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David Shaywitz
Peter Attia is a prominent physician-turned-California longevity guru, and (to paraphrase Woody Allen) as California longevity gurus go, he’s one of the best, striving to remain grounded in science and data.
Known for his popular book Outlive, and his affection for “rucking” (look it up), Attia is also the host of a long-form podcast called The Drive, and an engaging guest on other worthwhile podcasts including Patrick O’Shaughnessy’s “Invest Like the Best” (here) and Bari Weiss’s “Honestly” (here). He’s also the founder of Early, which describes itself as a science-based health program to “build your own, personalized, end-to-end longevity playbook.”
Attia’s latest podcast features a lengthy (two hour), exceptionally illuminating interview about AI and medicine with Zak Kohane, a physician-scientist at Harvard Medical School and head of the Department of Biomedical Informatics (with which I’m affiliated).
The discussion starts with a quick, knowledgeable review of the history of AI (interested readers might also enjoy several of the books summarized here), and then explores how AI is likely to impact health and medicine.
Peter Attia
The entire episode – with thoughtful questions from Attia and nuanced replies from Kohane – is unquestionably worth the time (and extra credit if, like me, you listen while jogging, even if not quite rucking).
However, I wanted to highlight three related topics raised by these two senior medical experts that were especially striking:
AI is already poised to impact medicine. Kohane highlights the promise of AI in image-based specialties such as dermatology and radiology, where high-resolution images, fed into machine learning models, can identify image abnormalities as well as (and in many cases even better than) the human eye.
He also points out that in contrast to the infamous prediction of legendary AI expert Geoff Hinton (who suggested in 2016 that radiologists would be obsolete in 5-10 years), AI’s “are not replacing the doctors because image recognition process is only part of their job.”
Focusing on the use of AI for physician augmentation (rather than replacement), Attia suggests the adoption of AI would likely occur in two stages. The first specialties to be impacted, he says, will probably be those he describes as visually focused: pathology, radiology, dermatology, and cardiology (especially those most involved in interpreting cardiac imaging studies). Next would be specialties he sees as focused on integrating “language data” and visual data, like primary care doctors and pediatricians.
Zak Kohane, Chair of the Department of Biomedical Informatics, Harvard Medical School
While Kohane says he agreed with Attia’s proposed order of adoption, he emphasizes that a more immediate consideration is the shortage of doctors in key areas like primary care.
“You have to ask yourself, how can we replace these absent primary care practitioners with nurse practitioners, with physician assistants augmented by these AIs, because there’s literally no doctor to replace.”
More broadly, medicine’s challenge and AI’s opportunity, as Kohane describes it, is that fewer doctors are choosing to go into specialties not associated with highly financially remunerative procedures. While there doesn’t appear to be a shortage of future interventional radiologists or dermatologists (which he describes as high-paying and high prestige), there aren’t enough traditional radiologists or primary care doctors.
“I go around medical schools and ask who’s becoming a primary care doctor? Almost nobody,” Kohane said. “So primary care is disappearing in the United States. In fact, Mass General and Brigham announced officially they’re not seeing [new] primary care patients [see here].”
Kohane continues,
“There’s a huge gap emerging in the available expertise. So, it’s not what we thought it was going to be, that we had a surplus of doctors that had to be replaced [by AI]. It’s just we have a surplus in a few focused areas which are very popular. And then for all the work of primary care and primary prevention kind of stuff that you [i.e. Peter Attia] are interested in, we have almost no doctors available.”
The gap in “expert clinicians,” Kohane suggests, might be filled by non-MDs like nurse practitioners and physician-assistants augmented by AI.
The tremendous potential of AI today, Kohane explains, can be attributed to the compounding effects of large data sets, neural networks, and suitable computer chips (GPUs).
Kohane describes the tremendous importance of rich clinical datasets, the sort of information one might associate with electronic health records (EHRs).
However, he notes that the EHR “turns out not to be the answer in the United States. Why? Because in the United States, we move around. We don’t stay in any given health care system that long. So very rarely will I have all the measurements made on you.”
