3
Jun
2024

A New Outlook on Life With Sickle Cell Disease: Jimi Olaghere on The Long Run

Today’s guest on The Long Run is Jimi Olaghere.

His story will take your breath away.

Jimi Olaghere; technology entrepreneur, Dad, functionally cured sickle cell disease patient

Jimi was born with sickle cell disease. He suffered from severe pain episodes, fatigue and shortness of breath through much of his life. Then in September 2020, he enrolled in a clinical trial when he got the CRISPR-gene edited therapy known as exa-cel, or Casgevy, developed by CRISPR Therapeutics and Vertex Pharmaceuticals.

He was one of the first handful of people in the world functionally cured of sickle cell disease.

Today, Jimi is a 38-year-old technology entrepreneur and father of three who lives with his wife in Atlanta.

He now feels so good physically that he can play soccer, chase after his kids, and bring the kind of stamina to his work that he couldn’t before. All of this without the fear and anxiety that he might have a crippling pain episode that might send him to the Emergency Room. He was able to quit taking all the other medicines he had relied on for years.

For scientific entrepreneurs out there, hearing Jimi’s story will give you goosebumps. Creating medicines that transform the lives of patients – allowing them to fulfill their full potential – this is the stuff of dreams.

There’s more. Jimi is now a patient advocate. He wants to uplift kids with sickle cell disease who maybe haven’t gotten as many fortunate breaks in life. To this end, he is participating in the Timmerman Traverse for Sickle Forward.

It’s a biotech community drive to raise $1 million for Sickle Forward – an organization that advances access to newborn screening and basic treatment for kids in Africa. Jimi is part of this team of biotech executives and investors who are training this year to climb together in September to the summit of Kilimanjaro, the highest peak in Africa at 19,341 feet.

Maybe Jimi will go to the top. Maybe he will go part way. We’ll see. But the fact that he has a clean bill of health to even attempt such a thing is a tremendous testament to his determination to help others, and the stunning success of the treatment that altered the trajectory of his life.

I’m honored to have gotten to know him during this campaign.

If you’d like to donate to Jimi’s campaign for Sickle Forward, please CLICK HERE. 

Before we get started, here’s a word from the folks at Andreesen Horowitz’s Bio & Health team, and the producers of their terrific podcast: “Raising Health

Imagine a future where technology can analyze your health data in real time, and where AI can match patients with the best treatments.

For discussion on all this and more, check out Raising Health, the chart-topping life sciences podcast from a16z Bio + Health.

Each episode, they dive into the heart of biotech and healthcare innovation to explore real challenges and enormous opportunities – of how drug discovery and development works, the way healthcare is delivered, and how lifespan itself might be engineered. Hear from distinguished guests like Greg Meyers of BMS, Benjamin Oakes of Scribe Therapeutics, and more.

Follow Raising Health wherever you get your podcasts.

Now please join me and Jimi Olaghere on The Long Run.

 

30
May
2024

Recognizing 11 Asian-American Executives Shaping the Future of Biopharmaceuticals

Dr. Jingyi Liu, clinical fellow in medicine, Brigham & Women’s Hospital

As we celebrate the end of AAPI Heritage Month, we acknowledge the vital role that Asian American and Pacific Islander professionals have made in the biopharmaceutical industry.

We are honored to present an update to our 2021 feature on 11 AAPI professionals shaping the future of biopharma, again selected for their commitment to solving health problems, integrity in leadership, and dedication to patients and future innovators.

Eric Dai, investor, Dimension

Recent data from the MassBio 2023 DEI Report highlights progress since our last feature, with the percentage of Asian-identifying board directors rising from 13% in 2021 to 16% in 2023. However, biopharma professionals identifying as Asian remain significantly under-represented when it comes to positions of leadership, representing 23% of the biopharma workforce, but only 15% of executive leadership. 

This year, we asked honorees to share a personal note to the question “why is AAPI representation in biopharma important to you?”, a few of their responses can be found below. Join us in honoring these exceptional individuals, recognizing their commitment to equitable healthcare for all and advocacy for a more inclusive biopharmaceutical sector.

Rod Wong, managing partner and chief investment officer, RTW Investments

Rod Wong, managing partner, chief investment officer, RTW Investments

Rod manages the firm’s investments focused on innovative drug development. Investments include Rocket Pharmaceuticals, Immunocore Holdings, and Mirati Therapeutics (acquired by Bristol Myers Squibb for $5.8 billion in January). 

Why is AAPI representation in biopharma important to you?

When I was young, I saw many Asian Americans in science, but extraordinarily few in leadership positions. I’m inspired and grateful to those who have helped reduce barriers, and also see it as a reminder of our responsibility to ensure progress continues to be made for those who follow.”

Arthur Kuan, CEO, CG Oncology

Arthur Kuan, CEO, CG Oncology

Arthur serves as Chairman & CEO of Irvine, Calif.-based CG Oncology. Arthur lost his father to cancer, a loss which inspired him to take bold steps in advancing oncolytic immunotherapies. The company’s lead program is for non-muscle invasive bladder cancer. 

At Moffitt Cancer Center, Arthur serves on the IP Commercialization Strategy Committee. Arthur is a Founding Member of Ally Bridge Group, a global healthcare-focused investment platform, and played an active role in managing the fund’s portfolio companies.

He led CG Oncology through a $437 million IPO in January.

Gaurav Shah, CEO, Rocket Pharmaceuticals

Gaurav Shah is the co-founder and CEO of Cranbury, NJ-based Rocket Pharma, a developer of gene therapies. He previously worked as a Global Program Head in the Cell & Gene Therapies Unit at Novartis, where he had strategic oversight of 12 functions and helped spearhead pivotal trials with CART-19 for patients with leukemia and lymphoma.

Rocket’s marnetegragene autotemcel (Kresladi) for Leukocyte Adhesion Deficiency-1 (LAD-1) is under review by the FDA with a PDUFA date of June 30, 2024. Another program for Fanconi Anemia is under review by European regulators.

Najat Khan, Chief R&D and Chief Commercial Officer, Recursion Pharma

Najat Khan is chief R&D officer and chief commercial officer at Salt Lake City-based Recursion, a leader in applying machine learning and other technologies to drug discovery. She leads Recursion’s research and development, oversees its emerging commercial capabilities, and serves on Recursion’s Board of Directors.

Najat Khan, chief R&D officer, chief commercial officer, Recursion

She previously was the chief data science officer and global head of strategy and portfolio organization for innovative medicine R&D at Johnson & Johnson.

Why is AAPI representation in biopharma important to you?

Representation matters in building trust and engaging diverse patient populations. Having AAPI professionals in leadership and research roles ensures that the health needs of the AAPI community are addressed. For example, this ensures diversity in clinical trials, so our medicines are developed in representative populations, leading to more effective and safer therapies for everyone. Moreover, representation shifts traditional mindsets, fostering sustained change and evolving society toward a more inclusive culture.”

Ying Huang, CEO, Legend Biotech

Ying Huang, CEO, Legend Biotech

Ying Huang is the CEO of Somerset, NJ-based Legend Biotech, the developer of cilta-cel (Carvykti), the BCMA-directed T-cell therapy for multiple myeloma.

Why is AAPI representation in biopharma important to you?

I have encountered numerous Asian American colleagues working in the biopharma industry. Their roles range from R&D, clinical development, manufacturing, regulatory affairs, sales & marketing, and management. However, I can tell from firsthand experience that there are far fewer AAPI folks in leadership roles than in R&D. We call it the “bamboo ceiling”.

Part of that may be rooted in the Asian culture in which we were encouraged to pursue a professional career such as science, engineering, or medicine by our parents. Part of that was from the stereotypic perception that AAPI are not outgoing and good at just following instructions. I feel strongly about AAPI representation in the industry as I see many outstanding AAPI leaders who have demonstrated capability of leading companies big and small. They may come with strong science and technical background, but they can also lead a franchise or a company with business acumen and people skills. We must encourage the next generation AAPI biopharma leaders to be the spokespersons and role models.” 

Jingrong Jean Cui, scientific founder, president and CEO, BlossomHill Therapeutics

Jean Cui, founder and CEO, BlossomHill Therapeutics

Jean Cui is the scientific founder and CEO of San Diego-based BlossomHill Therapeutics, the developer of small molecules for cancer and autoimmune disease that raised $100 million Series B financing in February. She is the lead inventor of three FDA approved medicines — crizotinib (Xalkori), lorlatinib (Lobrena) and repotrectinib (Augtyro).

