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Alex Harding, MD, entrepreneur-in-residence, Atlas Venture
Curon, Chimagen, Hengrui, LaNova…the list goes on of Chinese biotech companies that have recently licensed potential blockbuster drug candidates for cancer, autoimmunity and more to US pharma and biotech companies for further development.
Over the past year or so, there has been a dramatic increase in both the number of deals to obtain rights to assets discovered in China, and the prices paid for those assets.
China has become more than a source of low-cost, high-quality manufacturing and contract research services. It’s now an important source of new drug discovery. US and European companies are taking these new discovered-in-China assets forward into global development, in some cases sending back significant milestones and royalty payments to the company that did the original work.
A symbiotic relationship has been evolving between the US and China. But it all could come to a halt now if the incoming Trump Administration and new Congress deliver on the promise to crack down on trade with China.
The timing couldn’t be worse, just as US-China relations in biopharma have started to blossom.
While in the past many people in the West have traditionally been skeptical of the quality of drug discovery work performed in China, often assuming (wrongly, it seems) that Chinese assets either have liabilities due to cutting corners or amounted to nothing more than trivial ‘patent busts’ – uncreative modifications to molecules to work around a competitor’s published patents—there is today broad respect for the quality and in particular speed of work being performed by Chinese companies.
Companies on both sides are benefitting from this relationship. Here’s how:
Thus, Chinese molecular discovery and early development work is bookended by Western mechanistic and target discovery work on one side, and Western late-stage development and commercialization on the other.
This situation is evolving rapidly. Over the past year or so, there has been a feeding frenzy among venture capitalists and scrappy entrepreneurs. US-based VCs have scoured Chinese patent literature in search of assets matching their interests, either by using Google Translate, or, for the lucky ones who can read Chinese, in the original language. More recently, some pharmas have strengthened relationships with Chinese companies and are gaining access to these assets directly.
Already, as Western companies become more familiar with this source of high-quality molecular assets and Chinese firms become more adept at marketing their products externally, prices have increased and now nearly match the price for similar assets that originated in the West.
It will be important to watch what comes next. Chinese companies will probably continue to adapt rapidly. Will they take on more of a Western presence, and begin to develop drugs for Western markets on their own?
There are already a handful of global biotech companies with Chinese roots. BeiGene recently rebranded to BeOne to distance itself from its Chinese origins. Zai Labs’s President & COO was previously a US pharma executive. Other Chinese pharmas and biotechs have already hired experienced US-based executives, particularly to execute on business development.
Perhaps Chinese companies will begin to take on more late-stage development and commercialization in Western markets. Some Chinese companies could establish US operations and begin to run clinical trials in Western countries and even build sales forces there.
However, for Chinese companies that are either state-owned or have close ties to the Chinese government, this may not be possible, necessitating continued dealmaking with Western companies to enable development of their assets in Western markets.
I do expect Chinese companies to encroach into the earlier-stage discovery work still dominated by Western companies. Now that they have established themselves as skilled drug hunters, Chinese companies will likely invest more into basic research to discover and validate novel targets and biological mechanisms.
Rather than just being fast followers, Chinese companies will soon emerge as true competitors with Western firms on the cutting edge.
Western companies should be concerned. I am less confident that Western companies will adapt to remain competitive with the agility and relentless pace of Chinese companies. The speed with which they can create new molecules is impressive and should be studied. It may be hard to replicate.
Western biotech and pharma companies at times focus too much on elegant and innovative science at the expense of speed. ‘Cool’ science doesn’t always translate to better drugs, and it usually takes more time and costs more money.
On the other hand, Paragon Therapeutics is a US company founded in 2021 that has adopted a model of developing me-better and me-too biologics that imitate approved or otherwise derisked drugs and bring them expeditiously through clinical trials. It’s not the most creative approach scientifically, but it has led to exceptional financial returns on the public markets (see: Apogee, Spyre, Oruka, Jade, and Crescent).
Not only are Chinese labs moving fast to discover assets, but they also move fast into the clinic. While similar data packages are often required for a Phase 1 IND in China as in the US, there are timeline efficiencies in drafting regulatory documents, review, and subsequent trialing that enable rapid readouts.
Especially for a complex product like antibody-drug conjugates and cell therapies, where iterations on multiple components of the overall construct are needed, China has proven to be an effective Phase 1 testing ground for identifying the optimal product, gathering data quickly and efficiently not just from animals, but from healthy volunteers and patients.
Cell therapies developed in China often start with investigator-initiated studies, for example, to rapidly progress through multiple iterations of these cellular constructs. Will FDA and European regulators increase flexibility to enable Western companies to better match the speed of their Chinese counterparts?
All of this progress is threatened by the geopolitical tension between China and the US. The BIOSECURE Act has made it more difficult for US companies to work with certain Chinese companies, but it has not yet seemed to impede the in-licensing and purchase of discrete assets from China. Chinese government restrictions have made it difficult to transfer certain data and materials outside of China (e.g., genetic data and patient samples), but so far we have not seen major issues with acquiring molecular assets for development outside of China.
