Your Edge In Biotech.
5
Apr
2021

COVID-19 Testing: Going to the Dogs?

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05 Apr 2021

Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University.

For at least the 15,000 years since the first-known burial of two humans with their dog, dogs and humans have cooperated intimately. Dogs get food and shelter in exchange for performing work they can do uniquely well.

Working dogs use capabilities, such as strength, speed, alertness and willingness to please (trainability).

From the very beginning, it is likely that it has been the dog’s uniquely sensitive sense of smell that is the superpower that fed the relationship, in which dogs help humans by tracking prey, avoiding threats and being willing and able to learn any new smell-related task. 

Estimates are that dogs can detect one particle in 1,012 to 1,015. That is equivalent to detecting a single drop diluted into 13 million gallons of water (i.e. 20 Olympic size swimming pools).

Genie Joseph, dog trainer, Emmy-Award winning filmmaker and Executive Director of The Human-Animal Connection

Dogs achieve this exquisitely sensitive sense of smell with only one-third more smell receptors than humans. The big difference is that evolution has tuned every part of their nervous system and their brains to enable a sense of smell that is up to 1 million times better than humans.

Dog stories are always popular — especially with dog owners! — and several scientific papers from the past year examined whether dogs might be able to help detect COVID-19.

Using dogs in scent detection work is not new. They are used at airports to detect contraband and foods not allowed entry. They are used in prisons to find drugs, cell phones and stashes of cash. They are used by law enforcement to detect drugs, in search and rescue missions, and by the military to find bombs and landmines.

Airports are a logical place to start with dogs attempting to sniff whether a human has COVID-19. A government-sponsored test program at Finland’s Helsinki-Vantaa Airport had dogs examine 4,000 sweat samples on cloth. This way, no direct dog/human contact was required, posing no risk of transmission to the dogs.

When the dogs called out a potential positive case, the passenger was taken to the health office for a follow-up PCR confirmation test.

Officials at the Beirut airport designed a similar experiment. They used the two best of 18 trained dogs to screen 1,680 passengers. Of that cohort, 158 positive cases were found – and  92% of those positive cases were confirmed as positive by PCR.

Negative results were 100% accurate (unpublished results).

“This is very accurate, feasible, cheap, and reproducible,” says Riad Sarkis, a surgeon and researcher at Saint Joseph University in Beirut quoted in a Nature commentary.

Intriguing as the results are, they shouldn’t come as a surprise.

There is a long recent history of reports of canine abilities in diagnosing human cancers, including lung and ovarian cancers and melanoma; as well as clostridium difficile intestinal infection, among others.

Medical alert dogs can anticipate seizures, high or low blood sugar, and perform many other life-saving functions in a companion role. There are many advantages to asking dogs to serve us in this way. Dogs can survey large numbers of people over large areas, results are immediately available and, in a high traffic location such as an airport, one dog can perform hundreds of “tests” per hour.

They don’t cost much either – a little food, water and human companionship can go a long way in a day’s work.

What is it that dogs are actually detecting through smell? The human body is a biological “factory” that changes its internal operations in the presence of disease. These operations emit a dynamic mixture of about 1,000 separate volatile organic compounds (VOCs) in breath, sputum, saliva, feces, urine and in sweat, the chemical composition of which reflects the changed metabolism of cells infected by virus combined with the immune system’s attempts to eradicate it. These volatile organic compounds are what alert the dog to something being amiss.

The biggest differences dogs can detect are between healthy and infected individuals. The specific nature of the infection they’re detecting is less clear to us – they can’t deliver to us a distinct bark for COVID vs. HIV, for instance.

None of the scientific research published to date tries to tease out this cross-reactivity, only asking dogs to distinguish COVID-19 samples from healthy controls. It will be essential to explore how disease-specific canine discrimination is before adopting it as an official COVID-19 identification technique.

Unfortunately, and in spite of strong but intermittent interest by the medical community, there are only small pilot studies and anecdotes because very few scale, controlled studies have been funded and performed. Careful experimental design would be required, but it’s conceivable that a large study could tell us whether dogs can specifically detect a COVID-19 signal in an otherwise “noisy” environment of other potential co-morbidities.

Scientists have a long history of thinking about canine smell. The first scientific paper on canine scent capabilities appeared in Nature in 1887. Since then, interest has ebbed and flowed, but no serious systematic investigation of canine capabilities in medicine has been carried out.

In January, 2021 a brief meta-study found only three original peer-reviewed research papers: Grandjean et al; Jendrny et al; Vesga et al; plus a plan for future research by Robert Jones and colleagues at the London School of Hygiene & Tropical Medicine. All three of these are small proof-of-concept pilot studies, with similar COVID versus healthy controls trial design.

Even in this limited context, however, these studies show promise.

They uniformly concur that dogs are almost as accurate as conventional RTqPCR and about equal to the best antigen tests for COVID-19.

To review:

  • Paula Jendrny and colleagues at University of Veterinary Medicine Hannover in Germany selected eight previously trained detection dogs and spent one week training them with saliva and sputum from positive and negative individuals. (Watch this 37-second video of the dogs in action). Some dogs were better than others. The all-out champion was a 12-year-old retired explosives female who was correct in 96% of 115 trials. Overall, all eight together correctly identified 157 of 190 true positives and 792 of 822 true negatives for a sensitivity of 83% and specificity of 96%. In other words, positives were 84% correct (Positive Predictive Value — PPV) and negatives were 96% correct (Negative Predictive Value–NPV). This is not RTqPCR territory in terms of gold-standard accuracy, but it’s well-within the range of accuracy we see with single-use antigen tests. It is likely that volatile organic compounds (VOC) generation is correlated with viral load and infectivity so, in a small feasibility study like this, we cannot know how many of the false positives were pre-symptomatic or asymptomatic true positives, nor to what extent reported false negatives were caused by later post-infection patients who were no longer contagious.
  • Omar Vesga and colleagues at Hospital Universitario San Vicente Fundación in Medellín, Colombia selected six non-working dogs of three different breeds and trained them for a longer time period – 49 days in all. The testing set up was less automated, but the results were consistent with but even better than achieved by Jendrny: 95% sensitivity; 100% specificity; 86% PPV; and 100% NPV.
  • Dominique Grandjean and colleagues at the national veterinary school at the University of Paris studied auxiliary sweat (armpit) carried out in three separate locations with eight experienced search and rescue or explosive detection dogs. Reported accuracy was high: Four of the eight dogs made no errors in 176 trials, and the others were correct in 83-94% of 192 trials.  Interestingly, two of the seemingly “false” positives were referred back to the patients’ hospitals and were found to be positive on RTqPCR re-testing.

Since the dawn of the scientific age, humans have discounted canine help with tasks connected to clinical diagnosis. Our new tools of the molecular biology age must be vastly superior to a dog’s scent, right?

In certain cases, yes.

Then again, seeing results like those above begs a question — why, after 134 years of interest and investigation, has essentially no progress been made on systematically using dogs to help us detect disease? 

It is broadly acknowledged that dogs accurately sense human distress and disease, even the changes of scent that distinguish stress from an innate inflammatory response. But can they be trained to detect the very subtle differences between human pathologies, and can they do it sufficiently consistently, repeatedly and accurately? 

Can they do this with COVID-19?

Increasingly, the answer appears to be “yes.” Dogs are already patrolling high-traffic public spaces today. Adding COVID-19 testing to their work would be a highly cost-effective and practical solution that could allow a return to some degree of normalcy.

2
Apr
2021

Building An Easy On-Ramp For Consumer Fitness

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02 Apr 2021

David Shaywitz

A comprehensive 2018 review of the scientific literature commissioned by the Department of Health and Human Services reported that physical activity not only helps you “sleep better, feel better, and function better,” but also “reduces the risk of a large number of diseases and conditions,” including dementia, hypertension, diabetes, and a range of cancers.

The report specifically highlights the benefits to individuals who “perform no or little moderate-to-vigorous physical activity.” 

Just adding light-intensity physical activity, the report notes, “reduces the risk of all-cause mortality, cardiovascular disease incidence and mortality, and the incidence of type 2 diabetes.” Similarly, sedentary individuals who gradually add at least some moderate intensity physical activity “can reduce their health risks.”

(Moderate intensity activities like brisk walking, gardening, and biking under 10 MPH raise your heart rate but still allow conversation; vigorous intensity activities like hiking uphill or running are difficult to do while talking. Light intensity activities include cooking and walking at a leisurely pace.)

This again leads us back to the opportunity of digital fitness, technology platforms like Peloton that seem incredibly good at engaging and motivating users – but generally users who already are at least “exercise-curious,” and often trying to decide between one form of exercise and another.

But how do you motivate exercise in the first place?

I had the chance this week to pose this question directly to executives from three leading digital fitness companies, at a Wharton digital fitness panel moderated by legendary Wharton marketing professor (and self-described fitness enthusiast) Americus Reed. You can watch a recording here.

Americus Reed, Whitney M. Young Jr. Professor
Professor of Marketing, University of Pennsylvania Wharton School of Business

The companies represented were Nike (in the context of their digital platforms like the popular Nike running club app), Tonal (the digital strength training company that just this week announced a $250M series E raise, at an associated valuation of $1.6B), and WHOOP (the physiological parameter monitoring company used by many elite athletes; Lisa Suennen and I interviewed the founder, Will Ahmed, on Tech Tonics in 2016, here.

The question I submitted, and posed by Reed to the group, was, as I recently discussed, how these platforms think about reaching beyond the already-athletic, to speak to “future former couch potatoes.”

Chris Stadler, head of marketing at Tonal, frames the opportunity this way: “76% of Americans,” he says, “believe strength training is important,” yet most don’t do it. 

Why not?

“Most of them,” Stadler continues, “are either intimidated to go to the gym or don’t have the equipment or knowledge to strength train at home. [The traditional equipment required is] big and bulky.” By enabling strength training from the privacy and comfort of home, and using equipment that occupies a much smaller footprint, he believes Tonal can serve this unmet need. 

This seems logical, though I imagine it’s one thing for survey respondents to passively agree with a statement asserting “strength training is important” and quite another for that same person to feel sufficiently motivated to consider it for themselves. 

Kristen Holmes, the VP of Performance Science at WHOOP, highlighted the health-promoting values she sees in the rich physiological data (including heart rate variability, respiratory rate, sleep dynamics) the program offers.   

This information provides “the keys to the kingdom,” Holmes said, adding, “To the extent that you can understand how your body’s adapting, you increase longevity, you stave off disease, you have higher level of cognitive functioning, physical functioning….”

Fundamentally, Holmes argues, “this isn’t just about athletic performance. This is about owning your health. That is 100 percent what this is about. And every human is responsible for owning their health.”

The hope of improving performance through rich personal data sounds a lot like what drove many “quantified selfers” to embrace wearables a decade ago; yet many (such as, famously, Wired editor Chris Anderson) were disappointed by the lack of utility and value. 

As reviewers of WHOOP such as Mashable’s Tim Marcin point out, there may be too much data for the casual user, leading to what he described as “information overload.” Others have cautioned about confusing information with insight, and worry the platform over-extrapolates from the data it collects, leading to oversimplified conclusions and recommendations.  

In short, while WHOOP may highlight the benefit outside of sports to general users, it’s not immediately clear that the casual user, and particularly the sedentary user, would gravitate to, benefit from, or enjoy this powerful data collection and analysis platform.

