EUA) — did not include enough hospitalizations to make firm conclusions on this endpoint. There were five hospitalizations (1.6%) among all three treatment doses—including the doses that did not reduce viral load—and nine hospitalizations (6.3%) in the placebo group.

In summary, there was a reduction in viral load in the middle dose that you might be able to see if you squint, and insufficient evidence to draw any conclusions about hospitalizations. It is a weak body of evidence to support a drug authorization—a strain to justify, even during a pandemic.

But the authorization was not just a strain. It was bizarre. Instead of authorizing the middle dose—the only dose that actually showed a reduction in viral load—the FDA authorized the low dose, which showed no benefit in viral load. The FDA’s explanation was that there would be more drug to go around if each patient got the lower dose. Yet every doctor I know would prefer to treat one patient effectively than four patients ineffectively.

The other treatment that the FDA recently authorized for outpatients is casirivimab/imdevimab, Regeneron’s dual antibody cocktail. The data for this combination looks similar to the bamlanivimab data. The reduction in viral load was modest but statistically significant for both doses tested. There were fewer hospitalizations and emergency department visits in the treatment groups than the placebo group, although the number of events was again too low to draw any conclusions.

The good news with this treatment is that the FDA authorized a dose that appears to actually do something (since both doses showed viral load reduction). The bad news is that the complete data from the clinical trial has still not been published, over three weeks after the authorization went into effect. The FDA included snippets of data in its EUA, but Regeneron has still not published a complete dataset in a peer-reviewed journal, or even on a pre-print database. As such, it is impossible for me to have an informed opinion on the utility of this drug for my patients.

Further complicating the muddy data for bamlanivimab and casirivimab/imdevimab is the logistical complexity of administering these treatments. Both are intravenous (IV) infusions. For outpatients, IV infusions are usually administered in an infusion center, a dedicated clinical unit. However, since these patients are infected with COVID, they cannot mix with other patients, requiring the creation of entirely new infusion spaces specifically for this purpose.

At MGH, a hospital fortunate to have the resources to create such a space, a central team reviews every patient case and determines who would be eligible for treatment, then places them in a lottery to see who can get the treatment. I don’t even have control over the prescribing process for my own patients.

We lack more than just medicines to treat outpatients with COVID. Many of the basics of clinical management of these patients remain undefined. We know that most patients with COVID have only mild disease, but a significant minority of patients develop severe, life-threatening illness. One of my biggest challenges is identifying the patients who are at risk for rapid clinical worsening. Several research groups are investigating tools to risk stratify patients, but none seems to be a definitive solution so far.

My colleagues and I are running a prospective trial in our clinic to see if exertional oxygen saturation (a patient’s blood oxygen level during light exercise) can identify the patients who are at risk of getting worse. Other groups have used machine learning to pull clues from patients’ charts. Chest X-rays and blood tests might be helpful. This is a huge clinical problem and I hope that one of these approaches turns out to be a reliable predictor of outcomes, so we can act accordingly to help patients early in their course of disease.

Management of a plethora of other clinical situations in outpatients with COVID also remain uncertain. Here are a few examples:

  • Should patients with confirmed COVID and infiltrates on chest X-ray (i.e., pneumonia) be prescribed antibiotics for a possible secondary bacterial infection? If so, what antibiotics and for how long?
  • Should patients with COVID who also have asthma be prescribed oral steroids, or should these be avoided when possible given potential harm of dexamethasone in mild-moderate COVID?
  • How should chest pain be evaluated in a patient with COVID and low/moderate cardiovascular risk factors?
  • How should longer term effects of COVID be managed? What is appropriate counseling regarding these longer-term effects?

These questions come up nearly every day I am in clinic, yet there are no clear guidelines for handling any of these situations. There is an enormous amount about this disease that we still don’t know.

On top of better guidance on those clinical questions, we are in dire need of better therapies for outpatients. I am grateful for the antibody therapies that are being developed, but what we really need are potent, oral antiviral therapies. These drugs are probably a year or more away, because medicinal chemistry efforts to discover novel compounds with desirable pharmaceutical properties are necessarily slow. Repurposing existing compounds, as was done with remdesivir, is unlikely to be the solution because these compounds rarely have the potency and desired properties to make for a truly transformative therapy.

 

Let’s return to my phone conversation with my patient with worsening COVID.

“What can I do to get better?”

What could I say? I seriously considered telling her to go to the emergency department right then, but because she was young and in satisfactory health at baseline, I decided against it. I encouraged her to sign up for the clinical trial of bamlanivimab—that way, she would at least have a chance of getting the dose that reduces viral load. And I told her that if she started to feel any worse at all, she should call an ambulance.

I kept a close eye on her chart over the next week. She did enroll in the bamlanivimab trial, although I’ll never know which dose she received, or if she got placebo. In any case, she did not need to be admitted to the hospital and has since recovered from her illness. Her case was a small victory in a season full of losses. While I take pleasure in her recovery, I probably can’t take credit for it.

Not without better tools at my disposal to manage patients like her.

14
Dec
2020

Seeking Impact: Servier’s David Lee on The Long Run Podcast

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14 Dec 2020

Today’s guest on The Long Run is David Lee.

David is the CEO of Boston-based Servier Pharmaceuticals. It’s the US subsidiary of France-based Servier Group.

Servier, for those unfamiliar, is a rare bird in the pharmaceutical world. It markets both branded drugs and generic drugs. It is a truly global company with 21,000 employees in 148 countries, but it has only recently entered the world’s biggest pharmaceutical market – the US.

David Lee, CEO, Servier Pharmaceuticals

There’s more. It’s governed by a nonprofit foundation. As part of its mission as a nonprofit dedicated to improving health, it invests 25 percent of its annual revenue in R&D – quite a bit higher than the industry standard.

David is an industry veteran, having been around the block as a consultant and at a variety of business roles at pharma companies – Novartis and Shire, prior to its acquisition by Takeda. He came over to Servier with some assets that were being divested. Those assets provided a foundation for Servier’s US expansion, which includes R&D operations in Boston. David oversees all of that.

Now, please join me and David Lee on The Long Run.

13
Dec
2020

The US is Teeming With SPACs, Why is the UK at Zero?

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13 Dec 2020

Uciane Scarlett, principal, Oxford Sciences Innovation

Biotech startups from the UK traditionally have a financing strategy that leads to one of two places – the NASDAQ or the NYSE. This means learning how to follow a US-centric playbook.

About 10 percent of the biotech IPOs on the US markets this year come from companies based outside the US. This is consistent with trends of the past and something my firm, Oxford Sciences Innovation (OSI) expects to continue for years as our 5-year old life sciences portfolio matures.

Financial capital is so abundant in the US that we now see large “blank checks” being bandied about in search of promising startup companies.

These Special Purpose Acquisition Companies, aka SPACs, more recently are being run by private equity and venture capital firms looking to the public markets as a unique channel to raise large sums of capital other than traditional limited partners that come from the world of pension funds, endowments, and foundations.

Bruce Booth’s blog on Oct. 15 provided a good summary of the trends observed regarding healthcare SPACs. In 2020, almost 24 healthcare SPACs were raised or announced with the goal of putting $3.4 billion to work in emerging companies. For some perspective on how much money that really is, Booth compared the boom in SPACs to the entire US healthcare IPO market in 2019.

That year, before the pandemic, biotech companies raised a total of $4 billion through IPOs.

In the past, SPACs weren’t in favor with US investors. But now there are entirely new pools of capital seeking biotech opportunities. They are turning to biotech specialty funds for help in identifying opporutunities. The list of quality investors taking advantage of the SPAC boom this year includes 5AM Ventures, MPM Capital, Deerfield Management, and RA Capital, among others.

The resurgence of SPACs is being driven by the volatility in the markets amid the COVID-19 pandemic, combined with rising awareness of opportunities in biotech, according to Bloomberg and Pitchbook in their 2020 COVID-19 market impact reports. SPACs have their appeal for healthcare companies because they present a fast and cost-effective way to raise capital.

Now that prominent investors have entered, SPACs also provide the opportunity to have a high-quality healthcare investor as a sponsor. That’s an important signal to generalist investors seeking to separate the wheat from the chaff.

For investors who sponsor these blank check entities, it’s a familiar private equity structure with liquidity, regulations, and transparency provided by well-functioning capital markets. The typical financial structuring of a SPAC would consist of 3-10% capital provided by the sponsor in order to identify assets and operate a nascent company within a 18-24-month window. Once that initial work is done and all the financing flows into the SPAC, the initial sponsors, on average, own up to a 20% equity stake. The rest of the money comes from investors who follow the leader (the sponsor). It’s a fairly lucrative line of work for those firms seen in the marketplace as worthy of being a sponsor.

So, there are plenty of reasons why investors and companies would want to get in on this trend.

Why then, with about 100 SPACs launched in the US already in 2020, aren’t we seeing this activity in other established markets like the UK? In the UK – a region with a variety of attractive biotech startups and a steady pipeline of IPO candidates – why do we see exactly ZERO SPACs in 2020?

The UK has experienced SPAC surges, according to data compiled by Paul Hastings, a UK-based law firm. The years following the 2007/2008 financial crisis, when public investors sought alternative structures, provided one such opportunity.

Some context is required to understand what’s going on in present day. When I asked Nooman Haque of Silicon Valley Bank London, he reflected on the public markets of 20-25 years ago, when the dot-com boom coincided with the debut of the Alternative Investment Market (AIM) of the London Stock Exchange (LSE).

The AIM caters to later-stage, often revenue generating or lower-risk companies and provides them with an opportunity to grow rapidly. Over 2,500 companies have been admitted to the AIM, and those companies had collectively raised more than $140 billion through 2019. Haque highlighted the early 2000s and how the financial crisis made it more difficult for companies to raise capital for a few years, and eventually created something of a brain-drain from the UK. He concluded that the country ended up with fewer technical analysts who could make credible recommendations on stocks to generalists.

The current UK public market now has a lean analyst base and narrower set of healthcare investors. The result is a lower volume of coverage overall and coverage that exists tends to be tightly concentrated in certain areas, such as genomics.