However, he adds, this isn’t the case in other countries, and cites the example of the Clalit in Israel, which he notes “published all the big COVID studies looking at the efficacy of the vaccine. And why could they do that? Because they had the whole population available, and they have about 20, 25 years’ worth of data on all of their patients in detail and family relationships.”
In the U.S., he asks, “Where is that data going to come from?”
Some organizations in the U.S. believe “they can get enough data” on their own, he says, and cites the Mayo Clinic as one example. He also notes that “there are some data companies that are trying to get relationships with health care systems where they can get de-identified data,” although he doesn’t sound very optimistic about this approach.
Attia, for his part, strongly agrees that health data is exceedingly “unfriendly,” and cites a pain point from his own practice.
When lab tests are obtained for patients, he says, and “we want to generate our own internal reports based on those…it’s almost impossible to scrape those data out of the labs because they’re sending you PDF reports. Their APIs are garbage. Nothing about this is user friendly.”
“Just because our patients own the data doesn’t make it easy to get,” he continues. “There is no aspect of my practice that is more miserable and more inefficient than data acquisition from hospitals. It’s actually comical, absolutely comical.”
Attia adds, “Is there a more user-hostile industry from a data perspective than the health industry right now?”
Kohane agrees, and explains, “There’s a good reason why. Because they’re keeping you captive.”
Going forward, he says, he’s most concerned about the tendency of “the medical establishment” to “pour concrete over practices.”
He explains that hospitals are huge entities that bring in huge revenue but have very small margins. In this situation, he argues, “you’re going to be very risk averse and you’re not going to want to change.”
Consequently, while Kohane said he remains excited about the potential of new businesses that come up with ways of delivering data-driven insights to patients about their individual health needs, he’s concerned about what these startups are up against. Specifically, he warns of “hospitals doing a bunch of information blocking … that will make it harder for these new businesses to get created.”
A key theme of both Kohane’s recent book about GPT-4 (including in particular the sections written by co-author Carey Goldberg) as well as Kohane’s conversation with Attia is the embrace of generative AI tools by patients. “They’re being used by patients all the time in ways that we had not anticipated,” Kohane says.
Kohane cites the example of a mom whose child had confusing symptoms that doctors struggled to synthesize into a diagnosis. Frustrated, she typed the information into ChatGPT, which suggested something called “tethered cord syndrome,” subsequently confirmed by imaging.
At this point, Attia asks a critical question: was it surprising that none of the doctors had tried to use ChatGPT to assist with the diagnosis?
Kohane’s deeply discouraging response was that “most clinicians I know do not have what I used to call the Google Reflex” – the instinct to look up and pursue curious and confusing observations.
The reason, he suggests, is that “doctors are in a very unhappy position these days. They’re really being driven very, very hard,” and morphing “into data entry clerks.”
Essentially, Kohane explains, physicians are too busy with the operational aspects of medicine – in particular, documentation and billing. This means they have less time to think, and perhaps less incentive to think.
(I anticipated and discussed this challenge – preserving creativity in medicine – 20 years ago, see here.)
Consequently, Kohane sees patients, and those invested the most in them (especially their families), as the most powerful disruptive force in medicine.
(I’ve also emphasized the critical role of patients and families as key drivers of care – including in the NYT here, here, as well as in The Atlantic here).
Kohane points to patients without primary care doctors who might be worried about a rash, for example. They recognize that they have a power tool, he says, and given the choice between waiting months to potentially be seen or using the tool, they’ll use the tool.
“It’s better than no doctor for sure. And maybe better.”
Kohane also emphasizes that because patients have the legal right to their own data, even though accessing these data can often be difficult, the legal right creates opportunities.
He points to Apple Health, which he says has partnered with 800 hospitals and makes it easy to get some of your key health data on your phone or computer.
“Now, there’s not a lot of companies that are taking advantage of that,” he says, “but right now, that data is available on tens of millions of Americans.”
