Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
David Shaywitz
Many of us first experience exercise as kids playing sports.
Think back to the coach yelling at you and your teammates to run the extra lap. Maybe this helps explain why fitness and competition seem inextricably linked to so many adults, so many years later.
Digital fitness companies know this. Many digital fitness offerings lean heavily into the competitive aspect, urging us forward with leaderboards. The apps, and the coaches on the screens are always encouraging us to beat our previous times, or strive for an improved physique. A recent digital fitness company with a $1 billion valuation was recently described by Wired as “a home gym for folks who want to get ripped.”
I’m not sure this framework works for everyone. It may not even work for most of us.
Many people who would reap big health benefits from more regular exercise are actively discouraged from even getting started by this relentless emphasis on competition and maximizing performance. This aversion to contrived competition may be especially acute among the least fit — the “future former coach potatoes” — who aren’t likely to be living near the top of leaderboards any time soon.
Other potential participants — reasonably — might be inclined to focus not on achieving a new personal best one mile run, or developing Terry Crews pecs, but rather trying to maintain an existing level of performance, or attenuating age-related decline.
Yet, almost everywhere I look in the digital fitness world, I see jocks-turned entrepreneurs creating platforms that seem designed for similar athletes, participants who tend to skew relatively young, and seem motivated (or motivatable, at any rate) by competitive zeal.
Perhaps these platforms are competing for a particularly high-value demographic. (Wall Street firms are apparently populated by some serious athletes, for example.) Alternatively, developers of digital fitness companies simply may be oblivious to the opportunity to serve a large population of potential users who are turned off by the emphasis on competition.
Motivating exercise is an intrinsically difficult problem. Exercise is, by definition, hard work and pointless except as an end itself. (Unfortunately, it also happens to be good for you.)
Daniel Lieberman, professor of human evolutionary biology, Harvard University
As Daniel Lieberman, a human evolutionary biologist at Harvard University, discusses in Exercised (see here), purposeful activity was an important aspect of early human societies, generally involving the pursuit of basic needs (food, shelter, safety, and community — e.g. ceremonial dancing). But until modern times, no person, and probably no living creature, would ever engage in gratuitous activity, and expend precious calories solely for the perceived long-term benefit of doing so.
Telling people to exercise because it’s good for you may work for some especially disciplined individuals, but clearly many have yet to be inspired. Putting a stationary bike or a treadmill in front a TV set may help others, but this gets stale quickly.
A few new entrants in the digital fitness industry have shown that an engaging and immersive experience, led by an encouraging guide, can be captivating. The model for this, of course, is Cody Rigsby of Peloton, who inspires participants with his stories about topics from high school to pop culture to disease awareness, mixing in personalized shout-outs, while also adjusting the cadence and resistance of the ride.
What if you could take these aspects, and disentangle them from the leaderboard and performance component?
Imagine, for example, a treadmill program that led walkers, joggers, or cyclists on virtual tours of famous natural parks and historical sites, with progress through the tour keyed to your rate of movement. Maybe, virtually, you could stroll Versailles, walk the fields of Gettysburg, climb Masada, explore Robben Island, seeing the sites and learning history while you are exercising from home.
There are so many ways to integrate exercise, media, and education. A social component could even be woven in to foster camaraderie and community.
Existing companies have components of the sort of offering I’m envisioning. Peloton, for example, has not only recognized the value of motivators like Cody (distinguished by their extraordinary ability to engage and relate), but more recently has added scenic ride options for participants, an alternative to the usual class format.
Other fitness companies are pursuing distraction via gamification – eg Zwift for serious indoor cyclists (a good interview with co-founder and CEO Eric Min is here), and the VR-delivered Supernatural (reviewed here) – though it’s hard to imagine Grandma drawn to either one.
The company that seems most interested in targeting a diverse range of participants (diverse in age and athleticism if not in disposable income) is Apple.
First, Apple (not surprisingly) has developed remarkably good hardware – Apple Watch, for example, out-performed a number of competitors in a well-executed academic study out of Jessilyn Dunn’s group at Duke. These data are in line with my own recent disappointing experience with another wrist wearable; in my direct comparison, Apple Watch measured heart rate more reliably, while the other product produced conspicuously spurious readings on several occasions.
Second, Apple is already a media company, so it has both the resources and the mindset to make its hardware products quite interesting. Apple seems to have started developing a rapidly-expanding range of offerings, through the “Fitness+” platform, to motivate participants, including walkers (via the “Time to Walk” feature – I’ve discussed here) and older individuals (“Workouts for Older Adults”). The overall strategy feels brilliant.
I appreciate the insight that competitive athletic entrepreneurs bring to the fitness platforms so many seek to develop, and in which many competitive athletic investors seek to invest (there seems to be a proliferation of athletic-focused venture funds these days).
But as we’re envisioning the future of digital fitness, and thinking about how to leverage these emerging tools to sustain health, let’s ensure that the limits of our collective entrepreneurial imagination aren’t defined by the singular framework of competitive athletics.
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Today’s guest on The Long Run is Daphne Zohar.
Daphne is the founder and CEO of Boston-based Puretech Health.
Daphne Zohar, founder and CEO, Puretech Health
Puretech has been around since 2005, seeking to capitalize on some of the big trends in biotech.
It started out seeking to test concepts from academic labs that could be the basis for new biotech companies – what’s now commonly called the venture creation model. This work led it to start an eclectic batch of companies focused on wide-open fields like the microbiome (Vedanta Biosciences), digital therapeutics (Akili Interactive) and obesity treatment (Gelesis).
These companies and others now operate with a degree of independence, with Puretech as a top shareholder.
More recently, Puretech itself has transitioned into what could be considered a more traditional biotech R&D company. It has a thesis focused on what it calls the Brain-Immune-Gut axis, specifically on treatments that intervene in the lymphatic system. It’s now seeking to take therapies further along in clinical development on its own.
Daphne has been there through it all, as the driving force. One of her earliest supporters at the beginning of Puretech was Bob Langer, the famous bioengineering professor at MIT and prolific entrepreneur (and previous guest on The Long Run). Langer gave her an early vote of confidence as co-founder of Puretech, and he’s still on the board today.
When I asked Bob about his first impression of Daphne 15 years ago, when she was just getting started as an entrepreneur, he wrote:
“I thought she was smart, very determined, wanted to do important health related things, had definite leadership ability, and really wanted to make things happen. And she has.”
In this conversation, Daphne discusses her journey and her longstanding efforts to apply science for the betterment of human health.
Please join me and Daphne Zohar on The Long Run.
Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University
Over the past 16 months, 192 billion COVID tests have been carried out globally. A majority are real-time polymerase chain reaction tests (RTqPCR) tests.
Every one of those has been reported to patients as an either/or result: positive or, more usually, negative.
These tests are capable of doing much, much more than just giving a simple yes/no answer.
The “q” in RTqPCR measures “quantitative” viral load. We know this matters a lot — and every RTqPCR provides the “q” in terms of Ct value — how many cycles it took to detect a real signal from your samples.
Why do we systematically discard this data which is absolutely critical to both public health and clinical decisions?
Without an apples-to-apples standard to compare RTqPCR results, an individual with a high 3,000,000 copies/milliliter viral load will get the same positive lab result as another with a low 50 copies/ml. The clinical and public health consequences of these two results are definitively very different.
The value of quantitative readouts has become more clear in recent months. The higher the viral load, the higher the chance of serious disease, hospital admission, and transmission to others, non-pharmaceutical interventions (NPI) notwithstanding: physical distancing; mask wearing; well-ventilated spaces; quarantine; etc.
Simply put, the higher the viral load, the higher the chance of a patient ending up in the ICU.
The lower the viral load, the more likely the patient is not capable of viral transmission. Asymptomatic patients and those with only mild symptoms are less likely to transmit the virus to others because there is less virus to be broadcast in aerosolized respiratory droplets. All patients will be recorded as positive long after any likelihood of transmissible infection. Patients recovering from COVID-19 often remain PCR-positive for days or weeks, even up to six months, when the virus being detected may be only residual virus fragments.
The first evidence these patients may get is when they take a required PCR test two days before a flight — then they are surprised to find out they are “positive.”