Prior to BlossomHill, she was the scientific founder of San Diego-based Turning Point Therapeutics. That company was acquired by Bristol Myers Squibb in June 2022 for $4.1 billion

Alice Zhang, co-founder and CEO, Verge Genomics

Alice Zhang, co-founder and CEO, Verge Genomics

Alice Zhang is the co-founder and CEO of South San Francisco-based Verge Genomics. Verge uses artificial intelligence to develop drugs diseases like ALS, Parkinson’s disease, and Alzheimer’s disease. She discussed the company’s platform and strategy on The Long Run podcast in April 2018 and co-wrote a guest editorial on TR in Feb. 2023 about how drug discovery needs to first generate more and better data before it can fully take advantage of the latest advancements in artificial intelligence.

Why is AAPI representation in biopharma important to you?

AAPI representation is important to highlight the critical contributions that immigrants and children of immigrants have made to creating the thriving innovation economy we have today.”

Mathai Mammen, president, CEO and chairman, FogPharma

Mathai Mammen, chairman, president and CEO, FogPharma

Mathai Mammen is CEO, President and Chairman at FogPharma, a clinical-stage biopharmaceutical company based in Cambridge, Mass., that is dedicated to creating medicines that deliver potentially life-changing impact for people and patients. Before joining Fog Pharma in June 2023, Mathai was a member of the executive committee at Johnson & Johnson, where he served as executive vice president of pharmaceuticals, R&D. Under Mathai’s leadership, Janssen R&D executed 40+ acquisitions and licenses and 350+ strategic partnerships and collaborations. A key component of his strategy was data science, which he sought to apply to every aspect of discovering and developing medicines. Mathai led his team to global approvals of eight new medicines, including Tremfya, Darzalex Faspro, Balversa, Carvykti, Rybrevant, Ponvory, Spravato and Tecvayli.

Why is AAPI representation in biopharma important to you?

I fundamentally believe that the success of a group or team rests on our differences as individuals. Its impacts also reach far beyond the walls of any one company: Inclusive representation in drug development is essential if we are to develop medicines that can address the diverse healthcare needs of our global community.”

Seemay Chou, Founder and CEO, Arcadia Science

Seemay Chou is the co-founder and CEO of Arcadia Science, a science company and start-up incubator focused on leveraging a more diverse set of research organisms for scientific innovations.

Prior to founding Arcadia Science, Seemay served as an Assistant Professor of Biochemistry and Biophysics at UCSF and Faculty Investigator at Chan Zuckerberg Biohub, where she made contributions to understanding of microbial interactions and host-pathogen dynamics.

Brinda Balakrishnan, EVP, chief corporate strategy and business development officer, Biomarin

Brinda Balakrishnan, EVP, chief corporate strategy and business development officer, Biomarin

Brinda Balakrishnan is the chief corporate strategy and business development Officer at Biomarin, with responsibility for the company’s corporate strategy, competitive intelligence, business development, alliance management organizations. She joined the company in early 2016.

Aradhana Sarin, group CFO and executive director, AstraZeneca

Aradhana Sarin is currently executive director and chief financial officer at AstraZeneca. She previously served as chief financial officer at Alexion, and prior to that served as chief business and strategy officer.

29
May
2024

On The Bright Side: Better Medicines, Shared Purpose, Good Listens

David Shaywitz

While visiting my parents on Memorial Day weekend, I reflected on the wonder and joy of a life in medicine and science — theirs as well as mine. 

Incredible Progress in Medicine

My parents are academic physician-scientists at Yale Medical School, where they founded and continue to lead the Yale Center for Dyslexia and Creativity. Now in their early 80s, they are as active and engaged as ever, reading the literature, leading a research team, and giving talks. Just a year or so ago, their Coursera course, “Overcoming Dyslexia” went live, and has now enrolled over 40,000 learners.

David, Sally and Bennett Shaywitz

On the morning of Memorial Day, my dad and I, both early risers, were sipping coffees at the kitchen table when he began to reflect on how much medicine has changed over the course of his career in pediatric neurology.

He described clinical neurology before contemporary neuroimaging like CT and MRI scans.  Before their arrival, my dad said, neurologists had few tools beyond the classic neurological exam, an approach that is elegant, even charming in theory, but historically has been largely unfalsifiable in practice.  This changed, he said, when noninvasive neuroimaging arrived and gradually revealed the limitations and often specious conclusions of the beloved physical exam. 

Procedures were different as well. In the days before advanced noninvasive imaging, I was told, children with meningitis often received a subdural tap, meaning a needle was stuck into the skull to remove a potential effusion (fluid buildup). With the advent of CT imaging, neurologists quickly learned that effusions were common in these patients and would typically resolve on their own.  Bacterial meningitis itself has become far less common than it was decades ago, due to the introduction of vaccines that protect against the most common causes

My mom, who soon joined us at the table, reminded me that imaging also impacted other medical specialties, including obstetrics. When she was pregnant with twins, I learned, doctors struggled to make this determination; a plain X-ray film (with its associated radiation exposure) was ultimately required to be certain. Obstetrics was considerably riskier than today, and pediatricians (particularly pediatric neurologists) would often see infants with injuries from difficult deliveries.

It was also common, my mom recalled, for pediatricians to encounter children who suffered from viral conditions now preventable with vaccines. She saw many kids who were born deaf following maternal infection with rubella. There were also a number of children each year who she saw die from measles. In addition, it was not unusual to encounter adults (including my mom’s best friend) who were crippled because of a polio infection in childhood.

My parents also recall frequently seeing young patients with lead poisoning. Sometimes children would come in with seizures, or occasionally in a coma, because of lead-induced encephalopathy. Often, this happened when small children would pick up and eat bits of lead-containing paint. Since the late 1970s, when the manufacture of lead-based paint was banned and awareness of the health risks rose, fewer kids now suffer these symptoms.

(I would be remiss not to point out that our ability to identify and effectively support children and adults with dyslexia is also far better than it was years ago, reflecting the work of researchers like my parents and others.)

The progress my parents have seen across their careers – largely attributable to improved imaging technology, the development of highly effective vaccines, and impactful public health measures likes universal childhood vaccinations and the mandated removal of lead — is extraordinary. The capabilities we have today to diagnose and treat illness are so much more powerful than when they started.  To me, this reinforces why, if asked the question “If you could pick any time to live, when would you choose?” the response must be today — unless tomorrow is an option. 

Things are getting better – as neuroscientist Steven Pinker, among others, reminds us.

To be sure, while improved technology and medicines offer the possibility of better health, this promise will only be realized through access, and this remains a profound concern. A recent Wall Street Journal headline announced, “Cancer is Capsizing Americans’ Finances,” while a recent South Park lampooned the byzantine process required in the U.S. healthcare system to access GLP-1 medicines for diabetes and weight loss. 

Our challenge here is finding a way to address the urgent need to ensure access to the best care available today while simultaneously continuing to incentivize the development of even better diagnostics and therapeutics (including those like vaccines aimed at preventing rather than treating disease) for future generations.

Craig Garthwaite, professor of strategy, Northwestern University’s Kellogg School of Management

As Craig Garthwaite, a health economist at Northwestern University, nicely frames it, the need for better treatments can be seen as another category of access challenge. 

“I’ve lost close family members to cancer that didn’t yet have treatments available,” he writes. “The hardest part for them wasn’t affording it. A lack of innovation is the access problem we often overlook because it isn’t as salient — but it is a far larger barrier than price (emphasis added).”

Today, no one can access desperately needed transformative medicines for conditions like glioblastoma, pancreatic cancer, and Alzheimer’s Disease; they haven’t been invented yet.

Diversity of Global Science

While home, I also came across mementos I saved from lab experiences over the years. One example: a 24-well plate signed and gifted to me nearly four decades ago by a colleague (now a professor at UCSF) in tribute to the weeks we spent one summer in the Janeway lab at Yale doing an assay using these plates over and over (and over).

Reflecting on my experiences in science, both in academia and industry, I was struck by the incredible diversity of people I’ve worked with, reflecting so many different paths and life experiences and even politics. 

For instance, while most researchers tend to shade to the left, I vividly remember a phenomenal technician from the Janeway lab who proudly wore a belt buckle proclaiming “God, Guns, and Guts Made America Great.” I also recall a postdoc from my PhD lab who was emphatically pro-life, and who has gone on to a highly successful career in science, now leading drug discovery at a prominent AI company.

Science is intrinsically international. Difficult and compelling problems attract passionate researchers from across the world. An incredible privilege of a life in and around science is how second nature it becomes to collaborate with colleagues from everywhere. 

In college, I learned molecular biology next to brilliant colleagues who had grown up in places like India and Iran and are now accomplished biomedical scientists and entrepreneurs. In the labs I’ve worked in, it was routine to see a postdoc from South America next to a postdoc from Eastern Europe next to a graduate student from Michigan. 