In Reed’s framing of the original question, there are three segments to consider: “super hardcore athletes,” “people that are interested in wellness,” and “a group of people who are even before the interest in wellness.” 

This third group, in principle, could benefit the most from activity, and it wasn’t yet clear to me how the emerging technology platforms were speaking to them. 

Then there was Nike.

At first, I had considered it charmingly old school to include a speaker — Vikas Mehta, the CFO of Nike’s $15B direct to consumer business — from this (relatively) venerable shoe company.

Vikas Mehta, chief financial officer, Nike Direct

But as he spoke, I was reminded that this popular consumer brand, famous for encouraging us to “just do it,” clearly knows a thing or two about how to attract and bring into the fold even the most sedentary among us.

According to Mehta, Nike is especially focused on targeting three important population segments: kids, women, and the underserved. 

Kids, he pointed out, have been moving less and less since the pandemic began. It’s also in childhood where life-long interest in and attitudes towards activity may be first formed. The Nike apps offer specific programs for parent/son and parent/daughter dyads, to encourage intergenerational participation.

Mehta also seemed concerned about ensuring women remain engaged in athletics, engagement Nike seeks to sustain and promote with its app. Mehta was particularly pleased to report that during the pandemic, more women than men reported completing runs on the Nike App.

Finally, Mehta emphasized the importance of engagement with underserved communities, and the need to create “resources and opportunities where we can see a higher involvement.”

While reflecting on what was said, I was reminded of the same dialog we hear about digital in the context of biopharma. 

Digital technology offers tremendous potential to transform the industry, but who will drive the change? Will it be digitally-native upstarts, who really understand their technology, and hope to find a focused, useful application, or will it be the incumbent behemoths, who have extensive experience in drug development, and are trying to figure out how to adapt to and embrace the new, less familiar digital technologies.

It’s difficult — especially as someone already excited about fitness — not to be intrigued by the sexy, tech-enabled, still somewhat niche offerings of WHOOP and Tonal, but from a population health perspective, you can’t help but think companies like Nike and Apple may be onto something.

I’m especially intrigued and excited by the promise of pilot efforts like Time To Walk, offered by Apple Fitness+. I can easily envision this deliberately constructed audio walk accompaniment expanding into an important “fitness media” category of its own, including video (including VR) as well as audio; this has exceptional promise for sustained consumer engagement.

Finally, it’s interesting to think how companies might encourage consumers to progressively ramp up their participation and engagement. Peloton provides a particularly informative example of how this might work. While of course best known for their expensive stationary bikes (and associated, engaging classes), they have expanded not only to include other expensive exercise machines like their treadmill, but, significantly, to welcome consumers who may not own any exercise equipment. 

Peloton bike owners need to fork over about $39 a month to subscribe to classes, but anyone can subscribe to the Peloton app for $13/month. This app, like its competitor, the Apple Fitness+ app, offers a range of exercises for all levels of users. Moreover, to get the most out of the Apple app, you need an Apple Watch; Peloton, one imagines, hopes to use the standalone app to draw users in, then collect the big money later on, when the customers are engaged, motivated, and ready to upgrade.

As captured so vividly by Reed’s palpable excitement, this is a remarkably exciting moment for digital fitness – and perhaps, ultimately, for population health. The sheer volume of chronic disease – heart disease, diabetes, depression and more – shows us the value in even a little bit of prevention that could come from improved physical fitness.

It’s encouraging to see the velocity and variety of innovation, embracing software and hardware, technology and media. It will be even more encouraging to see these technologies impact our happiness and health at scale.

31
Mar
2021

Asian Americans in Biotech: Breaking the Silence

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31 Mar 2021

Nancy Hong, managing director, RiverVest Venture Partners

As a first generation Asian-American working in biotech in San Diego, I identified with the many good points in Kevin Kwok’s piece on Mar. 9 about the rise in hate crimes.

Fast forward to the end of March, and we have seen more horrific attacks. The element of race (and gender) in these attacks is sometimes overtly declared; at other times it’s an unavoidable subtext. But the pattern is clear.

There were the shootings in Atlanta. Then came reports of violent attacks in New York, including one against an elderly Asian American woman on a sidewalk while witnesses stood by and did nothing.

As Kevin wrote here, many Asian Americans have remained silent for reasons that are deeply ingrained in family and the immigrant experience. But as he said, silence doesn’t mean everything is OK.

Today more and more Asian Americans are bringing an end to the silence. We are thinking about what to do.

A fellow investor, Dave Lu at Hyphen Capital, has organized 1,000 Asian American business leaders to sign on to his effort to show ourselves, see each other, and take positive action against Asian hate.

This group has bought a full-page ad in the Wall Street Journal today and created a website, standwithasianamericans.com. Our goal is to build public support, both through the power of names attached to prominent companies in the US and the dollars to organize. We are asking allies to join us in this effort. Zoom, DoorDash, Peloton, BMS, JNJ are already there – it would be great to add some more biopharma names as well.

To me, the question boils down to the American dream, which isn’t so much about buying a home with a white picket fence (sadly too expensive for too many today).

Instead, it’s about meritocracy. Which America do we believe in, the one where your talents and spirit drive your achievements or the one that uses racism to devalue other humans and hold them back? I believe the biotech community sees how immensely difficult our goal to improve human health is and largely welcomes people from all over the world to the challenge.

There are biases at work, some overt and some implicit. We have work to do. Have we conquered microaggressions, hiring for fit as a code for lack of diversity, bias against non-native English speakers, or even the (over)reliance on past performance when predicting future success?

All of these tendencies reinforce the status quo – supporting the people in power and those who look like them. These biases undermine a true meritocracy.

These problems are deeply embedded in our broader culture. It’s not a problem we can outsource to one activist group or another. It takes conscious behavior change in school, work, government and organizations of all kinds. Biopharma’s mission is to use science to alleviate suffering of all people. It’s a humanistic enterprise at the core. This work includes us.

Friendly reminder to colleagues: while we go about our work creating and testing new medical treatments, remember your Asian American colleagues — people who often play crucial roles in this work — may be feeling unsafe.

As a California resident surrounded by plenty of Asians, I think I may have been in denial until recently about the rising tide of anti-Asian hostility in the US. I bought into a “safety in numbers” mindset. It’s a feeling of security knowing people are used to seeing a lot of Asian Americans. That clearly doesn’t work if bystanders are not around or unable or unwilling to help in a moment of crisis.

Since these most recent attacks, I took off the blinders. I have heard from Asian friends about hate incidents — way too many hate incidents — even where I live in sunny, chill San Diego.

Please consider checking in on your Asian American co-worker to lend a caring ear or other show of support. Showing some empathy is a start. It’s meaningful.

The pandemic has broken down some walls between work and home. This might be a good time to send some love to your fellow human at work, even if you can’t yet give your colleague a hug. I know I’ve had some despondent moments, when this rising tide of hate feels overwhelming.

The care I have lately received from fellow biotech people has buoyed my mood and helped renew my hope for the America I cherish.

29
Mar
2021

Flying Blind on the Origin of a Pandemic

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29 Mar 2021

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

I was always curious. 

An early elementary school memory is my mother returning from a parent-teacher conference to report that my teacher thought I had “an enquiring mind.”

Curiosity is what led me to a life of research, as a biostatistician and population scientist. Because in research, the questions you ask are just as important as their answers. The questions I ask have to do with the inevitable gaps in evidence that get in the way of making well-informed medical decisions. 

So I am having a hard time fathoming why people around me are not more curious about how on earth this pandemic began. Without knowing where the SARS-CoV-2 virus came from or how it began to infect people, it’s hard to be strategic about preventing the next pandemic.

The standard explanation is that the virus started in a bat, a bat transmitted the virus to another animal, and then at some point the virus began to infect humans. Scientists call this a zoonotic event, transmission of a pathogen from animals to humans.

But there are gaps in the evidence.

A recent New York Times article by Thomas Friedman titled, “One Year Later, We Still Have No Plan to Prevent the Next Pandemic,” focuses squarely on the illicit wildlife trade and how it facilitates the leap of viruses from wildlife to humans. While Friedman interviews some wildlife veterinarians, the prevailing zoonotic explanation involves an intermediate animal host.

Virologists believe an intermediate species is critical, because bat viruses need to have an opportunity to adapt so that they are able to infect and transmit between non-native species such as humans.

But natural zoonosis is not the only possible explanation. 

Another explanation is that the SARS-CoV-2 virus could have accidentally escaped from a laboratory. This was posited by former CDC director Robert Redfield in an interview with CNN’s medical correspondent, Dr. Sanjay Gupta. It’s his view, Redfield said, the virus escaped from a lab in Wuhan where genetic research was being done on coronaviruses.

Although Redfield is not alone in suggesting lab escape, the newly published WHO report termed this possibility “highly unlikely.” And CNN immediately labeled his comments as “a controversial theory without evidence.” Other media outlets were quick to jump in to the fray, dismissing Redfield’s assertion as “baseless.”

Since theory, evidence and likelihood are my bread and butter, I started thinking about whether CNN’s characterization was appropriate. What is a theory? What is evidence? And how would one even begin to assess how likely any explanation might be when thinking about how the pandemic began?

My goal is not to try and convince you about what happened, because I don’t know. Rather, I hope to convince you that the question is important, that the evidence about every explanation is lacking, and that healthy curiosity is warranted. 

Like many of you I spent hours every day last year reading news stories and research articles about the coronavirus, yet I saw relatively little about the question of its origins, at least in the mainstream media. 

That may be changing. More voices are clamoring for answers. In addition to CNN’s reporting, CBS just aired a 60 Minutes segment, “What happened in Wuhan? Why questions still linger on the origin of the coronavirus.” (Watch segment here).

According to Merriam-Webster, a theory is “a hypothesis assumed for the sake of argument or investigation,” or “an unproved assumption.” But both zoonosis and lab escape are more than assumptions. Rather, they are potential explanations that are made plausible by our experience in other settings.

Avian influenza viruses have been definitively isolated from animals, shown via genetic sequencing to be the source of human infections among exposed individuals such as poultry workers, and then implicated in human-to-human transmission as household members and other contacts of these workers have fallen ill.

Lab escape, even from supposedly secure facilities working with dangerous and highly contagious pathogens, has been documented in labs across the globe. As it turns out, there was a lab — the Wuhan Institute of Virology — doing genetic research on bat coronaviruses just a few miles away from the wet market originally suspected to be the site where the zoonotic leap happened. 

Evidence, on the other hand, is defined by Merriam-Webster rather vaguely, as, “something that furnishes proof.” The Oxford Dictionary is more specific here, defining evidence as, “facts, signs, or objects that make you believe that something is true.”

Here things get fuzzy. 

While bats are known to harbor coronaviruses, the original bat virus that was the definitive source has not been found, there is no clear sequencing trail that matches what has informed our understanding of avian influenza, and there is no identified intermediate host. Civet cats were implicated as the source of the 2002 SARS-CoV-1 outbreak, and were immediately considered suspects this time around, along with pangolins, mink, and ferrets. 

More than a year into this pandemic, none of the extensive sampling of animals at the market has yielded any useful “facts, signs or objects” that would have confirmed the market to be ground zero. So far, that natural zoonosis generated the pandemic seems therefore to be largely an argument of precedent — it happened before so it could happen again.