Kohane predicts that in “the next 10 years, there’ll be a company, at least one company that figures out how to use that patient’s right to access through dirty APIs, using AI to clean it up, provide decision support with human doctors or health professionals to create alternative businesses.”
Yet, he acknowledges, “I don’t want to underestimate the medical establishment’s ability to squish threats, so we’ll see.”
Rapidly improving AI is likely to impact medicine by augmenting the capabilities of specialists, particularly those focused on visual diagnoses. AI might also provide the expert insight to enable non-MDs to provide care in situations where MDs are increasingly unavailable. The development of AI for clinically focused applications (in healthcare as well as in drug development) depends critically on the availability of relevant clinical data, which (despite the existence of at least some legislation) remains excruciatingly, maddingly, disturbingly difficult to pry from the grip of incumbent health organizations.
But if these organizations are an immovable object, then patients and their families might represent an irresistible force, determined to leverage all available tools to accelerate diagnoses and identify potential treatments (David Fajgenbaum’s own miraculous story, as well as the journeys chronicled by Amy Dockser Markus, come to mind – see here). Ideally, despite institutional and occupational hurdles, inquisitive physicians such as those celebrated by Judah Folkman will also drive the use and acceleration of AI technologies in service of improved patient care.
Sean McClain is today’s guest on The Long Run.
He’s the founder and CEO of Vancouver, Washington-based Absci.
Sean McClain, CEO, Absci
Sean started the company on his own in his early 20s, straight out of the University of Arizona, with the encouragement of his Dad. You could call it a scrappy garage biotech, with no traditional VC backers at first. He found a way to do something useful, developing an E.coli assay to test antibodies quickly and cheaply against molecular targets of interest to biopharma customers.
The business evolved. AI emerged. One of the key questions five years ago was how to feed AI with relevant data sets from wet labs, so it would have quality data that’s the essential grist for machine learn from. Absci embraced the new tool with an eye toward using it to speed up discovery of biologics drug candidates. It decided to discover and develop its own medicines.
Absci is now a public company. It has 200 employees. McClain, as the founder/CEO, has raised more than $530 million. The company is preparing to take its first drug candidate, an antibody against TL1a for inflammatory bowel disease, into clinical testing in 2025.
This wouldn’t be a first in class medicine – there are two other notable antibody programs against TL1a that are further ahead in development, and which were recently acquired by Merck and Roche. The AI drug discovery wave has had some big ups and downs over the last five years. McClain is one of the entrepreneurs out there seeking to strike a balance between the optimistic sense of what’s possible, tempered with the knowledge of how little we still know about biology, and how far AI still has to go in drug discovery.
This was an interesting conversation that I think is both uplifting and grounding at the same time, if that makes any sense.
Now please join me and Sean McClain on The Long Run.
David Shaywitz
“It was all mixed into one, enormous, overflowing stew of very real technological advances, unfounded hype, wild predictions, and concerns for the future. ‘Artificial intelligence’ was the term that described it all.” – Cade Metz, Genius Makers
The buzzy excitement around artificial intelligence (AI), and most recently generative artificial intelligence (genAI), has inspired some biopharma leaders, exasperated many others, and touched almost everyone.
Leading management consulting firms have sold an enormous amount of business by persuading biopharma companies that:
Within biopharma R&D departments, most researchers remain predictably skeptical of the incessant hype, even as many are authentically curious about promising advances (like AlphaFold, whose inventors received the 2023 Lasker Award for Basic Medical Research). They are also politically astute enough to genuflect to senior management’s imperative to demonstrate the organization’s embrace of AI.
One result has been an AI version of innovation theater, where there’s all sorts of demonstration projects, working groups, PowerPoint decks, partnerships, and celebratory speechifying. A huge amount of heat is generated, but so far, relatively little light.
At one level, none of this is surprising. As I discussed in 2019 in the context of precision medicine, and more expansively in 2023 in the context of AI, it historically takes a very long time for us to figure out how to productively use new technologies. As economic historians like Paul David, Carlota Perez, James Bessen, Robert Gordon, and others have consistently reminded us (as I discussed here), we don’t tend to wring productivity of out new technologies overnight; more typically, it takes decades, and many rounds of successive incremental innovations.