Scientists at the companies where I’ve worked also came from around the globe; in my last role, at a company headquartered in Japan, the Chief Data and Technology Officer hailed (very, very proudly) from Ireland; innovation in pharmaceutical sciences was driven by a brilliant colleague from Austria; and the physician-scientist leading the gastroenterology, immunology, and inflammation therapeutic area had emigrated from Nigeria when he was eighteen.

Diversity in science includes religion as well. 

In the Tonegawa lab, at MIT, a Mormon graduate student helped me better understand the purpose and fulfillment of missions. At Takeda, a talented epidemiologist and officemate shared his experience fasting for Ramadan, and the joy of Eid al-Fitr as the month-long observance concludes.

That’s not to say, of course, that science is as representative as it needs to be if it is to truly capture the full potential of the most capable minds in the world. In my last role, an exceptionally effective African-American vice president and science technology leader would poignantly lament how few African-American colleagues there were at senior levels in the organization, a disparity he worked passionately to address.

Compared to the perfect state, science clearly has a distance to go. 

But there is so much about the community of science that is encouraging, including its ability to attract global talent with diverse viewpoints to pursue collaboratively the shared goal of better understanding nature, and if we’re lucky, translating this understanding into more effective treatments for patients wherever they live, and whatever their politics and beliefs.

Good Listens

My drive from Massachusetts to Connecticut also afforded me the opportunity to catch up on some podcasts; here are a few episodes that might be of interest.

  • Acquired episode, discussing Microsoft’s early days. Fun fact: Windows was Plan B. 
  • WSJ – The Future of Everything episode featuring the always interesting “Science of Success” columnist Ben Cohen discussing how Birkenstock’s became such a big deal.
  • Invest Like The Best episode, discussing how Mitch Rales built Danaher into the life science tools colossus it is today.
  • Running Through Walls episode – Venrock’s Bob Kocher sits down with Mark McKenna, the former CEO of Prometheus, which was acquired last year by Merck for $10.8B.
  • Honestly podcast: for readers looking for a fresh perspective on journalism-related topics, two recent episodes may be of interest:
    • Here, host (and former New York Times reporter) Bari Weiss interviews (former) NPR senior reporter Uri Berliner about how the media business is changing;
    • Here, Weiss interviews (former) New York Times reporter Nellie Bowles about Bowles’s recently published Morning After the Revolution – one of my favorite recent reads.
26
May
2024

The Tao of Drucker: Lessons For Drug Developers from GLP-1

David Shaywitz

The two broad categories of medical discovery that command the most attention are insights resulting from rare, informative genetic conditions (see here) and advances resulting from fortuitous observations.  

A canonical example of the value of extreme genetic phenotypes is the patient with familial hypercholesterolemia who inspired Brown and Goldstein’s scientific pursuit of cholesterol metabolism and led to the statins. Similarly, Vertex’s promising pain medicine was directly inspired by rare genetic conditions associated with pain hypersensitivity and hyposensitivity.   

Meanwhile, as we’ve discussed frequently in this column, many medicines, particularly in neuroscience, have been discovered by “happy accidents” – tricyclic antidepressants are one example.

Decades of Painstaking Science

But GLP-1 medicines like semaglutide (Wegovy) and tirzepatide (Zepbound) do not fall into either of these categories. Their development reflects decades of meticulous biology and physiology, of researchers working slowly and painstakingly through the complicated science.

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

As pioneering researcher Daniel Drucker and colleagues wrote in a comprehensive review in 2017, “the field was built slowly with a series of non flashy yet solid studies examining the physiology, pharmacology, and pleiotropic actions of native GLP-1 and multiple GLP-1R agonists.”

Drucker notes that most papers in the GLP-1 field (at least until recently, one imagines) “were published in traditional physiology or endocrinology subspecialty journals and might be described as ‘descriptive’ or ‘incremental’ by many colleagues.”

His summary:

“Taken together, the story of discovery and characterization of the GLP’s highlights how old-fashioned biochemistry, physiology, molecular biology, and traditional analyses of hormone action provides a firm scientific foundation for the development of multiple novel therapeutics for the treatment of obesity, diabetes, and intestinal disorders.”

To put a finer point on it: genetics were not a key component of the GLP-1 story.  Drucker explicitly pointed this out in his interview with Eric Topol (discussed in previous column), noting that physiologically, removal of GLP-1 or GLP-1 receptor doesn’t seem to have profound consequences. In contrast, molecules identified through genetic analysis, like leptin, have not proven to be of great therapeutic utility.

Similarly, the potential of GLP-1 medicines to cause weight loss was also not a happy accident – rather, it was seen from some of the earliest rodent studies of GLP-1, and a key thesis of the Novo GLP-1 program from the earliest days. 

Key Enablers and Challenges

There were some lucky breaks, to be sure. 

For one, as discussed in my last column, the adverse effects associated with GLP-1 initiation – nausea and vomiting in particular – generally wane over time, while the therapeutic effect (suppression of appetite) endures. 

The biology could easily have gone the opposite way. 

Also helpful: encouraging results from large cardiovascular outcome studies for long-acting GLP-1 medicines used for the treatment of diabetes (high-risk patients were found to have a significantly lower rate of adverse cardiovascular events – here, here). 

These results, together with a decade of reassuring experience using GLP-1. The first, exenatide (Byetta), was approved by the FDA for use in diabetes in 2005. That molecule, originally a twice-daily injection and then formulated into a LAR version allowing once-weekly injection, helped provide confidence in the safety of this class.

Weight loss was consistently observed in patients with type 2 diabetes. The clean safety profile over time, combined with the long-term cardiovascular benefit, helped encourage companies to take a shot at a much larger patient population – people who are overweight or obese but don’t have diabetes.

Drucker acknowledges that translation of promising GLP-1 science into approved therapeutics was a particularly challenging task that required decades. 

He cites several hurdles, including:

  • Need for a longer-acting peptide (endogenous GLP-1 has an incredibly short half-life in the blood – only about two minutes); legendary Novo researcher Lotte Bjerre Knudsen famously spent years focused on figuring out how to create a longer-lasting therapeutic version this before finally developing a solution that become liraglutide (Victoza), a once-daily injection.
  • Need to figure out dosing to address GI side effects; Drucker points out that in every clinical study, GLP-1 medicines cause GI discomfort including nausea and vomiting; eventually, Drucker says, researchers recognized that these side effects can be significantly mitigated through slow titration.
  • Need for better assay reagents to detect levels of key molecules like GLP-1, GLP-2, and their receptors. Some large pharmas have analytic lab groups specifically focused on developing such tests for R&D; I recall a particularly capable team at Merck Research Labs in Rahway, NJ when I was there nearly 20 years ago.

New diabetes medicines – as well as potential obesity medicines – also require large cardiovascular outcome trials, to prove that the benefit delivered by these medicines outweigh any risk.

These concerns were motivated on the diabetes side by the experience of GSK’s rosiglitazone (Avandia), an insulin sensitizer which seemed to have a positive effect on diabetes parameters but, unexpectedly, a negative effect on cardiovascular outcomes. The high-profile safety controversy led the FDA to mandate cardiovascular outcome trials for future diabetes medicines – a move that added considerable time and cost to type 2 diabetes R&D programs. 

Obesity medicines have long concerned regulators both because of the perception that they might be widely utilized as so-called lifestyle medicines, and more specifically because of the experience with the combined use of two drugs individually approved by the FDA, fenfluramine and phentermine. Used together (“fen-phen”), the combo caused some patients to develop valvular heart disease and pulmonary hypertension.

The key point here is that in many ways, GLP-1 drugs were ideally suited for large pharmas, given the time, resources, and range of expertise required to address all of these drug development challenges. 

Lessons for Drug Developers

I asked Drucker what he saw as the key lessons for drug development. He cited three.

  • “We should embrace multiple lines of evidence, and not just pursue human genetics-based leads”
  • “Nice to use human genetics to screen out for worrisome oppositional signals or for supportive directional biology but not exclusively as a must-have criteria (or we would not have SGLT2i in heart and kidney disease, or GLP-1RAs etc)”
  • “The solid reproducible non-flashy tortoise (careful papers in solid mid-tier journals) often beats the spectacular Nature/Science/Cell

There may be an addition lesson as well.

In reviewing Drucker’s many publications, I was struck by the insight and brilliance that seemed to be required to drive the science in this complicated area. Yet when I put this to Drucker, he suggested instead that the most important attributes he’s brought to the field were his tendency to be “careful, persistent, and tenacious.” 

I suspect these characteristics apply to the vast majority of successful drug developers.

We’re often attracted to the idea of science and drug development advancing through a series of brilliant ideas, eureka moments, and incandescent insights. Without question, narratives with these features make compelling stories.