Records from the Wuhan lab and its collaborators have been blocked from the scientific community so any evidence that might confirm a lab escape as being the source of the pandemic is missing. Documentation of the types of bat viruses being held in the Wuhan Institute of Virology and the experiments being conducted there would be useful “facts, signs or objects” that could discredit or support this explanation.

We just don’t know, because these data are being kept away from the international scientific community. While lab escape has precedence in other settings, in this case the argument seems to be largely one of mechanism — the existence of such a lab could have led to a chain of events that could have seeded a pandemic.

When evidence is lacking, uncertainty reigns, and it becomes natural to start thinking in terms of probabilities. The new report from the WHO calls the lab escape explanation highly unlikely and dismisses it as the least plausible of four possible explanations. (The report finds natural zoonosis to be most likely despite the evidence gaps.) But whether something is likely or unlikely is an assessment of probability.

To know the probability of lab escape would require meticulous documentation of the number of times per year such escapes happen – in labs like the the one in Wuhan and, more specifically in the Wuhan lab itself.  The number of escapes would need to be normalized by the number of pathogens being handled or experiments being carried out, further complicating the calculation. There is no register of lab escapes and there likely never will be.

And to know the probability of a zoonotic event seeding a coronavirus pandemic like the one we are still living through would require identifying all possible encounters of humans with animals carrying such viruses and counting the ones that succeeded – not only in infecting humans but infecting humans in a manner that makes them contagious to one another. It’s hard to imagine getting any idea of this probability.

In summary, we have at least two origins for the pandemic that are more than theories. One seems to rest largely on precedent, the other on mechanism. Both are lacking definitive evidence.  And the likelihood of either is impossible to assess. 

Are you curious yet?

29
Mar
2021

Writing with DNA at Scale: Emily Leproust on The Long Run

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29 Mar 2021

Today’s guest on The Long Run is Emily Leproust.

Emily is the co-founder and CEO of South San Francisco-based Twist Bioscience. It’s a DNA synthesis company. It uses a silicon-based system to “write” in the language of DNA – that is, make synthetic genes to test ideas in a lab, or to perform some basic biomedical or industrial workhorse function.

Emily Leproust, co-founder and CEO, Twist Bioscience

Many people have heard of “reading” DNA with high-speed, low-cost sequencing. That opens up a lot of possibilities in biotech. Fewer may be familiar with the “writing” part, but it goes hand-in-hand.

Twist Bioscience has been on a wild growth run. The 52-week range for the stock is between $25 and $214. Investors can debate what the right near-term valuation ought to be, but there’s no question there’s a secular trend in the upward direction, in which Twist is a key enabler of both medical and industrial progress.

In this episode, Emily talks about her life story growing up in France, coming to America to become a scientist, and then becoming a scientific entrepreneur.

Enjoy this episode with Emily Leproust on The Long Run.

28
Mar
2021

Needed: Planet Fitness for The Digital World

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28 Mar 2021

David Shaywitz

Digital platforms such as Peloton and Tonal have clearly learned how to use emerging technologies to cultivate healthy exercise habits and a loyal base of fitness-focused customers.

These same technologies would seem ideally suited – if presented in the right way – to coax more people off the couch in the first place. 

This represents an enormous health — and market — opportunity, as well as a notoriously difficult challenge, one that remains largely unsolved.

The digital fitness world I see reminds me so much of the academic sports medicine and “human performance lab” world: inhabited largely by the already-fit and exercise committed. 

The concern is whether there’s something a bit hermetic about this – if you spend your life living among the fit and fit-obsessed, it may be easy to lose touch with the many who avoid exercise but desperately could use some. 

Research efforts aimed at exploring and extending the extremes of human fitness, say, or reducing injuries in athletes may uncover principles and insights that apply to the rest of us, but there may also be important learnings that require dedicated focus on the exercise-avoidant, who are unlikely to find their way into a sports medicine clinical center.

To adapt a phrase, and a mindset, from Pete Buttigieg: both sports medicine and digital fitness need to spend a lot more time thinking about how to embrace “future former couch potatoes.”

Pete Buttigieg, Secretary of Transportation

While campaigning for the 2020 Democratic nomination for President (he now serves in the Biden Administration as Transportation Secretary), Buttigieg famously emphasized the importance of speaking not just to Democrats and swing voters, but also to traditional GOP voters – or as he termed them, “future former Republicans.” 

For Buttigieg, this wasn’t just a slogan but a strategy. Unlike the many candidates from both parties who tended to cling to media perceived as friendly, Buttigieg enthusiastically, and deliberately, appeared on Fox, for example, which he described as an opportunity to get in front of voters who might not otherwise have a chance to hear his views directly.

The analogy to fitness feels especially apt. While nominally embracing all comers, many digital fitness platforms – and sport medicine researchers – remind me of the Republicans who do appearance after appearance on Fox, or the Democrats doing the same on MSNBC or CNN. In both cases, the politicians are targeting their appeal to viewers most likely to respond. 

While I understand the appeal of such “fan service” from a business perspective (essentially, the customer acquisition cost is far lower), ultimately both industry growth and population-level health impact will require broadening the outreach.

Moreover, unlike with politics, where evidence suggests we cling incredibly tightly to political affiliation as a core part of our identity, fitness status identification is likely to prove far more malleable. Many exercise-avoidant people, I suspect, might be even happier to re-identify themselves as exercise initiates if they found an activity that sufficiently engaged them.

In summary, from a health perspective, it seems like there’s a huge segment of the population that could benefit from digital fitness if only they were deliberately approached.

Remarkably, the view from Wall Street seems strikingly similar. 

Aarti Kapoor, who follows the health and wellness space closely at a top investment bank (you can catch an enlightening discussion with her here) tells me that “the majority of institutional capital over the last few years has gone towards digital fitness concepts in the premium segment, which are targeting consumers who are already focused on fitness (if not ‘fitness enthusiasts’ or athletes).” 

The category has attracted significant interest from investors. In 2020 alone,” Kapoor reports, “digital fitness concepts that received significant capital investments included Hydrow (June 2020), Mirror (June 2020), Tempo (July 2020), Tonal (September 2020), Zwift (September 2020), Strava (November 2020), and Echelon (December 2020) among others.” 

She notes that most of these companies sell a platform that requires “a hefty multi-thousand dollar upfront purchase of equipment / hardware followed by ongoing monthly subscription fees.” 

Wirecutter (the go-to product review website, owned by New York Times) reports similar figures, noting that between the initial equipment cost and recurring monthly subscription feeds, “Becoming a member of the Peloton pack is an investment: roughly $2,500 for the first year and nearly $500 each year thereafter. And that’s for the base model.”

Kapoor adds that institutional investors were comfortable with these companies because the investors felt that “the ‘sunk cost’ of the upfront hardware purchase … makes for a stickier consumer base in the long-term.” 

In contrast, she points out, institutional investors remain wary of digital fitness offerings that involve “content only” (i.e. no equipment like a Peloton bike). While content-only offerings come in at a more manageable price point for customers, and are relatively easy to scale, Kapoor says investors worry these products won’t be especially sticky, leading to lots of churn as customers surf from platform to platform to platform.  

One brick-and-mortar company that has done incredibly well by targeting first-time fitness customers is Planet Fitness. Kapoor says the company has built “robust brand equity on the premise of a welcoming, non-intimidating environment (coined the ‘Judgment Free Zone’).” 

According to Kapoor, Planet Fitness, with more than 2,000 locations and more than 15.5 million members, “has demonstrated an unmatched ability to offer broad demographic appeal catering to 80% of the U.S. population that does not belong to a gym — for example, approximately 35% of new members have indicated that they are first-time gymgoers.”

Planet Fitness relies both on local marketing as well as a well-conceived national campaign that astutely targets new customers through commercials that position the brand as an approachable alternative to competitive boutique cycling classes (this “Bike of shame” ad) and high-end gyms populated by buff narcissists (this “Mirror guy” ad).

Looking at the category as a whole, Kapoor ultimately lands on the exact question that I’ve been fixating on: “Where is the Planet Fitness of the digital world?” 

Such an offering, in targeting “future former couch potatoes,” seems remarkably promising from both the perspective of both health and economics. 

It’s an opportunity that’s in plain sight, for those who are looking.

27
Mar
2021

Digital Health: From Pharma To…Fitness?

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27 Mar 2021

David Shaywitz

Astute TR readers might have noticed that I’ve been writing a lot about digital fitness lately, in contrast to digital pharma. 

This is deliberate, and represents an evolution of my thinking.

I was first drawn to digital health over a decade ago, in the context of a translational medicine training program for medical scientists that I developed with Dr. Denny Ausiello at Massachusetts General Hospital.  This initiative was called PASTEUR – Patient-Associated Science: Training, Education, Understanding, and Research. The core tenet was an emphasis on the patient-participant in medical science.  Our tagline was “Our patients as partners in discovery.”

Our focus on better understanding the patient experience led us to an early interest in digital health and digital technologies. Here seemed like an excellent way to connect with patients, leveraging their smartphones and other digital tools to help advance clinical understanding and accelerate biomedical discovery. We established CATCH – the Center for Assessment Technology and Continuous Health — to explore applications of these emerging technologies.

When I moved to California in 2010 for a biotech role, I was also really excited about the opportunity to immerse myself in the culture and expertise of the Valley.  I was especially eager to explore how my sense of the needs of healthcare matched up with the possibilities afforded by the emerging technologies that were being developed all around me.  You couldn’t grab a coffee in town without overhearing energetic pitches and animated discussions; so many smart engineers and entrepreneurs were seeking to extend technology into new markets, including healthcare.

Yet I was struck almost immediately by what felt like a disconnect between my understanding of biology and medicine and the view that seemed so prevalent out here, a solutionist perspective that often underestimated the messiness of biology, the deep humanity of medicine, and the often perverse market incentives of various healthcare stakeholders. I said as much in 2011, with a shot across the bow entitled “What Silicon Valley Doesn’t Understand About Medicine,” and have returned to this theme quite often since.

The potential for digital technologies in healthcare remains extraordinary – and extraordinarily difficult to harness, at least in some of the areas we care most about: using digital technologies to come up with important new drugs, on the pharma side, and iteratively leveraging experience to continuously improve the care of patients (the ideal of the learning healthcare system), on the care delivery side. 

Despite some important, authentic progress (protein folding prediction comes to mind) – and an almost unfathomable amount of extravagant expectation and incessant, endlessly escalating hype, the goals remain largely aspirational, as Derek Lowe, in particular, has expertly chronicled.

In a range of roles – including chief medical officer of a healthtech startup, senior partner at a pharma corporate venture group to which I tried (unsuccessfully) to add a digital vertical, and my current work advising senior pharma execs about digital and data – I’ve developed a deep appreciation of how difficult it is to bring emerging digital technology into legacy organizations. Change is hard. Especially at more senior levels, pharma tends to be extremely cautious and skeptical.

I’ve come away with a particular sense of awe and admiration for the digital/data champions within pharma organizations, who often have nominal, high-level organizational blessing but typically very little ground-level buy-in.  Not only are their efforts often received with polite skepticism, but when something does succeed, there are often others who immediately rush in to take credit. This is the exact response to innovation Safi Bahcall describes perfectly in Loonshots. 

It’s also, by the way, exactly – exactly – the same thing I’ve heard from top doctors working in leading tech companies.