There is consensus that frequent, while-you-wait community testing is best to inform both individual and public health actions. Traditional laboratory high-volume RTqPCR testing is automatically disqualified – it is too expensive to be used “frequently” and too slow to be “while-you-wait” (fastest results take 12-24 hours, and during the peak of the epidemic it stretched to 7-14 days – effectively useless except to inform an historical perspective).
Rapid antigen tests are cheap enough to be used frequently; and sensitive enough (~95%) to result positive in the period of highest viral load when individuals are infectious.
How do we judge what level of viral load is infectious?
Every infectious disease has a minimum quantity of virus necessary for an infection to take hold. This varies by virus and by an individual’s immune competency. The Lab gold standard to determine this is to infect a cell culture with SARS-CoV2 virus — these experiments indicate that anywhere from 1,000 to 100,000 viral copies per milliliter are required to create a viable COVID-19 infection.
There are caveats to these in-vitro lab tests – lab grown cell targets may not be representative of cells in patients; lab growth conditions are artificially optimized; there is no innate or adaptive immune reaction in a petri dish; etc.
However, this threshold is consistent with clinical experience — very few patients with moderate to severe disease sample below this level. (See this ASU T3 Blog from October 2020 “COVID-19 Test Accuracy – when is too much of a good thing bad?” for a fuller discussion of these issues and a bibliography.)
Why even perform RTqPCR tests at all?
Because the “q” is important in two ways: informing a patient’s clinical care; and if it can help identify individuals destined to become infectious early enough to pre-empt them from transmitting to others.
The key question is just how long is the pre-infectious stage?
Is it very small as shown below (green segment) (NEJM September 2020) or is it longer?
If the ramp up is fast and steep, the chance of any pre-infectious person receiving a traditional high sensitivity test quick enough is diminishingly low. Reliable data is hard to come by, since very few people are identified early enough to initiate the frequent repeat testing required to provide it.
Recent case reports from Caltech and the Pasadena Department of Public Health suggest that this detectable pre-infectious period can be as long as four days, especially among younger individuals. This implies there’s higher value to detecting individuals before they can infect others.
This finding reinforces the need for either: rapid antigen series testing (FDA announcement) or higher sensitivity (103 viral copies/ml or better) emerging point-of-care molecular tests (i.e. true PCR systems, more sensitive than most current POC LAMP systems).
PCR tests are exquisitely sensitive — the median test can detect 1 genome in a microliter of sample: the best are 100 times more sensitive; the worst 100 times less so, but even these are still able to detect the vast majority of infected individuals.
Every test reports a “q” — the cycle threshold (Ct, aka Cq, or Cp). However, the specifics of the test protocol affect what this Ct is — the same sample tested with different protocols will likely not generate comparable Ct numbers: it will vary protocol to protocol based on differences in pre-PCR processes (sample collection; use of transport medium; cDNA generation; reagent selection and purity); locations and base content of genome regions selected; primer design to bridge those regions (e.g. off-target binding or primer-dimer formation); probe design to detect amplified product; efficiency of the PCR cycler instrument used; etc.
Across all samples run on the same protocol, Ct will accurately reflect relative viral load differences sample to sample.
Generating comparability beyond that requires each lab to publish what is called a “Standard Curve” for each test protocol it performs. This translates “apples and oranges” Ct counts to more comparable viral loads expressed in terms of number of viral copies per milliliter.
This is done by taking a sample of known viral concentration (available commercially) and running a series of 10x dilutions on the same protocol and recording the resulted Ct with each known level of viral load — for that specific test, run in that particular way, by that particular lab.
As a demonstration we plotted Ct versus viral load for a more-or-less random group of 8 assays reported in the academic literature.
The vast majority of these have similar slopes – because they all use PCR which at 100% efficiency doubles the amplified product with each cycle. However, they have very different intercept Ct counts. A reported 20Ct for the most sensitive protocol implies a relatively less transmissible 1,000 to 10,000 (103-104) copies/ml in the sample.
While an apparently identical 20Ct for the least sensitive protocol means a highly infectious 10,000,000,000 (1010) copies/ml in the sample. At 100,000 (105) viral copies/ml Ct counts vary from 18Ct to 32Ct.
To talk of viral load only in Ct terms is both misleading and effectively meaningless beyond the bounds of any one individual assay protocol, unless the standard curve is created and Ct translated to viral load. (There still remain non-analytic issues that can erode comparability, for example: SARS-CoV-2 is tissue resident so the load available to sample from the respiratory tract may not directly reflect active virus driving clinical outcomes for the patient and their risk of transmissibility.)
All labs do calculate a standard curve as part of assay/instrument calibration for FDA-cleared, quantitative assays. However, this type of calibration is not required and rarely performed for qualitative assays, even if — as with RTqPCR — assays are inherently and robustly quantitative.
Current SARS-CoV-2 assays are approved by the FDA only for yes or no answers. The FDA has never before allowed reporting of a quantitative result from a qualitative viral test without requiring the calibrated standard curve in viral copies/ml on which the yes/no answer is based, and therefore allowing cross-assay comparison.
Even though the FDA hasn’t done this before, it’s easy to see how it could clear the way for this more quantitative view.
SARS-CoV-2 calibration curves for each individual assay are straightforward to establish with the appropriate standards. Many are commercially available or have been established by clinical laboratories with an interest in robust understanding of the performance of their SARS-CoV-2 PCR assays.
However, this essential data is rarely reported — some clues appear in limit of detection claims, but very few standard curves are published outside academic literature.
It is frustrating and tragic that the major (perhaps only) advantage of qPCR is ignored. Practices must change to require that a standardized viral load measure is routinely reported to physicians, epidemiologists and patients to inform their critical decisions.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Larry Corey, MD
Clinical trials have given us a wealth of information about the effectiveness, and safety profile, of vaccines for COVID-19. But the work of gathering evidence, and weighing the results in the context of an ongoing pandemic, isn’t done.
The importance of developing population-based effectiveness and safety profiles associated with a mass vaccination campaign — the sort of deep datasets that go far beyond what’s possible in a controlled clinical trial — has been urgently demonstrated over the past three weeks.
Extraordinarily uncommon, but severe, adverse events have occurred with the administration of the AstraZeneca vaccine in Europe and the Johnson and Johnson (J&J) vaccine rollout here in the United States. Intense public scrutiny of these rare adverse events in adenoviral vector vaccines prompted a brief “pause” in administration of the J&J vaccine, after about 7 million doses were given in the US.
When a mass vaccination campaign is rolled out, adverse events are observed more acutely and more accurately than the slow trickle rollout that goes with any other kind of vaccine or drug distribution. The infrequent becomes more frequent because the number of people vaccinated is so large—a one-in-a-million problem becomes one per day rather than one every 2 to 6 months.
Critics of mass vaccination argue that these campaigns are fraught with difficulties. In some ways, this is true. Beyond the safety and efficacy profiles, there are logistical issues in mass production, quality control, and distribution. There are also the ongoing issues we’ve seen with limited access and certain populations being left out and feeling a continued sense of separation from the vaccination process, reinforcing a distrust of the entire vaccine effort and the people leading it.
It is also true that from a historical perspective mass vaccination campaigns have brought real risks: Guillain-Barré syndrome was associated with the swine influenza vaccination campaign in the mid-to-late 1970s.
Today, we have a new disease to study called vaccine-induced thrombotic thrombocytopenia (VITT). It’s sometimes called Thrombosis with Thrombocytopenia Syndrome (TTS). This phenomenon has now been linked to both COVID-19 adenovirus vaccines—AstraZeneca’s and to a lesser extent the J&J vaccine.
This rare event was detected because it was unusual, like Guillain-Barré syndrome with Swine influenza vaccine. The persons affected by VITT had presented with severe clots in their head, and when surgeons were looking at this and trying to treat it, these clots would reoccur right in front of their eyes. In addition, the blood cells that were involved that were usually high in clotting disorders were low and beside the clots, there was bleeding.