Yet in the case of the GLP-1s, a category of medicine that is poised to transform everything in our world, these blockbuster medicines seem to have resulted from something quite different: decades of slow, determined science, both on the part of academics like Drucker, and companies like Novo and Lilly, patiently and deliberately nudging the work relentlessly forward.

Prediction is Hard

Finally, just to emphasize how difficult the future is to predict in medicine and science, even by the most informed experts, I feel obliged to call out a particularly revealing sentence from Drucker’s 2017 review.

Drucker writes, “market penetration for many GLP-1R agonists remains disappointing, raising questions about the potential clinical appeal, expense, and commercial success of newer formulations.” 

In other words, as recently as 2017 — twelve years after the first FDA-approved GLP-1 medicine, exenatide (Byetta) for diabetes, and three years after the approval of liraglutide for obesity (marketed as Saxenda), after previous approval for diabetes (as Victoza) — it was clearly not a foregone conclusion that GLP-1 molecules were tracking to be the blockbuster obesity drugs they are today.

Michael Moritz

As legendary Sequoia VC Michael Moritz said (and as I recently discussed here), even great successes aren’t obvious early on: “I have never been involved in an investment that became a very successful business without fearing earlier that the business was going to fail, not even once.”

The problem, as Judah Folkman observed, is that to succeed, you have to proceed with conviction, but you don’t know until the end (in the case of the GLP-1 drugs, the randomized controlled trials demonstrating profound weight loss) whether you’re persistent or obstinate.

So where does this leave R&D leaders? 

One thought: we should be humbled by the challenges of forecasting, cognizant of the limitations of genetics (useful as it often can be) or of any single approach to drug discovery, inspired by accomplishments of determined academic researchers and pharmaceutical scientists, awed by the intriguing complexity of human biology, and deeply grateful for our collective opportunity, as contemporary drug developers with an unprecedented set of tools and capabilities, to fashion transformative new medicines for patients. 

20
May
2024

SynBio and AI for Discovery: David Younger and Randolph Lopez on The Long Run

Today’s guests on The Long Run are the co-founders of Seattle-based A-Alpha Bio — David Younger and Randolph Lopez.

David Younger, co-founder and CEO, A-Alpha Bio

David is the CEO and Randolph is the chief technology officer.

The company was founded in 2017 as a spinout from the University of Washington’s Institute for Protein Design. The company has built a platform for doing high-volume synthetic biology to make protein constructs that are the basis for evaluating protein-protein interactions at scale. Those interactions are then analyzed with machine learning to identify drug candidates with certain optimal characteristics – for instance, the ability to bind with a certain epitope with high affinity.

A-Alpha has sought to apply the work to its own drug candidates, and on projects with partners. Gilead Sciences has sought help with identifying long-acting biologic therapies for HIV. A-Alpha has also announced partnerships with Amgen, Bristol Myers Squibb and Kymera Therapeutics to develop molecular glue therapies.

Randolph Lopez, co-founder and chief technology officer, A-Alpha Bio

In this conversation, we spoke about the technology idea, but also how David and Randolph met, how their skills meshed, and how they thought about starting and sequentially building the company as a couple of young scientific entrepreneurs who weren’t automatically on speed-dial with the top VC firms of Kendall Square and Sand Hill Road.

 

Before we get started,

I’m looking for a business representative. This person will be asked to sell group subscriptions to Timmerman Report, sell sponsorship packages to The Long Run podcast, and negotiate my speaking engagements. This position will pay a base salary plus commissions. The ideal candidate is someone seeking to grow their knowledge and network in the biotech industry. Interested? Email me at luke@timmermanreport.com

Now please join me and David Younger and Randolph Lopez on The Long Run.

20
May
2024

Timmerman Traverse Eclipses $10M for Cancer, Poverty, and Sickle Cell Disease

The Timmerman Traverse campaigns have now catalyzed the biotech community to give back more than $10 million to tackle cancer, poverty, and sickle cell disease.

It’s a moment to celebrate.

These biotech community drives have succeeded beyond my wildest dreams.

They’ve raised awareness, corralled funds, and stitched together a network of meaningful relationships.  

More than 120 people have become part of the alumni network since these campaigns began in 2017. Another 45 people are currently in training. 

These people have propelled the careers of young cancer researchers with bold ideas. They’ve supported programs to feed the hungry, shelter the homeless, and attracted a diverse new generation of biotech professionals. They’re pouring resources into a traditionally neglected disease – sickle cell disease.

Through all the mental, physical and emotional heavy lifting required in these campaigns, folks have formed deep and lasting friendships.

Some have started new companies. Spearheaded new initiatives. Opened doors for each other. They’ve discovered new sources of joy and fellowship. Many have become friends for life.

The best part? These Timmerman Traverse campaigns are still in the early days.

Thanks to all who have participated, donated, sponsored, and cheered. Special thanks to the staff at the main beneficiary organizations: Fred Hutchinson Cancer Center, Life Science Cares, Damon Runyon Cancer Research Foundation, and Sickle Forward. And to Eric Murphy and my partners at Alpine Ascents International.

Let’s all keep climbing higher.

Luke

13
May
2024

Here’s The Skinny on Four New GLP-1 Podcasts

David Shaywitz

GLP-1 medicines are obviously having a real moment – medically and culturally. 

These once-weekly injectables, which reduce appetite and result in significant, long-lasting (so long as you’re taking them…) weight loss, have been demonstrated to have a number of important health benefits beyond simply shedding pounds. 

In March, Novo Nordisk’s semaglutide (Wegovy) was approved by the FDA for its ability to reduce the risk of heart attack, stroke, and death from cardiovascular disease in patients who are obese or overweight.  

This new wave of effective weight loss drugs has elevated the pharma companies that make them, Novo Nordisk and Eli Lilly. Novo Nordisk reported $1.3 billion in Wegovy sales in the first quarter of 2024 – about double the amount from the same period a year earlier. Eli Lilly’s rival GLP-1 and GIP receptor agonist, tirzepatide (Zepbound), recorded an extraordinary $517 million in US sales in the first quarter of 2024, in the first full quarter after being approved by the FDA in November.

The progress and momentum has also generated significant interest from other pharmas suddenly seeking to enter a therapeutic area that they have long been avoiding.

The availability of an apparently safe category of medicines that address a key societal preoccupation – obesity – has reverberations that have been felt everywhere from the Oscars to the diet industry – and, potentially, many other sectors of the economy.

Many companies focused on weight management, for example, have decided that instead of competing directly with GLP-1 medicines, it makes more sense to incorporate these medicines into their offerings (eg Weight Watchers) or to position themselves as an off-ramp (Virta).   

On a personal level, I appreciate their motivation. After significant success on Virta (discussed here, here), I’ve found it increasingly difficult to sustain (a common experience, it seems). As my weight, sadly, starts to creep back up despite regular exercise, I find myself actively contemplating a switch to GLP-1s, especially as I encounter more and more physician colleagues experiencing success with these powerful medicines.

Keeping up with the GLP-1 story can be difficult; fortunately, several recently-released podcasts, each with a slightly different focus, can help get you up to speed quickly – ideally while you’re exercising.

Ground Truths: Eric Topol interviews Daniel Drucker

Let’s start with the science. Here, the one person you’d most want to speak with is endocrinologist and physician-scientist Daniel Drucker, who has spent his career focused on incretins – molecules such as GIP-1 (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) that potentiate the secretion of insulin after meals.

Eric Topol (left) and Daniel Drucker (right) on the Ground Truths podcast.

His website, glucagon.com, has for years served as a central repository of information in this field, including the many foundational studies and integrative reviews authored by Drucker and his colleagues.

In the latest episode of famed cardiologist Eric Topol’s invariably interesting podcast Ground Truths, he asks Drucker key questions about the underlying science.  What I found particularly striking was how much is still unknown.  (This seems like another example of a phenomenon I’ve frequently encountered, where real experts are comfortable enough to recognize and acknowledge the vast extent of our collective ignorance; in contrast, many with a more tenuous grasp of the material tend to present it with more certitude and bluster.)