One year ago, shortly after moving to the UK, I attended a dinner hosted by Lazard & Co, a London-based investment bank. The theme was “Genomics Innovations” and we discussed the immense opportunity within the UK relative to other regions, especially given the role of the national health record system operated by the NHS.

The UK is within reach of cheap, high-volume gene sequencing, meaning it has the opportunity to link genomic databases with clinical manifestations of disease – something notoriously difficult in a place like the US, with a decentralized, privatized set of healthcare providers and insurers. This has contributed to a heightened sense for measures for success, as well as an increased appetite for innovative companies with genomics platforms by UK analysts covering healthcare.

So, while Haque is correct in the reduced breath of coverage, the UK retains significant expertise in not only genomics, but also tools, diagnostics, and novel models for IP, commercialization, and financing.

This is exemplified in the fact that a majority of small-mid cap healthcare companies listed on the LSE/AIM, broadly fall within  these  categories:

  1. Tools and services, e.g. Horizon Discovery, which raised $113M in 2014.
  2. Medical devices and diagnostics, e.g. Creo Medical whose market cap more than doubled to $260M in 2019 after it IPO’d with a market cap of $103M 3 years prior.
  3. Novel or innovative financing models, e.g. Syncona, a life-sciences investment trust, which came to market through a reverse merger into BACIT, which raised >$500M 3 years prior, in 2016.

Typically, small-mid cap companies within the categories outlined above tend to be thinly traded on the NASDAQ. That tends to be the case, even after they raised large sums via IPO.

Case in point: Oxford Immunotec, a UK-based company and maker of tests for latent tuberculosis raised $64 million on the NASDAQ in 2013 – a choppy year in the markets, before things picked up in 2014-2016. Nooman Haque noted that Oxford Immunotec might have had a more vibrant post-IPO market experience if it had listed on AIM, instead of the NASDAQ.

Furthermore, select US-based companies have chosen to list on the LSE in past years:

  1. Tools and services, e.g. Maryland-based, MaxCyte was one of the top-4 performing IPOs in 2016 on the LSE, with a >200% performance almost a year after it IPO’d.
  2. Novel or innovative R&D models, e.g. Boston-based, PureTech Health has nearly tripled in value from its 2015 LSE IPO and is now in the FTSE250

Some US based companies have expressed interest in listing in a region where investors understand their model. For example, when Boston-based Allied Minds listed on the AIM in 2016, its CEO, Chris Silva, highlighted that their IP commercialization model was deeply understood by UK and European investors. That decision made sense, because UK investors were familiar with comparable models, such as Sheffield-based Fusion IP,  founded in 2001.

These examples each tell a story, but how are the UK healthcare markets performing overall, compared with the US?

UK investors are doing better than most would expect. In Q2 2020, the AIM 100 and AIM All Share’s percentage change was on par with that of the NASDAQ 100 and NASDAQ Composite at ~30%. While some of this growth was forecasted, the AIM listed diagnostic companies Novacyt and Genedrive shot up by a remarkable 365% and 894%, respectively, by Q3.

Not surprisingly, these companies have COVID-19 offerings that captured significant headlines and investor interest.

Additionally, the LSE remains more diverse vs. the NASDAQ when it comes to its investor base. For example, an LSE 2018 Life Sciences report highlighted that 31% of the domicile investors in securities in London were North American and included marquee names like Vanguard, State Street, Wellington, and BlackRock. The LSE has attracted global investors for several reasons, including lower underwriting costs and lower rates of litigation.

With this obvious opportunity, why has no group looked to the LSE in 2020 for a SPAC?

Several factors come to mind:

  1. The COVID-19 pandemic: Not really; in 2020 we’ve seen strong performance in healthcare relative to other sectors, like automotive and travel. Healthcare is where investors are placing their surplus cash in 2020.
  2. Market dynamics: the remaining uncertainty around Brexit, possible trade wars and a potential economic slowdown are additional factors that might be making investors “gun shy” about investing in LSE/AIM listed SPACs.
  3. High-profile failures: the wind down of the Woodford fund has possibly impacted market sentiment, but it’s unclear the overall degree of impact.
  4. Hong Kong Stock Exchange (HKSE): with a developing healthcare market in Asia, the launch of the HK Biotech Index, and the 2.5x increase in the number of healthcare company listings observed to date, there is clearly a new international player in town. The HKSE has seen >$1B in SPAC volume in 2020!

Stefan Hamill, a Senior Life Sciences analyst at Numis Securities in London, however, emphasized Brexit as a key driver which has impacted international allocations to the UK. This has seen global fund flows underweight the UK market for the last couple of years.

Numis has reported record revenues of late, Hamill said. Only 2% of revenues of the investment bank’s revenues were related to IPO fees – a remarkably low number. As recently as 2014, fees from IPOs were greater than 20% of revenues for Numis. Today, 20 percent of its corporate fees come from helping private companies raise capital, Hamill said.

There are signs of a return of the UK IPO market in the most recent quarter, Hamill said.Partly, this is because funds are beginning to get more comfortable with investing now that they can see a post-Brexit future.

While we cross our fingers that there is some sort of a Brexit deal in early 2021, which would facilitate a continuation of this trend, Hamill also highlighted lingering regulatory issues to navigate to facilitate SPACs. Given UK guidelines, SPAC sponsors in the UK have fewer options than in the US. Their US counterparts can redeem their shares if they don’t want to invest in the underlying target. UK sponsors cannot optout.

In short, there needs to be a reform of the LSE to enable UK’s participation in a more meaningful way given the rise of quality sponsors and the obvious opportunity within the UK market for healthcare companies.

The LSE remains 15-20 years behind the US, but there is a density of quality investors and analysts who understand distinct areas within healthcare, possibly better than other regions.

Coupled with greater comfort around the impact of Brexit, high quality US (and for that matter, UK VC funds) sponsors should be considering the UK for SPACs in 2021.

Several pieces of the puzzle are already in place – technology, management teams, and pools of capital looking for biotech opportunities.

11
Dec
2020

The Vaccine Is Coming, and Scientists Need to Keep the Focus on Equity

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11 Dec 2020

Michele Andrasik, PhD. Director, Social & Behavioral Sciences and Community Engagement,
HIV Vaccine Trials Network at Fred Hutch; Clinical Assistant Professor, Global Health, University of Washington

As we navigate this pandemic, the discourse has often created a fog.

Science has been doing what it does – forming hypotheses, testing them, gathering vast amounts of data, and pressure-testing conclusions with unprecedented urgency. The ideas that pass scrutiny are being elevated into recommendations, while others are being discarded.

Science isn’t perfect. It is practiced by people, and people have flaws and biases. Communities of Color and other marginalized groups have been leaders in advocating for and securing the establishment of safeguards to reduce bias, increase inclusion and ensure the ethical conduct of science.

The HIV epidemic, where I have focused most of my scientific career, certainly was influenced by politics. This pandemic has been mired in an even more difficult stew of political ideologies, the need to continue operating the economy, and starkly different views about the limits of personal choice.

Lately, I’ve noticed more frequent rays of light shining through during this divided year. Public discussions this fall have begun to more often center on the larger public health implications and the personal and emotional impact experienced by those most impacted by COVID-19.

For example, witness the evolving discussion about school reopening, especially for young children, as we begin to better understand the risk they present of COVID-19 transmission, and the increasing risk of social, educational, and emotional delays they are suffering from school closures.

In December 2019, when the news was first announced that a novel virus that was spread through respiratory droplets was discovered and multiple cases confirmed, I braced myself. 

I knew what this meant for my community and communities of color across the US.  We were going to be hit and we were going to be hit hard. Numerous opportunities for exposure to a virus that spreads this way exist for communities of color. 

Greater percentages of people of color work in essential service occupations. Disproportionate numbers live in high-density housing, which increases close contact with others and creates more possibilities for exposure and transmission.

More people of color live in multigenerational households. This places our elders at greater risk, because they are in more frequent contact with younger family members. Many racial and ethnic minorities are especially vulnerable to this virus because of higher rates of pre-existing conditions, lack of insurance and limited access to quality health care. 

It is no surprise that nine months into the pandemic, communities of color are severely disproportionately impacted – greater cases of coronavirus infection, more instances of severe COVID-19 disease requiring hospitalization and a higher burden of mortality. The disparities persist as the COVID numbers continue to grow exponentially in the US.

Several weeks ago, we received the incredibly promising news that the Pfizer mRNA vaccine demonstrated over 90% efficacy in the prevention of COVID disease.  This was followed a week later by a similar announcement by Moderna, another mRNA vaccine developer. 

These developments have the potential to substantially ease the burden and address the disproportionate impact of COVID disease in communities of color.

To achieve this goal — of bringing the pandemic to an end for everyone — we must, as a scientific community, continue to prove that we are trustworthy.

That starts with communication. We need to provide information as soon as we have it, and ensure that we are forthright, transparent, and honest about what we know, what we don’t know and what we hope to learn as we obtain additional data.  

As the Emergency Use Authorizations roll out, it is imperative that we discuss the allocation of vaccines with transparency. This requires being mindful in our explanations of what emergency use entails and ensuring that we offer resources that will help providers and the general public make informed decisions. Mandates for vaccination won’t work, but clear communication about the benefits of vaccination will allow people to come to their own conclusions.

Ensuring that the information we provide is written in clear language, inclusive of diverse communities, and respectful of everyone is critical.

Efforts to ensure that the efficacy data results are well understood should be at the foundation of these bi-directional dialogues with community.

In our recent discussions about efficacy results with communities of color in Washington state and around the country, it has become abundantly clear that many do not understand the data. There is some confusion about the prevention of illness versus the prevention of infection.

It is imperative that we effectively communicate that efficacy (at least according to the Phase III Pfizer and Moderna vaccine results) indicates the prevention of severe COVID-19 disease. That will greatly reduce hospitalizations and death but will not translate into relaxing infection prevention measures.

The vaccines may be effective at preventing people from shedding and transmitting the virus, but we don’t know that yet, so this remains an important open question. This means that ongoing messaging about the importance of wearing masks, physically distancing and avoiding congregating in large groups is critical.

Given that these early vaccines will prevent severe disease and death, ongoing education about who is at most risk for severe disease progression is imperative.  