Rare as it may be, physicians and scientists have seen something like this before. This observation was similar to an unusual immune response to the anticoagulant heparin. Immediately, investigators in Europe—mainly in Germany and the UK—described this phenomenon in recipients of the AstraZeneca vaccine. They detected an antibody in the blood of people that activated the platelets (platelet factor-4) that causes blood to clot. This antibody seems to put the platelets in one’s body into overdrive, which then results in a simultaneous clotting of the blood and depletion of the platelets, which causes bleeding.
Clotting and bleeding at the same time—this is a very difficult condition and highly unusual.
It is a clinical condition that’s so unusual, it was instantly recognized and now it seems clear that it’s a rare side effect of the adenovirus vaccines. VITT seems to appear after the first dose, generally in younger people, mostly but not exclusively in women and usually within 4 and 14 days but as far out as 28 days post vaccination.
We’ve now learned how to diagnose this disease by doing a blood test of anti-platelet factor-4, using the sensitive ELISA assay. We can treat it by giving high doses of IV immune globulin to neutralize the autoantibody; and (sometimes) administering steroids. It can also be managed by giving other kinds of blood thinners. Crucially, patients with this syndrome can’t be given heparin, which has shown to worsen the disease.
The disease is rare but sobering; about 30% of the persons with intracranial thromboses and bleeds have died.
To date, in the United States, there are 15 cases of VITT among the 7.5 million persons receiving the J&J vaccine; 14 of the 15 cases are in women and almost all are under the age of 50, which equates to a case rate of about two cases per million vaccinated persons. A thorough review of the risk benefit of the vaccines was performed by both the CDC and the FDA and both of these organizations advised that people should be alerted about the possibility of VITT and to seek medical evaluation if they experience prolonged abdominal pain, worsening headache, or shortness of breath in the days post vaccination.
Further, the FDA and the CDC made the determination that the enormous number of lives saved by the J&J vaccine outweighed the risk of developing VITT and hence restarted the Emergency Use Authorization vaccination program.
To give you a real-world example of the kind of personal risk benefit ratio we’re considering, the data out of the CDC estimate that here in the United States, the odds of being struck by a car is about 1 in 4,292. And the odds of dying as the result of being struck by a car are about 1 in 47,273. And yet, this is a risk we all manage most every day, usually without even thinking about it. VITT, of course, is a new risk related to a new vaccine, so yes, we are all understandably cautious, but it’s important to keep the risk in perspective.
The advantage we have at this point is that we know how to diagnose and treat it, so there’s at least a potential to lessen the impact of the disease. With this knowledge in hand, is it worth it? I think at the moment we have to look at the number of deaths in our country and globally from COVID-19 and weigh the risk of this rare and serious side effect with the overwhelming benefit of the J&J vaccine to fight COVID-19 symptomatic disease, keep people out of the hospital and alive.
And at the same time, we should continue to weigh the risk versus benefit as we learn more. The regulatory authorities, and the scientific community, should continue to communicate the risks and benefits of the vaccine in real-time as we gather more evidence.
We should, and I think will, continue to use the science to drive policy. There are clear benefits for the one-dose J&J vaccine during this ongoing pandemic. Given its less stringent cold-storage requirements, the J&J vaccine is often the only viable option for hard-to-reach communities, and it’s important to remember its effectiveness has been demonstrated in a well-controlled global clinical trial. It works not only against severe disease, but against a wide variety of variants. We also have an effective adverse event surveillance system set up—and the wherewithal—to rapidly diagnose and treat people who develop VITT.
This is an ongoing and important conversation, and there is much work to be done. The blood samples from the 44,000-person Phase III clinical trial need to be evaluated and we need to determine whether a large percentage of people actually develop antiplatelet factor-4.
If so, is it just a few who get such high levels that it sets this cascade off? If it’s uniform, then we’ll have to look at it more closely and determine what really is the risk benefit ratio? Is it good news because that means we can detect it early? Or bad news because it will mean we’re going to need to continue careful monitoring? Or both?
One thing is certain: we need to spend the time, energy, and resources to continue to ensure we do good surveillance.
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 US 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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David Shaywitz
The first iteration of the “Quantified Self” movement largely fizzled out about five years ago. Avid self-trackers, at the time, started to worry they were drowning in data, but lacking in insight.
Today, we seem to be entering Quantified Self 2.0. Once again, an expanding assortment of consumer devices promises to measure every parameter of our health and well-being.
The obvious question: “has anything changed?”
Let’s start with some context.
The “Quantified Self” movement was born in 2007, the brainchild of Wired magazine editors Gary Wolff and Kevin Kelly. The term was used to describe “a collaboration of users and tool makers who share an interest in self-knowledge through self-tracking.”
This initiative was propelled by powerful, emerging consumer technologies, as Lindsay Rothfeld captured in Mashable in 2014:
“Before things like smartphones [note the iPhone debuted in 2007] or wearables, we’d have to consult doctors or data technicians or manually log activities to determine how many calories we consume and burn. But now, with Fitbits, Fuelbands, Jawbones, and Whistles (even our dogs are tracking activity!), we can capture this data in a snap, see it updated in real time and use it to make better, more healthy decisions.”
Observing the evolution of this ecosystem back in 2011, I wrote,
“It will also be important to ensure that even as we recognize — and seek to capture, leverage, and ultimately monetize — the value associated with the collection of an ever-increasing amount of data, we also recognize that most people don’t want to be perpetually monitored (at least not intrusively). While there’s a much-discussed movement called “Quantified Self,” focused on capturing and sharing vast quantities of physiological data using sensors and other devices, this sort of excessive monitoring is almost certainly not something most of us want. One challenge will be figuring out how to capture useful physiological information in a way that offers benefit while also remaining unobtrusive and respecting privacy concerns.”
Putting a finer point on it in 2014, I noted the disconnect between the promise of digital health and the demonstrated impact. “The goal,” I wrote, “is to find solid evidence that a proposed innovation actually leads to measurably improved outcomes, or to a material reduction in cost. Not that it could or should, but that it does.”
I was not alone. After nearly a decade of escalating hype, many users started to take stock, and asked what they learned from such obsessive monitoring. Frequently, the answer turned out to be, “not much.”
Wired editor Chris Anderson, a previous acolyte of the Quantified Self movement, seemed to put the nail in the coffin, tweeting in 2016:
“After many years of self-tracking everything (activity, work, sleep) I’ve decided it’s ~pointless. No non-obvious lessons or incentives 🙁 “
It seemed like this was the end.
But instead, it may have proved to be only a short Quantified Self winter.
Today, everywhere you look, there are companies promising to quantify nearly every aspect of your behavior and habits, your physiology and activity, your physical performance and your mental health.
Consumers are now offered continuous glucose monitoring, heart rate variability assessment, and even “brainwave feedback,” via devices which are claimed, respectively, to enable improvements in metabolic health (for non-diabetics), exercise recovery, and “mental strengths and weakness” (to enhance performance on videogames).
Less clear is whether anything has substantively changed. Are we measuring parameters in a fashion that’s now more accurate? More useful? Or are we just essentially repackaging old approaches with a fancier user interface and the promise of AI, yet selling consumers the same dubious message that more data inevitably equates to better insight into how individuals can improve their day-to-day state of health and wellness?
Prior experience (to be Baysean about this) suggests we should remain skeptical. The fact that a device can generate a number and ascribe it to a particular parameter doesn’t mean that the measurement is either accurate or meaningful. We tend to measure what we can, which isn’t necessarily what we should. It’s also challenging to translate even reliable data into relevant insights, and notoriously difficult to translate actionable insight into durable behavior change.
At the same time, science evolves, technologies improve, and more importantly, entrepreneurs adapt. Sometimes — as venture capitalist Ali Tamasub highlights in Super Founders — it takes a number of tries to get it right. Google was hardly the first search engine; Facebook was not the first social network.
At a minimum, we should remain open to the possibility that on occasion, someone will crack this difficult nut, and turn the promise of data abundance into durable evidence of meaningful impact.
I embrace this hope – and look forward to the evidence.
Vikas Goyal, SVP, business development, Pandion Therapeutics (now part of Merck)
The news release crossed the wires 6:45 am Feb. 25. Within minutes, my inbox started filling with some awesome congratulatory notes. In a few of those notes, there were also some questions about how fast it all happened.
