15
Oct
2024

Engineering Protein Drugs for Cancer & Autoimmunity: Chris Garcia on The Long Run

Today’s guest on The Long Run is K. Christopher Garcia.

Chris Garcia, professor, Stanford University; investigator, Howard Hughes Medical Institute

Chris is a professor of biochemistry at Stanford University and an investigator for the Howard Hughes Medical Institute. To be a bit more specific, you can call him a structural immunologist – the kind of scientist who uses the vivid tools of structural biology to better understand fundamental workings of genes, proteins, and cells of the immune system.

His work is rooted in basic science – basic questions of how life works. But it has paved the way for significant applications, such as new drugs for cancer, autoimmunity, and platforms for further discovery.

Garcia is a scientific co-founder of multiple companies, including Synthekine (the developer of custom-designed cytokine drugs), ALX Oncology (a company working on the ‘don’t eat me’ signals sent out by cancer cells, and 3T Biosciences, which works on TCR antigen discovery. He’s also a frequent collaborator with Nobel Laureate David Baker of the University of Washington.

Garcia’s accolades are starting to add up as well. He recently won the Max Cooper Prize in Immunology, named for one of the field’s pioneers. The nomination paper from professor Toni Ribas of UCLA describes a jaw-dropping list of contributions Garcia has made to the field. The nomination paper cites Garcia’s:

“Groundbreaking structural discoveries which revealed how immune receptors signal in response to ligand engagement, which have revolutionized our understanding of the immune system and are leading to novel engineered therapeutics currently being tested in patients with cancer.

It goes on:

Dr. Garcia elucidated how cell surface receptors signal in response to ligand binding at the cell surface and used protein engineering to translate this structural and mechanistic information into therapeutics. Dr. Garcia resolved groundbreaking three-dimensional structures of ligand-receptor complexes which play critical roles in human biology and disease, including the structural basis for how most immune cytokines engage their receptors (IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-15, IL-17, IL-21, IL-22, IL-23, IL-27, and Type I, II and III IFNs).”

Whew.

Aaron Ring, a researcher at Fred Hutch Cancer Center, a previous guest on The Long Run, and one of the most brilliant young scientists I know tells me that Garcia is simply “the best protein engineer alive.”

This episode traces Garcia’s life story, including his improbable route to the pinnacle of science, and why he thinks staying super-fit through long-distance running helps him in his day-to-day work.

Now, before we start, a word from the sponsor of The Long Run.

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Please enjoy this episode with Chris Garcia, an exceptionally talented and driven scientist.

8
Oct
2024

Call for Entries: Join the Timmerman Traverse for Damon Runyon Cancer Research

Are you ready for a bucket list adventure?

Join me and a team of biotech executives and investors on the Timmerman Traverse for Damon Runyon Cancer Research Foundation.

It’s a trek to Everest Base Camp (17,600 feet) in April 2025.

Who’s on the Team?

What Will I Do?

  • Raise awareness for cancer research
  • Raise money to propel the careers of young scientists
  • Form meaningful relationships
  • Have fun

When is the Trip? Apr. 11-27, 2025.

L to R: Henry Kilgore, Luke Timmerman, and Will Chen on Kilimanjaro, Feb. 2024. Henry and Will are Damon Runyon Fellows at the Whitehead Institute and the University of Washington, respectively.

Where: Everest Base Camp trek in Nepal. It’s one of the superb high-altitude treks in the world.

Why Damon Runyon? It supports brilliant young cancer researchers across the US.

Damon Runyon has a keen eye for talent. In its more than 75-year history, its grant recipients have gone on to win:

  • 13 Nobel Prizes
  • 7 National Medals of Science
  • 104 elected members of the National Academy of Sciences

Damon Runyon grants have catalyzed many major advances in science, including:

  • The first chemotherapies to cure a solid tumor.
  • The first targeted ALK inhibitor for lung cancer.
  • The first demonstration that CRISPR could edit genes in mammalian cells.
  • Cancer immunotherapy with checkpoint inhibitors and CAR-T cell therapy as far back as the mid-2000s, long before these treatments became mainstream.

How Will I Do It? You will work hard to prepare physically and mentally.

Ten spots are taken.

Seven spots left.

If you work at a company committed to cancer R&D, this is a rare opportunity for your company to sponsor you and a network of brilliant young scientists.

Are you ready for this experience of a lifetime?

Ask me for more information by Oct. 18, 2024.

luke@timmermanreport.com.

 

WATCH to Learn More:

6
Oct
2024

What If You Can’t Pick Winners in R&D? 

David Shaywitz

Peter Thiel, the contrarian investor, had a favorite question for interviewees: “What important truth do few people agree with you on?”

My answer: No one can pick winners in pharma R&D. 

When I think of the most significant blockbusters in the industry involving novel mechanisms of action (follow-ons are a different story), I see a huge amount of luck on the exploration side, followed by exceptional focus on subsequent exploitation.

Pembrolizumab (Keytruda), Merck’s oncology blockbuster is one example (see here).  Millennium’s (later Takeda’s) bortezomib (Velcade) is another (here).  The GLP-1 medicines developed by Lilly and Novo and achieving stratospheric sales for the treatment of obesity are additional examples (see here, here). 