The entire, relatively short (36-minute) podcast is an obvious must for anyone interested in a data-driven, grounded, sophisticated perspective on GLP-1s, but several points of particular relevance for readers of TR and this column include:

  • Subtle biology of GLP-1: Drucker say, “if we take GLP-1 away or we take the receptor away, you don’t really develop diabetes without GLP-1. You don’t really gain a lot of weight without GLP-1. So physiologically it’s not that important.”  In other words, for all our interest in leveraging genetics to find new drugs, GLP-1 is an example of how this approach can be limiting – the pharmacological effects of GLP-1 might not have been predicted by extrapolating from observed physiology and pathophysiology.  Moreover, Drucker notes, molecules that were associated with more informative genetics, like leptin, have not translated thus far into broadly effective medicines for the treatment of obesity.
  • GLP-1 seems to “talk to the brain,” but indirectly; the mechanism seems unclear:  Drucker explains that GLP-1 “doesn’t directly get into the brain to a meaningful extent,” and how it communicates with the brain is “is not well understood … in the magic that we see.”  Given the impact of GLP-1 on appetite control, this seems like a glaring gap in understanding – or rather, an important opportunity for future study.
  • Role of serendipity: GLP-1 medicines emerged from decades of meticulous research (including foundational and continuing work by Drucker).  In other words, the discovery of GLP-1 and the elucidation of their biological and pharmacological effects weren’t simply a happy accident.  But what was unbelievably lucky, it seems, is that the medicines work as well as they do with an apparent paucity of serious side effects.  Drucker notes that while there are some side effects when patients start taking GLP-1 medicines, these tend to dissipate, while the positive effects on appetite suppression persist. (The most common side effects are nausea, vomiting, and diarrhea).
Acquired: Novo Nordisk

The Acquired podcast – recently described by the Wall Street Journal as what “the smartest people in the room are all listening to” – is a monthly, in-depth discussion of a leading company, hosted by former-VCs Ben Gilbert and David Rosenthal

In January, Gilbert and Rosenthal took on their first life science company, Novo Nordisk, reviewing its fascinating history, and contextualizing its strategy in the context of other businesses.  Listening to two smart, enthusiastic business analysts, who aren’t pharma insiders, wrap their heads around the complexities of healthcare and drug development was engaging and illuminating. The episode, as usual for Acquired, is long (this one runs over three and half hours!) but captivating and worth your time.

Key points for TR readers:

  • Importance of a champion: Drug development requires champions (see here, here, here).  In this case, the champion is Novo Nordisk’s Lotte Bjerre Knudsen, who led the effort to develop a long-acting GLP-1, and then to guide it towards obesity.  The magnitude of this achievement is especially remarkable since the CEO at the time, Lars Rebien Sorensen, was initially skeptical about developing GLP-1 for obesity.  “Obesity is primarily a social and cultural problem,” he once said. “It should be solved by means of a radical restructuring of society. There is no business for Novo Nordisk in that area.”

    Lotte Bjerre Knudsen

  • Focus on obesity from the beginning (this is actually from ACQ2, a second podcast hosted by Gilbert and Rosenthal, in an episode focused on Knudsen): “The target market was also obesity from the beginning,” Knudsen says about GLP-1 molecules, pushing back on idea that they somehow stumbled into obesity.  “We did have a strategic intent to go after obesity early on.
  • Recognition of the risk of drug development: Perhaps my favorite part of the episode was when Gilbert and Rosenthal discuss the remarkable challenges and exceptional risks of drug development, in the context of other businesses.  Their recognition and articulation of the difficulty and urgency of coming up with new medicines represents a level of insight that seems to have eluded many others.

As strong as this episode is, the hosts may overstate their case when they suggest Novo’s exceptional business performance may be attributable to their concentration in, and singular focus on diabetes and metabolism. While Novo’s deep experience in diabetes and metabolism unquestionably facilitated their development of GLP-1 medicines, they are also incredibly lucky that these medicines turned out to be such a breakout hit, and not (as discussed above) saddled with all sorts of side-effects or other challenges. 

Concentrating efforts in any one area is like putting all your chips on a particular Roulette number – if you’re lucky, you can win big, but if not (for example, if you went all-in on Alzheimer’s Disease, an incredibly urgent medical need that hasn’t yet seen great therapeutic success), you might fare poorly. 

If you are going to bet big, however, it makes sense to do it in an area where you are expert, and can both choose as wisely as possible, and also be prepared to take advantage of a win if you get one. Gilead’s acquisition of Pharmasset for $11.4B in 2011 – derided by many analysts at the time, just before they started applauding Gilead’s subsequent success in curing hepatitis C – seems like a similar example.

Honestly: Bari Weiss interviews Johann Hari

Bari Weiss and the Honestly podcast offer independent-minded takes on a range of issues, including topics related to health. Here, she interviews author Johann Hari about his latest book, Magic Pill (I discussed his previous effort, Stolen Focus, for TR readers here).

Hari’s new work features reporting on GLP-1 medicines including in particular their social context, a perspective he succinctly summarizes in a recent New York Times op-ed.

It was especially interesting to listen to Hari’s distillation after hearing Drucker’s, because Drucker’s presentation emphasized the limitations of science and the many areas of ambiguity and uncertainty, while Hari offered a tidy narrative that at times felt scientifically dubious.

Key highlights for TR readers:

  • View that the American diet is responsible for altered satiety setpoint:  Hari tells us about a neuroscientist, Paul Kenny, who early in his career was struck by the differences between the United States and his native Ireland, and his sense that American food was affecting his mind as well as his body.  Kenney later discovered that rats who were raised on a normal diet and then offered American food “went crazy for the American diet…within a couple of days, they were different animals. And they very rapidly all became obese.”
  • Examples of healthier food in other countries like Japan, where the obesity rate is 4%, compared to a rate of 42% in the United States:  Hari describes visiting a “typical” school in Japan, and discovering processed food is banned, kids are served “unbelievably healthy” freshly-prepared meals, and children express preferences for healthy vegetables like broccoli.  (Like Hari, I found this unimaginable, and wasn’t surprised to hear his first thought was that he was being trolled by the kids; he wasn’t.)
  • Examples of approaches to obesity management in the work setting that seem unimaginably over the top.  Hari tells us about a law in Japan mandating that “every company in Japan has to weigh its entire staff on a particular day. And if your weight has gone up, you have to make a plan with your employer to bring it down. And if as a company overall your staff’s weight has gone up, you are fined by the government.”
The Journal: Trillion Dollar Shot

One of my favorite podcasts is The Journal, co-produced by Gimlet and the Wall Street Journal.  Most days, they look in depth at a topic in the news, but occasionally they put together a series taking an even deeper look at an important topic, seeking and sharing multiple perspectives across several episodes. I recent highlighted another Journal series (With Great Power) that focused on the birth of Marvel studios.

The current series (as of this writing only the first episode has dropped) promises an examination of GLP-1 medicines – how they were developed, and the effects they are having on “bodies, fortunes, and industries.”

Key highlights for TR readers:

  • A recurrent theme of innovation has been the need for persistence and conviction, along with the uncomfortable fact that, as Judah Folkman said, “If your idea succeeds, everybody says you’re persistent. If it doesn’t, you’re obstinate.”  The problem is you can’t figure out until later the category in which you belong. It’s clear from this podcast that Lotte Bjerre Knudsen, the champion we met earlier, was persistent. The former CEO of Novo, Lars Rebien Sorensen, describes Knudsen as “a person that’s very, very difficult to say ‘No’ to,” someone whose team succeeded “because of their stubbornness and their skills and their professionalism.”
  • Industry view of obesity drugs: Sorensen also highlights the initial concerns of pursuing GLP-1 medicines for obesity, noting that “at the time, almost all without exception, weight-lowering drugs had failed, some even so badly that companies were sued. So I knew that if we started talking too much about the obesity effect of GLP-1, we might taint a very good diabetes drug.” (As noted earlier, Sorensen also viewed obesity as a social rather than a medical challenge.)

    Dr. Fatima Cody Stanford, obesity medicine expert, MGH

  • Unexpected high discontinuation rate: Perhaps the most striking fact I learned from all of these podcasts was the exceptionally high discontinuation rate from GLP-1 medicines.  The Acquired podcast that noted “one out of six patients have side effects that are so severe that they discontinue the drug,” and “as many as 68% of people roll off it after a year.” This is especially surprising since most of the weight lost due to GLP-1 medicines returns if the drug is discontinued. The Journal podcast offered the most compelling insight into the potential reasons for the high rate of discontinuations; one of the journalists reporting the story actually stopped taking the medicine himself although it seemed to be working well for him.  The key reasons for discontinuation seem to be (a) cost (a huge factor and the reason the reporter stopped); (b) side effects; (c) the inconvenience of needing to hunt for supplies of a medicine where manufacturing can’t keep with the demand. Dr. Fatima Cody Stanford, of the MGH Weight Center, tells me that the most significant issue in her experience has been serious ongoing challenges with the supply.

Collectively, these podcasts offer different but overlapping perspectives on GLP-1 medicines, and provide insight into the history, science, and strategy around these medicines. They also remind us of the complex interplay between transformative medicines and broader society, and the need for life science companies to engage with it – ideally with authentic curiosity, humility, and empathy.