Pandion Therapeutics, the Watertown, Mass.-based company where I worked as chief business officer for 18 months, had just been acquired by Merck for $1.85 billion, or $60 a share in cash.
We were a startup, developing treatments for autoimmune disease, and barely four years old. We had only spent about $85 million to date. The concept was outlined in this January 2018 story in TR about our Series A financing.
Three years later, by anyone’s estimation, this was the stuff of biotech startup dreams.
How did it happen? What did we do? Why were we so fortunate?
From my perspective, the story starts where all biotech stories do – with the science.
Science Comes First
T cell maturation is a chaotic and iterative process. V(D)J recombination creates an almost infinite range of immature immune cells. Clonal selection then curates these cells down to a subpopulation that are able to recognize pathogens (positive selection) but do not react to self (negative selection). For T cells, this elegant natural selection happens in the thymus.
Of course, in reality, biology is stochastic. A percentage of self-reactive immune cells will escape clonal selection and can, unfortunately, go on to attack normally healthy cells, resulting in autoimmune disease.
To counterbalance those fugitives, a very special and idiosyncratic subpopulation of a subpopulation of immune cells is also created in the thymus: the self-reactive FOXP3+ regulatory T cell (Treg).
Perhaps uniquely among immune cell populations, some of our self-reactive T cells are allowed to mature because they present a magical set of properties. Instead of attacking our body, these Treg cells protect our body from their more hostile effector T cell and other immune cell cousins.
Pandion’s lead program, PT101, was designed to activate and expand these Treg cells in people, with the therapeutic goal of helping these special cells do their job more effectively in patients living with autoimmune disease.
Jo Viney, CSO, Pandion Therapeutics
Since the company’s founding by Jo Viney and Alan Crane, our mission has consistently been to build a platform and pipeline of drugs that activate the regulatory immune system. Our human proof-of-mechanism data for PT101 and our broader autoimmune pipeline were catalyzing factors in our acquisition by Merck.
Getting to that deal was also an iterative process with a fair amount of chaos and selection along the way. Looking backwards, the success of our business development approach at Pandion centered on (1) creating momentum; (2) setting hard goals that would be unambiguously expressed in term sheets; and (3) having some leverage.
Chaos, oddly enough, can help build momentum.
We approached a broad set of potential partners. We sought out trusted introductions to partners, and created introductions where we needed. Whenever we caught a whiff of interest, my job was to lean in and create sustained momentum that might lead somewhere productive. Often, it was a matter of listening carefully for subtle clues, and letting strategic interest reveal itself over time.
One way I embraced chaos was simply by including every program at Pandion in all of my introductory meetings. Most people seemed interested in our most advanced programs, but this was not always the case. Some pharma companies were much more interested in our PD-1 agonism approach. Others wanted to focus on our skin tethers to add on to their existing dermatology pipelines. Of course, Astellas Pharma was most interested in our pancreas-targeting work for type 1 diabetes (see Oct. 2019 partnership press release).
Before building momentum for any partnership or acquisition, we first had to build trust in the quality of our data.
We shared a lot of information with interested parties. We openly answered questions about our data, brainstormed potential new experiments, and revealed our lingering uncertainties and internal disagreements about our science. We walked through our R&D decisions and changes to these decisions based on data on hand. And where sharing information risked our patent filings or critical know-how, we said as much and worked to align the business and science discussions. In the background, I was sharing our business situation, strategic goals, and economic desires with my business development counterparts.
One main goal was to make sure one interaction would lead to another, and not let the interest just fizzle out. Obviously, this required continued strategic interest by the pharma. But we did our part to keep stoking the campfire.
Our scientists were flat-out relentlessly generating new data. In my 18-month tenure at Pandion, PT101 progressed from preclinical development to Ph1b ready. We identified PT627, a non Fc dependent PD-1 agonist, and progressed it into cell line development. We generated multiple in vitro and in vivo data demonstrating the activity of our tissue-tethered programs for gut, skin, and other autoimmune diseases. In parallel, other companies were publishing data with their IL-2 muteins and their PD-1 agonist mAbs.
While all of this was going on, it helped to get a little lucky. It certainly helped when Sanofi acquired Synthorx, valuing that company at $2.5 billion in December 2019. That deal validated Synthorx’s engineered IL-2 for oncology indications, along with its preclinical work on autoimmunity. Other companies could see something stirring in this space, and they became a little more curious about the science we had been describing.
Our data sharing and focus on repeat meetings was about building personal trust and a desire to work together.
Over the course of 14 months of relationship building with Merck (i.e., from the day when I first introduced myself to Merck to shortly before they approached us with an acquisition offer) I participated in almost 40 meetings with Merck; and my BD counterpart and I called each other’s cell phones almost 60 times. Our chief scientific officer Jo Viney, chief medical officer John Sundy, and broader R&D team participated in at least a dozen meetings. Our CEO Rahul Kakkar selectively joined at least half of these meetings to show we were serious.
Rahul Kakkar, CEO, Pandion Therapeutics
A secondary goal from each of these meetings was gauging where the discussions were going. I kept an eye on who joined the meeting from Merck. What was their role? How deep and informed were their questions? Was Merck still evaluating us, or were they now thinking through go-forward plans? Did they want to meet again and how soon?
I could pick up on clues, but ultimately couldn’t see the whole picture without gathering some intel from my network. The broader biotech community helped me gauge how much momentum Pandion really had. I spoke with executives from multiple companies who had partnered with or been acquired by Merck to understand how other companies’ interactions had progressed, when key decisions were made by Merck, and who at Merck made those decisions. These case studies were each benchmarks I could compare against Pandion’s ongoing discussions. It gave me confidence that we were getting somewhere.
In addition to pushing the momentum, I also tried really hard to reduce friction.
One easy place to reduce friction is the deal process. For example, when working out our Astellas collaboration, Liz Mayo and Steve Singer at WilmerHale had a draft contract to Astellas before we had even signed the term sheet.
For the acquisition by Merck, we were represented by Eric Tokat’s team at Centerview Partners. That team had recently represented ArQule, VelosBio, and Peloton Therapeutics in their respective acquisitions by Merck. Our merger agreement was closely modeled on ArQule’s and executed by the same legal team under Graham Robinson and Laura Knoll at Skadden.
In my opinion, the advantage of working with experienced deal advisors was not about getting to a better deal — the advantage was getting to a better deal faster. These people had strong pre-existing relationships with Merck, and weren’t likely to damage those relationships or risk an entire deal by haggling excessively over some small item.
So given I’m clearly a big fan of working with experienced deal advisors, you may be wondering what my job is 😉
The right TCR-antigen-MHC interaction between a cytotoxic effector T cell and an infected or cancerous cell initiates a cascade of perforins, granzymes, Fas ligands, and other kinds of nasty signals to initiate cell death. But the process is highly targeted and usually spares neighboring healthy cells.
Being goal oriented has benefits. When I transitioned from a Pandion board member representing SR One to leading business development inside the company, my goal quickly evolved from thinking about what deal we should do, to simply focusing on seeking the term sheet.
The term sheet crystalizes the IP we are expected to share, the drug programs we are expected to deliver, and what people and resources we will need to commit. The first term sheet also signals how much money we can expect to receive.
The simple act of writing down what matters in the term sheet clarifies your own thinking about how much momentum you really have in a way no meeting can.
Receiving a term sheet also instigates and enables a focused decision process for the biotech, across the whole management team and the board.
Rather than the open-ended, “What deal should we do?” the term sheet forces a clarifying set of simple yes/no questions. Should we do this deal? Do we need this cash enough to give up this program? Will we create more value together in the collaboration than we would have independently?
Once those questions can be clearly tackled, a good term sheet is almost always self-evident.
Getting a term sheet written down also creates more momentum in the biotech’s favor.
To get you that term sheet, the larger pharma just went through a slew of meetings, diligence hours, and committees involving people from R&D, finance, legal, transactions, as well as C-level executives. A critical mass of those people are now fans of your biotech. And that organizational effort built significant sunk cost such that the many individuals involved will want to see the deal through. They don’t want to waste their time, and like a macrophage chasing a bacterial cell, they don’t want to let a good one get away.