Yet, it’s easy to imagine, in the context of breathless pitches and extravagant promises, that perhaps this time it’s different – perhaps AI has found a way to beat the historical odds, and is leading to the sort of immediate, measurable productivity gains that enthusiasts promise and biopharma executives desperately seek.
For biopharma in particular, the excitement is understandable. As visionaries like Mustafa Suleyman argues in The Coming Wave (my 2023 WSJ review here) and Jamie Metzl argues in Superconvergence (my just-published WSJ review here), the thesis that accelerating revolutions in biotech and AI are compounding each other, and leading us towards a promising, tech+bio future is not just compelling but directionally correct. The question, of course, is when will we realize this AI-infused bio-rapture?
According to a recent, arresting Goldman Sachs (GS) report, entitled “GenAI: Too Much Spend, Too Little Benefit?” perhaps we shouldn’t hold our breath.
The GS report is worth reading in its entirety, but I’ll focus on several salient sections: an interview with the distinguished scholar and MIT economist Daron Acemoglu; an interview with GS’s Global Head of Equity Research Jim Covello, and an interview with two GS Senior Equity Research Analysts, Kash Rangan and Eric Sheridan.
Before we get to these details, it’s worth noting how refreshing it is to read a corporate document that conveys multiple, at times conflicting viewpoints around complex issues like the future state and anticipated economic impact of AI. While top management consulting firms typically offer a singular, consensus view on topics like the path forward for AI, this report from GS acknowledges and systematically explores differences in perspectives and assumptions. The result is an unusually substantive and credible report that conveys nuance and embraces uncertainty.
Daron Acemoglu is a distinguished economist at MIT and the co-author, most recently of Power and Progress. A WSJ review by Deirdre McCloskey described Acemoglu as “a shoo-in for Nobel Prize” in economics, and said the book expressed the authors’ view that “The invisible hand of human creativity and innovation…requires the wise guidance of the state.”
Daron Acemoglu, Institute Professor, MIT
In his conversation with GS, Acemoglu expressed excitement about the promise of genAI, noting it “has the potential to fundamentally change the process of scientific discovery, research and development, innovation, new product and material testing, etc. as well as create new products and platforms.”
However, he cautioned, “these truly transformative changes won’t happen quickly and few—if any—will likely occur within the next 10 years.”
Instead, he suggests, “AI technology will instead primarily increase the efficiency of existing production processes by automating certain tasks or by making workers who perform these tasks more productive.”
He also thinks AI, even with more data and fancier chips, will still struggle with open-ended tasks, like improving “a customer service representative’s ability to help a customer troubleshoot problems with their video service.”
In addition, like many others, Acemoglu worries “where more high-quality data [to power future AI models] will come from and whether it will be easily and cheaply available to AI models.”
He recognizes the future possibilities of genAI, he says, and hopes AI creates new tasks, products, business occupations, competences – but adds this is “not guaranteed.”
While emphasizing that “Every human invention should be celebrated, and generative AI is a true human invention,” he is concerned that “too much optimism and hype may lead to the premature use of technologies that are not yet ready for prime time.”
As Jim Covello, the Head of Global Equity Research at GS sees it, one critical concern around AI relates to the “substantial cost to develop and run” the technology; the investment only makes sense if AI can “solve extremely complex and important problems for enterprises.” But solving complex problems, he says, is something the technology “isn’t designed to do.”
Covello challenges several familiar assertions used to justify current costs.
“Many people attempt to compare AI today to the early days of the internet,” he says. “But even in its infancy, the internet was a low-cost technology solution that enabled e-commerce to replace costly incumbent solutions.”
In contrast, he argues, AI technology is starting out “exceptionally expensive.”
He adds that the idea that technology “typically starts out expensive before becoming cheaper is revisionist history.” E-commerce, he asserts, “was cheaper from day 1.”