The decision to partner with a Chinese company for drug manufacturing is not without its risks. In recent years there have been several Form 483s and Warning Letters issued by FDA to Chinese manufacturing firms for issues ranging from lack of sterility to willful destruction of documents. Of course, plenty of US-based contract manufacturers have had challenges with regulatory compliance, but there is a question of increased scrutiny for foreign-based manufacturers.
Politicians and government officials in both countries may feel pressure to show that they are tough on trade between the two countries. The flow of Chinese assets into Western companies has only recently begun in earnest, yet it feels like the spigot could be turned off at any time. Until it is, however, biotech and pharma professionals from both countries will be busy negotiating deals to bring attractive drug candidates into Western countries.
Thanks to Aimee Raleigh for her excellent comments on a draft of this article.
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David Shaywitz
“Does the crowd understand?
Is it East versus West
Or man against man?
Can any nation stand alone?”
Burning Heart, by Survivor – Rocky IV
In national politics, the culture wars may pit the coasts against the rest of the country. In biotech, however, the AI culture war seems to pit the coasts against each other.
Consider this recent LinkedIn post by Chandana Haque, Executive Director of Recursion Pharmaceutical’s startup incubator, Altitude Labs (because they’re based in the mountains of Utah – get it?)
After back-to-back trips to Boston and SF this month, I’m reflecting on some key impressions about the differences between the coasts—especially when it comes to trends in early-stage biotech investing. 🚀
Where did Boston investors get excited? Core biotech: engineering cell machinery, new modalities, and regenerative medicine. This is their strength, and they know it well. But bring up machine learning, and you’ll see a shift; ML just isn’t on the radar for most of New England’s investment crowd, which sticks closely to traditional biotech.
In SF, it’s a different story. AI/ML is seen as critical to understanding complex biology, and it’s almost assumed that every startup will evaluate how ML fits into their approach. SF investors are also intrigued by ADCs, structural biology, and even spatial biology—areas where I found Boston often disengages. The West Coast’s interdisciplinary approach, mixing tech and bio, seems ingrained.
Time will tell how each approach shapes the field, but if you’re traveling coast-to-coast, you’ll feel the difference. What are you seeing?
In short, in the Bay Area, AI is what’s captivating everyone. This passion inevitably finds expression in the contemplation of biotechnology.
Chandana Haque
The attitude in Boston is, for the most part, rather more reserved. While there are obviously high-profile exceptions, including investors like Flagship Pioneering (which has embraced AI as tightly as any Bay Area fund), and young companies like nference, on balance I think Haque is spot on.
At a recent Boston area healthcare conference (which I can only discuss in general terms because it was held under Chatham House rules), I was struck by the code-switching I observed on a venture panel where a prominent West Coast investor at a firm championing the transformative potential of AI offered a conspicuously understated perspective.
It was not so much the substance but rather the emphasis and affect that was different from what I’ve heard him say in other contexts. Here, speaking to somewhat buttoned-up East Coast business audience, his tone was more guarded, his perspective more grounded, and the changes he foresaw more gradual.
It’s also possible that in California, even VCs focused on biotech are bankrolled by limited partners who are captivated by the promise of technology and are drawn to VCs and startups that speak the language of radical transformation.
In Boston, the focus tends to be different – not least because of the overwhelming presence in Boston of biologists, physicians and other life science experts whose lived experience has reminded them (as it has reminded me) of the staggering complexity of biology and messiness and inherent humanity of medicine.
Exhibit A for East Coast early-stage biotech investors (as it has been for many previous years) is the latest iteration of Atlas Venture’s annual Year In Review (watch it here), presented by Bruce Booth, summarizing the state of the biotech industry and ecosystem.
Bruce Booth, partner, Atlas Venture
As in previous years, the entire presentation should be required viewing for everyone in the life sciences.
Booth doesn’t spend all that much time on AI, but he calls it out as an area with “great investor interest.” The challenge, he says, is that because of the “incredible amount of buzz and hype” in this space, it’s been “difficult to figure out where the reality is.”
He points out that in 2014, “Recursion said they wanted 100 clinical programs in 10 years” (an aim that I imagine struck tech investors as admirably bold and biotech investors as hopelessly naïve).
“Unfortunately,” Booth deadpans, “they missed that,” achieving only five clinical programs.
Yet even that represents an important achievement, Booth says, pointing out that “any biotech company that’s just ten years old that has five drugs in the clinic is actually incredibly productive.”
Booth believes AI isn’t just wispy and aspirational. “The reality is there,” he asserts. “AI and machine learning will have targeted impacts up and down the R&D process.”
Preclinical examples he cites include the use of AlphaFold to predict protein structure, and the potential of AI “to predict toxicities or create better routes for manufacturing drugs.”
On the development side of R&D, he suggests AI may contribute to patient selection and enrollment in clinical trials. Moreover, given the established capabilities of large language models, he thinks AI is also likely to provide assistance with regulatory documentation and writing.
But he struggles to find what might be termed West Coast conviction:
“Fundamentally, in the drug R&D space, given the complexity of human biology and the lack of massive datasets, we think that the impact of AI machine learning on R&D is going to be more likely around evolution than revolution. We’re not going to see drug discovery go from a multiyear process to just weeks or days.”