The term sheet also marks a shift in leverage. Before the term sheet, my business development goal is creating demand and momentum to get through the pharma’s evaluation process. Immediately upon receiving a term sheet, for at least one brief stage in the BD process, the small biotech takes over the driver’s seat.
We now control the timeline to share a response, as well as the form of the response. We can now ask much more detailed questions about the potential partner’s budgets and people. And we ultimately control the decision whether to even respond.
When crafting the response, one type of leverage that was helpful to Pandion, and that aligned our and partners’ interests, was having a reasonable perspective on what was right for the program.
We really believed our pancreas discovery program would benefit if we could parallel track at least three targets. Once we aligned on this core question of scope with Astellas, we were able to easily settle the research budget and milestone structure. We also believed, given our modular TALON™ technology and the US courts’ view on obviousness type double patenting, that Pandion should own and prosecute the collaboration patents for our pancreas work. Again, many contract terms were easily settled once this key technical IP issue was agreed to with Astellas.
In all deals, competitive tension is one of the most important types of leverage. In addition to potential competitive bids from other pharma partners, Pandion significantly benefited from competitive tension between partners and investors.
We were able to parallel track partnership and financing discussions several times during the last two years. Prior to the acquisition offer, Merck previously made two partnership proposals to Pandion. In both cases, our alternative to partnering with Merck was a financing event.
Merck’s first proposal came on January 31, 2020, in the middle of Pandion’s Series B discussions. Momentum from Rahul and I joining the team, executing the Astellas collaboration, progressing PT101 into the clinic — and of course Sanofi’s acquiring Synthorx — supported a compelling $80 million crossover Series B that came together during Q1 2020.
At the time, we were able to directly compare one business path against the other. The B round gave us enough cash to simply not need a partnership. We knew we could continue to create value independently. Our cash position as an independent company got even stronger three months later, in July 2020, when we raised $135 million in an IPO backed by high-quality investors who were very focused on PT101.
Raising equity dollars also gave me leverage in pharma discussions by limiting my ability to accept certain business structures. In October 2020, Merck subsequently proposed a 50-50 collaboration for our IL-2 mutein programs. Pandion’s board and management understood that such a partnership might provide meaningful additional resources to PT101. However, we did not believe such a partnership could be a tenable path for Pandion to pursue given our post-IPO runway all the way into 2024. Post-IPO my belief was that any collaboration involving PT101 would have to return meaningful capital to the shareholders who supported our IPO.
Competent T cells are an amazing manifestation of evolution. But really the goal of most organisms is to not get infected in the first place. Our skin barrier, skin RNAses, stomach acids, and other first lines of defense do most of the heavy lifting.
Ultimately, Pandion’s best leverage was the leverage to do no partnership at all. Our pipeline progress and balance sheet allowed us to politely decline several proposals and not have to engage in extended negotiations.
Our pipeline progress was the fundamental driver of Merck’s desire to acquire us. Our business development strategy, with a focus on momentum and goalseeking for the term sheet, played an important part. Certainly, the favorable financing environment of today was an important factor in our favor.
All deals come with their own special set of circumstances. We are fortunate and thankful to have gotten here. With a different set of circumstances, perhaps we would have been clonally selected for a different outcome.
David Shaywitz
We’re drawn to stories. We understand the world through stories – both the narratives we read, and those we create and develop for ourselves.
It’s the very power – the unreasonable effectiveness? – of stories that also leaves us so vulnerable to deception, including self-deception.
This is a key message from “Super Founders,” Ali Tamaseb’s soon-to-be-published analysis of the factors behind “unicorns” – startups that attain a valuation of at least a billion dollars.
A venture capitalist at the deep tech firm DCVC, Tamaseb found himself wondering whether there were features of unicorns that distinguished them at an early stage from startups that wouldn’t go on to such prodigious success. It’s a relevant question for a VC who must sort through hundreds of companies a year to identify the most promising investments.
He was aware, of course, of the many popular narratives associated with outsized startup success. One story that’s been often told is about young founders who drop out of Ivy League colleges to pursue a technology-fueled dream (think Bill Gates and Mark Zuckerberg).
A related common narrative are founders relentlessly driven to solve a problem that’s rankled them for years. Typically, successful founders are presumed to have refined their dream through an accelerator program like Y Combinator or Techstars, and are often imagined to have advanced an idea that was first-to-market, perhaps even creating a market.
Ali Tamaseb, partner, DCVC
A critical thinker, Tamaseb asked himself whether these narratives – and associated venture heuristics guiding investment – were true, pressure testing the conventional wisdom around startups in the way Stanford business school professor Jeffrey Pfeffer has challenged so effectively the comforting nostrums surrounding leadership and power.
Rather than simply rely on expert opinion, Tamaseb approached the question more scientifically, and did the hard work of collecting and crunching the data. He conducted a case-control type of study, comparing the attributes of the 200+ startups founded between 2005 and the end of 2018 that achieved $1 billion or greater valuations, and a similarly sized group of randomly selected startups, founded during the same time range, and who had raised at least $3M in initial funding, but who never became unicorns.
Tamaseb is admirably upfront about the limitations of this approach, which he acknowledges doesn’t have the level of rigor of an academic study, and involves a lot of subjective interpretation on his part. He also notes that the key outcome measure – unicorn status – is hardly the only or even the best definition of startup success. But it certainly captures an achievement, and one that’s highly relevant for investors and employees holding equity in the company.
So what did he learn?
Most significantly, the data highlighted the limitations of conventional wisdom. The median founder age (at the time of founding) for future unicorns in his sample, Tamasab learned, was 34. That’s far older than many might have guessed; moreover, the range was 18-68. That data point alone shows there’s no one single stereotype of what a founder looks like, or what set of experiences prime someone to start a company.
David Duffield, for example, was 64 when he founded Workday, an enterprise software company for finance and HR functions.
Educational backgrounds were also quite varied among founders. One out of three (33 percent) had an advanced degree. That figure is even higher among founders of healthcare and biotech companies. Founders who were dropouts proved to be almost vanishingly rare.
The variety in educational background of the unicorn founders was matched by a similar variety of educational experiences in the non-unicorn sample.
Interestingly, while about a third of unicorn founders attended schools ranked in the top 10, another third of founders attended schools that were not ranked in the top 100, Tamaseb reports.
What about work experience? It turned out that fewer than 50% of founders of future unicorns had significant work experience or domain expertise in the area their company would pursue; this was equally true among founders in the non-unicorn sample. However, this pattern doesn’t hold for biotech and healthcare companies, where 75% of founders had relevant experience.
As a cautionary healthcare aside: Flatiron is presented (accurately) as an example of a healthcare company where founders had no relevant domain expertise (Tempus, a precision medicine company started by founder of Groupon, might have been another interesting example). However, the key inflection point for Flatiron, as I understand it, was when Dr. Amy Abernethy — a professor at Duke University and an expert in clinical trials, cancer outcomes research, and clinical informatics — joined and guided a company that was somewhat adrift at the time. Instead, the origin story that one of the founders shares with Tamasab omits Abernethy, and focuses instead on a familiar narrative (often embraced by journalists) emphasizing the founders’ charming naivete (“We were fresh; we had no preconceived notions, no bad habits. We questioned everything”).
Perhaps the most prominent difference between founders of unicorns and founders in the non-unicorn sample was that 60% of unicorn founders had previous experience as startup founders, vs 40% of founders in the non-unicorn sample. Moreover, of the founders with previous startup experience, 70% were relatively successful in the unicorn sample, and only 25% were in the control sample. (Here, success is provisionally defined by Tamasab as achieving either a relatively modest threshold of either a $10M valuation at exit or $10M in revenue.) Doing the math, this means that 42% of the unicorn founders had previously founded a relatively successful company, vs only 10% of the founders in the control group.
Tamasab was so impressed by this distinction that he called this group of founders “Super Founders” – and selected this name as the title for his book.
It’s also the finding that seems to guide Tamasab’s current approach to investing. While “most VCs have thesis areas on industries, spaces, or ideas they like to see happen and when they pitch an opportunity to their partners,” Tamasab tells me, “they first talk about the ‘what.’ My thesis in on ‘people.’”