While the researchers leading the initial development of each of these medicines were passionate about the program’s prospects, each medicine had to overcome profound skepticism within a large pharma before it was eventually embraced and exalted. When Merck acquired Schering-Plough (and when Schering-Plough acquired Organon before that), the acquiring company had no idea a future blockbuster was lurking in its portfolio. Similarly, when Millennium acquired Leukosite, no value was attributed to the bortezomib program. 

In the case of Lilly and Novo, their work on incretins like GLP-1 represented an outgrowth of the longstanding interest in and involvement with diabetes in general, including the biology of insulin secretion (modulated by incretins). While early rodent studies of GLP-1 demonstrated an impact on appetite, diabetes — not obesity — was the initial focus.

Daniel Drucker, professor of medicine, Lunenfeld Tanenbaum Research Institute of Mt. Sinai Hospital and the University of Toronto.

When a leading incretin expert, Dr. Daniel Drucker, reviewed the field in 2017 – three years after the first GLP-1 was approved for obesity – he lamented the “market penetration” and worried about the “clinical appeal, expense, and commercial success of newer formulations” (see here).  While his concerns about expense were on target, these medicines have emerged as outsized successes, both clinically and commercially.   

The point is that while all these companies were transformed by those successful products, no one in R&D leadership at these companies saw this coming far in advance or had shaped their R&D strategies around the anticipation of such extraordinary results. 

What each company did do successfully was (eventually) recognize the promise of the medicine and work intensively to realize this potential.

The difficulty of replicating R&D success

One measure of the role of luck in R&D success is how difficult success is to replicate – how hard it is for companies to find their next blockbuster. 

My experiences suggest that in many ways, success makes finding the next blockbuster harder, because companies invariably develop a tidy narrative around the success – a comforting series of “lessons learned” (it was our culture, it was our focus on biomarkers, it was our clinical operations, etc), and then seek to impose these learnings on future company efforts. 

Yet if we’re in a domain where luck plays a critical role in determining success (spoiler alert: we are), then (as discussed here) you need to be really cautious about assuming that the occasional success represents the manifestation of your exceptional skill, rather than involving a combination of real skill coupled with a hefty amount of luck.  As Pixar’s Ed Catmull emphasizes, there isn’t a playbook (big pharma’s go-to crutch) for creative success like an original film (or, I’d add, an innovative drug) – you need to reinvent the approach each time.

There’s also an unfortunate tendency to fall prey to “selecting on the dependent variable,” as Cass Sunstein nicely explains in How To Become Famous (see here).  This approach, so familiar in companies and among the management consultants who advise them, involves looking at a set of successful companies/products/leaders and then trying to pull out what they have in common, and then concocting a compelling narrative around this.  Yet without knowing, rigorously, if these same traits are present among the many failures, you’re just coming up with a good story, with little actual validity or predictive value.

Are dart-throwing chimps the answer?

What is to be done?  Should the head of R&D at Lilly, Dan Skovronsky, acquire a trained chimp to throw darts at potential targets and programs, akin to the blindfolded monkey that economist Burton Malkiel famously asserted (in A Random Walk Down Wall Street) would pick stocks as well as expert investors?

At a fireside chat last Tuesday at Harvard Business School (where, disclosure, I serve as an advisor to the MS/MBA program in life sciences), I had an opportunity to see how Skovronsky viewed this exact challenge, as he responded to questions posed first by Professor Amitabh Chandra, then by members of the audience.

Refreshingly, Skovronsky emphasized the contingency of R&D, the role of chance, and the futility of commercial forecasts (a topic I’ve discussed frequently, see here, here, here).  He said (only half-jokingly) that the most important trait in a Chief Science Officer was being lucky.

He also emphasized that while some might urge Lilly to take its pile of GLP-1 cash and undertake either a transformative acquisition or acquire a derisked late-stage product, he wasn’t enthusiastic about either, noting that large M&A is profoundly disruptive, requiring massive corporate reorganizations which wasn’t his focus or interest.

Meanwhile, fully derisked products, he said, were typically acquired either by the company with the most excessive sales forecast (a concept referred to by economists as the “winner’s curse”) or by the company that is the most desperate.  Neither of these seemed like especially attractive prospects.

In contrast, Skovronsky suggested that a large pharma’s greatest strength is its ability to develop drugs, a notoriously complex task with which smaller organizations often struggle.

Interestingly, he suggested that because he was operating in an organization (and at a moment) where there was an uncommonly high tolerance for the inevitable failures, this represented a competitive advantage. 

Other pharmas, he suggested, might be less willing to invest in early, risky assets because leaders were worried about the career consequences if too many of these bets went south.

The notion of a large pharma arbitraging risk aversion (big if true…) seemed particularly interesting, and reminded me of PayPal’s ability to take advantage of large company risk aversion (specifically in the context of regulatory risk) to outmaneuver the combination of eBay plus Bank of America – see here.

Daniel Skovronsky

Daniel Skovronsky, president of Lilly Research Labs; SVP of science and technology at Eli Lilly

Skovronsky also suggested that because of its location in Indianapolis, Lilly was somewhat protected from the latest hype cycles and had relatively more patience to pursue promising but difficult programs. 