Consequently, Atlas plans to continue its existing (and, Booth says, proven) strategy of leveraging cutting-edge biomedical science to generate promising novel therapeutics. If AI contributes to the development of a promising target or approach, they’re all for it, but they’re not looking to AI itself as the basis for a platform, nor do they see AI as the transformative unlock for biomedical discovery.
The Atlas view, perhaps not surprisingly, also represents the mindset of most senior pharma R&D executives that I’ve met.
Yet, this skepticism may start to evolve if — or I suspect, when — AI’s impact is more palpably felt. 
As I discussed in my last column, young physicians have quickly embraced an AI clinical app to help guide them through care of individual patients. This should serve as a reminder that while steps enabling change may be imperceptibly small, when change finally comes, it can be rapid. Before long, even big pharmas may find themselves persuaded to embrace their inner Californian.
Meanwhile, leading AI-first biotech companies seem to have become more aware of the essential expertise and implicit knowledge across a range of capabilities that veteran drug developers have accrued and are increasingly recognizing the importance of tapping into this vital experience, found in such abundance along the Charles River.
Perhaps, the next great biotech successfully integrating the approaches represented by the coasts will arise somewhere in the middle.
“If I can change,
And you change,
Everybody can change.”
Jimi Olaghere, technology entrepreneur, Dad, sickle cell disease patient advocate
On his fourth birthday, Adamu couldn’t celebrate.
The boy, from a rural village in Nigeria, had a flare up of his sickle cell disease known as a pain crisis. His parents tell me the rare days when he’s full of energy and playing with his friends feel like a precious gift. This year, he was given a cruel reminder of the daily battle he faces.
I was fortunate to be one of the first patients to receive a CRISPR gene edited cell therapy that cured my sickle cell disease. Adamu isn’t so lucky. There is no such cure immediately available for him.
Adamu’s father, after reading about my participation in a gene-editing clinical trial, held onto the hope that one day this breakthrough could rewrite his son’s fate. But the reality is sobering. The closest treatment center is thousands of miles away, and the cost of treatment is prohibitive. The life expectancy for SCD patients in regions like West Africa is often below five years. I suggested hydroxyurea as a possible treatment for Adamu, only to find out that his father had never heard of it. As a relatively cheap generic therapy, it is available in parts of Africa. But even access to low-cost generics can’t be taken for granted in a place with limited healthcare resources.
Adamu’s story is not unique. In low- and middle-income countries, particularly in sub-Saharan Africa and parts of Asia, healthcare systems are under-resourced, ill-equipped, and unable to manage chronic diseases like SCD. Every year, over 300,000 infants are born with SCD, and many don’t survive past childhood without early diagnosis and treatment. An estimated 5 million people worldwide suffer from chronic sickle cell disease – the vast majority of whom live in Africa.
SCD is caused by a genetic mutation that results in red blood cells becoming misshapen. These cells can’t flow smoothly through blood vessels, causing painful blockages and depriving the body of oxygen. These malformed cells break down faster, leading to constant fatigue, chronic pain, organ damage, and shortened lifespans.
By National Human Genome Research Institute (NHGRI) from Bethesda, MD, USA – Sickle Cell Disease, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=52360077
There is hope on the horizon through new gene therapies that could potentially transform the lives of those with SCD. By editing genetic instructions, scientists can restore red blood cells to their healthy form, reducing the frequency of painful crises, renewing energy, and extending life. The tools to save SCD lives already exist in the form of Ex Vivo gene therapy.
The main challenge today is the cost.
To make an impact, we must reduce the cost of these existing solutions instead of waiting for future therapies that may take years to develop.
Ex Vivo gene therapy for SCD involves removing a patient’s blood stem cells, modifying them outside the body to fix the genetic problem, and then reintroducing them into the bloodstream. This approach directly addresses the disease’s root cause rather than merely managing its symptoms.
The FDA recently approved two groundbreaking Ex Vivo therapies: Bluebird Bio’s Lyfgenia and Vertex Pharmaceuticals’ and CRISPR Therapeutics’ Casgevy. Lyfgenia works by adding a special anti-sickling gene into a patient’s blood-forming stem cells, helping their body make healthier red blood cells. Casgevy, using CRISPR-Cas9 technology, reprograms stem cells to produce higher levels of fetal hemoglobin by targeting and disabling a specific gene that usually suppresses it in adults.
The result is a flow of healthy red blood cells that deliver oxygen effectively, reducing painful blockages.
I am living proof of the success of Ex Vivo therapies. After 35 years with SCD, I was at the brink of a catastrophic ending, but I made a miraculous turnaround after an infusion of Casgevy in September 2020. It changed my life for the better.
These therapies offer real hope to patients like me, but they remain out of reach for the majority. The proven efficacy of Ex Vivo gene therapy makes it the most viable solution at present.
In Vivo gene therapy is an exciting concept that many scientists are pursuing. It takes sickle cell treatment a step further by editing genes directly inside the patient’s body. In Vivo therapies deliver gene-editing tools into the bloodstream, where they can target and correct the genetic issue within the body.
One key advantage is they don’t require multiple blood collections, or toxic pre-conditioning treatments, like the ones I had to endure to receive an ex vivo cell therapy. They offer the theoretical possibility of short hospital stays, and one-and-done treatment.