He also says we can’t count on AI prices declining significantly; the dramatic historical decrease in the price of semiconductor chips, he says, was due to fierce competition; but at least today, “Nvidia is the only company cable of producing the [computer chips] that power AI.” Consequently, Nvidia is likely to maintain pricing power in the near-term.
Covello is also skeptical about the transformative potential of AI, arguing “people generally substantially overestimate what the technology is capable of today.” He adds, “I struggle to believe that the technology will ever achieve the cognitive reasoning required to substantially augment or replace human interactions.”
He also contends, “Humans add the most value to complex tasks by identifying and understanding outliers and nuance in a way that it is difficult to imagine a model trained on historical data would ever be able to do.”
Covello points out that he was a semiconductor analyst when smartphones arrived and followed the evolution of smartphone functionality closely. As he remembers it, the ensuing roadmap was clear, “with much of it playing out just as the industry had expected.”
In contrast, he argues, “No comparable roadmap exists today. AI bulls seem to just trust that use cases will proliferate as the technology evolves. But 18 months after the introduction of generative AI to the world, not one truly transformative—let alone cost-effective—application has been found.”
Of particular relevance for biopharma, he notes that “companies outside of the tech sector … face intense investor pressure to pursue AI strategies even though these strategies have yet to yield results. Some investors have accepted that it may take time for these strategies to pay off, but others aren’t buying that argument.”
He warns that “The more time that passes without significant AI applications, the more challenging the AI story will become. And my guess is that if important use cases don’t start to become more apparent in the next 12-18 months, investor enthusiasm may begin to fade.”
A somewhat more positive perspective on genAI, at least in the long-term, was expressed by Kash Rangan and Eric Sheridan, both Senior Equity Research Analysts at GS.
Noting that “hardly a week goes by without reports of a new, and better, AI model,” Rangan said he remained enthusiastic about genAI long-term potential, but acknowledged, “we have yet to identify AI’s ’killer application.’ ”
Similarly, while acknowledging that the technology “is still very much a work in progress,” Sheridan said “it’s impossible to sit through demonstrations of generative AI’s capabilities at company events or developer conferences and not come away excited by the long-term potential.”
Rangan acknowledges that “AI technology is undoubtedly expensive today” but argues (in contrast to Covello) that “the cost-equation will change.”
Pointing out that “people tend to overestimate a technology’s short-term effects and underestimate its long-term effect,” Rangan adds “Nobody today can say what killer applications will emerge from AI technology. But we should be open to the very real possibility that AI’s cost equation will change, leading to the development of applications that we can’t yet imagine.”
Sheridan agrees the economics of AI are challenging now: “I readily acknowledge that the return on invested capital (ROIC) visibility is currently low, and the transformative potential of AI will remain hotly debated until that becomes clearer.”
He concludes, “people didn’t think they needed smartphones, Uber, or Airbnb before they existed. But today it seems unthinkable that people ever resisted such technological progress. And that will almost certainly prove true for generative AI technology as well.”
I remain optimistic and energized by the promise to be found at the intersection of AI and biotechnology, and view digital technologies like AI as increasingly essential tools for understanding biology as well as for effectively managing biopharma R&D. But even if at times genAI seems magical, we can’t treat it as magic. We can’t operationalize it as magic. We can’t invoke it as a force that will descend from the rafters, deus ex machina, and somehow fix what ails our organizations. Nor should we set it aside, dismissing it simply the newest new thing. By steering a path between credulous mysticism on the one hand, and reflexive cynicism on the other, we can inquisitively explore and thoughtfully interrogate this powerful emerging technology, and identify meaningful opportunities for productive application in biopharma R&D.
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Jeff Stein is today’s guest on The Long Run. He’s the CEO of San Diego-based Cidara Therapeutics.
Jeff Stein, CEO, Cidara Therapeutics
Jeff has led teams that have successfully developed a novel antibiotic, and a novel antifungal, all the way through FDA approval. This latest project with an antiviral could be the most important of his career.
Cidara has a platform for making drug-Fc conjugate therapies, which can be engineered to treat a variety of diseases in a long-lasting injection.