Tamasab continues,
“One of the key signals I look for is people who have built, hacked, and sold something of value before, even if that was a small outcome in the world of mega acquisitions and venture capital. I pay more attention to this than whether someone had a big leadership role at a FAANG [Facebook, Amazon, Apple, Netflix, Google] company or a high growth rate in the past month. When I source startup deals, I source people, decide on the founder, and then see what is the idea they are working on.
I’d say the biggest difference for me is to try to not let my preconceptions about an idea, about founder’s background, how large a market is now, or competition, come into the way of backing an extraordinary founder who will go against all those odds (most of which, as the book suggest, are actually not statistically significant, so it’s not even going against the odds, but going against stereotypes).
Ideas change, companies expand to different markets or expand an existing market, competitors come and go, but a Super Founder is resourceful to go and create a giant company in the long-run.
At the end of Super Founders, Tamaseb writes:
“If there is one takeaway from this book, it should be that the path to a billion-dollar startup often begins with a bug for creating. The best preparation for starting a wildly successful company is starting a company. If you have never started a company, the best preparation for doing so is to start something, maybe a club or side hustle.”
I’d add an additional takeaway — the idea that each of us — investors, founders, and others involved in the ecosystem – need to liberate ourselves from the idea that there’s a definitive path towards success. Even the concept of Super Founders. Remember: 40% of unicorns were founded by someone who was not a previous founder.
There is not a universal archetype of a successful founder.
Of all the popular founder narratives we can leave at the curb, or at least reframe, one is certainly the notion of startups as formed to pursue a life-long mission. Despite the appeal and prevalence of these narratives, many unicorns evolved in a far more iterative and “top-down” fashion: a founder, or founding team identified “a market, a customer type, or a trend and then hunted for problems to be solved.” (The founding of Incredible Health by Dr. Iman Abuzeid – described here – represents a particularly compelling example of how this can work.)
Entrepreneur and investor Elad Gil (he co-founded Color Genomics – see here), quoted by Tamasab, offers valuable insight into why the iterative, top-down approach may be underappreciated.
“I think there’s a lot of founder myths in Silicon Valley that are kind of made up, and one of the reasons they’re made up is because it’s a more compelling story and the press wants to cover founder stories. They don’t want to cover companies. They want to cover the personal connection that the founder had going back, you know, to when they were five years old…”
In other words, narrative bias – bias in the way the media covers startups — underweights the frequency of what turns out to be a remarkably common if unsexy approach of iteratively seeking a market in a top-down fashion.
Some of the confusion may also come because many companies develop missionary zeal for their mission once they discover it – it helps drive the team and the company.
As Gil observes, “belief in mission” can be present from the outset, but “sometimes it comes later as the company is successful and people realize that they’re onto something and then it turns into their life mission.”
As Tamasab astutely recognizes: “You can be opportunity-driven but still love and have a passion for the product you are building or the customers you are serving.”
Indeed, this perspective (as I’ve discussed) is shared by Dilbert creator Scott Adams, who challenges the popular “follow your passion” trope, arguing that in his experience, “success caused passion more than passion caused success.”
At a minimum, this should free would-be founders from desperate vision-quests, anxiously searching for their life-calling.
If there’s a final takeaway, it might be Slack CEO Stuart Butterfield’s comment: “Be super lucky.”
This is echoed in a Stanford business school study Tamasab cites that asked early-stage VCs what qualities they looked for in investments, and then what qualities distinguished their successful portfolio companies. “Team” was the top answer in both cases, but both “timing” and “luck” also feature prominently — and specifically — in the look back.
Luck, as Tamasab takes pains to emphasize, also includes the privilege and associated accumulated advantage. He urges us to “acknowledge the role that luck, privilege, and access played in the success of many of these founders,” and specifically highlights examples “like having the privilege to drop out of school or work on building a startup without a salary, rather than taking a safe job to pay back student debt,” or “the privilege of coming from a family that has the right connections.”
Commenting that “while doing this research I could not help but notice the lack of diversity among these founding teams,” Tamasab writes he will “donate proceeds from this book to nonprofits and charitable causes that help with upward social mobility and diversity.”
I hope the rest of us find as much meaning and value as Tamasab clearly has from his thoughtful and considered exploration.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Today’s guest on The Long Run is James Sabry.
James is the Global Head of Pharma Partnering for Roche. He’s based in Basel, Switzerland.
James Sabry, global head of pharma partnering, Roche
He did his PhD in neuroscience at UCSF, and spent the bulk of his career in biotech in California. After leading a couple of startups, he joined Genentech in 2010 as vice president of partnering. It was a pivotal moment in the company’s history, as it was being integrated into Roche.
A lot has changed in biotech over the past decade, and James has been in a position to see it all at one of the industry’s leading companies. That includes everything from gene therapy to gene editing to cell therapy to targeted RNA medicines.
We talked in this episode about how things have changed over the years at Genentech and Roche, how James likes to approach the business development game, and what some of the megatrends are that make him optimistic about biotech over the next 20 years.
Please join me and James Sabry on The Long Run.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Luke Timmerman, founder & editor, Timmerman Report
Like many people, I’m itching to get outside.
Today, I’m excited to announce a new outdoor experience for a good cause: The Timmerman Traverse for Life Science Cares.
It’s a Presidential Traverse hike scheduled for Sept. 13-15, 2021.
A fantastic group of 20 biotech leaders — 10 women and 10 men — will hit the trails. We’ll cover the iconic 20-mile hike over Mt. Washington, Mt. Adams, and Mt. Jefferson. All told, we’ll experience 8,000 feet of elevation gain up and over 7 summits in the White Mountains of New Hampshire.
Each team member on this trip is committing to raise at least $25,000 for Life Science Cares.
Team goal: $500,000 to fight poverty.
We are well on our way to crushing this goal, with more than $225,000 raised.
For those unfamiliar, Life Science Cares is a fantastic organization that mobilizes the biotech community to support antipoverty nonprofit organizations, education groups and job training programs. The work began in Boston and has now expanded to chapters in Philadelphia, San Diego and the Bay Area.
The inaugural Timmerman Traverse team includes:
This team is showing tremendous spirit in the early days, having already helped secure a deeply committed group of sponsors to support Life Science Cares.
Sponsors:
You can show your support a few different ways.
DONATE: Go to the JustGiving.com page for Timmerman Traverse, and find a hiker you know. They’ll appreciate whatever you feel comfortable giving — $100, $500 or $1,000 or more – to help them hit their goal of $25,000.
SPONSOR: If you’re thinking big as an organization, and able to donate between $5,000 and $50,000, you could join that outstanding group of sponsors above. See a team member you know, or contact Sarah MacDonald and Christine Casalini at Life Science Cares for more about sponsorship opportunities.
LACE UP YOUR BOOTS: Would you enjoy an outdoor experience with biotech leaders? Are you willing to work hard to support Life Science Cares? I am compiling a list of alternates, and also gauging interest in future expeditions. luke@timmermanreport.com.
This will be a wonderful way to appreciate nature, give back to community, and build relationships with tremendous biotech people.
Let’s show what the biotech community is capable of when it sets its mind to supporting the most vulnerable members of our society.
Bill Newell, CEO, Sutro Biopharma
I can never forget the video of George Floyd, a black man, being suffocated to death under the knee of a white police officer.
My worldview was changed by it.
As the CEO of a mid-sized public biotech company, I supported equal rights and opportunities. In my day job, it mainly meant hiring and promoting a diverse team, and supporting industry initiatives to promote diversity in employment and in clinical trials. As a citizen, I tried to do things consistent with these values – donating to charities, voting, treating others with respect and decency.
Watching that video and hearing the cries of protest that followed led me to the realization that more needed to be done.
George Floyd’s murder resonated because it cast a spotlight on police brutality that has been going on for so long, against so many of our fellow Black Americans. Too many of us just hadn’t been able to see it, to fully reckon with it, until that video made it impossible to miss.
It changed the way I think about race in America, and how I think about what to do about it within my own sphere of influence as a corporate leader.
The recent spotlight on hate crimes against Asian Americans has further broadened my perspective. I have come to the inescapable conclusion that simply trying to be color blind is no longer enough.