Perhaps related, he also offered a decidedly reserved perspective on AI, allowing there was promise in assisting with molecule creation, but otherwise fairly guarded about the impact.

I hope Skovronsky’s approach succeeds, though it’s difficult not to look at Moderna as a concerning example. Moderna may have slipped silently into obscurity were it not for the opportunity afforded by COVID, an incredibly fortuitous (from the perspective of the company at least) event for which it was ideally positioned. 

Of course, the success narratives soon followed – it was their embrace of digital, or their adoption of AI, or their culture, that enabled them to be successful, and would surely pave the road for future success.  Betting on themselves, they invested significantly in R&D.

Unfortunately, these efforts, to date, haven’t panned out; their stock has been crushed by investors, and after much outcry from analysts, Moderna recently announced massive R&D cuts.  Mr. Market can be very unforgiving.

I hope this isn’t Lilly’s future, and I also hope that Moderna’s pipeline and approach yields future impactful medicines. But whether we should count on this happening is a more difficult question.

Contingent, but not Random

If, as I believe, there isn’t a leader of R&D on the planet who has a magical or uncanny ability to “pick winners,” how do you approach this role?  What role does good luck play?  Is it time to bring in the blindfolded chimp?

Before we answer this, we should come to terms with perhaps a second truth about R&D that can be difficult for those outside the process to appreciate: R&D programs are not discrete, static, or hermetic – it’s not like betting that a roulette wheel lands on “36.” 

Rather, drug development requires constant effort to perfect and refine a new medicine, at every stage of the process including in clinical trials, where the right patient population and dosage scheme could make the difference between a failed and successful product. 

The most significant challenge facing any head of R&D is balancing the recognition that, on the one hand, outsized success is generally impossible to predict in advance, and most projects involving novel mechanisms will fail.  On the other hand, for any project to have a chance at success, it must proceed with full and authentic conviction, with leaders absolutely convinced that there’s a path for success to be found.

Balancing these two is incredibly challenging, particularly the need to believe deeply in programs while somehow compartmentalizing enough to avoiding getting sucked entirely into the program’s narrative, and maintaining enough objectivity to make difficult, data-driven decisions (see also here).

Sometimes, as Skovronsky points out, the issue isn’t data but politics; as previously reported in the Wall Street Journal, he described how Lilly (and other pharmas) historically, would advance programs with shaky data because the program would fulfill an identified commercial need (a concern VC David Grainger has raised as well, as I’ve discussed here).

Since these ill-advised programs would generally fail in subsequent, more expensive later phase clinical studies, they are huge wastes of time and resources, and Skovronsky has worked aggressively to eliminate them.

But in many (arguably most) cases, it’s less clear whether a program is six months away from a breakthrough (as teams tend to argue) or six months away from just digging a deeper hole.  Management gurus will tell you that the ability to discern one from the other is the secret of great leaders. This is wishful thinking. 

Many top scientists, like famed Harvard surgeon-researcher Judah Folkman, acknowledge that when you’re in the midst of an impassioned pursuit, you have no way of knowing whether you are persistent or obstinate; that distinction is revealed only by the outcome

Given the need for R&D leaders to come to terms with the inherent uncertainty associated with their roles, they would do well to remove sterile information where possible. In a futile effort to domesticate uncertainty, many R&D organizations, especially when things seem to be going poorly, decide they will improve decision making by imposing stricter discipline, and start affixing all sorts of quantification (e.g. probability of technical success, estimated net present value [NPV]) across R&D. These tend to be falsely precise numbers that typically provide far more illusory comfort than true insight. 

I would love to see the NPVs that Merck associated with pembrolizumab when it acquired Schering-Plough, that Millenium associated with bortezomib when it acquired Leukosite, or that Novo and Lilly associated with obesity indications of GLP-1 programs during their early days (or even their not-so-early days, as the Drucker experience suggests).

Bottom Line

The fundamental challenge for R&D leaders is that while success is highly contingent, your only way to achieve it is through convicted pursuit, though such pursuit is not (at all) a guarantee of success. The ability to muster conviction in the face of inherent overwhelming uncertainty is the critical quality required for R&D leaders and others who seek to leave their mark on the world.

26
Sep
2024

Boundless Bio Takes on Oncogene Amplified Cancers: Zach Hornby on The Long Run

Zach Hornby is today’s guest on The Long Run.

Zach is the CEO of San Diego-based Boundless Bio. The company is seeking to target cancer cells in an unusual way. It is developing small molecule drugs that take aim at DNA that resides outside the usual home on a chromosome.

Zach Hornby, CEO, Boundless Bio

These oncogene amplifications occur in loops outside the chromosome. This extra-chromosomal DNA – in rather sneaky fashion, you might say – can help cancer cells resist the pressure put on them by some of today’s targeted drugs. These oncogene amplifications are one reason why so many cancer drugs appear to help patients for a while, but only for a while until the cancer bounces back.

Boundless Bio wants to shut down this form of cancer drug resistance.  