Stanford Business School professor Jeffery Pfeffer would surely shake his head knowingly and say this represents typical organizational power dynamics. As usual, Pfeffer would be right. The inconvenient truth: if you’re a data science person in a biopharma organization, or a medical person in a tech company, you can find yourself without a meaningful power base, and struggle accordingly.

I remain extremely bullish on the long-term opportunity for digital and data in biopharma and healthcare, though it promises to remain a brutal and painful struggle for the next decade. The good news – the best news – is that we are beginning to train a cohort of physician/data-scientists and biologist/data-scientists, experts who are intrinsically bilingual and who recognize and incorporate data science as an intrinsic and vital component of the medical science of the future.

Erik Reinertsen, director of data science and engineering, Prometheus Biosciences

An example in biopharma is Dr. Erik Reinertsen, a whip-smart physician/data scientist from Emory and Georgia Tech who interned with me in venture capital, went on to do some fine work at the Broad Institute, and is now leading data science efforts at Prometheus Biosciences.

Or consider Dr. Griffin Weber, a physician-data-scientist from Harvard and a standout example in care delivery who Lisa Suennen and I interviewed on our last Tech Tonics episode.

Perhaps not surprisingly, my advisory work has tended to focus less on product strategy than on organizational executive coaching, and I plan to continue counseling data science champions within biopharmas. 

At the same time, I am finding myself increasingly drawn to consumer health in general, and digital fitness in particular, as it seems to represent an expression of digital health that is already positively and palpably impacting lives – right now, today — and seems poised to meaningfully impact so many more people in the future.

Griffin Weber, Associate Professor of Medicine, Beth Israel Deaconess Medical Center
Associate Professor of Biomedical Informatics, Harvard Medical School

It’s difficult not to be struck by the foundational role regular exercise plays in the lives of so many physicians, scientists, and entrepreneurs I know and admire – and the role exercise has played in my own life – including helping me lose 80 pounds several years ago (and keep it off), as well as helping me stay both fit and centered during this last tumultuous pandemic year.

I’ve also been impressed both by the engagement so many have with exercise, as well as by the opportunity that exists to use technology to bring exercise and a sense of community to the many people who’d benefit from exercise but find it difficult or daunting.

The opportunity to leverage emerging digital technologies to improve both physical and mental health by offering engaging and compelling fitness experiences seems too powerful to ignore, and too promising to be reserved only for those who are already athletic.   

For years, doctors have advised their patients to exercise more, with almost zero expectation that anyone actually would. As Harvard anthropologist Daniel Lieberman points out in Exercised, we didn’t evolve to pursue pointless activity. 

Even so, the many physical and psychological benefits associated with exercise (after all, we didn’t evolve to sit at desks all day long either) suggest the wisdom of this timeless medical advice. 

The challenge and the opportunity before us: leveraging digital fitness technology to turn the tedium of prescriptive exercise into engaging, delightful, and healthy activity.

We can do this. Eye of the tiger.

25
Mar
2021

Can Digital Fitness Extend Beyond Hardy Base To Reach Those Who May Benefit Most?

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25 Mar 2021

David Shaywitz

Whether you are an “exercist,” who relentlessly talks up the benefits of regular exercise to anyone who will listen, or instead are like the vast majority of people and conscientiously avoid exercise, you will find something appealing in the recently published Exercised, by Harvard anthropologist Daniel Lieberman.

Those who assiduously avoid unnecessary exertion – pretty much the definition of exercise – turn out to have years of evolution on their side. According to Lieberman, “let’s go strenuously exert ourselves for the next half hour, just for the heck of it” is a sentiment no living creature has ever expressed (at least until quite recently). 

Instead, movement was always purpose driven – to find food, escape predators, procreate, celebrate, socialize. No wonder, then, that few are thrilled to hop on a treadmill and plod drearily, step by tedious step, to absolutely nowhere.

On the other hand, throughout the history of our species, a lot of activity was baked into life –including through old age.  (Yes, old age. “Contrary to the widespread assumptions that hunter-gatherers die young,” Lieberman writes, “foragers who survive the precarious first few years of infancy are most likely to live to be 68-78 years old.”)  

Today, with the ubiquity (at least in the United States) of electricity, running water, and grocery stores, you can meet many of your essential needs with little physical effort. 

The problem, Lieberman argues, is that there is now an overwhelming amount of data pointing out that exercise is good for you – really, really good for you. While not a magic bullet (cue Jim Fixx invocation, as Lieberman dutifully acknowledges), exercise seems to help forestall a surprising range of diseases, and can improve cognitive performance (including perhaps through improved sleep) and elevate your overall sense of well-being.

While the mechanisms underlying these benefits remain to be worked out (unless you accept the reductionist explanations offered by Lieberman, which I suspect even he might acknowledge are frequently tidy and simplistic), the underlying message is compelling. 

As Lieberman summarizes, Michael Pollan style:

  • “Make exercise necessary and fun
  • Do mostly cardio but also some weights
  • Some is better than none
  • Keep it up as you age.”

Given the pronounced benefits of exercise across the lifespan – and the particular benefit for those who may be older, less fit, or both – it seems mystifying that leading digital fitness programs seem intent on targeting primarily those who are young and already fit, or at worst, fit-adjacent. The toned models who famously (or infamously) grace Peloton ads are clearly positioned as aspirational examples – “This could be you if you sign up today!”

While some non-exercisers have surely been inspired to join Peloton, many users (especially during the pandemic) would otherwise be exercising in a boutique class. Home cycling may be more convenient, but it’s attracting many of the same customers, or at least seems to be pulling from the same pool of (relatively young, fit — and affluent) customers.

My mind keeps returning to the vast majority of people to whom these ads are clearly not speaking, and who, when they see these ads, are likely put off by and discouraged by depictions of such dissimilar people.

Yet many of these same disaffected viewers, as Lieberman reminds us, could benefit profoundly from exercising more, and while fancy digital fitness equipment is hardly required, the ability of technology to afford users an engaging, compelling experience and a sense of community also should be utilized to serve the enormous population of older and/or less fit customers as well. 

This feels like an obvious and compelling business and health opportunity that so far seems to have been all but ignored.

One physician who has locked onto this need is Dr. James Beckerman, a cardiologist in Oregon who I knew from my internal medicine training at Massachusetts General Hospital in Boston, although we had largely lost track of each other since then. It turns out, he is now focusing his efforts on encouraging exercise and building communities – including an inspirational and apparently highly impactful effort known as “Heart to Start.”

As you watch this video – and you should – not only will you feel authentically inspired, but the contrast between the very real participants in this video, and those featured in the typical digital fitness commercial couldn’t be more striking.

(And if you find yourself thinking “Gosh this could be the basis for a TED talk,” turns out – you’re right. Beckerman gave one on the topic, in 2017 – enjoy it here.)

You don’t have to be Yenta the Matchmaker to see the possibilities. 

  • Imagine if the cutting-edge technology that has delivered transformative products like Peloton could be channeled toward the millions of far less fit people who might be interested in getting healthier.
  • Imagine also that such a platform could help foster the sense of community and connection that Beckerman’s participants clearly savor — and that Peloton’s current user base, for example, already enjoys.
  • Imagine what could be accomplished just by bringing these existing technologies to an established population – the remarkable possibilities for the health and well-being of participants. 
  • Imagine the upside for the business able to deliver this.

Seems time to stop imagining and start working.

25
Mar
2021

A Glimpse Into a Price-Controlled Future

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25 Mar 2021

Luke Timmerman, founder & editor, Timmerman Report

Imagine if H.R. 3 — the drug price-control bill that has significant support in the House of Representatives — were to become law.

What would it look like if some of the bill’s provisions, like indexing US prices to 120 percent of prices in Europe, were enacted?

How would entrepreneurs adapt? What types of drug discovery programs might be prioritized, and which ones cast aside as impractical? How would management teams have to adjust their strategy, and pitches, to successfully attract investors? How would certain patient groups be affected? What would it mean for the sector?

There are many questions. It’s fascinating, when you dig in, to think through the implications of this thought experiment.

Students at the University of Texas Southwestern Medical Center were challenged to think along these lines through a business plan competition on Mar. 20. Small teams of postdocs, grad students and MBAs were asked to think of a product profile, a relevant disease indication, and — assuming success in clinical development and regulatory approval — a price that could withstand the hard calculations of Incremental Cost-Effectiveness Ratios (ICER) and Quality-Adjusted Life Years (QALY).

The goal was to come out with an investment pitch that investors might buy into.

RA Capital Management, the Office for Technology Development at UTSW, Biotech+ Hub at Pegasus Park and McKinsey supported the competition. RA Capital managing partner Peter Kolchinsky served as a judge with Jeb Keiper, CEO of Nimbus Therapeutics, and Sara Nayeem, partner at Avoro Ventures. I observed.

The students clearly did their homework.

The results were eye-opening.

One group imagined it had an antibody-drug conjugate for lung cancer that delivered an 85 percent Complete Response rate, few side effects, and an average improvement in life expectancy of 10-11 years. Such a drug could be administered for about two years on average, and priced at $210,000 a year in Europe and $250,000 a year in the US, they figured. At that price, the fictional company would beat existing PD-1 inhibitors from Merck and Bristol Myers Squibb on a QALY-based comparison.

Kolchinsky shook his head. Sure, payers would pay for that. But there is no such drug on the market, or in R&D.

Peter Kolchinsky, managing partner, RA Capital

“We never see this kind of efficacy,” Kolchinsky told the students. Turning to his fellow judges, he said: “What they are asking us to do is stop investing in plausible, realistic science and start investing in fantasy.”

Another group sized up a new treatment for irritable bowel syndrome with constipation or diarrhea, and imagined generating three times as much sales volume in Europe to make up for an anticipated shortfall in the US.

Next came a team with an mRNA vaccine for HIV that elicits broadly neutralizing antibodies. The students thought the vaccine could be given to everyone in the US. They considered a low price for a national population and a higher price for a subpopulation deemed to be “high risk.”

The team concluded that it didn’t make sense to develop such a product as a low-volume/high-priced ($9,000) product for the high risk population. Forget about it.

A few days later, I asked the judges to reflect. How were students forced to adapt to the new environment? What did it tell us?

Kolchinsky wrote:

“The participants made an admirable effort, but every single team was forced to make unrealistic assumptions to try to make their business pitches seem fundable despite the limitations of price controls.

“A lot of the submissions were based on actual drugs in development by real companies. But the actual programs are funded because those companies and investors have an expectation that, if successful, those drugs will get reimbursed at prices close to those drugs we have on the market now, which are all higher than prices that HR-3 would allow. And when these teams tried to win funding for these programs but asked investors to accept a much lower price, they couldn’t. Some teams resorted to asking the judges to imagine that these drugs were better than they actually were, had a higher chance of succeeding that they actually have, or would treat more patients than could possibly be true. Bottom line, price controls killed investment in the R&D that is actually possible and forced teams to resort to making promises they couldn’t keep…”

If health economists who run conventional cost-effectiveness are put in charge of setting price, innovators probably won’t be able to win funding from any knowledgeable investors. There may some investors who fall for a pitch claiming a high probability of success and larger market than is real, but in time they will lose enough money to realize the price controls set rewards too low for the risks involved in making new medicines.”