8
May
2024

Enduring Uncertainty, Hoping for Luck, Touched by Magic

David Shaywitz

A main theme of this column – perhaps even the dominant theme – is how to operate in a power-law domain like drug development where there are few, outsized successes, where most efforts end in failure, and where it’s incredibly difficult to predict in advance how you are likely to fare.

Earlier this week, I discussed the parallels between film and drug development, highlighting how messy and unpredictable the road to success can be as highlighted by the Marvel Cinematic Universe (MCU) in cinema, and Keytruda and Velcade in pharma. 

My conclusion was that in both these domains, success is contingent, but not random; you need to be really lucky in order to succeed, but you can also make choices along the way both to increase your exposure to serendipity and to maximize the opportunity to benefit from it.

Despite, or more likely, because of the incredible uncertainty that inevitably underlies their decisions, many investors and founders tend to project a disproportionate degree of confidence regarding choices and paths that you know are extremely high risk.  It’s easy to confuse this projected conviction with actual knowledge, and to allow yourself to believe that these individuals must really know what they’re talking about. 

On the other hand, as we’ll see, the very uncertainty of success makes achieving it all the more special.

Several recent interviews help provide a sense of perspective here.

Scott Galloway: Luck, timing, and the cultivation of allies

NYU Professor Scott Galloway, co-host of the popular Pivot podcast with Kara Swisher, was recently asked about what distinguishes highly successful people from everyone else.  He replied that “something that plagues people, especially tech bros, is they conflate luck with talent,” adding “the most common attribute” of successful people is that “they were born at the right place and the right time… the majority of people’s success is not their fault.”

This, of course, aligns extremely well with a central theme of Malcolm Galdwell’s Outliers, discussed earlier this week, and reviewed here.  Gladwell emphasizes the importance of being born in the right time and place, pointing to examples like Microsoft co-founder Bill Gates, and Sun Microsystems’ co-founder Bill Joy, among others.

Timing is also an underappreciated factor in VC returns.  A recent piece from the StepStone Group described the “Vintage Year Power Law… the notion that a small number of vintage years within venture capital have historically produced most of the returns for the asset class.”  

Galloway also emphasized the value of soft skills like ensuring you “collect allies,” which increases the chances that you are “are constantly put in rooms of opportunities.”

Michael Moritz: Even great success not obvious early on

Legendary Sequoia investor and former journalist Michael Moritz, in a wide-ranging interview, was asked about the ability to discern early on whether a founder and a company are likely to make it big.

Michael Moritz

His candid response (emphasis added):

“When you invest in a company … you hope it will work, that the product will be enthusiastically received by customers, but you don’t know that in real time. I have never been involved in an investment that became a very successful business, without fearing earlier that the business was going to fail, not even once.”

The interviewer followed-up, “Not even when you worked with the founders of Google in their early days?”

Moritz replied:

“Not even then. The initial business model was very different from the business model we know today, and during the first eight months of the investment the company lost a huge amount of money and I was afraid we would run out of cash.”

This echoes my favorite adage from famed Harvard surgeon-scientist Judah Folkman, discussed earlier this week, and also in this 2017 piece about success narratives:  

“If your idea succeeds, everybody says you’re persistent. If it doesn’t, you’re obstinate.” 

The key point is you need conviction to achieve success, you need to move in a particular direction (former Pixar CEO Ed Catmull makes a similar point in Creativity, Inc).  But – and this is what’s so hard – it’s often impossible to figure out along the way whether you are brilliant or deluded.  As Moritz points out, even Google – today a $2 trillion (with a “t”) company – wasn’t obviously a success early on.

Sam Blackman’s Story

Sam Blackman, a physician-scientist, is a pediatric oncologist by training (you can hear about his origin story on this 2018 episode of Tech Tonics) who pivoted to drug development.

He’s now the co-founder and head of R&D of Day One Biopharmaceuticals, a developer of cancer drugs for children. In late April, their lead drug candidate, tovorafenib (Ojemda), was granted accelerated approval by the FDA for use in a type of pediatric brain tumor.

This story is worthy of our attention for several reasons.

Sam Blackman, MD, PhD; co-founder, head of R&D, Day One Biopharmaceuticals

First, there’s the drug’s convoluted path to approval: as summarized independently by Bruce Booth, Jacob Plieth, and Ron Leuty, the “molecule was discovered in a collaboration between Sunesis & Biogen that started 20 years ago” as Booth notes, then reverted to Sunesis after Biogen deprioritized oncology.  Takeda licensed it in 2011, and spent seven years developing it for multiple myeloma, without success. 

Day One licensed it from Takeda in 2020, targeting a specific condition for which it seemed especially well-suited. (See Timmerman Report from May 2020 on the origin story of Day One Biopharma, and this deep-dive interview from Aug. 2021 with Blackman and co-founder Julie Grant on The Long Run podcast.)

Last month, their years of effort culminated in the FDA granting accelerated approval. This medicine is the first of its kind approved for children with pediatric low-grade glioma. It has shown it can shrink tumors in more than half of patients. This means that many children with this terrifying diagnosis may be able to avoid high-dose chemotherapy and all its toxic side effects, and instead take this medicine as a bridge to a healthy adulthood, when these types of tumors tend to subside.

It’s a life-changing medicine.

Those basic facts make for a compelling story. But what this account fails to capture, is the tortuous emotional journey of drug development from the perspective of those doing the developing.  Here we are unusually fortunate, because Blackman – an expert story-teller and Moth veteran – has given us a treat.

In a 12-minute video shared on LinkedIn, Blackman walks us through the experience of developing this medicine.  Blackman captures, in the most effective way I’ve ever seen, the interior monologue of drug development – the feeling of confronting tremendously long odds, the persistent hopes, the crushing disappointments, and all at a very personal and relatable level. 

It’s essential viewing for anyone curious why we in life science do what we do, and an expression of what, at our best and most fortunate, we can achieve.

While the video absolutely must be watched in its entirety – yes it’s worth your 12 minutes – I can’t resist summarizing just a few relevant highlights.

  • A formative experience first learning about drug development during an in-house course at GSK, when the instructor told attendees to look at the person sitting to their left and to their right, and explained, “the odds are that none of you will ever work on a drug that gets approved. None of you.”
  • His experiences in early cancer drug development, where he’d “work on programs where the science seemed totally understood, where the preclinical data was so compelling that it made me want to get that IND filed and get that drug into patients as quickly as possible — only to have something unexpected blow the program out of the water.”
  • The feeling of constantly anticipating each new drug was going to be successful, and imaging what that would feel like, and then “a year would go by or two and it wouldn’t work. I’d see the data. They’d be meh.”

On his reflections after failures:

“I’d look back across failed programs, and sometimes I’d see the decisions that we made along the way about how to develop the molecule, and I’d see that those decisions were right, but the science was wrong. Or sometimes I look back and I see that the science was right, but we made the wrong decisions and choices. I’d look backwards and see all the could-have-beens and should-have-beens and the never-could-have-beens, and I realized, yeah, it’s possible that no matter how hard I work or how hard I tried, it may very well be that I could spend the remaining years of my career and have nothing to show for it, but having worked on a bunch of programs, never having made a new medicine.”

On the challenges of making critical decisions with incomplete and imperfect information.

“All of the times that we had to be right, and all of the times we had to not be wrong.”

On the contingency of success:

“I can look back now and see how rare it is to be at this point for all of us at Day One, to have arrived in this place and at this very moment together, because so many things had to work out just right.”

These small excerpts don’t begin to do justice to the magnificence of Blackman’s talk (again: please watch!), but they highlight just how incredibly difficult and fraught it is to get a new drug to patients. 

But when it happens — when, as Blackman says, you touch your dream for the first time — “it feels absolutely magical.”

4
May
2024

Success in Film and Pharma: Contingent But Not Random

David Shaywitz

Film and pharma, like many creative endeavors, exist in a world of power law economics, where a handful of exceptionally successful products account for a massively disproportionate share of the total revenue. 

Consequently, in both domains, there’s a powerful incentive to “pick winners.” Every studio head and every R&D leader tries desperately to do this. 

But there’s a problem: as screenwriting legend William Goldman (The Princess Bride, All The President’s Men, Butch Cassidy and the Sundance Kid) famously observed.

“Nobody knows anything.”   

The full quote, from Goldman’s classic 1983 memoir, Adventures in the Screen Trade, continues, “Not one person in the entire motion picture field knows for a certainty what’s going to work. Every time out it’s a guess and, if you’re lucky, an educated one.”

Similarly, distinguished physician-scientist and former head of R&D at Merck, Dr. Roger Perlmutter, bluntly acknowledges, “we have no idea what we’re doing,” adding, “It’s a bloody miracle if you ever make a drug that works.”