Before becoming CEO of Boundless Bio, Zach worked as chief operating officer at San Diego-based Ignyta, the company that developed entrectinib (marketed as Rozlytrek by Roche/Genentech). The company was acquired in late 2017 for $1.7 billion.

Boundless has a couple of ongoing Phase I/II clinical trials.

The stock market is currently pretty skeptical toward development-stage biotech companies that haven’t yet shown proof of concept data from clinical trials. This effort will take some time and perseverance.

I hope you enjoy listening to Zach discuss his journey in biotech, and that of Boundless.

First, a word from the sponsor of The Long Run. 

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17
Sep
2024

Sickle Cell Patient Cured With CRISPR Summits Kilimanjaro, Setting World Record

Four years after being functionally cured of sickle cell disease with a CRISPR gene-editing therapy, Jimi Olaghere has set a new world record for patients with this chronic and deadly disease.

Olaghere, a 39-year-old business owner from Atlanta, became the world’s first patient with sickle cell disease to reach the summit of Kilimanjaro at 7:30 am Tanzania time on Sept. 16. It’s the highest peak in Africa at 19,341 feet above sea level.

Jimi Olaghere, technology entrepreneur, Dad, sickle cell disease patient advocate

Patients with sickle cell disease are at serious risk of complications and death in low-oxygen environments. Doctors advise patients to avoid elevations greater than 10,000 feet.

Olaghere was able to set a new high-altitude record on Kilimanjaro after being functionally cured in a 2020 clinical trial of one of the first CRISPR gene-editing therapies – Vertex Pharmaceuticals and CRISPR Therapeutics’ exagamglogene autotemcel (Casgevy).

“While this challenge was really difficult, it showcases the raw power of cell & gene therapies,” Olaghere said. “I went from being bedridden to standing atop the highest free-standing mountain in the world. This will no doubt bring hope to the millions suffering from sickle cell disease across the world. It’s paramount that we make gene therapies for sickle cell disease accessible.”

About 100,000 patients in the US have sickle cell disease, and an estimated 25 million people worldwide suffer from the disease in which red blood cells form crescent shapes that harden, clump and damage blood vessels. Those sickling events can lead to heart attacks, strokes, kidney damage and other potentially deadly complications. Patients regularly suffer excruciating pain crises that send them to the emergency room.

Olaghere has now been free of such pain crises for four years, since his infusion of Casgevy. He joined this Kilimanjaro expedition as part of the Timmerman Traverse for Sickle Forward. This expedition of 20 biotech executives and patient advocates raised $2.2 million to improve diagnosis and treatment of sickle cell disease in Africa, and to support sickle cell disease research at the University of Alabama Birmingham.

“Jimi’s accomplishment of reaching the roof of Africa will bring hope to patients around the world. It showcases the new heights that sickle cell patients can reach with emerging therapies,” said Alan Anderson, director of the comprehensive sickle cell disease program at Prisma Health in Greenville, SC and executive director of Sickle Forward, a nonprofit. “We are excited that the funds raised through this expedition will be a critical first step in our mission of advancing screening, diagnosis and treatment of sickle cell disease in Africa.”

Alan Anderson, physician-scientist, executive director, Sickle Forward

“As an advocate for sickle cell patients, I’m so excited about Jimi’s success and the continuing advances in treatment of sickle cell disease,” said Ted Love, chairman of the board of BIO. Love was a co-chair of the fundraising campaign, and a member of the team that reached the summit of Kilimanjaro.

All 20 members of the team reached the summit of Kilimanjaro together around 7:30 am Tanzania time on Sept. 16. The group was guided by Eric Murphy of Alpine Ascents International and a team of 10 Tanzanian guides.

For me personally, seeing Jimi reach the summit of the highest peak in Africa was exhilarating. It was the culmination of months of hard work and preparation.

His is an inspiring story of the human spirit, and the potential for biotech.

Most importantly, it will provide hope to millions of sickle cell disease patients around the world.

Timmerman Traverse for Sickle Forward on the summit of Kilimanjaro, Sept. 16, 2024. All 20 team members made it to the top.

Jimi Olaghere on the summit of Kilimanjaro, Sept. 16, 2024. Olaghere, 39, was functionally cured of sickle cell disease by an infusion of Casgevy in September 2020.

Members of the Timmerman Traverse for Sickle Forward on the final push to the summit of Kilimanjaro. Photo credit: Peyton Greenside.

9
Sep
2024

The Enchantments Traverse: A Photo Gallery

The 4th annual Timmerman Traverse for Life Science Cares wrapped up last month, but I’m feeling a bit remiss for not telling the whole story.

This year’s successful $1 million campaign came in two parts.

First, there were a pair of back-to-back day hikes in the North Cascades with a team composed mostly of newcomers to the Life Science Cares national network. Most of them were beginning hikers, too. This was the public-facing part of the program.

But after that group went home, a second group came to my beloved Washington state for a next-level adventure.

This was a smaller, hand-picked group of alumni of the Timmerman Traverse who are especially strong hikers and elite fundraisers. Together, this group raised $160,000 to fight poverty through the Life Science Cares national network. These folks joined me Aug. 22 for a hike of The Enchantments.