The company’s current top priority – one with global health and pandemic preparedness implications — is called CD-388.
Cidara’s looked all the small molecule antivirals for influenza that have been developed and thought of a way to come up with what hopefully will be a compound with high efficacy, a clean safety profile, and a chance to be given in a single shot that will last an entire flu season.
For the scientists out there, it’s a small molecule neuraminidase inhibitor conjugated to an Fc fragment of a human antibody. That conjugation part makes the drug last longer in the bloodstream. Cidara thinks its small molecule can be injected once every six months, either via intramuscular or subcutaneous routes. For more on the science, see a recent preprint article on BioRxiv.
Based on cell-based assays, animal and human Phase I and II studies to date, Cidara believes it will provide universal protection against all circulating strains of influenza – the A and B types. That would include the H5N1 bird flu strains that have created some concern by leaping to cattle, and in a few cases, to humans who work in close proximity to cattle.
This treatment will be tested this fall in a 5,000-subject study, in a variety of doses and against placebo. If CD-388 can reproduce the broad-spectrum and long-lasting antiflu activity that it has shown in previous studies, it could have a very important drug to help governments around the world prepare for future flu pandemics. Because of its biological way of working, it should be effective for many more people than the current generation of flu vaccines, should have several years of shelf life for government stockpiles, and should be helpful for even the immunocompromised vulnerable populations who aren’t likely to gain protection from vaccines.
There’s also a somewhat circuitous business story here with CD-388, as Cidara developed it, worked on it with Johnson & Johnson for a while, had to buy it back at one point, and recently secured $240 million in funding to take it through a big 5,000-subject study on its own.
There’s a lesson in here for scientific entrepreneurs about resilience and staying power.
Now please join me and Jeff Stein on The Long Run.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
Ken Frazier, Tony Coles, Rob Perez and Ted Love are among the biggest names in the biopharma industry. They also happen to be Black.
But there are many other Black people making significant contributions, and who aren’t so widely known.
Let’s recognize some of these folks today on the Juneteenth holiday. On June 19, 1865 — long after the Emancipation Proclamation of Jan. 1, 1863 — the last remaining slaves in Texas were informed they were free.
This is a moment to celebrate freedom, progress and human potential. We can celebrate how far we’ve come, while also understanding how far we have to go with racial justice and equal opportunity.
More than 40 people were nominated. Today, consider the contributions of these 18 Black biotech leaders in alphabetical order.
Stephen Abreu — Partner at Sidley Austin in San Francisco; executive director for Biopharma Leaders of Color (BLOC). Abreu structures and negotiates complex intellectual property and commercial transactions for life sciences companies.
Stephen Abreu
“Stephen is a mover and shaker. He leverages his position at his firm to great benefit,” said Ted Love, the chairman of the BIO board of directors.
Rob Perez, founder of Life Science Cares and an operating partner at General Atlantic, added: “Stephen is one of the rising stars among the biopharma law community. He is well-known for his legal prowess, but also for the work he is doing to advance people of color in the industry.”
Freddie Bowie, CFO, Eikon Therapeutics
Freddie Bowie — CFO of Eikon Therapeutics. The Hayward, Calif.-based company is using super-microscopy and AI to advance its pipeline of novel therapies. Bowie has a wide range of responsibilities at Eikon that include finance, corporate strategy, investor relations, corporate communications, procurement, clinical supply, and real estate. The company has raised $775 million since its founding in 2019. (TR coverage, May 2021).
“Great guy, super smart. He will be a CEO one day,” Love said.
Rod Cotton — board member for Eisai, Castle Biosciences and Moleculera Biosciences. “Rod has been an inspiration to many, after a long career as an extremely successful executive at Baxter and Roche,” Perez said.
Rod Cotton
“He has now turned his attention to helping other companies as a highly sought after board member and is also giving back by working with and advising young people on their careers, as well as supporting other people of color through BLOC and other organizations.”
Love added: “Fantastic person. Lots of gravitas but remains so humble.”