So, I started a personal change process last summer. I sought to be more proactive, to use my role as a leader to do more to recognize and actively work to tackle systemic racism.
As I discussed this with good friends, one challenged me and others following a similar path.
Could we truly sustain this newly energized engagement for the many years it would take?
To me, the answer is yes. This is the biopharma industry. We need to have a long run mentality to be successful in our work. We can channel that same mentality toward diversity and inclusion in our industry.
Last June at an all hands meeting to discuss George Floyd’s murder and systemic racism, I said this:
I am a 62-year-old well-to-do white male – my life experience is limited in so many ways and even though I like to think I have led a good life where I do not judge anyone by the color of their skin or for any other difference they may have from me – have I? Have I? I have many questions to ask myself about how I have behaved in the past and how I behave today. These are not easy questions to ask oneself, let alone answer.
Since then, I have found that, while self-reflection is valuable, I also needed new and different inputs. So I have started to learn more about systemic racism, to listen more to different voices, perspectives and histories and to engage in discussions about racism. I can recommend the works of Ibram X. Kendi, including “How to be an Antiracist,” to start.
If you are interested in diving deeper, our Sutro team has suggested some additional resources on our website (see our Diversity, Inclusion & Social Justice web page).
By continuing to read and learn more about systemic racism, I hope to avoid complacency and to sustain efforts to dismantle it.
While not being a racist is important, that alone will never get our society to equality and justice. I believe we should heed Kendi’s call that we should do more, we should be antiracists. That word requires taking actions and engaging actively.
As a company leader, taking actions and engaging actively are part of my DNA. I have been directly involved in diversity issues on the relevant committees at both BIO and California Life Sciences Association (CLSA), our national and state trade associations.
The Sutro senior leadership team includes six women. Our 17-person senior team also includes two LGBTQ individuals, three Latinx and three Asian members. Our Board is well on its way to California’s AB 979 compliance with two women directors, one of whom is Board Chair, both of whom are also people of color.
As our company evolves, I am committed to fostering even more diversity across the staff over time.
If one individual can effect change, then how much more impactful is it if many individuals are actively committed to change?
Leaders of companies can empower others to be change agents as well. We can start by setting policy, and channeling it through the organization with the tone and example we set.
For example, as we planned our 2021 summer internship program, our team has again set the objective to have a diverse group of interns, including those from economically disadvantaged backgrounds. We intend to have a group of 12 interns, and our diversity goal is 75%.
These interns will work in person where possible, and remotely when necessary, with our staff of approximately 200 employees dedicated to targeted therapies for cancer. It’s a valuable real-life drug development experience for the interns, and an on-ramp for their careers. It’s also an opportunity for us to learn a few things from a younger generation.
We are also working to encourage young people to think about the future possibilities in biotech. Our team has promoted and supported our employees’ participation as volunteers in South San Francisco STEM education.
We have committed funding to a variety of industry-based initiatives, including CLSA’s Racial & Social Equity Initiative – We Commit to Change. We have supported and sponsored employees to attend educational experiences that broaden their knowledge of systemic racism and healthcare inequalities, such as programming from Impact Experience.
Is it enough to lean in personally and support efforts by your employees to lean in themselves? I would argue it is not. I believe it is in a company’s best interest, and in society’s best interest, for leaders to be vocal and demonstrate leadership on issues of equality.
Historically, few leaders have been willing to do so. It seemed disconnected from pure business interests.
Merck CEO Ken Frazier has rejected the notion that equality is not a matter for business leaders to address. He has set an example for us all in recent years. Last summer, he said businesses have to “go beyond just statements” and that “businesses have to use every instrument at their disposal to reduce these barriers that existed.” 
I agree. I have begun to use my and Sutro’s social media platform to reflect and advocate for equality and to denounce inequality.
Some investors may be uncomfortable seeing that sort of visible leadership. Shouldn’t we keep our heads down? I hope they will come to embrace the wave of environmental, social and governance (ESG) awareness that is growing in the investment community. All of us should be leaning into that wave.
There is no simple fix that will end systemic racism. Its roots run deep and are pervasive. Even when we believe we have made progress, as recent events have shown, back sliding happens too easily and too rapidly.
We need to acknowledge that being antiracist is to be on a long run. We need to acknowledge there will always be more to do. That may seem daunting and occasionally discouraging. Even so, I believe our industry’s long run mentality will serve us well as we strive for equality.
How do I plan to ensure that my efforts at Sutro are sustainable? I believe commitments and accountability are at the core of sustainability.
At Sutro, we have made our commitments public. In coming months, we will add a process of transparency and accountability that will also be public.
We will aspire. We will measure and we will report. We will do so for all to see.
We are far from perfect. But we are committed to continuous learning and improvement. Progress may come slowly but we are used to that in our industry.
Let’s remember Lao Tzu: “The journey of a thousand miles begins with a single step.”
Bill Newell is CEO of South San Francisco-based Sutro Biopharma.
Chris Garabedian, chairman and CEO, Xontogeny
John C. Martin was an unassuming man with an ordinary name. But his leadership qualities and accomplishments as a biopharma CEO were extraordinary.
Martin, the CEO of Foster City, Calif.-based Gilead Sciences from 1996 to 2016, didn’t seek to dominate the room or inspire legions with a charismatic personality. He didn’t make the cover of magazines, even when he led the company that did more than any other to transform HIV into a chronic, manageable disease.
When he died last week at age 70, Martin was essentially unknown to the public and not very well understood within his own industry. Yet he left a legacy of having built one of biotech’s most successful and enduring companies.
I’m fortunate to have seen Martin work at close range, and consider him a mentor. When I was serving in several roles as part of a lean and aspirational management team at Gilead in the late 1990s and early 2000s, Martin was the boss. I got to see how he set direction and how the organization responded. Long after I moved on, I saw how this quiet leader continued to envision and execute on the big, long-term strategies that he set in motion in Gilead’s adolescent years.
John C. Martin, former chairman and CEO, Gilead Sciences
John did not dress to impress, only donning a conservative suit and tie when it was necessary as a respectful obligation for an important meeting or an investment conference. His business casual attire of neutral colors and pattern-less sport coats seemed intended to not allow any distraction from his words and the ideas he wanted to convey.
He didn’t focus on selling a future vision of Gilead. He was more likely to be touting the latest approved drug or the importance of a recent company initiative. John didn’t try to persuade with a dynamic or stylized narrative, but rather by clearly communicating a core idea in the simplest and most straight-forward manner possible, often with just a short statement or a Socratic question.
He was a leader who listened and observed far more than he spoke. When he spoke, he did it with piercing intent.
When John asked you a question in a meeting, it sometimes felt like a test. John likely already knew the answer or had a better answer than what you might muster up. John could make one comment or a short statement in a meeting and change the entire trajectory of the conversation.
He displayed an efficiency of words that was focused on communicating with clarity about a key concept or an action to be taken. At the end of a meeting with John, there was little room for interpretation or doubt about what to do next.
He was uninterested in the spotlight. He let other executives do the talking for Gilead. He never sought awards. He let the company’s results speak volumes.
These performance metrics led Harvard Business Review in 2010 to rank Martin #6 in their first edition of “Best Performing CEOs in the World” (Steve Jobs was #1). A few years later, Martin moved up to #2 behind Amazon’s Jeff Bezos.
During John’s tenure, Gilead went from a company valued in the hundreds of millions to one of the few biotech companies to achieve a $100 billion-plus valuation. Today, it’s the second highest-valued biopharma company ranking behind only Amgen.
During my tenure at Gilead (1997-2005), Martin’s office was austere. He worked at a simple uncluttered desk. Framed group photos highlighting Gilead’s history decorated the walls. A few sample bottles of Gilead’s approved products sat on the windowsill. There was a small conference table where I remember weekly tactical meetings would be held with selected members of the management team to go through John’s questions and tasks that he would accumulate over the week and would write down as a to-do list on a yellow legal pad.
If John was not in team meetings or walking around the corporate campus dropping in people’s offices, he was often at his desk tapping away at his laptop.