However, In Vivo therapies are still experimental, with unknown long-term outcomes. SCD patients, especially in regions where medical care is limited, cannot afford to wait another decade or more for these treatments to become viable. Furthermore, since In Vivo gene therapy introduces genetic changes directly into the body, regulatory scrutiny is intense, adding years of research and testing before wide availability.
A significant challenge for In Vivo gene therapy is delivering gene-editing tools to the right cells — specifically, hematopoietic stem cells in the bone marrow. Ensuring accuracy and minimizing off-target effects remain technical hurdles. Additionally, In Vivo gene therapies may have unintended impacts on fertility due to potential effects on reproductive cells, a concern particularly in African contexts where family and continuity are culturally important.
Given these risks, Ex Vivo therapies, which allow for controlled editing outside the body, align better with the needs and values of SCD patients in Africa and parts of Asia.
One of the major advantages of Ex Vivo therapy is that the technology already exists. With streamlined protocols and increased access to treatment centers, we can begin saving lives much sooner. However, the cost remains a significant barrier today. The personalized cell therapy manufacturing process is labor-intensive and resource-heavy. Viral vectors and plasmids used in gene editing are among the most costly components.
To make Ex Vivo gene therapy more accessible, we need to reduce costs by automating and standardizing manufacturing processes. Advances in technology could make cell collection and gene editing more efficient, lowering overall costs. Reducing the cost of raw materials, such as viral vectors, will also be essential.
To reach patients in low-resource settings, investments in specialized treatment centers and training for healthcare professionals are essential. Lessons from other fields, like vaccine distribution, could provide valuable insights to build on.
The role of capitalism cannot be ignored in the conversation about curing SCD. The biotech industry’s profit motives have fueled immense investments in research and development, enabling the creation of cutting-edge therapies like gene editing. Success of ex vivo gene therapies certainly helps underwrite further scientific work on the new frontier of in vivo gene therapy. Without financial incentives, much of the progress in SCD treatment would not have been possible.
However, while the profit motive has driven innovation, it has also created barriers to accessibility. Companies can balance profit with patient needs by forming public-private partnerships and collaborations that share the financial risk of developing life-saving therapies. Additionally, relocating production and manufacturing to regions where labor is less expensive but skill levels are high can reduce operating costs.
Curing SCD in low- and middle-income countries is not just compassionate — it is strategic for high income nations as well. Reducing the global burden of SCD cuts healthcare costs worldwide by preventing chronic complications that lead to repeated hospitalizations. Healthier populations in low-income regions mean stronger economies and a more vibrant global workforce, benefiting international trade and market growth. Expanding SCD treatment globally also accelerates scientific innovation. Collaborating across borders to deliver effective therapies drives down costs and advances gene-editing techniques that ultimately benefit everyone.
Imagine what Adamu’s life could be if we save it. Today, he is a young boy whose life is defined by pain and uncertainty of when the next pain crisis might strike. But with access to gene therapy, his future could change. He could grow into adulthood full of vitality, free from SCD, able to pursue his dreams, build a career, and perhaps one day become a father himself.
Today, I am not just alive — I am thriving. I get to be a father to three beautiful, incredibly smart kids because I was given a second chance through gene therapy. Without it, I might not be here to watch them grow, teach them, and share in their accomplishments. Adamu and millions like him deserve that same future. By focusing on making Ex Vivo gene therapies more accessible, we can ensure that he, too, has the chance to build a life and pass on his strength and resilience to the next generation.
Timmerman Traverse for Sickle Forward on the summit of Kilimanjaro, Sept. 16, 2024. All 20 team members made it to the top. Jimi Olaghere, the first sickle cell disease patient to summit Africa’s highest peak, is third from the right (a patch of his teal jacket is showing).
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.
Luke Timmerman, founder & editor, Timmerman Report
Hard to believe, but the 10th Anniversary of Timmerman Report is coming up in March 2025.
Time to party!
The past 10 years of biotechnology have been remarkable. I’m fortunate. I’ve had a front-row seat to chronicle monumental advances at Timmerman Report, and occasionally influence events.
Join me and a group of biotech leaders in Boston on Mar. 6 and in Seattle on Mar. 13 for the TR10 Anniversary Celebrations.
Mar. 6, Alnylam Pharmaceuticals, 675 West Kendall St. Cambridge, Mass.
5 pm. Registration. Networking.
5:30 pm Welcome remarks. Alnylam and HSBC.
5:35 pm. Luke’s welcome.
5:40-6:20 pm. Toasts / Roasts / Predictions. How Will the Biopharma World Be Different in 2035?
Speakers:
6:20 pm. Networking
7:30 pm. END
Mar. 13, 2025, Adaptive Biotechnologies. 1165 Eastlake Ave. East, Seattle.
5 pm. Registration. Networking.
5:30 pm Welcome from Adaptive.
5:35 pm. Luke’s welcome.
5:40-6:20 pm. Toasts / Roasts / Predictions. How Will the Biopharma World Be Different in 2035?
Speakers:
6:20 pm. Networking
7:30 pm. END
All active TR subscribers are welcome to attend. Non-subscribers can purchase an annual subscription — for an individual or a group — at the door.
This will be fun. There may be some teasing. Some wisecracks. I can take it.