We covered 20 miles of rugged trail and gained 4,500 vertical feet in a single day through hike. We did it in good style, according to plan, in just under 12 hours. That meant moving fast early in the day to top out on Aasgard Pass (elev. 7,800 feet), and then slowing down in the Alpine Lakes Wilderness to savor some of the most spectacular scenery in North America.

Thanks to the TT alumni who joined me on this memorable outdoor adventure:

Julie Sunderland, Lalo Flores, Andrea van Elsas, Mark Murcko, Hamid Ghanadan, Dave Melville, and Doug Fambrough.

The photos don’t do this hike justice. The whole thing was special. The scenery, the fellowship, the impact of our work together.

If you are game for outdoor adventures of this magnitude, see me. luke@timmermanreport.com.

 

 

5
Sep
2024

Raising the Bar for Sickle Cell Patients: Ted Love and Alan Anderson on The Long Run

Today’s guests on The Long Run are Ted Love and Alan Anderson.

Ted is the chairman of the board of directors at the Biotechnology Innovation Organization. He’s perhaps best known for serving as CEO of Global Blood Therapeutics, the San Francisco Bay Area company that developed voxelotor (marketed as Oxbryta), a novel small molecule for sickle cell disease. The company was acquired by Pfizer for $5.4 billion in 2022.

Ted Love, chairman of the board, BIO

Alan Anderson is a physician-scientist who leads a comprehensive sickle cell disease treatment program in Greenville, South Carolina. He’s also the founder and executive director of Sickle Forward, a nonprofit that advances newborn screening and treatment of sickle cell disease in Africa.

I’ve worked closely this year with Ted and Alan as co-chairs on the Timmerman Traverse for Sickle Forward.

We’ve worked to recruit and lead a team of 20 biotech executives and investors to climb Kilimanjaro, the highest peak in Africa, and raise $1 million for Sickle Forward. The funds we raise will support low-cost, effective newborn screening in Africa. Kids who get diagnosed will get access to a series of practical interventions available in Africa – antibiotics, antimalarials, medications to deal with pain crises.

Alan Anderson, physician-scientist, executive director, Sickle Forward

A pilot program run by Anderson and colleagues has shown that newborn screening can save lives of these kids. The newborn screening tests only cost $1 apiece. That means a $1 million Kilimanjaro campaign can go a very long way to uplift kids with sickle cell disease in Africa.

I’m thrilled to announce that we have in fact exceeded our $1 million goal. We are now ready to go to the mountain, Sept. 8-19. 

Thanks to our major sponsors, including Silver Lake Research Corporation (the maker of the Hemotype SC test), Agios Pharmaceuticals, Vertex Pharmaceuticals, Bluebird Bio, Pfizer, Sickle Scan, BigHat Biosciences, CRISPR Therapeutics, Evercore, Beam Therapeutics, Fulcrum Therapeutics, Goodwin, and The Community Foundation for Northern Virginia.

Thanks to the more than 1,400 donors and counting who have chipped in donations of all sizes.

That’s not all. By hitting the $1 million team goal for Sickle Forward, we have triggered an additional $1 million matching gift from Ted Love and his wife Joyce. They have agreed to donate that additional $1 million to the University of Alabama Birmingham to support sickle cell disease research. That means this campaign has now raised more than $2 million total.

This doubles the impact of our work and ensures that our campaign addresses both short-term and long-term needs for sickle cell patients around the world. 

And we’re not finished. If you go to Sickleforward.com, you can learn more about the organization and click on the link to add your donation. It’s not too late. We have a number of folks who are still striving to hit their $50,000 individual fundraising commitments. They’d very much appreciate your support.

This trip is timed to coincide with National Sickle Cell Awareness Month. I can’t think of a better way to raise awareness of this long-neglected disease, and this moment that’s brimming with possibilities for sickle cell disease patients.

In this episode, I talk with Ted and Alan about the needs for sickle cell disease patients, the improving set of tools and therapies, and our campaign to rally the biotech community, the medical community, and the patient community, to keep raising the bar.

Please join me and Ted Love and Alan Anderson on The Long Run.

30
Aug
2024

Two New Books About Risk, Luck, and Skill Offer Insights For R&D Leaders

David Shaywitz

A central challenge of R&D, like many disciplines characterized by rare, outsized success, is how to think about risk, as well as the contributions of luck and skill. 

Two new books – How To Become Famous, by Cass Sunstein, and On the Edge, by Nate Silver, offer valuable perspectives. I’ll also highlight several articles that provide additional relevant insight, including two examples of conspicuous pharma failures.

How To Become Famous — Cass Sunstein

Cass Sunstein, a professor at Harvard Law School, is perhaps known for his interest in behavioral science, and is co-author, with Nobel Laureate Richard Thaler, of Nudge.

Cass Sunstein

Sunstein’s more recent effort, How To Become Famous, examines success, and focuses on how remarkably contingent it can be. He acknowledges early on that the title is “a bit of a cheat” since “one of my main points is that there is no recipe for how to become famous… This is not a how-to manual.”