Yusri Elsayed
Yusri Elsayed — SVP and global oncology therapeutic area head, Johnson & Johnson Innovative Medicine.
“Yusri has been instrumental in the development of a series of very successful hematology and oncology drugs that are having a profound impact on the lives of thousands of patients,” said Karen Akinsanya, the president of R&D at Schrodinger. “Yusri’s patience and dedication to people and the challenging process of drug development are the key to his success as a leader and innovator in product development,” she wrote.
Ian Estepan
Ian Estepan — EVP and chief financial officer, Sarepta Therapeutics and board member of Cellarity. Estepan has been with Sarepta for almost 10 years, closely involved in its growth into a company with a market value of $11 billion.
“Ian deserves as much credit as anyone for the long-term growth and success of Sarepta. After a successful financial career outside of the industry, he has applied his astute business knowledge and financial acumen to help guide Sarepta through many ups and downs to provide a meaningful benefit to patients with Duchenne Muscular Dystrophy,” Perez wrote.
Erik Harris
Erik Harris — EVP and chief commercial officer of Ultragenyx Pharmaceutical and board member of Denali Therapeutics. Harris has experience in both molecular diagnostics and therapeutics.
“Erik is one of the leading commercial minds in the rare disease space. He is also a co-founder of a terrific organization called The Just Society, consisting of some the most successful African American men in the industry,” Perez said.
Mel Hayes
Mel Hayes — COO of Fulcrum Therapeutics. Fulcrum is developing oral small molecules for facioscapulohumeral muscular dystrophy (FSHD) and sickle cell disease. Fulcrum agreed to a partnership with Sanofi in May to co-develop and market the FSHD drug candidate. Hayes joined the company as chief commercial officer in September 2021 and stepped up to be chief operating officer nine months later.
“Great guy, huge focus on the patient,” Love said.
Derek Hicks
Derek Hicks — EVP and chief business officer of Intellia Therapeutics. “Derek has had a long and very successful career in Corp/Bus Development and is one of the best in the business in this space,” Perez wrote. “After climbing the ladder at Pfizer he worked to help lead the BD effort at Spark, which had a highly successful exit to Roche, and now he is the business leader at Intellia, another extremely exciting company.”
Anthony Johnson
Anthony Johnson — CEO of Kodikaz Therapeutic Solutions and board member for NY BIO. “I have been impressed with him during the short time I’ve known him. As a successful entrepreneur, Anthony is one of the leading voices in the New York biopharma community,” Perez wrote.
BJ Jones – chief commercial officer, New Amsterdam Pharma. He was previously chief commercial officer for Biohaven Pharmaceuticals, a company acquired by Pfizer for $11.6 billion in 2022.
BJ Jones
“BJ may be the most innovative and successful commercial leader in the industry today,” Perez wrote. “He was the architect of the highly improbable success of Biohaven, as its migraine drug Nurtec took off and soundly beat a much more well-resourced competitor in a market that was previously thought to be scale-driven. BJ’s success has made many smaller biotechs re-think their ability to launch on their own in markets where they are facing larger competitors,” Perez wrote.
Charlotte Jones-Burton
Charlotte Jones-Burton — partner at 2Flo Ventures, board member at bluebird bio, and Founder of Women of Color in Pharma (WOCIP). She was previously a senior vice president of product development and strategy at Chinook Therapeutics, a kidney drug developer acquired by Novartis for $3.5 billion in 2023.
“Another mover and shaker. Has been an outstanding leader for advancing women of color in our industry,” Love said.
Cynthia Mazareas — senior partner, corporate law, WilmerHale. She has more than 30 years of experience at the firm.
Cynthia Mazareas
“Cynthia is a senior legal counsel for MANY biopharma companies, who rave about the support they receive from her. Her understated style provides few opportunities to highlight her impact on the industry, but that impact is highly significant. She was one of the founding Board members of Life Science Cares, and currently serves as its Governance chair for the National Management Committee. She and Wilmer Hale have been invaluable to the growth of the organization,” Perez wrote.