Risk for severe COVID-19 disease must be utilized to inform allocation decisions and the rationale for doing so must be highlighted as transparently as possible. The CDC’s Advisory Committee on Immunization Practices has followed a process along these lines – although these are recommendations. States, territories and the District of Columbia will be making their own decisions regarding allocation.

To address vaccine misgivings and questions about trustworthiness, we must clearly communicate the ever-changing vaccine landscape. This includes addressing concerns about availability and distribution.  This requires preparing communities for the potential scarcity of vaccines in early 2021, setting clear expectations about vaccine availability and providing transparent information about how long the period of vaccine scarcity is likely to last. 

Ongoing communication about vaccine safety and the actions being taken to assure vaccine safety must be a top priority. News of side effects are bound to spread around the world in minutes – whether they are serious concerns or not. See the two reported cases of anaphylaxis in the UK – it’s a concern that requires further monitoring and investigation.

This continuous monitoring for new signals as we engage in long term follow-up of vaccines, must be placed into the broader context of the vaccine’s safety and efficacy, and be accompanied by continuous education about what to expect upon vaccination.

What side effects are expected? Are they generally mild, moderate or severe? What is the vaccine efficacy after the first vaccination? Why are two shots needed for adequate efficacy? What will it mean if only one shot is taken? Why do I need to continue to take action to ensure reductions in the spread of the virus even after I am vaccinated? 

All of these questions and the many more that will, undoubtedly arise, require the provision of direct and clear answers to secure trust and effectively address vaccine hesitancy.  

Our reality will continue to shift as we obtain new data informing our path forward. Community members, scientists, essential workers, Americans are in this together. It will take all of us to move the science forward to see an end to this pandemic. 

Along the way we must continue to engage in open dialogue, sharing information as it becomes available, being transparent about what we know and what we don’t know.

In my lifetime, I have never seen a time wherein there was such a collective sustained focus on equity, inclusion, and social justice. Over the past year, I have seen the acknowledgement of, and importantly, the accompanying work, necessary to address supply chain issues, tribal sovereignty and data ownership and the effective utilization of the capacity, expertise and leadership of long-standing institutions serving communities of color.

This is progress.

The work must continue, and is continuing. Relationship building and strengthening partnerships among institutions, organizations and communities must be centered as we continue transparent communication and ensure that all of us have the resources we need to make informed decisions. Our group has done work with organizations like the YWCA, UnidosUS, the Mexican Consulate, the Urban League, numerous faith-based organizations and the Urban Indian Health Institute, and we believe these relationships will help establish a strong foundation for improving health during the pandemic – and potentially long after it’s over.

In the coming months, we will be presented with many opportunities to demonstrate mindful implementation of an effective public health intervention. Working together with a focus on strong communication, transparency and trustworthiness will help to ensure that all of us — particularly those most impacted — are protected.

Michele Andrasik, PhD is the director of social & behavioral sciences and community engagement for the HIV Vaccine Trials Network at the Fred Hutchinson Cancer Research Center and a clinical assistant professor of global health at the University of Washington.

10
Dec
2020

Pfizer, BioNTech Vaccine Gets FDA Advisory OK. Now Comes More Hard Work

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10 Dec 2020

Luke Timmerman, founder & editor, Timmerman Report

The good news this week was really one of those good news / bad news stories.

An expert panel of FDA vaccine advisors looked at Pfizer’s presentation for the mRNA COVID-19 vaccine candidate, and saw the outstanding results for what they were.

The vote was 17-4 (with one abstention) to recommend that the FDA give the go-ahead for an Emergency Use Authorization. This is the first step in the nation’s biggest-ever vaccination campaign. Next week, we can expect another step when the committee reviews Moderna’s application.

The bad news was that this meeting was a missed opportunity. There were technical sound glitches. Too much time was spent on picayune matters (include 16 and 17-year-olds in the label or just 18+?). Not enough time was spent on important questions (getting a careful read on potential anaphylactic reactions, vaccinations for pregnant women.).

The chairman was too fixated on sticking to the allotted time, and not fixated enough on fostering thoughtful dialogue. Panelists didn’t have a chance to explain their votes — usually the most revealing part of an FDA advisory committee meeting. Little was done to advance public education, and build public trust.

This last point can’t be emphasized enough. Within minutes, major media outlets and political leaders were butchering basic facts. The vaccine was not “FDA Approved!” as many headlines blared – it was a positive recommendation from an advisory committee. We all know that the FDA makes the actual decision to authorize, and its staff will craft important language in the prescribing information about safety warnings, restrictions, and what safety monitoring protocols will look like.

But just because we know it doesn’t mean everyone else knows it.

Which brings me to my main point today, the one that keeps twisting my stomach in knots.

We in the scientific community, and the biopharma community, have to do a lot of listening, and a lot of very careful communicating about vaccines in the months ahead. Really hard work lies ahead.

I’m not talking about distribution – the US military and FedEx and UPS are aces at this stuff. I’m talking about the messy business of communication and fact-based rational discussion – which our country doesn’t do well.

We all have work to do. Each of us can function like a trusted source, a knowledge node of sorts, for people in our circles – friends, family, neighbors, non-scientific colleagues.

My sense is that not enough people in biopharma have gotten the memo about how serious the vaccine hesitancy problem is in this country.

We are divided politically, to state the obvious. People are more than a little stir crazy being stuck at home, bombarded with endless gloomy headlines. Misinformation is everywhere.

How bad is this vaccine hesitancy you keep hearing about?

In November (AFTER the positive Phase III Pfizer and Moderna results), a Pew Research Center poll found:

  • About 1 out of every 5 people in this country said they would “definitely” not take a COVID-19 vaccine if it were available.
  • Another 1 out of every 5 people in this country said they would “probably” not take a COVID-19 vaccine if available.

That’s a lot of people — 2 out of every 5 people in America — expressing something between deep skepticism, and outright contempt.

Many of you are well aware that Tony Fauci and others have said we probably need 70-75 percent of the country to get vaccinated in order to achieve herd immunity that will bring the pandemic to an end.

We know that about 20 percent of the country – people on the far left who fear Big Pharma and people on the far right who fear Big Government – will not voluntarily take a vaccine. That means you have to assume that almost everyone who says they “probably” won’t take it will actually come around at some point and get the shot in their arm.

The margin for error is slim.

Now, consider this piece of data in Nursing World (h/t to TR reader Mike Kuczkowski for the pointer).

In October (BEFORE the positive Phase III vaccine results), a Pulse survey by the American Nurses Foundation was taken by 12,939 nurses across the country.

It found:

  • 34 percent of nurses said they would voluntarily take a COVID-19 vaccine.
  • 48 percent said they were “somewhat confident” a vaccine will be safe and effective.

It’s important to know this is a survey that doesn’t use scientific random sampling. Sentiment may also have shifted a bit in November, after positive news on the vaccines.

But I’m still alarmed that nurses – an educated group of healthcare workers who have been on the frontline doing heroic work this year – have so little confidence in the vaccine cavalry.

Nurses are among the most trusted of all professionals in America. If they send doubtful vibes, or traffic in misinformation about vaccination – then we have trouble ahead in this vaccination campaign to come.

I talk to many biopharma leaders, and I don’t think this is high on many agendas. Many of you are logical thinkers, like Spock. Many assume that a 95 percent effective vaccine with minor side effects is something everyone will want. Many of you aren’t surrounded by crazy people. Some of you may be thinking about the past, when you could shrug off “anti-vaxxers” in Marin County as fringe actors. Maybe you just color between the lines of what regulators say you can say about medical products, and assume communication is someone else’s job.

Maybe Obama, Bush, Clinton, LeBron and Ellen DeGeneres will take care of that.

Maybe these people can help to some degree. But I think this takes all of us. We are all knowledge nodes, trusted by people in our little network bubbles. We should take that responsibility seriously. Let’s pick up the phones, talk with people we haven’t talked with in a while, and spend more than half the conversation listening (even when cringe-worthy things are said).

But when the conversation is done, let them know you’re ready to roll up your own sleeve for that shot.

I sure am.

 

Science

  • Analytical validity of nanopore sequencing for rapid SARS-CoV-2 genome analysis. Nature Communications. Dec. 9. (Rowena Bull et al)
  • Temporal and Spatial Heterogeneity of Host Response to SARS-CoV-2 Pulmonary Infection. Nature Communications. Dec. 9. (Niyati Desai et al)

Vaccines

Long COVID

  • COVID Survivors With Long-Term Symptoms Need Urgent Attention. Summary of NIH Summit. NYT. Dec. 4. (Pam Belluck)
  • This COVID-19 Long Hauler is Still Trying to Recover. Timmerman Report. Dec. 7. (Blair Clark-Schoeb)

Science-Industry Relations

  • An Opportunity to Improve Innovation. Science. Dec. 11. (Holden Thorp)

Deals

South San Francisco-based Atara Biotherapeutics secured $60 million upfront through a partnership with Bayer. The companies will work together to develop off-the-shelf and personalized T-cell therapies for mesothelin-expressing cancers.

BridgeBio Pharma and Maze Therapeutics agreed to form a joint venture, Contour Therapeutics, to develop precision medicines for cardiovascular disease.

Financings

San Diego-based RayzeBio pulled in $105 million in a Series B financing to advance its platform for making targeted radiation therapies for cancer. Venrock Healthcare Capital Partners led.

Cambridge, Mass.-based Vigil Neuroscience raised $50 million to develop microglia-targeting therapies for neurodegenerative diseases. Atlas Venture and Northpond Ventures co-led. Ivana Magovčević-Liebisch is the startup CEO.

Cambridge, Mass.-based Remix Therapeutics raised $81 million in seed and Series A financing to advance its small-molecule discovery program aimed at RNA processing targets.

Mountain View, Calif.-based DeepCell, a company using AI for cell classification and isolation research tools, raised $20 million Series A led by Bow Capital and joined by Andreesen Horowitz.

Boulder, Colo.-based Edgewise Therapeutics raised $95 million in a Series C financing to advance oral treatments for Duchenne and Becker muscular dystrophies. Viking Global Investors led.

South San Francisco-based Sutro Biopharma, the developer of targeted drugs for cancer and autoimmunity, raised $126 million in a stock offering priced at $21 a share. The company raised cash after presenting clinical data at the American Society of Hematology.