Are you a long-term subscriber interested in offering a toast or roast? Perhaps you’d like to sponsor this fun biotech community event? See me luke@timmermanreport.com.
Thank you for your support of this experiment in independent biotech journalism.
Luke
Timmerman Report launch party, Cambridge MA. Mar. 2015
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.
Luke Timmerman, founder & editor, Timmerman Report
Happy Veteran’s Day.
For some reason, this day doesn’t receive the same level of attention of most holidays on the American calendar.
Let’s pause today to thank veterans in our communities. For real. Face to face. Or maybe on the phone. Not in a tweet.
As I wrote last year:
Today is a day when I honor my Dad.
He was a US Army Ranger who served in combat in Vietnam from 1969-1970.
He came home to a country boiling with anger and division. Many didn’t respect or value his service. He had some conflicted feelings, like many veterans.
Today he’s 75 years old. Retired. Healthy. Taught my sister and I some important life lessons. Cherishes time with his grandkids. Thankfully, he is still able to get access to quality healthcare at the Veterans Administration in Madison, Wis.
Our veterans deserve respect. Their sacrifice isn’t always visible or well understood. But their contributions are a big part of why we live in such a vibrant, creative, dynamic, optimistic, entrepreneurial, prosperous, safe and tolerant country.
Let’s remember these blessings. Let’s do our part to keep things this way. And work hard every day on creating the future of medicine, and on creating a more perfect union.
We need to find ways to better understand people in our communities who don’t look and sound exactly like us. Talking with a veteran and showing some respect for their service in a meaningful way is one way to start a true dialogue.
Members of the biotech community can seek to better understand the healthcare needs of veterans. You can share your enthusiasm for the health sciences. I bet most veterans would be fascinated to learn about what you do.
It’s one decent way to start rebuilding the bridges we need in our country.
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 Leslie Williams.
Leslie is the co-founder and CEO of Boston-based hC Bioscience.
Leslie Williams, co-founder and CEO, hC Bioscience
Her company is working to develop a new class of RNA medicines directed at transfer RNAs, also known as tRNA. The gist of the idea is to make these tRNA therapies, delivered with a lipid nanoparticle, that can carry instructions to overwrite a premature termination codon. The premature termination codons, or PTCs, stop the cell from producing certain full-length proteins. By overwriting the PTC, the hope is to coax the body to produce full-length, functioning proteins.
You could think of it like gene therapy in its ability to tackle disease at the molecular roots, but without the risk associated with viral vectors, and with the potential to re-dose the drug if the effect wears off over time. Those who want to dig into the science can read a seminal 2019 paper in Nature Communications, from a team at the University of Iowa.
In theory, this class of medicines has broad potential. An estimated 10-15 percent of all inherited diseases are caused by premature termination codons. hC Bioscience has lead programs for hemophilia A and Duchenne Muscular Dystrophy. Clinical trials are scheduled to begin in late 2025, and the company hopes to have the first batch of results from patients in early 2026.
One of the key questions for hC Bioscience and others in the field is whether they can deliver enough of the therapy to the relevant cell types to produce enough of the desired proteins to make a difference.
This episode includes some revealing insights about who Leslie is, based on her upbringing in a small town in Iowa, and how, over time, she gained skills and experiences that got her to where she is today.
Please enjoy this episode with Leslie Williams.
Luke Timmerman, founder & editor, Timmerman Report
My first real journalism job flashed to mind this week.
It was 1998. I was a kid reporter fresh out of the University of Wisconsin. My job was to cover Dane County government for The Capital Times, the progressive newspaper in Madison.
Dane County had about 400,000 people. Half lived in the beating liberal heart of the City of Madison – home to one of America’s great state universities and many government workers.
The other half of the county’s residents lived in suburban villages and rural farmland. Former Wisconsin Gov. Lee Dreyfus once famously needled Madison as “30 square miles surrounded by reality.” Think dairy farms, feed mills, rolling hills, and the occasional small-town Main Street.
The Dane County executive, who I was supposed to watch like a hawk and report on daily, was a former environmental activist. The editors of my newspaper were supportive of her political positions.
I loved that job. What an education this was for 23-year-old me.
Kathleen Falk struck me as a bright and dedicated public servant. But she had her work cut out. This was a tense, pressure cooker of a job.
Kathleen Falk
After years of being a legal activist on the outside, advocating fiercely and intelligently for clean water and clean air and all kinds of good environmental causes, she had weighty responsibility.
As County Executive, she had to manage the classic urban-versus-rural land use battles. Wisconsin was losing an average of 2-3 family farms per day in those years (my Mom and Dad’s family farm in Grant County included). Corporate agriculture was ascendant. Family farmers, left with no economic legs to stand on and not enough in the younger generation willing to carry on with that way of life, felt compelled to sell their land to housing developers in order to retire.
Farmland was disappearing under suburban cul de sacs. Wildlife – deer, squirrels, rabbits, pheasants, ruffed grouse, Canada geese – were being left with less habitat.
Falk had a North Star. She wanted to protect the land. But she also governed at a time when Money magazine ranked Madison as one of America’s Best Places to Live. Newcomers were coming, like it or not.