We learn, for example, about a fascinating study of authors of the Romanic period by University of Toronto Professor Heather Jackson, examining the trajectories of Wordsworth, Austen, Keats, and Blake on the one hand, and Crabbe, Southey, Cornwall, Hunt, and Brunton on the other. The names in the first group, but not the second, are now iconic, yet it wasn’t at all clear during their lives who would be remembered and who would be largely lost to history.

Jackson’s analysis, Sunstein says, “strongly suggests that accident, contingency, champions, and luck” played a “massive role” in guiding the outcome, rather than any difference in ability.  Roll the dice again and history might have come out differently.

Or consider music; we might believe that the most successful songs emerge from something intrinsically special about them.  Yet Sunstein presents data from an experiment called “Music Lab” revealing that preference for one (unfamiliar) tune over another can be driven by the putative relative popularity (which the experimenter can manipulate) of the two songs.  

“Everything turned on initial popularity,” Sunstein reports, and slight differences in initial preferences can play an outsized role in shaping the outcome. 

Success begets success, and popular songs tend to become even more popular.

Perhaps the most relevant lesson Sunstein has for biopharma executives is the fallacy of studies that select on the dependent variable. The typical examples here are approaches that examine outlier successes (prominent CEOs, startups, blockbuster drugs) and then extract common features, based on the idea these are critical factors presumably worthy of emulation. 

The problem, Sunstein says, is that this represents shoddy logic.  Such analyses, he argues, can offer “no idea whether the unifying characteristics were responsible for or even contribute to” the success. 

But he acknowledges that these narratives are hard to resist – hence the popularity (as Sunstein points out) of so many business books (and, I might add, consultant reports) premised on just this approach.   Everyone who has spent time in a pharma will recognize this pattern – generalizing on the “lessons learned” based on distinctive factors associated with an individual success. 

We might do well consider the insightful if uncomfortable reflections of former Pixar CEO Ed Catmull, who noted that there isn’t a template (or, in pharma parlance, a “playbook”) for a successful original film – you need to invent it anew each time.

Sunstein reminds us repeatedly about the ever-present role of randomness in success.  Consider, for example, the great (arguably the greatest) boxer Muhammad Ali.  When he (then Cassius Clay) was 12, Sunstein writes, growing up in Louisville, Kentucky, Clay’s bike was stolen, and he went to a police officer saying he wanted to “whup” the thief.  The officer he approached, Joe Martin, turned out to run a boxing gym, and told Clay that he might want to learn how to box.  He did.

Or consider the band Fleetwood Mac, best known for singer Stevie Nicks and guitarist Lindsey Buckingham. Founded in 1967 by drummer Mick Fleetwood, without either Nicks or Buckingham, it was a blues band and not very successful, Sunstein tells us. 

One day, when Fleetwood was evaluating a recording studio, an engineer happened to play a tape of Buckingham and Nicks (a pair of struggling musicians at the time) just to provide a sense of how the studio sounded.  A week later, one of Fleetwood’s guitarists left, and the band needed a replacement; they approached Buckingham, who agreed only if Nicks could join as well.   Before long, Fleetwood Mac’s dreams began to be realized.

Sunstein’s fundamental point is that “it’s a mistake to attribute spectacular success to the intrinsic qualities of those who succeed.  Of course, it is true that those who succeed may well be extraordinary…but their extraordinariness was hardly sufficient to get them where they ended up.  Countless extraordinary people never get very far.”

A member of the Obama administration from 2009-2012, Sunstein remembers a particularly salient observation made by the President about CEOs: “They’re lucky to be where they are.” 

Obama continued,

“They might be amazing, but still, they’re lucky to be where they are.  They got a lot of good breaks.  Some of them don’t seem to know that.  But it’s true.  Look at me.  I hope I’m doing a good job, but I had a lot of luck.”

On The Edge – Nate Silver

Best known for his political forecasts (he is founder of FiveThirtyEight, where he served as Editor-in-Chief until 2023), Nate Silver’s true passion, it turns out, is poker, which he played professionally before venturing into politics.

Nate Silver

In his new book, On The Edge, Silver offers a glimpse into the mindset of what he sees as a distinct category of people who view life in terms of risk and probability, aspiring to identify situations where the math is in their favor (in their parlance: where the “expected value” or “EV” is positive). 

Silver refers to this “ecosystem” as the River, which includes not only gamblers, but also many investors (especially Silicon Valley VCs, with whom he seems especially enamored) and some philosophers. 

Silver contrasts Riverians with citizens of the Village, which consists generally of highly educated members of the media, government, and academia who he sees as comparatively risk adverse. 

Silver also believes many in the Village have an unhealthy tendency to “couple” – let their political beliefs intrude upon their analytics – rather than “decouple,” which he contends is “a type of intelligence that is valued in The River.” 

He describes decoupling operationally as the use of “yes, but” statements.  For example, he says, a Riverian might say: “Yes, I disagree with the Chick-fil-A CEO’s position on gay marriage, but they make a damn fine chicken sandwich.”  

Silver’s point is the speaker may or may not agree with the CEO’s politics but can separate in her head her view of the politics and her view of the food.   