Mountain View, Calif.-based IGM Biosciences raised $200 million in a stock offering at $90 a share. The company also seized upon momentum from a positive presentation at the ASH annual meeting of its bispecific antibody directed at CD20 and CD3 for relapsed / refractory non-Hodgkin’s lymphoma.

Boston and San Francisco-based Pear Therapeutics, the developer of digital therapeutics, raised an $80 million Series D financing led by SoftBank Vision Fund 2.

Our Shared Humanity

  • Make it easier to stay safe from COVID-19, instead of shaming and punishing people. USA Today. Dec. 7. (Joshua Borcas and Gregg Gonsalves)
  • Headlines Don’t Capture the Horror We Saw in a New York Hospital. America Must Not Let Down Its Guard. The Atlantic. Dec. 6. (Kasey Grewe)
  • Medical Schools See an 18 Percent Increase in Applications. They’re Calling it the Fauci Effect. The Hill. Dec. 7. (Zack Budryk)
  • The Danger of Assuming That Family Time Is Dispensable. Americans who are desperate to see their loved ones need advice that goes beyond “Just say no.” The Atlantic. Dec. 9. (Julia Marcus)
  • The Hidden Fourth Wave of the Pandemic. America Hasn’t Begun to Face this Year’s Mental Health Crisis. NYT. Dec. 9. (Farhad Manjoo)

Our Fractured Political Discourse

  • Rick Santelli of CNBC and the Danger of Flouting COVID-19 Facts. Bloomberg News. Dec. 7. (Timothy O’Brien)
  • Trump and Friends Got Coronavirus Care Others Couldn’t. NYT. Dec. 9. (Sheryl Gay Stolberg)
  • ‘A Scary Time’: Researchers React to Agents Raiding Home of Former Florida COVID-19 Data Scientist. USA Today. Dec. 9. (Alessandro Marazzi Sassoon)

Science Features

  • Infected After 5 Minutes, From 20 Feet Away. South Korea Study Shows COVID-19 Spread Indoors. Los Angeles Times. Dec. 9. (Victoria Kim)
  • Blunders Eroded US Confidence in Early Vaccine Frontrunner. NYT. Dec. 8. (Rebecca Robbins et al)

Epidemiology

  • COVID-19 Mortality Among American Indian and Alaska Native Persons — 14 States, January–June 2020. CDC Morbidity and Mortality Weekly Report. Dec. 11. (Jessica Arrazola, Matthew Masiello et al)
  • Evidence of Long-Distance Droplet Transmission of SARS-CoV-2 by Direct Air Flow in a Restaurant in Korea. Journal of Korean Medical Science. Nov. 23. (Keun-Sang Kwon et al)
  • Racial Disparities in Patients with Coronavirus Disease 2019 Infection and Gynecologic Malignancy. ACS Cancer. Dec. 9. (Olivia Lara et al)

Management

Data That Mattered

South San Francisco-based Global Blood Therapeutics provided updates at the American Society of Hematology on inclacumab, an antibody directed at P-selectin, to reduce the frequency of vaso-occlusive crises (VOCs) in patients with sickle cell disease, and GBT021601, a hemoglobin S (HbS) polymerization inhibitor. GBT also said at ASH that its sickle cell disease treatment — voxelotor (Oxbryta) — was able to deliver greater than 1 gram per deciliter of improvement in hemoglobin improvement from baseline, through a 72-week study, for 90 percent of patients. The long-term follow-up is consistent with earlier presentations from 24 weeks of analysis.

South San Francisco-based Sutro Biopharma reported on its CD-74 directed antibody-drug conjugate at ASH. From 18 evaluable patients in a dose-escalation Phase I study, Sutro found the treatment to be well-tolerated, and saw no maximum tolerated dose. Of the 7 patients with diffuse large B-cell lymphoma, the company reported 1 Complete Response and 2 Partial Responses. Enrollment is continuing at a higher dose.

San Diego-based Fate Therapeutics reported at ASH on its iPSC-derived off-the-shelf engineered Natural Kill cell therapy in refractory diffuse large B-cell lymphoma. The NK cells are engineered to target CD19, the antigen where CAR-T cell therapies first found success. The company reported on a case study of a single patient who got a single dose, and achieved a Partial Response in the first dose cohort with 30 million cells. The response improved on the second dose, and no severe adverse events were reported, the company said. Shares rocketed from $60.71 a share prior to ASH to $96.85 at yesterday’s close.

Mountain View, Calif.-based IGM Biosciences reported at ASH on a Phase I dose-escalation study of its bispecific antibody directed at CD20 and CD3. Of the 14 patients with relapsed, refractory non-Hodgkin’s lymphoma on a variety of low doses, 9 showed evidence of tumor shrinkage, and 2 counted as Partial Responses. No severe side effects, particularly worrisome ones like cytokine release syndrome or neurotoxicity, were observed, the company said. Shares in the company boomed from $62.56 before ASH to a high of $133 a share on Wednesday, before cooling off.

Switzerland and Cambridge, Mass.-based CRISPR Therapeutics and its partner, Vertex, reported at ASH on their gene edited therapy for beta-thalassemia and sickle cell disease at ASH. All 7 patients with beta-thal – followed between 3 and 18 months after CTX-001 infusion, were able to stay off blood transfusions. All three sickle-cell disease patients, followed for 3 to 15 months, were free of vaso-occlusive crises – the painful episodes that often send sickle cell disease patients to the hospital. CRISPR Therapeutics now has a market valuation approaching $11 billion.

Cambridge, Mass.-based Evelo Biosciences reported on its orally available monoclonal microbial drug, EDP1815, from a Phase I study of 23 patients with mild to moderate atopic dermatitis (eczema). The drug showed a statistically significant improvement compared with placebo at Day 56, and improvements were observed as soon as Day 14.

Legal Corner

BIO, the California Life Sciences Association and Biocom filed suit in US District Court in Northern California against HHS and CMS over the administration’s attempt at drug price controls through the “Most Favored Nations” executive order.

Regulatory Action

The United Arab Emirates approved an inactivated COVID-19 vaccine from Sinopharm, the Chinese state-owned company. The UAE regulators said the Sinopharm vaccine was 86 percent effective in preventing COVID-19 infection, and 100 percent effective at preventing moderate to severe COVID-19 disease. The UAE didn’t provide a detailed breakout of the data. (See the statement). And NYT coverage.

Regulators in India declined to grant an Emergency Use Authorization to the AstraZeneca COVID-19 vaccine, asking for more safety and efficacy data, according to Reuters.

Personnel File

President-Elect Joe Biden selected Rochelle Walensky of Massachusetts General Hospital, an HIV researcher and savvy communicator, to be the new director of the Centers for Disease Control and Prevention. (STAT coverage by Helen Branswell)

San Diego-based Molecular Assemblies, an enzymatic DNA synthesis company, hired Phil Paik as VP of platform development. He was associate director of engineering at Illumina.

South San Francisco-based Global Blood Therapeutics hired Kim Smith-Whitley, M.D., the director of the Comprehensive Sickle Cell Center at Children’s Hospital of Philadelphia, to be executive vice president of R&D. She starts officially in 2021.

Andrew Peterson joined Broadwing Bio as founder and CEO. Broadwing is being formed by Maze Therapeutics and Alloy Therapeutics. Broadwing will develop targeted antibody drugs for ophthalmic diseases.

Science, Non-COVID

The Role of the Microbiota in Human Genetic Adaptation. Science. Dec. 4. (Taichi Suzuki and Ruth Ley)

10
Dec
2020

Vaccine Communication: Another Opportunity for Biopharma to Lead

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10 Dec 2020

We’ve all seen this movie, right?

It feels like we’re in the fake final scene before the jump-scare and the bad guy makes one final push. It’s that point in the 1986 sci-fi film “Aliens” where Bishop gets ripped in half and Ripley (Sigourney Weaver) realizes in horror that the Alien Queen snuck aboard her ship.

Normal, whatever that means for you, seems so close and real, doesn’t it? But I can’t shake the feeling the horizon’s farther away than we hope it is. And if so, that presents an opportunity I hope Biopharma grabs by the spike protein: the chance to help people understand that it’s not over yet and might not be for a while.

Without a doubt, the vaccine readouts are a huge milestone. I’ve read the reports over the past months with joy and excitement. The record pace for vaccine development would put Han Solo’s Kessel Run from “Star Wars: Episode IV A New Hope” to shame.

Photo of TR Contributor Kyle Serikawa

Kyle Serikawa

The coming Emergency Use Authorizations deserve big trophies, for Pfizer, BioNTech and Moderna. These are the kind you put proudly in the center of the display case, pushing aside the participation awards and moving the team spirit plaques to the back. But these heroic efforts won’t be enough.

A few weeks ago, Mike Kuczkowski penned a great call on this site for a new model of vaccine communication. He laid out a plan to push out a message on all fronts, appealing to left brain, right brain, and hopefully lizard brain. He called for pulling in advocates from across a range of sources, including some unexpected ones like employers.

After all, if the Broncos can elevate a rookie wide receiver from their practice squad with just twenty-four hours advance notice to start an NFL game at quarterback – the most difficult and important position in football — surely it’s not too much to ask the local hardware store owner to put out some PSAs for vaccine awareness?

It’s a great plan and could make a big difference in vaccine uptake and getting us to that normal if all of Kuczkowski’s ideas play out.

But here’s the Drosophila in the beer. The message won’t do as much good if the target audience never hears it, misunderstands it, or isn’t willing to listen to what’s been said. And it won’t be most effective if the message is only about vaccination.

There are two related roadblocks that could derail vaccination’s effectiveness. The first is people who do hear that they need to get vaccinated, but don’t get the full message about timelines and expectations The second problem is with people who aren’t listening at all.

In the first camp, are people who are just tired, man, of this damn virus and want it all to end. Many are going to be eager to get the vaccine. But in their eagerness, there’s the danger of not hearing the caveats.

There are always caveats. Like, “We don’t know how long immunity lasts.” Or, “We don’t know if the vaccine prevents you from being infectious.” Or possibly, “We aren’t sure of the effectiveness in your particular demographic.” Those are just a few. Some people might assume that once they get that dose, they’ll be fine to go back to doing everything just like in good old 2019.