Falk had to balance competing interests — do we allow more housing subdivisions on the periphery of the City of Madison? What about rebuilding some run-down neighborhoods? Would people want to live there? Where exactly were all these new people supposed to live, anyway? How were they supposed to get to and from work, without spewing too much CO2, or jamming up the roads and disrupting the wonderful quality of life which drew people to Madison in the first place?
County Executive Falk, to my mind, never abandoned her principles. But she realized that there is another side to the story, she needed to listen and needed to take it into account. Representing her tribe in Madison, and ignoring the rest of Dane County, wasn’t going to fly. It was her job to mediate, to carve out pragmatic solutions that both sides could live with.
This was not easy. These issues were emotionally heated with partisan rhetoric, even then.
To get anything of substance done, Falk had to work with a 39-member legislative branch, the Dane County Board. I covered their meetings that ran late into the night. Firebrand 1960s-style liberals from Madison (picture Vermont Senator Bernie Sanders) would step to the microphone and let it rip. When they were done, their counterparts from the rural parts of Dane County (picture Iowa Senator Chuck Grassley) would dish out their counterarguments, sometimes dripping with contempt about the liberals and their lack of “common sense.”
Some of these people really didn’t like each other. They’d come by the press gallery off to the side of the main chamber, and fill this reporter’s ear with gossip about how such-and-such supervisor was full of baloney, or how he or she was in the pocket of special interests.
Yet, these people had to find ways to work together to do basic things, like build and maintain roads, preserve the environment, take care of the most vulnerable citizens, and keep taxes in line with what people could stomach. Falk liked to describe her approach as “progressive policies with fiscal restraint.”
There was always the tension between individual rights and the common good. When you have a retiring farmer who’s worked hard his whole life and struggled to make a living with weak commodity crop prices, how do you tell him that he can’t sell his land to a housing developer?
What else is the farmer supposed to do?
Lord knows, our world needs activists to focus on injustice and demand change. But we’re all citizens in a democracy. We need to recognize this is a fractious country, and we have to balance competing interests. None of us is 100 percent right 100 percent of the time. None of us can win every battle. We need to seek common ground with people we strongly disagree with on some things if we want to accomplish anything.
Falk did her best. She clearly disappointed friends on the left at times. She never won over her skeptics on the right. But when she announced her retirement in 2010, as the longest-running Dane County Executive ever, a local newspaper wrote:
Part of what played into her decision to step down is the fact she fulfilled the two promises she made when re-elected in April 2009: building the nation’s first community manure digester and launching real cultural change around the big costs and wholesale suffering from the community’s abuse of alcohol. “Getting this manure digester and changing the paradigm of how we clean up our lakes was very important, and I am really proud that we have broken ground on that and will be flipping the switch in a few months,” Falk said.
That’s no punch line. Building a manure digester means dealing with waste from farm livestock in a way that allows farmers to continue making a living, while keeping Dane County’s beloved lakes clean.
That’s smart problem-solving, smart balancing of competing interests. This is what we want, and what we should demand, from our more competent public representatives.
We are in a very dark chapter in our country’s history, worse even than the Red Scare of the 1950s McCarthy era. We can’t go on like this.
I grew up in Wisconsin and still have friends and family there. Some are staunch conservatives. There are things on which I will not yield, and which they won’t either. But we do have things in common.
This might take the rest of our lives to dig ourselves out of this ditch and get our society back on a stable footing. Our society isn’t structured this way in the social media era, but if we talk less, listen more, and assume good faith from others, we can work together again and start solving some of our biggest problems.
[Editor’s Note: This article first ran on TR on Nov. 5, 2020.]
I have always kept my business and political lives separate – and have had no trouble doing so. But now my political beliefs and my industry are threatened by the same plague.
Donald Trump would not merely undermine our country, he would undermine the fundamental principle of our industry – and, speaking quite selfishly, my business…and yours.
That principle is truth. Absent devotion to facts, evidence, the scientific method – in short, truth and the search for it – our industry has nothing to say or to sell.
Donald Trump is all about lies and slander. His campaign of grievance is entirely based on an election lie – so often, so clearly, so utterly debunked that it is impossible for him (let alone his enabling acolytes, including JD Vance) not to know its baselessness.
He demands loyalty, a key test of which is slavish acceptance of his lies. And the fevered fantasies of his allies are fine with him (as long, of course, as they don’t contradict his own).
He has said, for example, that he will unleash the fabulist Robert (vaccines-cause-autism) Kennedy Jr. on the FDA.
“I’m going to let him go wild on health,” Trump told the crowd at his Madison Square Garden rally on Oct. 27. “I’m going to let him go wild on the food. I’m going to let him go wild on the medicines.”
And what would Kennedy do? As he said on Oct. 25 on X: the FDA aggressively suppresses anything “that advances human health and can’t be patented by Pharma. If you work for the FDA and are part of this corrupt system, I have two messages for you: 1. Preserve your records, and 2. Pack your bags.”
No one believes the FDA does everything right. It is hardly immune from politics. But an implacably corrupt system? Ask yourself: when the FDA has abandoned the scientific method, when clinical trials have devolved into anecdote, when your competitor’s TikTok claim is as valid as your 1,000-patient randomized controlled trial — what will your business look like?