Karen Nelson
Karen Nelson — chief scientific officer, Thermo Fisher Scientific. She has been in this position with Thermo Fisher for three years, and previously was president of the J. Craig Venter Institute.
“Karen is a highly experienced scientific leader with major accomplishments in the study of the microbiome and genomics,” Karen Akinsanya wrote. “In addition to her impressive scientific credentials, Karen is highly energetic and collaborative which I believe are two features that have led to her success in both academia and industry. I think everyone will agree that she is simply great to work with!”
Jeff Raphael — founding partner, OmniScope Partners. Raphael has a long track record on the investment side of the business, most recently at Evercore, before founding OmniScope.
Jeff Raphael
“After a successful stint as a Managing Director at Evercore, Jeff is utilizing his unique combination of talent and experience in a new venture, as founder of OmniScope Partners, helping emerging companies in the industry to navigate the financing and value inflection path towards success,” Perez said.
Deborah Telman
Deborah Telman — EVP, corporate affairs and general counsel of Gilead Sciences. She joined the company in 2022 and oversees government affairs and policy, public affairs, legal and compliance functions.
“Deborah is the real deal. Well-suited to be in the major leagues at Gilead,” Love said.
Tamar Thompson — head of global corporate affairs and policy at Alexion Pharmaceuticals, board member for Catalyst Pharmaceuticals and Avidity Biosciences and Chairwoman of the Board of MassBio.
Tamar Thompson
“Tamar has been one of the industry’s leading corporate affairs executives for years, helping to share legislation and policy that helps the industry to benefit patients. She is now taking on an even larger role, as Chair of the Board of MassBio, one of (if not THE) leading regional trade association in the country,” Perez wrote.
Chidozie Ugwumba
Chidozie Ugwumba — managing partner, SymBiosis Capital Management, based in Bentonville, Arkansas. The firm’s investments include eGenesis, Vedanta Biosciences, Tenaya Therapeutics, Recursion, Ensoma, Fog Pharma, and Endeavor Biomedicines. Prior to SymBiosis, Chidozie led the Direct and Impact Investment Group of WIT, LLC and worked on the Private Credit and Infrastructure teams at Partners Group, a global private investment manager.
Alethia Young
Alethia Young — CFO of Bicycle Therapeutics and board member for Pacira Biosciences and PTC Therapeutics. She was previously a Wall Street analyst before moving over to corporate leadership.
“Super smart woman. No limit on her career,” Love said.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
Abe Ceesay is today’s guest on The Long Run.
He’s the CEO of Boston-based Rapport Therapeutics.
Abe Ceesay, president and CEO, Rapport Therapeutics
Rapport started with a $100 million Series A financing in March 2023 from Third Rock Ventures, Arch Venture Partners and Johnson & Johnson Innovation. As the company name subtly suggests, it’s based on biology of R A Ps, or receptor-associated proteins.
The idea is to make small molecule drugs that specifically bind with these targets, found in specific neuroanatomical regions, to get more of the desired efficacy of a given molecule, with fewer systemic side effects that have dogged so many neuroscience drugs of the past.
Abe comes to this position with a long track record in neuroscience and rare diseases. He was previously president of Cerevel Therapeutics, a company acquired by AbbVie in December for $8.7 billion.
You can go back and hear about Abe’s early life and key career turning points in a Long Run episode that aired in July 2020.
In this more recent conversation, recorded in Boston in April 2024, we talk about the company’s biological approach, and the gap it aspires to fill in the neuroscience medical kit, where precision medicine hasn’t developed as quickly as in, say, oncology. The company has since filed paperwork to do an initial public offering.
This company can trace its origin story to the inaugural Timmerman Traverse for Life Science Cares in September 2021. Subscribers can read more about the origin of the company.
Before we get started, a word from the folks at Andreesen Horowitz’s Bio & Health team, and the producers of their podcast.
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 Abe Ceesay on The Long Run.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
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.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
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.
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.
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.
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.
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.
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.
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.
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:
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.
I asked Drucker what he saw as the key lessons for drug development. He cited three.
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.
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.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