Jeb Keiper, CEO, Nimbus Therapeutics

Jeb Keiper of Nimbus said the pressures would cause entrepreneurs to overpromise. “Like snake oil salesmen, [they] promise a cure in every bottle,” he said. “The constraints forced business plan competitors’ strategies to subvert price-control legislation by promising miracles.” 

That was one survival strategy. The winning team had a different plan. It pitched a reformulation of a proven drug. But in a hostile pricing environment, the students said they would need to accept a lower valuation in the next funding round — crushing the ownership stakes of earlier investors.

Keiper ruefully asked the team who was the CEO. That person would likely be fired.

“The implications are chilling,” Keiper wrote. “Existing biotech investors (including large scale mutual funds and pensions which many Americans have their savings in) get gutted, new medicines stop being developed for patients that need them, and the public only gets incremental improvements that industry watchdogs rightly hound against.”

Pain would be spread among entrepreneurs, investors, and patients. The patients most likely to bear the brunt, though, would be ones with the greatest needs.

Sara Nayeem, partner, Avoro Ventures

Sara Nayeem of Avoro Ventures wrote:

“Drug development for diseases where there have been many historic failures would be especially hard to fund.  For instance, pancreatic cancer is a devastating diagnosis for which we need breakthrough drugs; but because the historical probability of success is much lower than in other areas of oncology (per BIO, a drug for pancreatic cancer entering Phase 1 trials has only a 1.1% chance of approval), investors would need to know that a drug that shows needle-moving efficacy would be reimbursed at a higher price than the average cancer drug…groups like ICER don’t take into account the low success rates in certain diseases; nor do they quantify the value to society into perpetuity of branded drugs going generic.”

Some readers might think this boils down to the same old industry talking points about price controls causing investment to dry up.

But the students weren’t trying to score political points. They were imagining a future drug pricing environment, and trying to prepare.

It was a useful and humbling exercise. Lawmakers would be wise to think a few steps ahead, like this, when considering big changes to a complex market like this with so much at stake.

That’s not to say we should slavishly stick with the status quo. Biotech as an industry is creative and resilient under pressure. Management teams were forced to cut expenses and operate in more lean ways in the Great Recession years of 2008-2012. People in Congress warned the Affordable Care Act would crush incentives for innovation. That didn’t happen.

Instead, a crop of battle-tested, productive companies emerged. We have reaped the harvest of those innovations from the early 2010s. Year by year, the FDA approvals tell the story.

Markets have their vicissitudes. But the secular trend in biomedicine is upward. There’s a lot here in academia, government and industry that’s worth preserving and building upon.

Our elected leaders ought to guide regulations and set guardrails that keep companies honest, with an eye toward preserving a dynamic environment where startups can come along and knock off incumbents.

Kolchinsky, in his book “The Great American Drug Deal,” advocates for contractual genericization as one way to provide balance to pharmaceutical markets that are too often dominated by companies with incentives to primarily protect aging franchises. Many of these aging franchises should have gone generic years ago. Too many drugs, because of patenting games or other perverse incentives that involve middlemen, command sky-high prices that can’t be justified. All of these shenanigans end up wasting money, harming patients and discouraging entrepreneurs.

This publication believes in standing up for the proverbial little guy. Policymakers, health economists, and industry leaders should take action to rein in the excesses of the big guys, without forgetting that little guy (or gal) with a startup dream. That person should have an incentive, and a chance. That person shouldn’t become collateral damage.

If we want to create an environment where scientific entrepreneurs can flourish, we can do it. With scalpels, not sledgehammers.

 

Damaged Public Trust

If you missed Tuesday’s Frontpoints, it predicted this week’s AstraZeneca vaccine debacle. The NIH statement of Mar. 23 pointed out the company’s press release claiming 79 percent efficacy was based on outdated data. The NYT and Washington Post got ahold of a seething letter from the Data Safety Monitoring Board. AZ tried to do some damage control in a revised press release on Mar. 25, which dragged efficacy down to 76 percent. Given the company’s recent pattern of bad behavior and incompetence, I plan to read every line of the FDA briefing documents, and listen to every minute of the FDA advisory committee hearing for this vaccine candidate.

This is a test. Regulators, doing their jobs, will go over everything with a fine-toothed comb and review the application with full transparency. Then we can make informed decisions.

A lot of leeway has been granted to companies in this emergency, born from necessity and a generous spirit of “we’re all in this together.” Some standards about not doing science by press release, and not accepting company statements at face value, have gone out the window in the name of expediency. We put a lot of trust in companies and they have mostly delivered the past year.

But when a company abuses trust repeatedly, the credibility of science and industry itself gets called into question. AstraZeneca needs to make things right. This isn’t one of those cases where PR window dressing or a carpet-bombing of advertisements will make controversy go away. They need to fix things.

This Week in Drug Pricing

Are you a biopharma executive who breathed a sigh of relief about how the drug pricing pit bulls snarling at the industry have been neutered during the glory days of vaccine development?

Not so fast. Public opinion can be fickle.

The AZ imbroglio (see above) feeds into the confirmation bias of the industry’s harshest critics. While a majority are grateful for the vaccines, we still have perverse incentives in our health insurance system, healthcare profiteering, millions of our most vulnerable are being left in the cold, and we still have an information commons that downgrades fact-based discourse and amplifies conspiracy mongering.

Without systemic fixes to how we pay for healthcare — and how we provide fair access to healthcare for everyone — we could easily fall back into the brain-dead rhetorical rut about sticking it to those evil price-gouging drugmakers.

See this NYT op-ed, headlined “Taxpayers Fund Research and Drug Companies Make a Fortune” in which a patient advocate imagines a day when COVID-19 vaccines might cost money (the horror!).

I agree individuals shouldn’t be paying out of pocket for this most valuable preventive medicine. We should be paying for it with our tax dollars. We should be grateful about it because we’re getting an amazing bargain from vaccines that will get the global economy moving again and bring tremendous peace of mind.

Science Policy

President Biden is showing vision and guts. Who says we can’t solve problems, so why bother trying? Biden isn’t buying that nihilistic garbage. He’s acting like a young man in a hurry. Let’s ask serious questions that citizens in a serious participatory democracy ought to ask. Like whether we invest enough in science as a country. What more could we be doing to advance cures, fight climate change, and create meaningful career opportunities for younger generations?

A big investment like the one suggested below inspire a new generation to be drawn to science, and to value science.

Science Features
  • Pandemic whistle-blower: we need a non-political way to track viruses. Interview with Rick Bright. Nature. Mar. 19. (Amy Maxmen)
  • What scientists do and don’t know about the Oxford–AstraZeneca COVID vaccine. Nature. Mar. 24. (Smriti Mallapaty and Ewen Callaway)
  • Unlocking the COVID Code. NYT Magazine. Mar. 25. (Jon Gertner)
Science of SARS-CoV-2
  • Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study. The Lancet Microbe. Mar. 23. (Wan Chia et al Duke-NUS Medical School, Singapore)
  • Early Evidence of the Effect of SARS-CoV-2 Vaccine at One Medical Center. NEJM. Mar. 23. (William Daniel et al UT Southwestern)
Data That Mattered

Bristol Myers Squibb said it met the primary endpoint – progression free survival — in a Phase III clinical trial with its LAG-3 targeting antibody, relatlimab, in combination with nivolumab (Opdivo), the PD-1 directed antibody. The study looked at patients newly diagnosed with metastatic or unresectable melanoma. Overall survival data aren’t yet available. It’s the first time a checkpoint inhibitor for LAG-3 has passed a pivotal study.

Financings

Eric Schmidt, the former Google CEO, donated $150 million to establish a new center at the Broad Institute to support machine learning analysis of emerging biological datasets, including next-generation DNA sequencing, single-cell genomics, and advanced medical imaging. The Schmidt Center will be co-directed by Caroline Uhler, Associate Professor of Electrical Engineering and Computer Science and the Institute for Data, Systems, and Society at MIT and an associate member of the Broad Institute; and Anthony Philippakis, Broad’s chief data officer. 

Rivervest Venture Partners, with offices in St. Louis and San Diego, said it raised $275 million for Fund V to invest in early stage biopharma and medical device companies.

Seattle-based Eliem Therapeutics raised $80 million in a Series A financing led by RA Capital Management to develop treatments for chronic pain and depression. (TR coverage).

Emeryville, Calif.-based Zymergen, an industrial biotech company, filed an IPO prospectus to raise up to $100 million.

Cambridge, Mass.-based Apnimed raised $25 million in a Series B financing to develop a once-daily oral pill for obstructive sleep apnea. Morningside Ventures led.

San Francisco-based Ginger said it raised $100 million in a Series E financing led by Blackstone to improve mental healthcare offerings for employers, health plans, and strategic partners. (TR Frontpoints column on mental health, Mar. 4, 2021)

Cambridge, Mass.-based 1910 Genetics said it raised $26 million to advance its technology to design small molecules and protein drugs with AI and automated tools. M12 – Microsoft’s Venture Fund and Playground Global co-led.

Personnel File

Moncef Slaoui, the former head of R&D at GSK and leader of the Operation Warp Speed program for COVID-19 vaccines, was fired from the board of a GSK / Verily entity (Galvani Bioelectronics), and stepped down immediately from a new job as chief scientific officer of Centessa Pharmaceuticals, after GSK said it had learned of sexual harassment allegations and an outside law firm investigated the claim.

Amy Abernethy, the principal deputy commissioner of the FDA, will step down from her position next month. She has overseen a push to modernize the agency’s data practices.

Novartis said it’s closing down a factory in Colorado where it was planning to manufacture Zolgensma, the gene therapy for spinal muscular atrophy type 1. The company plans to shut down the plant in July, and lay off 400 workers. It apparently overestimated demand for the therapy, which it obtained through the acquisition of AveXis for $8.7 billion. (FiercePharma coverage).

Atul Dandekar joined South San Francisco-based Maze Therapeutics, a precision medicine company, as chief strategy officer. (TR coverage of Maze, Feb. 2019)

Josh Makower was named the new director of the Stanford Byers Center for Biodesign. He replaces the legendary founder of the center, Paul Yock, a medical device innovator. Makower will retain a relationship with NEA, in keeping with the center’s longstanding focus on academic-industry partnerships.

Merck promoted Caroline Litchfield from treasurer to CFO. She replaces Robert Davis, who is being promoted to president on Apr. 1 as part of a succession plan for him to take over from Ken Frazier as CEO on July 1.

Regulatory Action

Takeda Pharmaceuticals said its submitted an application for its dengue vaccine to regulators in Europe, and in dengue-endemic countries.

Our Shared Humanity

Bruce Booth of Atlas Venture wrote an unusually personal piece on his LifeSciVC blog Mar. 16. I let some time pass before asking him about the feedback from this article about divorce.

It was a rare example of a powerful business leader showing vulnerability.

If you missed it, this is a message that bears repeating. We should all try to be a little more empathetic to friends and colleagues at work who may be stressed by personal issues just beneath the surface. By listening a little more, and extending some understanding and grace, we do ourselves a favor and everyone around us.

I was really happy to hear Booth tell me yesterday that the feedback has been “uniformly positive.”

Hundreds of emails poured in. These weren’t the usual “Hey, nice article” notes that writers sometimes get.

Many of these correspondents got specific and personal, Booth said.