Then there are other people who aren’t first (or second or third) in line for the vaccine but hear that it’s being rolled out and think, “Ah, now that there’re vaccinated people out there, the overall risk is lower!” That may be true. But only to a small extent, at least until a majority of Americans get vaccinated. That could take quite a while. Pfizer has already had to walk back some estimated timelines for its rollout.

Anyone with a background in synthesis or formulation want to bet every other company’s rollout will go forward without a hitch? Not to mention the supply chain, storage and administration challenges.

There’s a need to communicate not just about the vaccine itself but about expectations and about needed behavior. Relaxing too early and dropping our most effective behaviors—meeting outside, in smaller groups, with distance and masks—could counteract all the benefits of a gradually increasing population of immunized people.

Biopharma could lead in this. Yes, the industry has a reputation problem, but it’s been trending up since the pandemic. Offering a clear voice, unified with local, state and federal leaders, not just urging vaccinations, but also providing measured guidance on when and how to begin relaxing pandemic behaviors, will help remind people that it would be a mistake to unmask too soon. And a conservative view of the future is needed all the more because of the other possible roadblocks.

The second group of people—those that PSAs can’t reach, those who reflexively distrust the media and the government (if you’re from the opposing party)—they worry me even more. In information theory terms, a vaccine communication strategy could do things to reduce entropy of the message (“Get vaccinated, keep wearing a mask”), but if the receiver is turned off, the message doesn’t get there.

We’re living in a strange time. No, not the pandemic. Or not that pandemic. I’m talking about the epidemic of misinformation and the willingness of people to listen to the misinformation, to embrace the entropy instead of the signal.

It’s been a frustrating realization for me, but we’re all far more susceptible to appeals to emotion and identity and confirmation bias than I wish was the case. The internet has always been a double-edged sword and it feels like, with its help, many have been pushed beyond some information black hole event horizon, where a good fraction of them won’t be able to get back.

Two things here. First, some of them can come back. They are another opportunity for Biopharma to make a difference, but perhaps through a different approach. Anecdotally, I and others have found that close relationships and local ties can help in breaking through science denialism. Could Biopharma start programs to train staff in science communication and encourage them to have calm two-way conversations with friends and relatives and neighbors who are expressing skepticism?

Second, because there are those who can’t be reached, there will be an even greater need to caution people to stick it out for a while longer. If a fraction of the population refuses vaccination, there is an upper bound to how high the vaccinated proportion can reach. If 80 percent of the population is open to the possibility of getting a vaccine, and we need 70-75 percent of the country to get vaccinated for herd immunity, that leaves very little margin for error. Almost everyone who’s open to getting vaccinated will have to actually get vaccinated.

Anything less than that high level of vaccination across the population means that conditions for a return to normal will take a longer time to arrive. That, in turn, means that all the pandemic behaviors we are so tired of will have to continue. Not just for our own health, but for everyone’s.

The next months will tell how effectively the messaging gets out, whether from Biopharma or other sources. I hope our industry embraces this chance to lead and shine. And I’ll be eagerly awaiting my turn in line for my needle stick, whenever it comes. But in the meantime, and for a while after, I hope you don’t mind if keep my distance and smize from behind my mask when we meet.

Disclosure: The author is a Program Manager at Adaptive Biotechnologies. All views or opinions expressed are his own and not of the company.

9
Dec
2020

Priority for Next Administration: Tech-Ready Health Leadership

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09 Dec 2020

David Shaywitz

From the moment Joe Biden takes the oath in January, his Administration will confront a brutal onslaught of urgent health challenges.

The work starts with the complex distribution of a multi-dose vaccine to a remarkably skeptical public. To do this job, and countless others, there is a desperate need to upgrade the nation’s health data capabilities, which were pressure-tested by COVID-19 and, with rare exceptions, found wanting.

Our country’s health data are scattered in thousands of local hospitals and health systems. Federal legislation such as the HITECH Act has driven, and subsidized, the digitization of much of this information. Even so, these data still tend to be organized and maintained locally. Sharing is publicly championed by all stakeholders, yet in practice, is limited and begrudging at best. Data hoarding remains the rule rather than the exception.

Leaders of health systems maintain their iron grip on data because, other than transiently positive PR, sharing is perceived to offer only downside risks. These include exposure of information to competitors (as important to most “non-profit” hospitals as to anyone else), risk of liability, and the cost and inconvenience of organizing the information in a fashion suitable for distribution.

Some technology tools and policy initiatives have facilitated a modicum of interoperability. But health data remains profoundly illiquid, impairing communication between health systems, and between health systems and local and national health officials. 

Data access and usability difficulties have also impacted the care delivered within an individual hospital. Like Lucy and the football, this is continuously frustrating the evergreen, ever elusive dream of a “learning healthcare system.”

The data sludge impairs the care of individual patients seeking care from their local physician; it also limits the ability of national health leaders to recognize, understand, and organize a response to a global emergency like the pandemic. 

Doctors in training are taught that the first step in a medical emergency is to take your own pulse, and calmly assess this situation before you. It’s hard to do this as a nation when you have such limited visibility into timely and reliable health data.  

To be sure, there have been distinct digital successes as well; telehealth, for example, offered a lifeline to many patients unable or unwilling to leave their homes. Adoption of this existing technology was catalyzed by the easing of regulatory and reimbursement constraints. Those barriers may well be reimposed when the emergency subsides. 

Virtualization – and temporary regulatory flexibility – also enabled clinical trials to continue during the pandemic. Whether these approaches – often far more convenient for study subjects – persist after the pandemic remains to be seen.

The pandemic has also exacted a huge economic toll on many physicians and care providers. In a fee-for-service system, revenue correlates with the volume of care provided. 

Many patients stayed away from hospitals because they were afraid of acquiring COVID-19, often adversely impacting both the patient’s health and hospital’s bottom line. This will surely prompt many physicians and health systems to once again contemplate alternative revenue models generally built around the concept of value-based care, and prioritizing health maintenance. 

Successful implementation of these approaches, however, will require a suite of digital capabilities – such the ability to reliably assess and carefully monitor the health of a population of patients – that most providers, unfortunately, currently lack.

All of these challenges, of course, also represent a tremendous opportunity to leverage technology to improve health, elevating not only the care provided by our leading hospitals, but also increasingly moving the locus of care outside the hospital, and enabling patients to access a greater variety of health and wellness services the way they already experience most other services, from media to banking – from the convenience of their home, office, car, or community. 

Importantly, this will also require a heightened awareness of, and attention to the lack of access to broadband Internet technology, and necessary computer equipment among some of our most vulnerable populations. This need for technology access includes both urban and rural populations.

As President-Elect Biden contemplates the composition of his incoming administration, he should ensure his incoming healthcare team includes proven executives capable of recognizing and leading through these important contemporary digital challenges.  

The combination of medical training and deep technology chops have not been a prominent feature among most top nominees identified to date. Xavier Becerra, for example, selected to lead the Department of Health and Human Services (HHS), is an attorney, as is the current Secretary of Health and Human Services, Alex Azar.  

Biden advisor and COVID-19 response coordinator Jeffrey Zients — a business executive who was CEO of the Advisory Board Company (a healthcare consultancy) and the expert called in to salvage the botched healthcare.gov rollout — surely recognizes the value, and perhaps even necessity, of digital sophistication on top of patient care experience for future healthcare leaders.  

It’s an elusive and essential combination of traits that Biden would do well to prioritize as he contemplates future appointments, such as the next FDA Commissioner and Director of the Centers for Medicare and Medicaid Services. 

The complexities of digital transformation sweeping across both healthcare and drug development require leaders with the tech expertise to grok these dramatic changes, and the clinical judgement to maintain focus on what really matters.

7
Dec
2020

Vaccine Trials: A Band of Brothers and Sisters

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07 Dec 2020

Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.

On Dec. 2, the New England Journal of Medicine published an article coauthored by many prominent medical scientists, including physicians, who advocated for extending the time in which volunteers in the placebo group enrolled in the Pfizer and Moderna COVID-19 clinical trials should be followed.  

Essentially, they are arguing that the study volunteers – people who sacrificed for the greater good to join the trials in the first place – should be prohibited from getting the actual vaccines, even after the vaccines become widely available under an EUA (Emergency Use Authorization), because there is “additional scientific information that can be learned.”

Of course, there are always new things we can learn from a clinical trial. But at some point, we know enough that the risk to persons not being given these markedly effective vaccines is greater than benefit that can be learned from withholding vaccination to these persons. 

As a physician and a scientist, I recognize no one clinical trial ever solves all the issues needing to be addressed for public health. However, in making decisions when to offer vaccine to placebo participants in a trial in which high efficacy has been demonstrated, one needs to carefully balance scientific interests with withholding the benefits of vaccination to clinical trial participants themselves.

We must consider the real issue of fairness, and perceptions of fairness, at both the individual and community level.

So, let’s discuss these issues.

First, let’s look at what’s to be learned from keeping people on placebo while the EUA is being evaluated and the early days of market authorization, when supplies will be scarce.

Both the Moderna and Pfizer studies, which enrolled 30,000 and 43,000 volunteers, respectively, have reached their goal. Enough information on the number of pre-defined cases of COVID-19 required to define the vaccines’ effectiveness has been reached. More than 150 cases of COVID-19 were found among participants in each trial, and the vast majority of those cases were in people who were on placebo.

The analysis which compared the vaccine to the placebo occurred nearly two months earlier than projected. We got the answer quickly because people at high risk of infection enrolled swiftly in trials, and the widespread epidemic of COVID-19 across our country meant we didn’t have to wait long for cases to appear among volunteers.

The endpoints were well defined. Scientists asked, first and foremost, whether the vaccine reduced the chance of people getting symptomatic disease. The most important secondary endpoint looked at whether the vaccine reduced severe disease (hospitalization).

The results were simply spectacular—approximately 95% efficacy in the primary endpoint; 100% in the secondary for the Moderna vaccine. Even more compelling is that the results were remarkably similar between both the Pfizer and Moderna clinical trials, which both are testing messenger RNA based vaccines.

That’s a key validation for this emerging type of vaccine technology.

To date, the only reported death related to COVID-19 in the trials was in the Moderna trial and that was in the placebo group.