Roger Perlmutter

Revenue predictions in pharma ahead of launch are also notoriously difficult to predict, as studies by both BCG and McKinsey have affirmed. Earlier stage (pre-Phase 2) forecasts – the sort of thing former NIBR head Mark Fishman wisely banned, but current management has reinstated – seem especially fraught (see here).

Yet beneath this truth lie two conflicting realities.

  1. As appealing as the narrative of drug development moving gracefully between biology and clinic is, with “line of sight” thinking and guided by a target product profile, the actual process tends to be far messier, particularly in the case of novel mechanisms;
  2. Even though a huge number of lucky breaks are required to achieve a blockbuster, this does not mean that such success is simply random, equally available to anyone who buys a lottery ticket.  Talent, taste, and teamwork are vital as well, not to mention judgement and determination. 

The real lesson is that in power law domains like film and pharma, success is incredibly difficult to achieve.  You need both a huge amount of good fortune and a team that actively seeks opportunities to benefit from serendipity.

A good team has the mindset, competence, and agility to leverage effectively whatever luck comes their way. 

Path To A Blockbuster Drug: Messier Than You’d Think

In a fascinating recent interview, R&D productivity scholar Jack Scannell (of Eroom’s Law fame) discusses what might be called the noble lie of drug development: the conceit that we have the ability to understand adequately and domesticate reliably biology. Nassim Taleb and I wrote about this in the Financial Times in 2008.

Scannell explained that to advance a candidate medicine in a drug development organization, you need a very clear and crisp story of why you think it’s going to work, in order to compete successfully for resources.  He also notes that every time a drug is successfully developed, there’s always a just-so story explaining why the process worked.

Jack Scannell

The problem, Scannell accurately points out, is that these narratives evolve over time – an approach that in retrospect seems logical and methodical (and hence, presumably, repeatable) yet was almost certainly far less structured and streamlined in practice. 

If there’s a canonical path for drug development, many first-in-class medicines never got the memo.  Scannell cites the example of anti-TNF drugs, which were initially developed for sepsis; they didn’t work.  Only later were anti-TNF candidates tried in inflammatory conditions like rheumatoid arthritis; products in this category today include Humira (cumulative global sales of around $200B) and Enbrel (cumulative sales of around $74M as of 2021, estimated to hit $100B by 2029). 

Similar examples abound.  Botox (as I’ve discussed, see here, here) was originally developed and FDA-approved as a medicine for strabismus; sildenafil (Viagra), famously, entered clinical trials as a potential treatment for angina.

Pembrolizumab (Keytruda), Merck’s blockbuster oncology drug, as I discussed in depth here, was initially developed by researchers at Organon Pharmaceuticals in Oss, the Netherlands, as part of a hunt for an inhibitor of the immune system to help patients with autoimmune disease. 

When a stimulator (technically, an inhibitor of an inhibitor) was discovered instead, researchers contemplated a range of uses including as an anti-viral medicine and as a vaccine enhancer, before setting on developing it as a potential cancer medicine.  Even so, it was effectively invisible to the R&D leadership of multiple companies for years, including Merck which was on the edge of out-licensing it, only pulling it back in at the last moment. 

Or consider my former employer, Takeda, which acquired Millennium Pharmaceuticals in 2008 for $8.8 billion in order “to bolster its cancer drug business,” according to Reuters. At the heart of this transaction was bortezomib (Velcade), a cancer drug Millennium acquired when it bought Leukosite in 1999 for its pipeline, most notably a share the drug Campath (later sold to ILEX which was then acquired by Genzyme).  At the time of the acquisition, Millennium “had no interest in bortezomib,” and was effectively unaware of its existence. 

Leukosite, for its part, had acquired bortezomib from a company called ProScript after it ran out of money; ProScript, meanwhile, began life as Myogenics, a company co-founded in 1993 by Harvard scientists Alfred Goldberg, Tom Maniatis, Kenneth Rock, and Michael Rosenblatt.  The company was focused on targeting the proteosome, which is involved in protein degradation.  The original goal was to help treat disorders of muscle wasting, hence the name.  But in 1994, after a compelling conversation with Israeli researcher and future Nobel laureate Avram Hershko, the startup’s head of research, Julian Adams, decided to pivot to cancer (and change the company’s name to ProScript). 

As Goldberg later reflected, “Most scientists do not realize how the progress of drug development depends so much on nonscientific issues and random events — and luck.” 

The broader point is that while both Velcade and Keytruda are important oncology medicines ultimately developed successfully by Millennium and Merck, respectively, the origin and early evolution of each was incredibly messy, and effectively the antithesis of the carefully scripted process we might have been tempted (or seduced) to imagine. 

Similarly, anti-TNF medicines weren’t initially developed to treat rheumatoid arthritis, Botox wasn’t developed to treat wrinkles, sildenafil wasn’t developed for erectile dysfunction. Moreover, as Morton Meyers documents in Happy Accidents (see my discussion here), many categories of medicines used in psychiatry were originally discovered through astute clinical observation rather than deliberate drug design focused on the particular indication.

Path To A Blockbuster Film Franchise: Messier Than You’d Think

The Marvel Cinematic Universe (MCU), featuring Spiderman, X-Men, Iron Man, The Hulk, Thor, Captain America, Black Widow, and many others is the single most successful franchise in movie history, netting nearly $30B in global box office so far, and much more in associated licensing.  These are impressive numbers even by pharma standards.

Much like the eventual success of Keytruda and Velcade, the triumph of the MCU was hardly inevitable, as a fascinating new book, MCU, and an engaging Wall Street Journal podcast series, “With Great Power,” both reveal.

Marvel Comics, founded in 1939 as Timely Comics, enjoyed its heyday in the 1960s, as writer Stan Lee led the development of such memorable characters as the Fantastic Four, X-Men, Spiderman, Ant Man, and Iron Man, among others.  After a series of financial transactions starting in 1968, Marvel wound up in the hands of corporate raider Ronald Perelman in 1989.  Perelman, in turn used the company as a vehicle to acquire other companies including a sports card company and a sticker company, loading up Marvel with extensive debt. 

In 1990, Marvel sold licensing rights to ToyBiz, a company owned by entrepreneur Ike Perlmutter, an emigree from Israel who had made his fortune in the U.S. as a liquidator, buying products from failing businesses and selling them to consumers at a small markup.  The profits from this enabled him to acquire and turn around distressed companies instead of products; for example, he acquired and later flipped Caleco to Hasbro, pocketing $40 million in the process. 

In 1990, Perlmutter acquired the struggling toy maker ToyBiz, and hired inventive toy creator Avi Arad (another Israeli emigree) to help the company come up with new products.  Having watched the sales of Batman toys go through the roof with the release of Tim Burton’s Batman in 1989 (ToyBiz had a non-exclusive license to DC characters), Perlmutter pursued and acquired the exclusive rights to Marvel characters from Perelman.  The sales of these were sufficiently encouraging to encourage Ike to strike a new deal with Perlman in 1993: Marvel would get 43% of ToyBiz and in exchange, ToyBiz would gain exclusive licensing rights for all Marvel characters into perpetuity.

To support Marvel’s struggling balance sheet in 1993-1994 – and to stimulate the sale of toys – Marvel, in a deal led by Arad, sold the movie rights to X-Men and the Fantastic Four to 20th Century Fox. But Marvel couldn’t stave off the inevitable, and in 1996, the company declared bankruptcy, with the intention of restructuring their debts.   

Unexpectedly, a fight ensued between Perelman and another well-known corporate raider, Carl Icahn.  In 1997, ToyBiz abruptly parachuted into the middle of this dispute with an unsolicited offer of their own to acquire Marvel, showing up uninvited to a meeting of creditors to make their pitch.  After a lengthy legal fight, ToyBiz was awarded the business in 1998. 

The future of Marvel was now in the hands of a toy company.

Desperate for cash, Perlmutter soon cut a deal for Spiderman with Sony (who already owned a sliver of the rights, from an earlier tractions).  Marvel received $10 million plus 5% of the profits – in addition to whatever they made from any Spiderman-related toys.  The movie, which came out in 2002, did fairly well, achieving a box office of more than $100 million.  When Perlmutter saw this, he was furious, and decided he gave away too much to Sony in this transaction. 

In 2003, a savvy young business whiz named David Maisel met with Perlmutter and floated what was a radical idea at the time: perhaps Marvel could make its own movies, rather than just license the rights to others.  By controlling the production, Maisel said, they could better coordinate the timely development and sale of movie-related toys, which was always what Perlmutter saw as the key source of revenue. 

Maisel eventually persuaded Merrill Lynch to provide $525 million, enough to make two movies; as collateral for this, Marvel offered up movie rights to a broad portfolio of their characters.  After conducting focus groups with children, Marvel decided that the most popular toy would be one based on Iron Man, and so this was nominated to be the movie they filmed first.