“They went on for paragraphs about a sick kid, a sick spouse, feeling unable to talk about it at work. There were other people who went through divorces, and talked about making it through. They were just sharing their stories. I got very emotional reading all the responses. It was really powerful.”

It took courage to write the article.

We men are taught to be brave from an early age, in a gladiatorial, competitive sense. Never let ‘em see you sweat. Bullies on the playground will bury you at the slightest hint of “weakness.” But at some point in life, we realize that “putting on your game face” at work, as Booth put it, isn’t always a show of strength.

Showing some vulnerability, and allowing people to be human beings with each other in your midst, can be a source of leadership strength.

The positive reaction to Booth’s article lifts my spirits. It reminds me that people in this industry are capable of many good things, in science and beyond.

22
Mar
2021

AZ Tells Us Its Vaccine is OK. Rebuilding Trust Will Take a While

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22 Mar 2021

Luke Timmerman, founder & editor, Timmerman Report

Credibility can be lost in a heartbeat.

It can take years to rebuild.

That maxim kept running through the back of my mind when reading the press release on the AstraZeneca Phase III clinical trial conducted with 32,449 participants in the US, Peru and Chile, in partnership with the NIH’s COVID-19 Prevention Network.

The top line was encouraging — 79 percent efficacy at preventing COVID-19 and 100 percent efficacy at preventing severe illness and hospitalization.

The company, following a rough couple weeks of rumors and innuendo, said independent data monitors found no increased risk of blood clots in people who got the vaccine.

“I’m thrilled,” said Ashish Jha, dean of Brown University’s School of Public Health, in reacting to the breaking news in Science. “This is the vaccine that I had always assumed would vaccinate a large chunk of the world.”

It’s a view rooted in practical reality. AZ’s is an adenoviral vector vaccine, given in two doses four weeks apart (or potentially further apart, according to UK officials). It’s manufacturable at global scale, easy to ship in refrigerators, and cheap — $2 to $6 a dose.

So far, so good.

I hope that everything in the company statement is right, and that there are no serious flies in the ointment. But despite our yearning for positive vaccine news, we have reason to withhold judgment until we get a good, hard look at the data.

This company has shot itself in the foot multiple times, damaging its credibility in the past year.

Consider the sequence of vaccine events:

May 21—company says it’s getting $1 billion from the Biomedical Advanced Research and Development Authority (BARDA) to develop, produce and deliver its COVID-19 vaccine in the US. Plan is to run a 30,000-participant Phase III trial, and deliver at least 400 million doses in 2020 and 2021. This was an assuring sign of a major league pharma company with a major league academic partner (Oxford), getting a major league vote of confidence from the richest and most scientifically powerful country in the world. At a time when mRNA was still seen as fairly speculative, this looked like a safe bet.

Sept. 6—company receives a report of an adverse event — transverse myelitis, an inflammation of the spine — in a vaccine participant in Britain. The company halts enrollment while investigating the adverse event, looking to see if its vaccine might have played a causative role.

Sept. 8—company has conference call with FDA officials, seeking clarity on what’s necessary for US regulatory approval. Company neglects to mention the transverse myelitis adverse event in the UK, and the decision to halt trial enrollment. The FDA was blindsided a few hours later when it heard about the revelations on the news. (The only reason we know this is because of a New York Times report from four months later). This confirms the absolute worst impressions critics have of the pharmaceutical industry. Not only that, but if you were working for the FDA and in the room that day, wouldn’t you be fuming that the company didn’t disclose the event, and didn’t discuss how to get to the bottom of the issue in partnership?

Sept. 9—As reports of the adverse event swirl, AstraZeneca CEO Pascal Soriot goes into a private conference call organized by J.P. Morgan for clients of the investment bank. From this well-controlled safe space, he assures everyone that the woman who suffered the severe spinal inflammation was improving and likely to be discharged from the hospital soon. We only learned this because STAT broke the story that day. Again, this was news of international biomedical significance, given in private to wealthy clients of JP Morgan — before the public.

Sept. 9—All AstraZeneca COVID-19 vaccine trials go on clinical hold as researchers seek to suss out what happened with the woman who got transverse myelitis.

Sept. 12—AstraZeneca vaccine trial resumes enrollment in the UK. Importantly, the big 30,000-participant study in the US, the one designed to yield the most rigorous evidence, remains on hold.

Oct. 23—the US FDA lifts the clinical hold, allowing AZ to resume enrollment of the 30,000-participant vaccine study. The clinical hold lasted more than six weeks – an eternity in a fast-moving pandemic. Pfizer/BioNTech, Moderna and J&J leaped ahead.

Nov. 23—AZ reports on a pooled analysis of 23,000 participants who got the vaccine in the UK and Brazil. Because of a dosing screw-up, a half-dose appeared to be 90 percent effective in a subpopulation of 2,100 subjects, while the full dose appeared to be 62 percent effective. The dataset, on its own, was a mess. Regulators here, in the best-resourced drug regulatory agency, already had good reason to be suspicious at the company for hiding a crucial piece of information. Now AZ is telling the world that its trial was bungled? There was no realistic path forward for the company to seek FDA Emergency Use Authorization on the basis of this unconvincing dataset.

Dec. 8—The NYT publishes its expose on AstraZeneca’s failure to disclose the adverse event to the FDA in September. Days later, the FDA approved the first two COVID-19 vaccines – one from Pfizer/BioNTech, the other from Moderna.  

Feb. 8.—South Africa health officials halt administration of the AZ vaccine, saying it was offering “minimal protection” against the B.1.351 variant of SARS-CoV-2 that was in wide circulation by then.

Feb.15—the World Health Organization authorizes the AZ vaccine for use in low and middle-income countries.

Mar. 15—European countries temporarily halt administration of the AZ vaccine amid anecdotal scary reports of blood clots in people who received the vaccine. Despite no compelling evidence to point to the vaccine causing those adverse events, health authorities in multiple countries, fearing the worst, shut down mass vaccinations with the AZ product, partly to allay public fears.

Mar. 22—AZ reports the long-awaited results from the US, Peru and Chile, in 32,000 participants. The top-line efficacy of 79 percent looks solid, if not spectacular. Some public health experts, like Ashish Jha at Brown University, cheer this development as a step toward vaccinating the world.  

For sure, 79 percent is solid efficacy. The more vaccines we have, the better. But before getting too excited, I want to see some more details on how the vaccine is performing against the variants and in subpopulations and what the immunogenicity data look like.

Part of me really prefers to withhold judgment for now, wondering if there’s another shoe to drop. Given the track record, it makes sense to wait and see for what the FDA staff come up with when they comb through the dataset with a kind of rigor that makes peer-review look like a stroll in the park.

Not only is the FDA rigorous, it has a long institutional memory. It can really put the screws to companies behind the scenes in multiple ways.

That’s one of the important lessons I learned many years ago in an FDA law class at Harvard Law School taught by Peter Barton Hutt, the attorney at Covington and a legendary former FDA counsel. (I’m not a Harvard Law graduate, but was able to audit classes at MIT and Harvard during the 2005-2006 academic year via the Knight Science Journalism Fellowship at MIT).

I practically heard shades of Peter Barton Hutt and FDA staff sharpening their pencils this morning when I watched a TV appearance by Anthony Fauci.

“The FDA is going to very, very carefully go over all of these data,” Fauci said, “You can rest assured, that the FDA will apply a great deal of scrutiny in every aspect of these data.”

Fauci is surely aware that while the US public may have forgotten some of AZ’s missteps, the FDA has not.

Even if the company turns in a thorough and squeaky-clean application and regulators agree that it deserves an Emergency Use Authorization (the most likely outcome), that will be just one step in building back public trust.

Yesterday morning, on cue with the company press release, the NYT published an op-ed from Heidi Larson, the preeminent voice on vaccine hesitancy.  

There’s a lot of work to do in building vaccine trust, she wrote.

Indeed.

[Update 6:45 am PT, Mar. 23: After this column was published, the National Institute of Allergy and Infectious Disease issued the following statement: “AstraZeneca may have included outdated information from that trial, which may have provided an incomplete view of the efficacy data. We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible.” AstraZeneca responded with its own statement, saying it would provide more updated data within 48 hours.

Financings

Taicang, China and San Diego-based Connect Biopharma raised $191 million in an IPO at $17 a share. The company is working on T-cell driven inflammatory diseases. Qiming Venture Partners, RA Capital Management, and Advantech Capital were among the principal shareholders heading into the liquidity event. Shares inched up to $18.61 at yesterday’s close.

Dallas, Texas-based Instil Bio, the developer of T-infiltrating lymphocyte therapies for cancer, raised $320 million in an IPO at $20 a share. It climbed to $26.80 at yesterday’s close, with a market valuation of $3.3 billion. CEO Bronson Crouch controls the Curative Ventures entity that holds 29.7 percent ownership in the company after the IPO. The other big stakeholders in the company include Venrock, CPMG and Vivo Capital.

Somerville, Mass.-based Finch Therapeutics, a microbiome therapeutics developer, raised $128 million in an IPO at $17 a share. A member of the Walton family, heirs to the Walmart fortune, is among the big winners in this IPO. Shares traded up to $19.15 at yesterday’s close.

Boston Immune Technologies and Therapeutics (BITT) said it completed a $10 million Series A/A1 financing to develop novel antibodies against members of the TNF superfamily. BeiGene participated, along with Hatteras Venture Partners and EGP Investments.

Malvern, Penn.-based Xylocor Therapeutics said it completed a $41.9 million Series A round to advance its gene therapy for coronary artery disease. Fountain Healthcare Partners led and was joined by new investors Longwood Fund and Lumira Ventures.

Seattle-based Dexcare, a new digital health startup, said it raised $20 million in investment led by Define Ventures. The round included Frist Cressey Ventures, Kaiser Permanente Ventures, SpringRock Ventures and Providence Ventures. DexCare describes itself in a statement as “an intelligent digital care operating system that manages health system capacity and demand across all lines of care.” It was developed internally at Providence, a large hospital chain on the West Coast, in 2016 and is now being spun out aas a business with a half-dozen customers.

Cambridge, Mass.-based Aura Biosciences said it raised $80 million in financing to advance virus-like drug conjugate therapies for cancer. Matrix Capital Management and Surveyor Capital led.

Legal Corner

The SEC brought charges against uBiome for allegedly defrauding investors out of $60 million. The complaint was brought in the US District Court in Northern California.