Whatever your feelings about Trump’s political views, you cannot believe that this man, whose disastrous floundering and foundationless assertions (bleach, anyone?) during the Covid crisis were responsible for so many excess deaths, will do anything to promote human health – let alone preserve the industry which has shown again and again its ability to demonstrably and dramatically improve our lives.
I don’t expect I’m changing anyone’s mind. But maybe you haven’t had enough reason to get to the polls in the first place. If you haven’t voted yet for Harris and Walz: do it now.
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.
David Shaywitz
In 2011, we were experiencing the ascension of technologies like the cloud and the smartphone. Apps had become a thing: social network apps like Instagram (the iPhone “App of the Year” in 2011) and Twitter, utility apps like Evernote and Dropbox, navigation apps like Google Maps and Waze, and game apps like Angry Birds.
Yet in medicine, as I wrote that year in Forbes, the “killer app” was…a comparatively old-school e-textbook known as Up-To-Date. The company that created it was founded in 1992.
Written and reviewed by medical experts, Up-To-Date was where everyone in medicine, from earnest med students to overworked residents to seasoned clinicians, turned in the 2010s to find current, reputable information about medical conditions they required to most effectively care for their patients.
Ten years later, in 2021, Up-To-Date was still the go-to app; same for 2022 and 2023.
Yet today, this may be changing. When a colleague recently mentioned that young doctors now seemed to be using an AI-based resource called “Open Evidence,” I was surprised and somewhat skeptical.
But when I asked clinical colleagues who work with young doctors every day, I learned that the rumors seemed to be true.
As UCSF Chief of Medicine Robert Wachter wrote on X, “I think [Open Evidence] is becoming go-to resource for residents. It handles complex case-based prompts, addresses clinical cases holistically, & really good references.”
Harvard clinical colleagues shared similar experiences; one told me the uptake has been “viral,” adding, “I’ve NEVER seen anything like this.”
I know that my academic colleagues will be examining closely both the use and the impact of Open Evidence, with particular emphasis on the effect on patient care.
For the biopharma-focused readers of TR, the Open Evidence example serves (or should serve) as a vivid reminder that things don’t change — until suddenly they do. A year ago, everyone was using Up-To-Date; today, many young doctors are embracing Open Evidence.
For emerging technologies, change tends to be driven by “lead users” (to use MIT professor Eric von Hippel’s term) – front-line workers who are focused on solving a pressing problem, and are glad to utilize whatever approach seems most effective.
When you are a medical resident, your pressing problem is the overwhelming number of things you are dealing with, coming at you from everywhere, all at once. You desperately want to provide the best care to your patients, and you are motivated to turn whatever resource seems most useful.
That Open Evidence seems to have met this threshold (at least for a number of early-career physicians) is strong testimony to its perceived value. Harried residents, presumably, are not using Open Evidence merely because they are curious about AI, or because there is a department initiative to utilize AI; they’re using it because they see the Open Evidence as the best solution for their problem. It’s a tool that’s been adopted because of the palpable value it provides.
To these busy young doctors, AI through Open Evidence isn’t a proverbial “solution in search of a problem.” It’s a customized tool addressing their immediate, pressing needs.
There’s an analogy from the field of genetics. For years, I remember hearing endless criticism of physicians for their reluctance to leverage genetics in clinical practice; the urgent need to better educate clinicians in genetics was a familiar, oft-repeated plea.
Yet, when a genetic diagnostic test (non-invasive prenatal testing, or NIPT) became available that could evaluate reliably specific fetal chromosomal abnormalities from a sample of peripheral blood, and in many cases obviate the need for an amniocentesis, the adoption was both rapid and widespread. Patients, doctors, and payors all seemed to embrace it – because the benefits were palpable.
Which brings us, predictably, back to AI in pharma.
In my last three pieces, I argued that:
Readers turned out to be even more skeptical about the application of AI to R&D than they were about the application of human genetics – and impassioned geneticists were often the most critical.
As one reader (not from the Boston area, incidentally) and genetics enthusiast wrote,
I also think you are far too bullish on AI – I really dislike statements like: “Emerging technologies like AI will help improve scientific understanding and enable better decisions”. We have no idea yet exactly how transformative AI will (or will not) be, and professing with certainty that it will provide value fans the flames of hype that drive so many scam companies to slap a branded faceplate on GPT4 or raise money from VCs with not real vision beyond “AI+$$$$$=awesomeness”.
I appreciated the candor and perspective, which were certainly familiar, and speak to the sizeable chasm that exists in pharma R&D between AI optimists and skeptics.
On the pro-AI side, there seem to be two largely distinct cohorts: a small group of scientifically sophisticated enthusiasts who are really excited to explore the promise of AI across R&D, and a larger group of “digital transformers.”
Aviv Regev
The AI-curious scientists, from what I’ve seen, tend to have very little status and organizational clout in most large pharmas, although there are exceptions (Aviv Regev at Genentech/Roche comes to mind). More often, at best, they seem to be viewed as adorable (a word I’ve actually heard used by digital transformers).
The mission of the digital transformers is to execute broad corporate initiatives that are launched from the C-suite, driven by management consultants and focused on operational efficiency, typically assessed by near-term process metrics. These organizational ambitions, invariably emphasizing the infusion of AI across the enterprise, are trumpeted by CEOs at Davos and by big pharma execs at industry conferences like HLTH.