While highlighting potential flaws within each camp, Silver proudly aligns himself with the River and describes a natural resonance with what he sees as their more probabilistic and contrarian view of the world.

Silver is clearly infatuated with poker and offers a level of detail reminiscent of Melville’s description of whaling.  Similarly, Silver’s extensive discussion of effective altruism and rationalism – not to mention Sam Bankman-Fried (Silver is not a fan, and considers him, in the words of Tim Wu, a “false prophet.) – will prove excessive for many readers (including this one).

Yet Silver’s ability to capture the mindset of Riverians feels relevant in R&D, a power law business driven by the exceedingly rare, outsized success – and where, I might add, key decisions are approached with a mindset that seems to combine extreme caution and faux mathematic precision.  It’s a domain where there’s an incredible premium on predicting success and “picking winners,” even though the actual ability of anyone to do this is arguably extremely low.

Of particular interest, Silver discusses how probabilistic thinking relates to two types approaches to knowledge. 

“The fox knows many things, but the hedgehog knows one big thing,” wrote the ancient Greek poet Archilochus, a formulation popularized in the mid-twentieth century by the philosopher Isaiah Berlin.  

A famous study by professor Philip Tetlock discovered (see this magnificent 2005 New Yorker review by Louis Menand), perhaps surprisingly, that the best predictors – “Superforecasters’ —  turned out to be foxes (particularly those with structured, probabilistic approaches), rather than hedgehogs.

Looking at Silicon Valley, Silver sees an ecosystem consisting of founders – hedgehogs – who tend to have a singular belief in the promise of their company, and foxes – VCs – whose job is to “herd hedgehogs,” assembling them into portfolios. 

Silver then invokes a useful poker analogy, envisioning a game where each turn, you need to either fold or go all-in.  He considers two strategies players might have – in one approach (“prudent”), the player decides based on her hand whether to fold or not.  In a second approach (“degenerate” or “degen”), the player goes all-in every single turn. 

What’s interesting here is that while the more cautious, arguably more skillful player does better on average, and winds up broke less often, the very highest scores are obtained by those who went all-in, even though on average, they do worse, and they go bankrupt most of the time. 

“Is this my way of saying that the richest founders in the world are just degenerate gamblers who got lucky?” Silver asks.  “No, I’m not saying that.  I think they’re highly skilled degenerate gamblers who got lucky.” 

Presumably, one might appropriately ask the same questions about the development of blockbuster drugs.  To give a particular candidate medicine the best chance of success, you need a highly skilled team – but ultimately, blockbusters likely require far more luck (and the resources to support the inevitable failures – see here) than the dialogue celebrating the rare success might suggest.

Four Articles Worth Reading
  1. This thoughtful, concise read by Wharton Professor (and AI guru – see here) Ethan Mollick discusses how survivorship bias, together with compelling narratives, often lead to the confusion of skill and luck. His focus is entrepreneurship, but the argument applies readily to biopharma R&D as well.
  2. A key paper cited by Mollick is this 2012 gem from Denrell and Liu, pointing out what savvy investors like Michael Mauboussin and Howard Marks have long recognized: in domains where luck plays a significant role in determining outcomes, the very highest performers are likely to have adopted an excessively risky strategy and happened to get lucky; in contrast, the most skilled performers are less likely to be at the very top most years, but will consistently do reasonably well.

Thus, seeking to emulate the characteristics of the top performers will not necessarily lead to the best results.  As the authors warn, “widespread use of this heuristic to identify whom to learn from can lead to diffusion of very risky behavior, and ‘nudges’ may be necessary to help people resist the temptation to praise, blame, or learn from extreme performers.”

A key point made by Nassim Taleb in Fooled by Randomness, and reinforced by Mollick, is that because of survivorship bias, it’s both essential and difficult to search out examples of failures and missed opportunities, to provide at least a measure of narrative balance. 

In this spirit, readers might consider:

  1. This captivating, insider account by distinguished endocrinology researcher (and former Harvard Medical School Dean) Jeffrey Flier, describing an early effort to pursue several novel approaches to diabetes, including GLP-1, in conjunction with a biotech company (CalBio), and partnered with a large pharma (Pfizer). The collaboration was born in the 1990s.  

Concluding that injectable diabetes medicines (other than insulin) had no future – Pfizer abandoned the partnership. That led the biotech to abandon it as well. Notably, GLP-1s achieved blockbuster status for the treatment of diabetes even before the obesity indication was added.

  1. This terrific STAT article by Jason Mast entitled “How Pfizer’s Grand Gene Therapy Ambitions Crumbled.” According to one Pfizer source with whom Mast spoke, “I think we promised probably too much without really understanding the limitations…We projected hope rather than reality.  We didn’t know.” 

One founder, Jude Samulski, explained that “We all expected it was going to be turnkey” – a standard delivery vehicle with different genes for different diseases.  He added “we were naïve in thinking that it was going to be a universal delivery system, in universally everybody, in universally every disease.”