Science Policy
  • Put this one in the ‘Never Forget’ Folder: Tom Frieden on the ‘Mind-Boggling’ Interference of the Trump Administration in COVID-19. The BMJ. Mar. 17. (Joanne Silberner)
  • Where’s the Science Behind CDC’s 6-Foot Decree and Transmissability? WSJ. Mar. 21. (Scott Gottlieb)
  • The Pandemic Year: The Hyper-Acceleration of the Life Sciences. WSJ. Mar. 19. (Eric Topol)
  • Five Myths About Coronavirus Vaccines. Washington Post. Mar. 19. (Peter Hotez and Maria Elena Bottazzi)
Science of SARS-CoV-2
  • Post-acute COVID-19 syndrome. Nature Medicine. Mar. 22. (Ani Nalbandian et al New York-Presbyterian/Columbia University Irving Medical Center)
  • Neutralizing Antibodies Against SARS-CoV-2 Variants After Infection and Vaccination. JAMA. Mar. 19 (Venkata Viswanadh Edara et al Emory University).
  • Infection and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant. Cell. Mar. 20. (Venkata Viswanadh Edara et al Emory University).
  • SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies. Cell. Mar. 20. (Markus Hoffmann et al University Gottingen)
  • Difference in SARS-CoV-2 attack rate between children and adults may reflect bias. Oxford Clinical Infectious Diseases preprint. Feb. 26. (Zoe Hyde et al University of Western Australia)
  • Transmissibility and transmission of respiratory viruses. Nature Reviews Microbiology. Mar. 22. (Nancy Leung)
  • Single-component, self-assembling, protein nanoparticles presenting the receptor binding domain and stabilized spike as SARS-CoV-2 vaccine candidates. Science Advances. Mar. 19. (Linling He et al The Scripps Research Institute)
Data That Mattered

Roche/Genentech said its PD-L1 directed antibody atezolizumab (Tecentriq), hit the primary endpoint of extending disease-free survival in the Phase III Impower010 study. The trial looked at patients getting adjuvant therapy after surgery and chemotherapy for Stage II-IIIA populations with non-small cell lung cancer. Participants were randomized to the drug group, or best supportive care. The company said the magnitude of disease-free survival benefit “was particularly pronounced in the PD-L1-positive population.” The company said it doesn’t yet have mature data on Overall Survival.

Roche/Genentech also said it shut down a Phase III clinical trial for tominersen, an antisense oligonucleotide for Huntington’s disease in-licensed from Ionis Pharmaceuticals. The drug was designed to reduce production of huntingtin protein (HTT), including its mutated variant, mHTT. An independent data monitoring committee made the recommendation. See Sek Kathiresan’s succinct summary of this head-scratcher below. (Phase I results in NEJM, 2019).

Exton, Penn.-based Idera Pharmaceuticals failed in a pivotal trial of tilsotolimod in combination with ipilimumab versus ipilimumab alone in patients with anti-PD-1 refractory advanced melanoma. The drug is a Toll-like receptor 9 agonist, being combined with the CTLA-4 inhibitor in this case. Shares lost two-thirds of their value.

Our Broken US Healthcare System

Major donors to South Florida hospital foundation got early vaccine access. Politico. Mar. 19. (Arek Sarkissian and Matt Dixon)

RIP

Jose Baselga, the prominent cancer researcher and leader of oncology R&D at AstraZeneca, died at age 61. (STAT obituary).

Personnel File

Diana Brainard was hired as CEO at Cambridge, Mass.-based AlloVir, a cell therapy company focused on viral diseases patients with weakened immune systems. She starts May 17. Brainard is currently senior vice president of virology therapeutics at Gilead Sciences. She oversaw teams that developed curative therapies for hepatitis C and remdesivir for COVID-19, among other areas. She replaces David Hallal, who is moving upstairs to be executive chairman. Hallal is also CEO of ElevateBio, the largest shareholder in AlloVir. (Disclosure: Brainard is married to TR healthtech columnist David Shaywitz.)

Jean-Frédéric Viret was hired as chief financial officer at South San Francisco-based Blade Therapeutics, a developer of treatments for fibrotic diseases. He was previously CFO at Coherus Biosciences.

South San Francisco-based Sutro Biopharma, the developer of treatments for cancer and autoimmunity, promoted David Pauling to General Counsel and Robert Kiss was promoted to senior vice president of process and analytical development.

South San Francisco-based Veracyte, a molecular diagnostics company, added Muna Bhanji to its board of directors.

Chart of the Day

The data out of Brazil are a concern.

Source: Outbreak.info, based on data from Johns Hopkins University Center for Systems Science and Engineering, New York Times, COVID Tracking Project, GISAID Initiative

20
Mar
2021

Enticing Some With Social Cues, Others With Health, Exercise Rewards Body And Mind

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20 Mar 2021

David Shaywitz

I recently discussed the rise of digital fitness, and specifically how companies like Peloton are succeeding by delivering an engaging experience.

The new crop of digital fitness companies have figured out how to make health-promoting activities that are intrinsically tedious – like riding a stationary bike – into something compelling and sustaining. A New York Times writer, Amanda Hess, captures the essence of this magnificently in her piece, “Your Brain on Peloton.”

I was reminded of another important component of healthy activities this week when I was chatting with my barber (as one does), and asked about his fitness routine. He told me he goes to his gym 3-4 times a week, and has for years. 

I wondered what gets him there each day. Simple, he said. He has a group of buddies there.  Sometimes, he says, they’ll go for drinks afterwards, or their families will go over to one another’s house afterward for dinner. 

In short: he’s motivated by a sense of community.

An anecdote is hardly data, but the idea that healthy behaviors may be linked to interpersonal influences is well established. 

An influential paper published by Nicholas Christakis and James Fowler in the New England Journal of Medicine in 2007, for example, examined decades of Framingham Heart Study data, and concluded that “obesity may spread in social networks.” They note “people are embedded in social networks,” which “suggests that both bad and good behaviors might spread over a range of social ties.”

Another Christakis paper, from 2016, looked at two years of Gallup surveys for clues about the influence of social networks. Analyzing the data, Christakis and colleagues concluded that individuals who tend to associate with a lot of heavy people are more likely to want to lose weight, but are less likely to be successful. Conversely, associating with thinner people is linked to more successful weight loss.   

“Gains and losses of even a single social tie with a thinner or heavier individual show important links to the probability of obesity,” the authors of the 2016 paper wrote. In other words: the probability of obesity increases with additional ties to heavier people and decreases with additional ties to thinner people, and vice-versa.

A very readable overview of the “power of community” in cultivating consistent healthy fitness behaviors, by industry analyst Anthony Vennare, can be found here.

My barber’s story also reminds us of Clay Christensen’s advice: make sure you understand the problem to be solved. In Christensen’s classic (and perhaps not so healthy) milkshake example, many customers purchasing a shake from a fast-food drive-through turned out not to be looking for a tasty beverage so much as for something to occupy them in the morning, while they were driving to work. 

By recognizing this initially obscure need, the vendor was able to increase sales by making the shakes thicker (to last longer) and adding bits of fruit (to make it more interesting).

Which brings me back to what the real issue is for the barber at the gym. He’s apparently not looking for the most efficient or effective workout. Instead, he’s looking for camaraderie, while engaged in a healthy activity. These social factors are often what draw customers to the gym, and keeps them coming back.  While these individuals may achieve a healthy outcome, their pursuit of physical health is only one motivator, and often not the primary one.

Of course, not everyone is motivated in the same way. Many people are drawn to exercise explicitly for the physical benefits (such as better endurance, an improved cardiovascular risk profile, a beach body, or wanting to keep up with the grandkids). Some then discover significant mental health dividends along the way.

As modern life becomes increasingly busy, with ever more demands on our attention, “exercise time” may represent our last protected space, a cocoon of time we give to ourselves.

Over the last several years (as I’ve discussed here and here), and continuing through the pandemic, I have savored my morning exercise routine. I’ve used that time — whether sweating inside on the treadmill, elliptical, or weight machine, or outside on my bike — to lose myself in audiobooks and podcasts. I avoid work during this early hour, never checking email or text messages, and avoid all but the most essential calls. I love this daily routine. I find it grounds me, and puts me in a relaxed and positive mindset – an ideal headspace – to start the day. 

I’m certainly not alone.

I also recognize that many people — including me — would have a really tough time taking an hour out of each day for reflection, meditation, or other self-soothing activities. For many similar Type A’s, it would feel difficult to justify, and easy to encroach upon. 

Yet because the time is allocated for an activity that’s both nominally health promoting and physically unpleasant (at least compared to sitting on the couch), it somehow seems easier to rationalize – a modestly uncomfortable sacrifice made in the name of disease prevention. 

In short, exercise creates the permission structure to give ourselves the headspace we so desperately need.

In short, exercise creates the permission structure to give ourselves the headspace we so desperately need.

This also makes me wonder how much of the benefits attributed to the physical aspects of exercise may actually come from the state of mind that exercise enables us to inhabit. Parsing the relative contribution of each seems difficult. 

The bottom line is less ambiguous. Whether you go to the gym to socialize and wind up exercising (delighting your cardiologist), or jump on the bike to stay fit and wind up rejuvenated because of your protected “me-time,” (pleasing your psychiatrist), the results are joyously similar: a healthier body, a happier mind, and a better you.

16
Mar
2021

Why Digital Fitness Companies Like Peloton and Tonal Are Exciting For Healthcare

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16 Mar 2021

David Shaywitz

A truism in healthcare is that a medicine only works if it’s taken. Unfortunately, many people don’t take the medicines they are prescribed.

Adherence rates for many drugs – especially for preventive medicines like statins – tends to be remarkably low, as I’ve discussed in the New York Times. 

About half of patients who start taking statins to reduce their risk of cardiovascular disease quit taking them in the first year, according to a 2019 paper. The authors note that adherence goes downhill from there.  

People find it even harder to stick with lasting healthy behaviors. Adherence to diet and exercise regimens is notoriously poor – just losing weight, for example, is hard enough, and keeping it off is profoundly more difficult; 95% of people who lose a significant amount of weight regain it relatively quickly.  (This is a fate I’ve thus far avoided on the Virta low-carb regimen, which I started in 2018 and lost 80 pounds, as I discussed here; I’ve kept the weight  off, as I wrote in TR, here, and I remain a self-pay, non-diabetic subscriber). 

It’s common for those who make New Year’s fitness resolutions to lose remaining resolve around now; after all – food is delicious and exercise is hard.

And yet, there’s hope: more than 90% of Peloton users are apparently still using the bikes a year later. This was true before the pandemic, and it’s still true. 

Moreover, as CNBC reported last month:

“the cycle maker continues to look for ways to entice its customers to exercise more…It recently launched a feature where users can ‘stack’ classes back to back, and have them play automatically one after another. It also recently added Pilates classes to its catalog.”

Physicians may be tempted to contrast this success rate with their own experience advising patients around diet and exercise. The comparison, of course, isn’t quite fair, given the self-selection of Peloton purchasers, whose level of motivation — and disposable income — are likely not representative of the population as a whole.

Yet doctors might see a pattern here. Recall the remarkable success of the lifestyle modification arm of the legendary Diabetes Prevention Program (DPP) study. It demonstrated that in vulnerable patients, impending diabetes could be significantly forestalled. The approach used in the trial – documented here – included individualized programs for each participant, tailored and delivered by “life-style coaches” who maintained intensive contact with participants. This program, as I’ve discussed, is also the basis of digital health companies like Omada.

A similar degree of engagement may be required to realize the benefit of exercise in depression, as highlighted on a 2019 episode of Wendy Zukerman’s wonderful “Science Vs” podcast.  Zukerman points to several relatively recent clinical trials that seem to show a benefit of exercise in patients with depression, in contrast to previous studies. 

Zukerman perceptively observes:

“One reason that these newer studies might be finding a benefit is that these scientists were really tenacious about getting people to do the exercise. Like in one study researchers gave participants free gym memberships and personal trainers – who hounded them if they don’t show up.” 

The genius of Peloton, it would seem, is in motivating participants to remain committed to the program, which they assiduously cultivate through a range of efforts intended to make the cycling both engaging and social.