These data are clear and compelling. It’s hard to believe any more data are needed to show that the vaccines reduce the likelihood of developing moderate-to-severe COVID-19. By keeping people on placebo, we are only subjecting them to a higher risk of contracting severe COVID-19 disease. Are we trying to show that hospitalization and/or mortality is only 90% rather than 100%? I doubt that.

Everyone wants to know how long the vaccine can protect people. More time is required to answer that question. But by the time January rolls around and more vaccine doses become available, we will have close to six months of data from the start of the clinical trials in late July.

As I’ll explain below, there is a very good way to assess vaccine durability. One way to assess continued vaccine effectiveness against COVID-19 would be by vaccinating the placebo recipients in a crossover design.

This literally allows people who were on the placebo to “cross over” to get the real vaccine in a second phase of an ongoing study. The participants, and researchers, would still remain blinded as to what they are getting.

By continuing in this way, we could ensure that everyone in the study is getting vaccinated, while we’ll also get the chance to learn something new what the difference is between early versus late effects of vaccination. These data can be obtained by vaccinating the placebo recipients in early 2021, rather than simply waiting and watching them as more and more of them acquire COVID-19 disease in the trial. 

Understandably, people want more safety data, and longer-term follow-up.

However, to assess the infrequent side effects of vaccination, it is not the vaccine cohort in the Phase III trials (about 21,500 for Pfizer and 15,000 for Moderna) that will discern this. Instead, this information will be gathered from the cohort of millions of people who receive the vaccine under the EUA and are then closely followed post-vaccination.

Respecting the thoughtfulness of the guidance documents from the FDA, regulators still want to know whether vaccination can result in enhanced disease. They also want to compare the background rate of severe pulmonary infection in placebo recipients. So far, there is no evidence in either trial of severe pulmonary disease from vaccination. In fact, it is quite the converse.

Between the two trials, there are between 40 to 50 cases of severe disease, and while the details of these cases are not known to me or the public (and such data are critical to unpack), it all says these pneumonias and hypoxemias are in placebo recipients.

Should we be more worried about a chance of enhanced disease from the vaccine – even though there’s no evidence to say that’s a real concern – or should we be more worried about exposing unvaccinated placebo recipients who self-identified as at-risk of COVID-19 infection?

In the Moderna trial, 30 (16%) of the 187 reported cases of COVID-19 were classified as severe over the four-month review period. Do we really want to see another 30 people get severe disease by watching them for four more months? 

The question in my mind is what scientific justification is there to not vaccinate placebo recipients who had participated in the trial in which there was 95% efficacy and 100% effectiveness from hospitalization?

One can mitigate these numbers by saying only the healthy, so to speak, should be left alone. The tactic of differential handling of placebo recipients is, however, problematic. To take placebo recipients who fall under the category of EUA eligibility—in other words, medical care or first-line workers, nursing home personnel, those who are elderly or essential workers—and provide the vaccine because they are in group 1 of the EUA in their state, or nationally, is logical. But to deny their companions who joined them in being a clinical trial participant is quite problematic both from a social justice, fairness, and public perception point of view.

First, trial participants are essentially a community bonded together in a clinical trial. Thirty to forty thousand people were grouped together and placed under common scrutiny and rules.  

We in clinical trials authenticate this bonding by calling them a study cohort. In this medical vernacular all are equal and each benefits from the other. The goal of the cohort is to achieve the study goal, which is not asking participants to get sick, but recognizing that in the course of human life some people will develop this disease.

Within the common community of trial participants, did the endpoints on the trial come from the medical workers or the non-medical workers? Was severe disease only in the elderly or in one group or the other? Does it matter? Does a medical worker who participated in the trial deserve vaccination more than the group of essential workers or someone who lived in the household of an essential worker who developed COVID-19 on the trial? Does either group feel good that the other is excluded when they entered the trial as equals in their own community? Differential access inserts nonequity among this “Band of Brothers and Sisters.” Are they being asked what they want? If so, would they say that they deserve the vaccine more than someone else in the trial? Did the medical worker who did not get infected sacrifice more than the bus driver who did or his friend who did not get infected?

Need I say more?

There are many dispassionate people who say we need and have a societal obligation to learn about the durability of the vaccine’s effectiveness. My colleagues at the CoVPN (COVID-19 Prevention Network) have, in fact, developed a proposal that would answer this quite effectively by vaccinating the placebo recipients, keeping the trial blinded, and following participants for signs of COVID-19 disease for the subsequent 18 months.

In this scenario, the people who got vaccine in the first place would get their blood drawn and be randomized to placebo injection. And those who initially got placebo would get their blood drawn and be injected with vaccine.

Let’s say we start in early January with the first dose, by the end of January after the second dose has been administered, everyone on the trial(s) would be vaccinated. Some could have been vaccinated last July 2020 at the start of the trials; some in January 2021.

By running the trial this way, we will be able to see the changes in durability in that six-month time difference, but everyone in the trials would then be vaccinated and therefore protected.

My colleagues and I feel this is best done blinded, but that is perhaps a lesser issue. The key point is that receipt of the vaccine is intended for all who originally signed up for the trials. Hopefully, most participants will want to continue with the study, and help answer this longer-term issue and continue to go to the clinic for COVID-19 testing and follow-up when they are ill.

With this proposed way forward, we can continue to learn about the efficacy and durability of the vaccine with the placebo group being vaccinated. It is medically difficult to justify keeping people on placebo when we don’t have absolute markers of risk — when we see that even some people ages 15 to 55 have been shown to experience severe disease, when we see increased hospitalization and death but have no clear marker of risk that can guide us as to who is at risk and who is not.

Keeping the vaccine from the very people who got us this far by participating in the trial, and who could benefit from it, is in my view, untenable. I, and almost all of my colleagues I surveyed who conducted these trials, honestly feel it is just not right.

Lastly, some people might argue that by vaccinating those in the placebo group, we would be taking vaccine away from others who are more deserving or who might have a higher risk. This is not the case. Vaccine vials labeled for research purposes are permanently labeled as such and are not those allocated to the general population.

If we’re going to adhere to the determinants of social justice; if we’re going to advocate for the underserved; if we’re going to declare the importance of altruism and act with principles of fairness, then we must treat all of the placebo recipients equally.

They themselves have become their own Band of Brothers…and Sisters, and we must honor their service to us all. 

Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.

7
Dec
2020

This COVID-19 Long Hauler is Still Trying to Recover

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07 Dec 2020

E. Blair Clark-Schoeb, SVP of communications, Aruvant Sciences (Photo credit: Fisk Foto)

Our daughter celebrated her 14th birthday on Mar. 14. It’s an event none of us will forget.

Our family invited a few of her friends to join us for dinner in New York City to celebrate.

Scary headlines about the COVID-19 outbreak in New York were everywhere in the days leading up to her birthday. We had to stop and think. We debated whether to cancel this gathering. But we decided to move forward since we were just going to be with a small group.

Five days later, we came down with the Coronavirus. My husband Scott felt exhausted. I had a headache. When I felt a weird sensation of shortness of breath, like I had never felt before, I knew we needed to be tested.

Scott got tested on a Monday. A day later, we all knew. My mother and father, 77 and 84, respectively, were staying with us at our home in Summit, NJ. They immediately jumped in a car to go back to their house in Delaware. Thankfully, neither of them developed any symptoms.

For the next two weeks, my husband and I essentially stayed in bed. It was a struggle to stand up and walk to the bathroom. Our kids, staying downstairs or somewhere at arm’s length in the house, brought us food and plenty of liquids. They would leave food for us and walk back downstairs.

We felt terrible. The symptoms were typical — headache, fever, body aches, sore throat, GI issues. Although we had shortness of breath, we never needed to go on supplemental oxygen or felt so sick we needed to go to the hospital. We had what doctors call a “mild” case.

After two weeks, we started to feel a bit better. Around three weeks out, Scott was on the road back to normal. (Although he says he is not the same as before, he now is able to run over five miles these days).

By mid-April, I felt like I was recovering as well. Then, by Week 5, I started going backwards. I got tested again. Sure enough, it was positive.

Over the next month or so, I continued to feel OK. Not terrible, not great. Looking on the bright side, we decided to get out of the house. In May, we wanted to go see my parents in Delaware. The stay-at-home orders had lifted by then, and the first wave of cases in the pandemic appeared to be subsiding. We all got tested, and — good news! — we all tested negative.

We were ready to put our COVID-19 experience behind us.

The summer months were a roller coaster. One day I took my daughter to an outdoor lacrosse event. A fever came over me. At the event check-in table, they checked my temperature, and asked me the standard questions designed to prevent spread of the virus. I told the young lady that I still had occasional fevers even though I recently tested negative.

I managed to sit in the shade to cool down from the original 101 degrees Fahrenheit I had shown at check-in.  (That, by the way, was the highest fever I have ever recorded, even when I was actively shedding detectable levels of the virus). They allowed me to stay to watch, from a distance. It was a hot day, and somewhat miserable.

Word got around at the event that I had a fever. A particularly pushy mom called the head of the lacrosse club to complain. Next thing I knew, I was getting chased out of the event. 

The confusion about this virus makes people nutty. I sat in the parking lot, with tears rolling down my face. The proverbial scarlet letter, in my case a “C” on my chest, was humiliating. It was also upsetting that I still felt like crap months after I was first infected.

Like every other long hauler, I can paint the picture of what I was like before I got this lovely virus. I was a working mother of four who exercised almost every day. I alternated cardio and yoga days. You can check my Peloton app and see that I was active. I was a college athlete, playing squash at Harvard University. Staying fit and healthy is an important part of who I am.

Since being infected, I have attempted to exercise a few times. Most days, I feel like an elephant is sitting on me.

What I find particularly frustrating is the lack of understanding. One day, about four months into our COVID experience, my husband and I were out for a walk. (Essentially, he was dragging me outside to try and get me some exercise.) I remember it was a beautiful day that normally I would have relished being outside, but I really just wanted to go back to bed. We ran into a family practice doc in our neighborhood. Scott was telling her how I still have symptoms.

“It’s probably something else,” she said dismissively.

Other people, who aren’t physicians, freely offer their own speculative diagnoses. “Oh, maybe you have Lyme disease,” — I’ve heard that more than once.