Also recommended

Success and serendipity:

  • This discussion of Seth Stephens-Davidowitz’s Don’t Trust Your Gut, focused in particular on how to increase exposure to positive serendipity — a “how to take action” component palpably absent from Sunstein’s analysis.
  • This WSJ review of Malcolm Gladwell’s Outliers
  • This discussion of Michael Mauboussin’s insightful perspective on luck and skill.
  • This discussion of the role of luck and skill in film and pharma
  • This 2008 Financial Times commentary about serendipity and pharma, co-authored with Nassim Taleb.

Narrative Bias:

  • This discussion of narrative bias and a caution about tidy success stories.
  • A discussion of VC Ali Tamaseb’s Superfounders, emphasizing the need to liberate founders from narrative bias.
  • This discussion of the how heroic founder narratives, amplified by VCs and journalists, can adversely impact entrepreneurs.

Therapeutics Stories:

  • This discussion of discovery of Keytruda.
  • This discussion of the arduous development of GLP-1 medicines.
  • This discussion of the early work on ibrutinib.
  • This WSJ book review about the discovery and development of Botox.

Probability, forecasting, and longshots:

  • This discussion of the fragility of pharma forecasts.
  • This WSJ review of a new book discussing Bayes Theorem.
  • This critique of “sterile information” associated with pharma forecasts.

The last word: Dr. Judah Folkman:

  • This WSJ review of Safi Bahcall’s Loonshots. To quote from the last paragraph of the piece, “… it is often impossible for an organization to determine, in advance, whether an innovative team is working on a hit or a flop. As the late Harvard researcher Judah Folkman used to tell his students: ‘If your idea succeeds, everybody says you’re persistent. If it doesn’t, you’re obstinate.’” 
26
Aug
2024

Timmerman Traverse for Life Science Cares Hits $1M Goal to Fight Poverty

We did it!

The Timmerman Traverse for Life Science Cares wrapped up last week. This team of biotech executives and investors hit its goal of raising $1 million to fight poverty in the United States.

We hiked about 20 miles together, gaining between 6,000 and 8,000 vertical feet of elevation in the North Cascades of Washington state.

This trip had it all.

Spectacular views of peaks, glaciers and alpine lakes.

Physical challenges on steep trails.

Camaraderie.

Shared purpose.

A few in-depth science conversations.

Lots of jokes and storytelling.

Most importantly, this campaign raised awareness of Life Science Cares’ national network of nonprofits. These organizations provide the short-term basics of food and shelter to those in need, and access to the long-term pathways out of poverty – education and job training. We raised funds to support the best organizations that do this work in our communities.

Our efforts will continue.

These mountaineering programs, in total, have now catalyzed the biotech community to give back $10.9 million since 2017. More than 135 people have accepted the challenge and participated in these experiences around the world. More than 10,000 people have given at least once to one of these campaigns.

The Timmerman Traverse campaigns are tapping into something deep and meaningful.

This is about getting out in nature, doing something hard, with friends, for a shared purpose. We are building community.  

The program for Life Science Cares, now in its 4th year, has sparked a national initiative to create 1,000 biotech industry internships for young people from underrepresented minority groups by 2027.

A newly minted public company, Boston-based Rapport Therapeutics, traces its origins to conversations on the trail between an executive and investor. A health equity initiative was started based on a generous gift from a two-time participant.

There are many more stories to tell. And more to come.

For now, please enjoy a few photos. And if you are interested in participating or sponsoring these Timmerman Traverse expeditions, please let me know. luke@timmermanreport.com.

Click on the photos to enlarge

 

14
Aug
2024

RNA Medicines to Treat Muscle Diseases: Sarah Boyce on The Long Run

Today’s guest on The Long Run is Sarah Boyce.

She is the CEO of San Diego-based Avidity Biosciences.

Sarah Boyce, CEO, Avidity Biosciences

Avidity is a developer of RNA medicines. It uses what it calls “antibody oligonucleotide conjugates”. These are molecules that connect an antibody — which hits a specific target on the surface of cells – with an RNA-silencing molecule. That RNA molecule can get inside the cell to shut down disease-related proteins.

The company has been working on this platform technology for years and has found a niche in delivering its therapies to muscle cells – a cell type that’s been traditionally hard to reach with RNA medicines. It has gathered some impressive clinical trial for an initial program for patients with myotonic dystrophy (also known as DM1) and for FSHD, another rare muscle disorder.

Just a couple days after recording this episode, Avidity announced some positive clinical trial data with its drug candidate for Duchenne Muscular Dystrophy. Clearly, the company is hitting a stride with its technology to target muscle diseases, and it’s translating into benefits for patients.

Sarah has been with Avidity since 2019. She came to the CEO job with a background on the commercial and business development side of the biopharma industry, with a lot of experience in rare diseases.

 

Now, before we get started, a word from the sponsor of The Long Run.

You want your biopharmaceutical or device to go to market as fast as possible. But, statistically speaking, low patient enrollment is going to stop your trial in its tracks. Elligo Health Research’s optimized trial model gives you direct access to untapped, diverse patients through Healthcare-First sites, HIPAA-compliant EHR data, and AI-powered analytics. No endless searching, no waiting.

Visit ElligoHealthResearch.com to get started

For sponsorship opportunities, contact chris@timmermanreport.com.

Now please join me and Sarah Boyce on The Long Run.

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