I saw his routines out of the corner of my eye. My office was two doors down from John and next door to the “other John,” John F. Milligan – the longtime chief operating officer and eventual CEO of Gilead. Early employees, to make sure they didn’t confuse one for the other, sometimes referred, with brevity, to ‘JCM’ and ‘JFM.’
I was an early riser, often arriving at work between 6 am and 6:30 am. That meant I was often first in the office. Let me correct that: I was often second, because John was already there. If he wasn’t, it probably meant he was traveling.
I didn’t want to leave that office next to John, even for a promotion. When I was tasked with leading Gilead Medical Affairs, I was supposed to move to the R&D building where my new boss, Norbert Bischofberger, was located. I dragged my feet for a year, with the lame excuse that I was too busy to move my things to a new office.
John loved to work. One Saturday morning on the day of Gilead’s annual company picnic, a beach event at Half Moon Bay, I stopped by the office in Foster City first to get a little work done. I was surprised to see John in the office.
I tried to make some small talk, which was always a bit awkward. That wasn’t his forte.
“Are you excited to go to the company picnic?” I asked.
He shrugged.
“I’d rather be spending the day working, but I guess people are expecting me to be there,” he said.
John would later be seen at the picnic chatting with employees, watching others play volleyball and eating barbecue. But the small talk of those huddled around him inevitably turned, and as most casual conversations almost always did with John, to the excitement of the work.
Yes, we talked shop at the company picnic.
Never have I experienced anyone with the tireless work ethic and persistent drive as John. His dedication to the vision of Gilead and getting quality products to the patients that needed them was an inspiration to all of us who worked for him.
John started his career on the science side. He received a PhD in Organic Chemistry from University of Chicago. He then worked at Syntex and Bristol Myers as a medicinal chemist leading antiviral drug programs.
While at Syntex, he decided to strengthen his business understanding and pursued an MBA in Marketing from Golden Gate University. John’s understanding of business and marketing along with his grounding in antiviral chemistry proved to be a potent combination.
Martin came to work at Gilead in 1990, when it was a startup working on antisense oligonucleotide drug candidates. He was named CEO in 1996. One of the first things he did was drop the antisense oligonucleotide work. The delivery challenges and high cost of goods meant it would probably take 20 years for these therapies to pan out, he reasoned.
That decision to stop doing antisense work was just as important as his decision shortly thereafter to bet the company on antivirals.
While thinking through this strategic pivot, John saw that antiretroviral cocktail therapies were emerging as the most potent weapons yet in the AIDS epidemic. The multi-drug combinations had turned the disease into a manageable chronic condition.
But many of the drugs required multiple pills taken several times throughout the day. Some had to be taken with food, some without. Patients had a pill burden of more than 20 pills taken at multiple time points over the day. Simply scheduling a daily regimen was a burdensome task and made it difficult for patients to fully adhere to prescriptions needed to keep the virus in check.
John unified Gilead around the easy-to-understand vision of “one pill, once a day.” It became the north star for the company. With that vision in mind, Gilead acquired Triangle Pharmaceuticals to obtain a second “backbone” nucleoside analogue to combine with Gilead’s own tenofovir. Rounding out the plan, Gilead formed a collaboration with BMS for the third drug component, the NNRTI efavirenz, and later for another BMS drug, the protease inhibitor atazanavir.
With those pieces in place, Gilead was on its way to dominating the HIV marketplace. Gilead’s drugs worked against the virus. That was clear. But they won in the marketplace because they enriched patient quality of life and made it easier for patients to stick to the instructions on the prescribing label.
In the mid-90s, almost every pharmaceutical company was seeking a piece of the HIV therapeutics market. Competitors included GSK, BMS, Pfizer, Abbott, Roche, and Merck. But the little biotech from Foster City, California, over the course of a decade, reigned supreme as the world’s largest maker of HIV medicines.
John didn’t stop there. The next clear goal was to develop or find the best-in-class treatment for HCV (hepatitis C virus). Gilead toiled on this work for more than a decade before acquiring Pharmasset and finishing work on what became the dominant cure for HCV.
Pricing and access to medicines were perennial thorny issues at Gilead. The critics were relentless and vocal. John handled these issues with aplomb — working methodically behind the scenes. He saw to it that Gilead’s HIV drugs could be manufactured at cost by local manufacturers in developing countries. He pressed teams to develop a pre-exposure prophylaxis, or PrEP, strategy to prevent HIV in high-risk individuals.
He persisted in multiple attempts to diversify Gilead beyond its core antiviral franchises. Not all of these acquisitions were successful – cardiovascular disease and pulmonary hypertension were a couple of areas where Gilead struggled to gain traction.
In his last major act as CEO, Martin oversaw the acquisition of Kite Pharma and its CAR-T platform to strengthen the company’s oncology and cell therapy bona fides. It’s a bold bet on the future that will take years to pay off.
Throughout, John emphasized that Gilead be outward-looking. This was exemplified during the development and commercialization of Gilead’s initial HIV and HBV drugs. John expected that the top researchers and clinicians would personally know the top managers at Gilead.
John set the example himself. Every month, he would visit clinicians, often with a Gilead sales rep. He used the opportunity to conduct his own market research to help the drive the company’s clinical development pipeline strategy, anticipate objections to product adoption or exploit opportunities to position Gilead’s products more favorably vis-à-vis our competitors.
My first few months at Gilead were spent traveling the world visiting every top expert HBV clinician to learn about the disease, the current state of treatment and what outcomes would be most meaningful. This was market intel we would use to shape clinical development strategy.
John hungered for this kind of market knowledge so much, that he wanted it woven into the company’s cultural fabric.
When I was asked to lead Medical Affairs a few months before the introduction of Gilead’s first HIV drug, tenofovir (Viread), John handed me a business card of a physician he had recently met in one of the largest HIV-treating practices in New York’s Greenwich Village.
Fly to New York the next weekend to meet him, John said. And don’t come back until the doctor agrees to join us as a medical science liaison, he added.
“How do I do that?” I blurted out.
John told me he had planted the seed and that I just needed to convince the doctor that he could impact more patient lives by helping to educate other clinicians on his experience and how they could treat their patients optimally using Gilead’s drugs.
That was the first of many MDs, PhDs and PharmDs that were hired to build credible relationships between Gilead and the medical community.
This close working relationship extended beyond researchers and clinicians to the patient community. While almost every rare disease company knows the power of engaging with patient advocates, John was doing it with many HIV advocates in a thoughtful, sensitive and collaborative manner long before it was vogue. We discussed access, pricing, and feedback on marketing messages.
I took many of these principles with me in meetings with Duchenne Muscular Dystrophy patients and advocates when I later became CEO of Sarepta Therapeutics.
John Martin didn’t feel compelled to show everyone how smart he was, but he had a fierce intellect. He was a man of ideas. It seemed as if his mind never stopped working and he was always 10 steps ahead of everyone else. He read philosophy with practical aims in mind.
A few days after a meeting on organizational effectiveness, John gave me a copy of Nietzsche’s “Beyond Good and Evil.” He explained the dynamics of managers and subordinates and how those in authority are often perceived wrongly in terms of ethics and intention by those who work for them.
A couple weeks later, I gave him Hobbes’ “Leviathan.” We discussed how to best tame a growing organization and keep it from getting unwieldy and unmanageable. Every discussion of ideas was anchored in application to our day-to-day work.
There is a long list of Gilead alumni and current employees, like me, who would call John their most influential mentor. While some of us left Gilead prior to John’s departure at the end of 2018 (I left in 2005), there was quite an exodus in recent years of senior leaders who spent the bulk of their careers at Gilead and have now moved on to be CEOs and board members for other companies. They are carrying forward John’s legacy.
John never sought glory, but was glorified by so many of us who knew him and had the pleasure of working with him. Glory is defined in numerous ways but the word most commonly means “high renown or honor won by notable achievements” and “magnificence or great beauty,” as well as “praise, worship and thanksgiving offered to a deity.”
As I read about his death last week, I realized that his understated and humble style did not allow him to receive the glory that he deserved from the industry that benefited so much from his contributions. But he has provided a tremendous legacy for those that learned from him and a beautiful standard for us to strive toward, to measure ourselves against, and to carry forward.