The worst of these baseless conjectures came during a recent trip to an urgent care facility. I was there having my son tested after he had been exposed. I overheard the nurse telling the doctor that I am one of those “long haulers.”

The doctor replied, “This is today’s version of fibromyalgia.”

The condescending tone, and the implication that this illness was all just my overactive imagination, was beyond annoying. The inherent sexism and insensitivity that provider showed still burns me today. 

I now feel like I can relate to what it must feel like for individuals who suffer from a rare disease with no cure. Everyone has an opinion and people aren’t sure how to interact with you.

I do not want pity from anyone. I hate being asked how I am feeling. Because it never changes, and my answer is always the same. At this point, I do not want to talk about it. But if we do talk about it, I certainly do not want to hear people’s uninformed theories on how maybe I have Lyme disease or something else. 

I want to find something to help me recover, and I’d be happy, as a member of the biopharma community, to participate in some way to help advance scientific understanding of what’s going on with COVID-19 long haulers.

Recently, I had a visit with the University Pennsylvania Post-COVID-19 Care Center. We tried a round of steroids. That did nothing. They had me wear a cardiac halter for two weeks. I am waiting on the results. The one thing the team at Penn says appears to make a difference is physical therapy. So I’m giving that a try. At the same time, I am exploring Eastern medicine. I have done acupuncture. They prescribed me some herbs that made my heart race.  I am open to anything. 

The latest vaccine developments from Pfizer and Moderna thrill me. Some people see those results and imagine a return to normal, which in their mind means eating out once again.

I am just hopeful that the vaccine will help me feel even a little bit more like my former self. I do not want to feel like an old lady whose hips hurt, who can’t sleep through the night because of leg pain, who has shortness of breath.

I want to feel young again — like the 46-year-old that I was just nine months ago. A day without a headache would be nice, especially a day without the kinds of headaches that make me jump at loud noises or that knock me out in pain.

Often, I have heard people talk about just wanting to have the virus so they can get it out of the way and build up their immunity.

I have also heard how this is like the flu. I have never had a flu that has lasted for nine months. I suggest trying to avoid it and get vaccinated as soon as possible. My husband has antibodies and has even donated plasma. I can’t do that, because I don’t appear to have any antibodies. I am hopeful the vaccine will help me produce antibodies so I can feel better.

I have asked if I qualify for any of the current available treatments, and the answer is always no. We joke that we are going to do our own experiment and my husband will donate his plasma to me.

It would be so nice to get some clarity — a clear and confident bill of health that would allow me to plan for the future with confidence.

So much of this experience is about dealing with endless uncertainty and surprise.

Remember my daughter’s fateful 14th birthday dinner on Mar. 14? Turns out that wasn’t the exposure event we all thought it was. After a recent visit to a local furniture store, I discovered that in all likelihood, I did not even contract the virus at a restaurant in New York after all. The furniture store owner shared that she had been infected five days prior to when we had seen her in early March.

“It’s fine,” I told her, trying to coolly absorb what she had just said. “It’s been a mild case…” 

 

E. Blair Clark-Schoeb is the senior vice president of communications at Aruvant Sciences a company developing gene therapies for rare diseases. She is a founding member of the Society of Healthcare Innovation. Twitter: @EBCS22 

3
Dec
2020

AZ’s Muddy Result, Regeneron Cocktail OK’d, and Biogen, Sage Bet Big on Depression

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03 Dec 2020

Luke Timmerman, founder & editor, Timmerman Report

Take two weeks between Frontpoints columns, and a lot of stuff happens.

On Monday Nov. 23, AstraZeneca presented a muddy picture from its Phase III clinical trial with a COVID-19 vaccine developed on adenovirus technology with Oxford University. It’s either delivering 90 percent efficacy or 62 percent efficacy, depending on the dose. So it’s either great or good, but we’re not entirely sure.

Importantly, it costs less than $3 per dose and it easy to manufacture at global scale. So there’s that. AZ might have to run a new trial to get a clear answer on safety and efficacy, and that will take time, and maybe be hard to conduct with actual approved vaccines on the market.

Even though AstraZeneca has done many things this year to undermine public trust in itself (no more private CEO calls to JPMorgan clients, and more transparency on adverse events, please), this generally effective third vaccine in line is still a positive development.

One week after AstraZeneca’s muddy but directionally positive announcement, Moderna released its extraordinary full results from its 30,000-volunteer Phase III trial with its COVID-19 vaccine candidate. A vaccine that’s 95 percent effective at preventing COVID-19, and that protected everyone from severe disease. Hot damn. That’s a home run.

Then there’s Pfizer. Like Moderna, they have lightning in a bottle — an awesomely 95 percent efficacious vaccine in their hands, thanks to years of innovative work by BioNtech. But it turns out Pfizer can only ship half of the 100 million doses they expected to be able to ship by the end of the year, according to the Wall Street Journal.

Messenger RNA, amazing technology that it is, has quite obviously never been manufactured at global scale before. We knew this, and should expect more hiccups in manufacturing and supply. When this happens, it’s not the end of the world.

Pfizer, I’m sure, will get this fixed and deliver the goods. The whole world is watching and counting on it. A manufacturing supply issue, even with intricate lipid nanoparticles at global scale, is challenging, but solvable. The hard part is figuring out whether you have a good vaccine at all. We do know that for Pfizer and Moderna.

The Emergency Use Authorization applications are on file with the FDA. The FDA vaccine advisory committee will consider Pfizer’s application on Dec. 10 and Moderna’s on Dec. 17.

Priorities are being set on who should get the vaccines first, and who will have to wait until supply can meet demand. See Larry Corey’s excellent summary of the vaccine scarcity challenge to come.

We have struggled with clear scientific communication about the pandemic this year — but this distribution plan is an opportunity to make that right. The stakes are as high as it gets now, when people are getting ready to get in line.

The story now is about doing everything possible to save lives through the next few months.

Most public health officials expect another surge of cases in weeks ahead, after a Thanksgiving weekend in which many Americans ignored advice and traveled to visit family.

The vaccines are on the way. Therapies that make a difference are here (Gilead, Regeneron, Lilly). Biotech has undoubtedly risen to the occasion.

But dark, dark days lay ahead. The death toll could exceed 450,000 by the end of February, according to the CDC director. We’ll all be wearing masks and physical distancing for many months into 2021, until we can get a critical mass of people vaccinated. Our country, suffering from a breakdown of trust in our fellow countrymen, is going to struggle to overcome the vaccine hesitancy that’s sadly become so common.

This weekend, I’m going to keep fingers crossed for Johnson & Johnson to nail its Phase III with a single-shot adenoviral vaccine. This one has been flying below the radar, but could provide a cheap, easy to manufacture, easy to distribute, effective vaccine option.

We need all the help we can get.

Biopharma, this is the time to show what it’s all about.

Our Shared Humanity
  • A Crisis Reveals What is In Our Hearts. NYT. Nov. 26. (Pope Francis)
  • What If We Had People’s Trust? Nov. 30. (Susannah Fox)
  • The Weather Outside is Frightful. Timmerman Report. Nov. 30. (Lisa Suennen)
  • This Pandemic Must Be Seen. Wired. Nov. 20. (Roxanne Khamsi)
Science of SARS-CoV-2
Treatments
Public Health
  • White House Coronavirus Task Force Warns States of Dire Situation, Compromising Patient Care. The Hill. Dec. 2. (Peter Sullivan)
  • CDC Shortens Recommended COVID-19 Quarantine Time to 7 to 10 Days, Down from 14 Days, to Encourage Greater Compliance. WSJ. Dec. 2. (Betsy McKay and Brianna Abbott)
  • Supporting US Public Health Experts. Nature Biotechnology. Nov. 25. (Ron Cohen and other leaders of BIO)
Vaccines
  • Absolutely Remarkable. No One Who Got Moderna’s Vaccine in Trial Developed Severe COVID. Science. Nov. 30. (Jon Cohen)
  • Public Needs to Prep for Vaccine Side Effects. Science. Nov. 27. (Meredith Wadman)
  • Vaccine Scarcity: Buckle Up for Debate. Timmerman Report. Dec. 1. (Larry Corey)
  • Don’t Hesitate in Getting a COVID-19 Vaccine. Forbes. Dec. 3. (John LaMattina)
  • Vaccines Don’t Protect People. Vaccination Does. The Bulwark. Dec. 3. (David Shaywitz)
  • Placebo-Controlled Trials of COVID-19 Vaccines. Why We Still Need Them. Dec. 2. NEJM. (WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation)
  • Many Trial Volunteers Got Placebo Vaccines. Do They Now Deserve the Real Ones? NYT. Dec. 2. (Carl Zimmer and Noah Weiland)
  • Find Your Place in the Vaccine Line. NYT. Dec. 3. (Stuart Thompson) *FYI–I’m No. 268,000,000 or so in the US, and No. 1,600,000 in King County, Washington. In other words, near the end.
  • Moncef Slaoui Says US Expects 100 Million Vaccinated by the End of February. Dec. 2. (Agence-France Press)
  • Novavax Says 2 out of the 3 Late-Stage COVID-19 Vaccine Studies Are Fully Enrolled, with 20,000 People Dosed To Date. Nov. 30. (Novavax statement)
Science (Non-COVID related)
Science Features
  • For Covid Long-Haulers, a Little-Known Diagnosis Offers Possible Treatments—and New Challenges. WSJ. Nov. 30. (Sumathi Reddy)
  • The Pandemic Heroes (in China) Who Gave Us the Gift of Time and Information. Nov. 30. (Zeynep Tufekci)
  • The Remarkable Race for a Coronavirus Vaccine. NYT. Nov. 21. (Sharon LaFraniere et al)
  • COVID Combat Fatigue. “I Would Come Home With Tears in My Eyes.” NYT. Nov. 25. (Katherine Wu)
  • Medicare and Medicaid Badly Need Attention. NYT. Dec. 1. (Peter Bach)
  • A Coronavirus Vaccine in 1 Year? Impossible. Meet Moncef Slaoui. USA Today. Dec. 1. (Karen Weintraub)
Corrections, Brother

It’s one thing to be wrong. Happens to everyone. But then there’s dead wrong. John Ioannidis of Stanford University, in my view, is one of the people who fell into that unfortunate latter camp, in a very public way. He argued on Mar. 17 in STAT that public health authorities didn’t have enough data on COVID-19 to order the drastic non-pharmaceutical interventions of that time. Apparently, he missed a lot of the memos on how to respond to deadly pandemic viruses that spread at exponential speed (act fast, act bold, don’t wait for perfect data). Now, along comes Scientific American with a retrospective about the controversy. It only made things messier. See this doozy of an Editor’s Note.