Overseeing this project would be a Marvel fanatic named Kevin Feige, who was hired by Arad in 2000 after seeing Feige’s contribution to an X-Men movie that was made in the late ‘90s and released in 2000, produced by Lauren Shuler-Donner, for whom Feige was working as an assistant at the time. 

Feige and Maisel, in turn, both selected Jon Favreau to direct Iron Man. This was critical to the movie’s eventual success, not least because Favreau identified Robert Downey Jr as the ideal actor to portray Tony Stark, and then passionately advocated for him despite Perlmutter’s strenuous objections (Downey was considered a risky choice because of his well-known history of substance abuse). 

Favreau eventually won, Downey joined the cast, and other talented actors and crew members were soon drawn by Downey’s presence.  Downey turned out to be perfect for the role, the movie was an enormous success, and the franchise was launched, steered by Feige’s vision for an integrated series of films all taking place in a coherent universe – the MCU.

Jon Favreau

Interestingly, Favreau got the opportunity to direct Iron Man in part because of his success directing the 2003 Christmas classic Elf, starring Will Ferrell. Favreau had heard about Elf in 2001 when he was guest directing an episode of a TV show called Undeclared, created by Judd Apatow, who shared a manager with Ferrell.  The TV show opportunity, in turn, resulted from the success of his 1996 cult classic, Swingers – a film that he wrote in less than two weeks after his dad sent him screenwriter software and for amusement, he thought he’d try it out. 

Favreau barely managed to get Swingers financed (ultimately a friend of the director’s father ponied up $200,000). He struggled to film the picture on this tiny budget, relying on friends, spare supplies, and unpermitted locations often requiring guerilla filming tactics to complete a take rapidly before he was kicked out.

In short: the MCU was launched from the success of Iron Man, driven largely by the appeal of Robert Downey Jr, who was cast only because director Jon Favreau had insisted, and Favreau was in the director’s chair only because of a remarkable series of fortunate events. 

Contingent but not Random

While the successful development of blockbuster movies and medicines clearly requires a huge number of unplanned and perhaps unplannable things to go right, their successes, critically, are not random either. 

Luck may be necessary, but it’s hardly sufficient.

The launch of the MCU, for example, clearly involved an exceptional amount of luck but it also required extremely talented people, in this case a balance sheet-focused business executive, Ike Perlmutter, joined by the creative Avi Arad; a visionary finance strategist, David Maisel; an imaginative, ultra-high-EQ subject matter expert, Kevin Feige; and a director with great taste and an expansive network, Jon Favreau. 

It would be a mistake to attribute the coalescence of this team to dumb luck.  Feige, for example, had attended film school at USC after applying six times (he was rejected the first five), and then pursued an internship with the Hollywood power couple of Laura Schuler-Donner and Richard Donner (Richard had directed the 1978 film Superman, starring Christopher Reeve). 

Maisel, drawn to the entertainment business, had apprenticed with legendary superagent Michael Ovitz after first attending Harvard Business School and spending time at the Boston Consulting Group.  Favreau, meanwhile, had spent years hustling in Chicago and Los Angeles as an aspiring actor and director; bit parts include “D-Bob” in Rudy (1993), and “Eric the Clown” on an episode in the fifth season of Seinfeld (1994).

In Outliers (my WSJ review here), Malcolm Gladwell discusses underappreciated factors that can contribute to success, such as hours of practice and hard work.  As I noted, “For the Beatles, the hard work of marathon engagements in Hamburg’s red-light district early in their careers was crucial. ‘By the time they had their first burst of success in 1964,’Mr. Gladwell writes, ‘they had performed live an estimated twelve hundred times. Do you know how extraordinary that is? Most bands today don’t perform twelve hundred times in their entire careers.’”  Similarly, Bruce Springsteen, in his captivating autobiography, cites his years of experience in a bar band as critical for his later success. 

Seth Stephens-Davidowitz, in Don’t Trust Your Gut (see my discussion here), also examines how artists can increase their exposure to serendipity by getting themselves out there rather than waiting to be discovered.  Maisel, Feige, and Favreau, in evolving their careers, all seem to have chosen, deliberately, to put themselves in the path of serendipity, maximizing their chance to get lucky.  Maisel worked with Ovitz, Feige went to USC film school and then worked with Schuler-Donner, and Favreau keeping himself in the mix as an actor (and later director), as frustrating as that must have felt for most of his early career.

The success of Keytruda and Velcade, also, required more than just good luck.  While Merck’s head of R&D Roger Perlmutter wasn’t responsible for the Keytruda’s discovery and early development, he soon recognized the promise of the drug, and ensured Merck was all-in on its development, independent of whatever his (and Merck’s) preexisting strategic plans might have been. Similarly, the championing of Velcade by Julian Adams was essential to its development — not least his role in persuading a skeptical Millennium to resource it after the acquisition of Leukosite.   

What Is To Be Done?

On an individual level, it seems like a good idea to stay in the mix as much as possible, not least because the people you work with on a failed program today might be some of the same people you might work with on a successful drug tomorrow, and the skills and instincts you develop along the way in the trenches enable you to become increasingly effective, assuming you are curious, industrious, and collegial.

On a company level, it’s more complicated. Most large pharmas are built around a degree of planning and projection that works beautifully in Excel and Powerpoint.  However, the approach generally doesn’t meaningfully acknowledge, much less come close to describing, the messy reality of novel product development. 

This discrepancy suggests there must be an incredible arbitrage opportunity here for more agile leaders and nimbler organizations, and presumably this is what venture-backed biotech start-ups are effectively doing. It’s not surprising to learn that only a quarter of new approvals in big pharma originated in-house, and unless big pharma can truly figure out how to industrialize and brute-force innovation, I’d be surprised to see big pharma’s in-house number go anywhere but down.

Stay Humble

It seems only appropriate to conclude a piece around uncertainty with several humbling reminders.

As Judah Folkman, a pioneering surgeon-scientist and a great champion of innovation at Harvard famously observed, “If your idea succeeds, everybody says you’re persistent. If it doesn’t, you’re obstinate.”  

In other words: to pursue any idea, at some point, you have to just put your head down and go after it; the problem is you have no way of knowing until afterwards whether you were right.

This lesson has particularly poignancy in the case of Folkman, who is perhaps best known for advancing the thesis that to grow beyond a certain size, cancers need to acquire their own blood supply, and if you can inhibit the grow of new blood vessels – for example, with drugs targeting VEGF — you might be able to starve and kill cancers.

It now seems, as Scannell points out in his interview, that these anti-VEGF cancer medicines, like Avastin, might work in other ways. As MGH cancer researcher Rakesh Jain wrote in 2014, these “agents could transiently ‘normalize’ the abnormal tumor vasculature, resulting in improved blood perfusion,” and helping other anti-cancer treatments (both drugs and radiation) work better. 

Thus, the medicines Folkman was championing might work, but perhaps not for the reasons he thought.

Ed Catmull

We might give the last word to former Pixar CEO Ed Catmull, who wrote an entire book, Creativity, Inc., about the challenges of serial creativity, and the need to successively reinvent yourself each time (see my discussion here). 

While readers “often thanked him for sharing his formula for surefire creative success,” the Wall Street Journal reported in 2023, the book conspicuously makes the opposite point: there isn’t “a template” for success – at best, he allows, there is perhaps “a way of thinking.”

Catmull’s insight bears repeating: inconveniently, there just isn’t a ready formula for creative success.  Catmull was talking about original movies in particular, but he could just as easily have been discussing original books, songs, drugs, or even venture investments, which all obey power law dynamics. 

Even if you are part of a team that has delivered an outsized success, or the CEO of the organization responsible, it doesn’t mean that you can now apply what you’ve learned and simply do it again, or that your organization can now apply these tidy “lessons learned.”  

I find it liberating to recognize that there isn’t a secret formula for innovative success in pharma (or any other creative domain ruled by the power law).  It means we don’t need to distract ourselves wondering whether we are doing it “right,” or worry if we’re not following the putative example of previous successes (which would be particularly misguided given the post-hoc narrative biases Scannell describes). 

Novel, impactful medicines – like novel, impactful films – are incredibly difficult to create, and require an exceptional amount of luck. 

What we can control, however, is how we approach this challenge:  with authentic intellectual curiosity, and colleagues who are talented, inquisitive, and nimble, approaching their work with conviction yet able to pivot in response to new information. 

True, we may not succeed.  Yet as screenwriter Charlie Kaufman observed, “If you don’t risk failure, you’re never going to do anything that’s different from what you’ve already done or what somebody else has done.” 

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