Other digital fitness companies such as Tonal (strength training) and Hydrow (rowing) are trying to follow suit, as are traditional exercise hardware manufacturers like NordicTrack, now a brand of ICON fitness, who have launched iFit to participate in the connected trend (though based on some reviews – here, also here — it seems like the software has a way to go).

Apple’s Fitness+ app has also arrived on the scene; it’s “Time To Walk” feature – featuring celebrities like Dolly Parton and Draymond Green telling stories while they walk – seems both well thought-out and expandable to other formats.   

As Zukerman reminds us, while you may not be able to exercise your way to weight loss (which is driven largely by what you eat), exercise contributes to your health in many other ways.

Accessing this benefit will require companies to master a range of competencies, including hardware, software, and media, given the importance of an engaging and immersive experience in motivating and sustaining participation. 

Successful connected fitness platforms will improve the health and well-being of their members — including, by the way, a number of academic physicians and scientists, many biopharma researchers and executives, and even some regulators. 

In learning how to sustain engagement with exercise, these digital solutions may point the way to helping us pursue other difficult but healthy activities, like diet modification or rehabilitation after injury. 

Finally, the volume and specificity of data around exercise (which leaps out from this podcast with Tonal founder Aly Orady) would seem to provide powerful collaboration opportunities for a wide range of motivated physicians and medical researchers – a real chance to explore and advance the state of the science. 

In short, the new generation of connected fitness companies offer not only the immediate promise of improved health, but also the intriguing possibility of future insights into both the physiology of health and the psychology of adherence. 

Ride on!   

15
Mar
2021

Software for the Cell & Gene Therapy Wave: Vineti’s Amy DuRoss on The Long Run

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15 Mar 2021

Today’s guest on The Long Run is Amy DuRoss.

Amy is the co-founder and CEO of San Francisco-based Vineti. The company provides software to manage the delicate logistical dance for cell and gene therapies.

Amy DuRoss, co-founder and CEO, Vineti

Vineti has raised about $115 million in three venture rounds of financing. Its backers include Cardinal Health, the big medical distributor, as well as traditional venture firms like Canaan Partners and Section32, plus the big cell therapy players Novartis and Gilead Sciences.

All those people are apparently converging on a challenge of the fast-growing world of cell and gene therapy. With more than 1000 Investigational New Drug Applications on file at the FDA, does it make sense to have 1000 different bespoke software and logistical solutions for cell therapies, or does it make sense to have a standard operating system of sorts to make life easier for investigators, for companies, for regulators, and for payers?

Vineti represents a wager on this field moving to standardized software, and a desire to be the company that sets and delivers on that standard.

This has taken a while to sink in with the biotech industry. Amy described the challenge to me a year ago in this Timmerman Report article, and provided an update in this recent conversation.

Before we dive in to the interview, a word from the sponsor of The Long Run.

Synthego is a genome engineering company that enables the acceleration of life science research and development in the pursuit of improved human health.

The company leverages gene editing, machine learning, and automation to build platforms for science at scale. By enabling unprecedented access to cutting-edge genome engineering, Synthego is at the forefront of innovation, accelerating the development of truly engineered biology.

Synthego’s expertise in CRISPR, combined with their proprietary software and technology, means you have a trusted partner whether you are at early stages of basic research or ready to take your therapy to the clinic.

Visit Synthego.com/timmerman to learn more.

Now, please join me and Amy DuRoss on The Long Run.

14
Mar
2021

One Vaccine Dose or Two? We Need Our Best Defenses Against the Variants

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14 Mar 2021

Larry Corey, MD

When there aren’t enough doses of vaccine to go around against the SARS-CoV-2 virus, and you’re trying to protect as many people as possible as fast as possible, what’s the right thing to do?

Does it make sense to take the Pfizer and Moderna vaccines and give them as single shots, in order to stretch out our existing supplies and vaccinate twice as many people right away? Or would we be better off sticking with the two-dose regimen that’s been shown to stimulate the immunity needed to keep people out of the hospital and alive?

The “one-shot or two-shot” question is a legitimate subject of debate among scientists, including leading epidemiologists. The media are giving it prominent air time.

My view, based on the underlying immunology and the clinical trial results, is that it’s better to stick with the proven two-dose regimen. Allow me to elaborate.

Proponents of the one-shot strategy acknowledge that a second dose should be given, but they don’t think that the timing of that second dose is as essential as one-dose partial protection in an urgent moment. Some say it’s OK to have a lag time between the first dose and the second, and that the second dose could be given two or three months later. The vaccines were tested in two-dose regimens given three or four weeks apart. By stretching out the time between doses, they contend, we’ll get more of the population partially protected, while buying a little time for the manufacturers to ramp up all the supplies needed for the second round of dosing.

When numerous esteemed people are saying the same thing, a reasonable observer should listen and consider the argument. These people have good faith reasons for taking that position.

But let’s pause and unpack these ideas a bit.

There are substantial data demonstrating partial efficacy after one dose of the Pfizer and Moderna vaccines. Data from the initial Pfizer trial showed that between day 12 and day 21—between the first and second dose—people in the vaccine group were less likely to get COVID-19 infection than their counterparts in the placebo group. The Pfizer vaccine’s efficacy as a single shot was 52% (39 participants in the vaccine group acquired disease compared with 82 infections in the placebo group).

Data from Israel, which had one of the most efficient vaccine rollouts of any country, confirms that a single shot of the Pfizer vaccine delivers about 50 percent effectiveness in the real world with all its messiness. The data in the Moderna trial were essentially the same. From randomization to dose two, there were 7 cases of infection in the vaccine group and 46 COVID-19 cases in the placebo group.

So, on purely clinical grounds, an epidemiologist can argue that more good could be derived for the whole population by vaccinating two persons with a 50% effective vaccine compared with one person taking a 95% effective vaccine.

This poses an interesting decision to make on a personal level with respect to informed consent. What would you rather have as an individual – 95 percent efficacy in two doses three or four weeks apart, or 50 percent efficacy while waiting another 2-3 months for the next dose?

I don’t think the real answer lies in a debate about the ethics of reduced efficacy from single-dose immunization or the efficiency of public health versus individual rights. The important question is: Would we actually be doing more harm than good by administering one dose of the Pfizer or Moderna vaccine to more people?

Why do I raise this question?

I say this as a virologist, knowing that the viruses we’re encountering today and the ones we will encounter in the next several months are not the same viruses that we tested the vaccines against and upon which the single-dose data are based on.

The SARS-CoV-2 virus in wide circulation today, with its myriad variants, is a more formidable adversary. The variants that are emerging and taking over have higher infectivity and have evolved new capabilities to escape from neutralizing antibodies. We have learned that the seeds of that escape are found among people with low/partial immune responses from natural infection. That means the virus, when it gets inside a host with only partial immunity, has a greater opportunity linger inside the body and keep replicating until it develops certain evolutionary advantages.

In this context, while the body is mounting a weak immune response and the virus is continuing to replicate, we’re likely to see a prolonged period of viral shedding from the nose and mouth. That raises the likelihood of sustained community transmission. Essentially, the viruses are stressed but not eliminated by partial immunity.

In such a situation, it makes sense to make the virus face off with our most formidable immune defenses. We force it to go up against people who have been fully immunized with the two-dose vaccine regimen.

There are data to support this view. When we look at the protective antibody levels at day 21 after the first dose of the Pfizer vaccine, we see that the 50% serum neutralization titer is 29. When people get the second dose, and their blood is evaluated for antibodies just 7 days later, neutralizing antibody titers shoot up to 270. After another 7 days – a full two weeks after the second vaccine dose – neutralizing antibody titers are all the way up to 437!

The data with Moderna are similar: after one dose, the mean titer of neutralization is only 18; 7 days after dose two, it’s 256; and 7 days after that, it’s 344.

For people unfamiliar with neutralizing antibody titers, a level of 29 is equal to a low-dose convalescent plasma treatment. We know at this point that low-dose convalescent plasma is associated with more harm than good — it is associated with being a precursor for escape variants to emerge among immunosuppressed persons.

It’s also important to recall that the data we have on efficacy are derived from the clinical trials that were designed to match the vaccine strain with the original—or what some call “wild type” (Washington strain)—virus. The new variants change the game somewhat, and require us to take another look at their impact on vaccine efficacy.

Data from the lab, looking at live virus versus neutralizing antibodies in the petri dish, shows two-or three-fold more antibodies are required to neutralize the B.117 variant now spreading throughout the UK and Europe. Lab results further show 8 to 10-fold more neutralizing antibodies are required for the B.1.351 variant emerging from South Africa.

This resistance to neutralization is associated with the reduction in efficacy observed in the latest clinical trials in geographies where those variants circulating. The reduced efficacy was seen in both the Novavax vaccine (93% efficacy in the UK and 43% in South Africa) and Johnson and Johnson vaccine (73% efficacy in the US and 58% in South Africa).  

This necessity for higher amounts of antibodies against the new variants is why I am concerned about having large numbers of people walking around for an extended time period with less-than-optimal levels of immunity. A 2-3 fold reduction in a neutralizing titer of 20 after one dose of mRNA equates to a titer of 5. That’s essentially no detectable neutralizing activity. An 8-fold drop results in neutralizing titers that “fall off the grid”. This is not the case with the second dose when a two-fold reduction from 450 is still a neutralizing titer of 225 and an 8-fold reduction is 60 — still three times the neutralizing levels above that seen with one dose of mRNA vaccine. 

The argument for the two-dose regimen is even stronger when you look at vulnerable subpopulations. Many elderly people have weak immune systems. One dose of the mRNA vaccine often elicits antibody titers of less than 20. The elderly invariably require two doses to get a detectable neutralizing response.

A similar situation is also seen among persons with a wide variety of chronic diseases; their less-than-robust immune response will have an even greater impact on levels of protection after one dose. Data on the origin of escape variants points to immune-suppressed patients and persons with untreated HIV as reservoirs for the selection of escape mutations, especially with the E484K mutation harbored within the B.1.351 variant.

My compatriots say if one dose works for the Johnson & Johnson vaccine, why not do the same with Pfizer and Moderna? There is a difference: there is a much greater CD8+ killer T cell immune response in the J&J vaccine at one dose than with the mRNA vaccines after one dose. It’s really a different mechanism of protection with the adenoviral vector-based J&J vaccine.

While my musings are inferential, so are the views espoused by those advocating for the one-shot strategy. This is the nature of pandemic response. We are all looking at the same data, asking pertinent questions, and doing our best to navigate the uncertainty in the moment.

It behooves us to solve the challenge of vaccinating our population by first immunizing with the regimens that we know have demonstrated extremely high levels efficacy. Even with our absolute best immune defense, the variants will pose a challenge. I believe we will do more harm than good by markedly increasing the population of people with partial protective immunity.

Weakening our best defense may be well-intended, but it could come back to haunt us. Depending on the past is not how an RNA virus behaves. It uses the past to change its future in order to survive. Good epidemiology does not necessarily mean good virology.

We need all the strength we can muster in the vaccine regimens. For the two mRNA vaccines, I want my friends and family to be immunized with the full two-dose schedules authorized by regulators at the FDA and the European Medicines Agency.

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 was intimately involved in the planning of the phase 3 vaccine studies conducted under the funding auspices of Operation Warp Speed. He is past President and Director and Professor in the Vaccine and Infectious Disease Division of Fred Hutchinson Cancer Research Center; and Professor of Medicine and Virology at University of Washington.

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