Deals

Biogen agreed to pay Cambridge, Mass.-based Sage Therapeutics $1.525 billion upfront as part of a deal to co-develop and co-commercialize zuranolone for major depressive disorder and postpartum depression, as well as SAGE-324 for essential tremor. The companies will split expenses and profits / losses 50-50 in the US. Biogen bought shares in Sage at $104.14 a share – a 40 percent premium over the company’s prior 30-day trading average.

Merck & Co. divested its equity stake in Moderna, after seeing the stock surge 7-fold this year. Merck purchased a $50 million equity stake in the mRNA vaccine and therapeutics developer in January 2015.

Merck agreed to acquire Oncoimmune for $425 million upfront in cash. OncoImmune recently announced an interim analysis of a Phase 3 study with its CD24Fc directed treatment for patients with severe and critical COVID-19. Merck said that patients in the study had a 60 percent higher probability of improvement in clinical status. Details to come in a peer-reviewed medical journal.

Penn Medicine, home of gene therapy pioneer James Wilson, agreed to collaborate with Regeneron Pharmaceuticals on an AAV viral-vector based approach to prevention of COVID-19. The gene therapy approach quite obviously doesn’t scale like a dirt-cheap vaccine, but scientists suspect it will provide rapid onset of antibody production, and lasting protection – features that might be useful for immunocompromised groups of patients and healthcare workers.

Janssen Pharmaceuticals acquired the rights to an experimental gene therapy for severe age-related macular degeneration from Hemera Biosciences. Terms weren’t disclosed.

AbbVie agreed to pay $100 million upfront to South San Francisco-based Frontier Medicines as part of a collaboration to make small molecules against E3 ligases and other difficult targets for cancer and autoimmune disease.

Germany-based Merck KGaA agreed to pay $30 million upfront to New York-based Artios Pharma through a deal to work on precision cancer drugs focused on DNA damage repair mechanisms.

Palo Alto, Calif.-based Eiger Biopharmaceuticals sold a Priority Review Voucher to AbbVie for a $95 million lump sum payment. Eiger will split the proceeds 50-50 with The Progeria Research Foundation.

Rockville, MD-based Macrogenics collected a $25 million milestone payment from Incyte for its continuing collaborative work on an anti-PD-1 antibody. Separately, Macrogenics said it formed a partnership with Eversana to commercialize margetuximab, its Fc-optimized HER-2 directed antibody for cancer. The FDA deadline to complete its review of the drug candidate is coming up on Dec. 18.

South San Francisco-based Sunesis Pharmaceuticals agreed to merge with San Diego-based Viracta Therapeutics. The merged company will have $120 million in cash to work on viral-based cancers, including its lead program for Epstein-Barr virus-positive lymphomas.

Cambridge, Mass.-based Agios Pharmaceuticals introduced a program called Anemia ID, in which people suspected of having hereditary anemias can get genetic testing at no cost. This sort of program makes sense, because this is America, where most people live in fear of being gouged by the healthcare system. As a result, many people are thought to be suffering from undiagnosed hereditary anemias. Agios has reason to do rigorous outreach to this patient community (see below).

New York-based Schrodinger, the computational drug discovery company, struck a multi-target partnership with Bristol-Myers Squibb. Schrodinger is getting $55 million upfront. (See my in-depth interview with Schrodinger CEO Ramy Farid, Jan. 2019.)

Data That Mattered

Cambridge, Mass.-based Agios Pharmaceuticals met the primary endpoint in a pivotal study of mitapivat in adults with pyruvate kinase deficiency, a rare form of hereditary anemia, who are not regularly transfused. Regulatory filings are on deck for the US and EU in 2021.

New York-based Ovid Therapeutics failed in a Phase III clinical trial of its drug candidate for Angelman Syndrome. CEO Jeremy Levin didn’t try to sugarcoat or spin the results, and demonstrated some class on a hard day for the company. I have no doubt his team will learn and move on in a productive way.

Financings

San Diego and Boston-based Resilience, a company aiming to create an more advanced biologics manufacturing ecosystem in North America, came out of stealth mode with $800 million in committed capital. ARCH Venture Partners managing director Bob Nelsen is the founder and chairman, and ARCH co-led the $750 million Series B investment round with 8VC. GV and NEA also participated.

Medfield, Mass.-based Kinaset Therapeutics raised $40 million in a Series A financing to develop an inhalable pan-JAK inhibitor for severe asthma. 5AM Ventures and Atlas Venture co-led. (Timmerman Report coverage)

Burlingame, Calif.-based Genesis Therapeutics raised $52 million in a Series A financing to further develop its AI platform for predicting the potency and bioavailability of drug candidates. Rock Springs Capital led. (Timmerman Report coverage).

Burlingame, Calif.-based Tallac Therapeutics, a company leveraging the innate and adaptive immune system against cancer, raised $62 million in a Series A. VenBio, Morningside Venture, Lightstone Ventures, Matrix Partners China, and MRL Ventures Fund participated.

San Francisco-based Spotlight Therapeutics, a company developing non-viral gene editing therapeutics for direct in vivo editing of target genes, raised $30 million in a Series A financing. GV led.

Seattle and Vancouver, BC-based Achieve Life Sciences raised $15 million in an IPO to develop cytisinicline for smoking cessation and nicotine addiction.

Personnel File

Boston-based Karuna Therapeutics named David Wheadon to its board of directors, replacing Ed Harrigan. Wheadon, a psychiatrist and former AstraZeneca executive, also serves on Karuna’s scientific advisory board.  

France-based Transgene, a viral immunotherapy cancer drug developer, named Hedi Ben Brahim as chairman and CEO. He replaces Philippe Archinard.

Chrissy Farr, health-tech reporter for CNBC in the San Francisco Bay Area, left to join OMERS Ventures as a principal, focused on health-tech investments. (See her Personal News column).

Arvin Yang joined Cambridge, Mass.-based Mersana Therapeutics as chief medical officer.

Shanghai-based Gannex, a unit of Ascletis Pharma dedicated to developing drugs for NASH, hired Melissa Palmer as chief medical officer. A hepatologist by training, Palmer was previously head of liver disease clinical development at Takeda Pharmaceuticals.

ASCO named a new chief medical officer. It’s Julie Gralow, professor of medical oncology and director of breast medical oncology at the University of Washington, Fred Hutchinson Cancer Research Center, and the Seattle Cancer Care Alliance.

Cambridge, Mass.-based Vedanta Biosciences, the developer of microbiome-based therapies, named Troy Ignelzi to its board of directors. He’s the chief financial officer of Karuna Therapeutics.

Ann Arbor, Mich.-based Penrose Therapeutics, a cancer drug developer, named Mark de Souza as CEO.

Scott Atlas resigned from his role advising the White House on coronavirus response.

Regulatory Action

Regeneron Pharmaceuticals won an Emergency Use Authorization from the FDA for its double-antibody cocktail, casirivimab and imdevimab, for mild to moderate COVID-19 in patients ages 12 and up (weighing at least 88 pounds). It’s not for patients who are hospitalized or on oxygen. Now the pressure is on to see how far and wide Regeneron can manufacture and distribute this important medicine, which in all likelihood will save a lot of lives. See Meg Tirrell’s Tweet on the supply timelines.

New York-based yMabs won FDA clearance to start selling naxitamab-gqgk (Danyelza) for neuroblastoma in kids age 1 and older. It’s given in combo with GM-CSF. The new drug, first developed at Memorial Sloan Kettering Cancer Center, is an antibody that targets ganglioside GD2.

Tarrytown, NY-based Regeneron Pharmaceuticals won EU clearance for dupilumab (Dupixent), as a treatment for eczema (atopic dermatitis) in children ages 6-11. Nearly three-fourths of kids with this condition saw a 75 percent or greater improvement in their disease extent and severity, compared with 26 percent who did that well on placebo in a pivotal study. As a coincidence, a friend asked me recently about new treatments for two kids with this condition. I was happy to be the bearer of good news, encouraging him to look into the data, and ask his kids’ doctor about it.

Palo Alto, Calif.-based Eiger Biopharmaceuticals won FDA approval for lonafarnib (Zokinvy) as a treatment for Hutchinson-Gilford Progeria Syndrome (HGPS or Progeria) and processing-deficient Progeroid Laminopathies (PL). These are ultra-rare diseases in which young kids are struck with premature aging.

Boston-based Rhythm Pharmaceuticals won FDA approval for setmelanotide (Imcivree) to treat chronic weight management in patients with certain genetic abnormalities confirmed by genetic testing.

Genentech won FDA approval for baloxavir marboxil (Xofluza) as a one-time treatment for influenza in people who have been exposed to an infected person. The approval is for patients ages 12 and up.

New York-based Kantaro Biosciences won FDA Emergency Use Authorization for an antibody test for COVID-19 that provides a quantitative readout on SARS-CoV-2 IgG antibodies.

AI for Predicting Protein Folding

This was a big deal for AI in drug discovery. Read some solid summaries of the results below.

  • Artificial intelligence solution to a 50-year-old science challenge could ‘revolutionize’ medical research. Nov. 30. (CASP14 Statement on London-based DeepMind’s AI protein folding achievement).
  • The Game Has Changed. AI Triumphs at Solving Protein Structures. Science. Nov. 30. (Robert Service)
  • DeepMind’s Protein Folding AI Has Solved a 50-Year Old Grand Challenge of Biology. Tech Review. Nov. 30. (Will Douglas Heaven)
  • Protein Folding, 2020. In the Pipeline. Nov. 30. (Derek Lowe)
Tweetworthy

Nobel laureate Frances Arnold of Caltech was impressed with the AlphaFold achievement, using AI to predict protein folding.  But yes, there’s more.

Science Communication (What Not to Do)

 

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