But turning a means into an end can be problematic. Goodhart’s Law (see here)observes that “When a measure becomes a target, it ceases to be a good measure.” Similarly, when the mere use of AI becomes the goal, rather than a tool, the result can be a perfusion of performative AI and a dearth of thoughtful application to address the most critical problems a pharma faces: discovering and developing the next original, impactful medicine.
Consequently, it’s understandable why the vast majority of pharma R&D veterans remain generally skeptical about AI in R&D, since it seems to bear all the stigmata of The Next Great Corporate Initiative that needs to be endured in the process of actually doing great science and coming up with impactful new medicines.
The wild hype around AI doesn’t inspire confidence either. While most startups aspire to lofty goals and tend to launch with brash promises, the extravagant expectations offered by AI startups may be in a league of their own.
As industry chemist and distinguished “In the Pipeline” blogger Derek Lowe recently reminded readers, in 2014, Recursion Pharma “stated back then that they were going to develop 100 drugs in ten years” – an outlandish proposition that made it difficult for many experienced drug developers to take them seriously.
Derek Lowe
My concern is that understandable skepticism can easily bleed into reflexive cynicism (I’ve discussed the “cynicism trap” here), that might lead R&D teams to overlook early but authentically promising opportunities that could be truly transformative.
It’s especially disappointing to me to sense some of this cynicism emanating from geneticists in particular, since at the time that many these geneticists were leaning into the tools and technologies of large-scale genetics, they were on the receiving end of critics who doubted the promise of the approach.
A representative article, from Stephen S. Hall in Scientific American in 2010, was titled “Revolution Postponed: Why the Human Genome Project Has Been Disappointing.”
The subheadline to Hall’s piece reads: “The Human Genome Project has failed so far to produce the medical miracles that scientists promised. Biologists are now divided over what, if anything, went wrong—and what needs to happen next.”
Yet over time, and with a huge amount of effort (and financial resources), the value of the Human Genome Project and related endeavors (like the UK Biobank) started (arguably) to prove themselves. (See, for example, this 2020 article by Richard Gibbs.)
True, genetics has perhaps not lived up to some of the most hopeful early expectations (see the thoughtful comments of Princeton geneticist and computer scientist Olga Troyanskaya here), but by any reasonable estimation, the efforts have proved extraordinarily enabling for science, medicine, and biopharma R&D.
I expect AI will ultimately prove similarly transformative, and, when developed wisely and utilized thoughtfully, will be viewed as an essential tool for managing the burgeoning complexity of biopharma R&D. Less certain is when such palpably useful AI tools for advancing R&D science will start to arrive: this year? This decade?
Like the young doctors now relying on Open Evidence, pharma R&D scientists may soon discover – perhaps sooner than you think – that the use of AI has become second nature for us, part of the fabric of our work, and we may wonder how we managed to survive so long without it.
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.
David Shaywitz
Two weeks ago, I wrote about how difficult it is for R&D leaders to “pick winners,” despite the enormous incentives to do so. I explained how we tend to underestimate the role of chance, and overestimate our ability to “domesticate uncertainty,” as Nassim Taleb and I wrote in the Financial Times in 2008.
Mostly, efforts to systematically improve success rates seem to have come up short.
However, as The Princess Bride (the font of all knowledge, as VC Lisa Suennen explains here) reminds us, “mostly” doesn’t mean “completely.” Occasionally, at least for a period of time, it may be possible to find an “edge” (a term Nate Silver discusses at length in his recent book). In R&D, this would mean finding an approach, an insight, a team, an organizational structure that might be able to beat the odds consistently. 
Earlier this week, I suggested that perhaps Vertex’s approach to human causal biology has provided them just such an edge. As I emphasized, their secret sauce (if it exists) certainly isn’t the invocation of “human causal biology,” a phrase that, as BioCentury’s Karen Tkach Tuzman recently observed, “is on the lips of research heads and early-stage investors,” and seems to be associated with most every current R&D program.
I argued that Vertex (unlike many competitors) is taking this concept particularly seriously, using it as an ultra-stringent criteria for target and program selection. Unless they can find compelling evidence (usually but not invariably from human genetics) that a particular protein is associated with disease, and also that targeting it is likely to improve the disease, they’re just not interested.
Vertex’s thesis is that most programs fail because they ultimately don’t generate adequate efficacy in people, and they hope to mitigate this by ensuring that they have a very high degree of confidence in their targets.
There are obvious tradeoffs with this approach.
For one, they are deliberately not pursuing a range of compelling conditions because they don’t believe they have adequate human causal biology to support such an effort.
Vertex also strives to remain agnostic about modality, often partnering with platform companies that presumably bring the requisite expertise. Their successful campaign to develop an effective (combination) therapy for most CF patients is a vivid reminder of just how difficult it can be to develop small molecule drugs; deploying emerging technologies is likely to contribute additional degrees of difficulty and uncertainty.
I anticipated that my two recent pieces about R&D might generate some discussion around what is actually meant by “causal human biology,” and how might this term be defined most usefully if the goal is to increase the odds of successful therapeutic development.
I also expected some discussion around how computational efforts to quantify causality (as reviewed by Tuzman in BioCentury) might contribute to improved decision-making in pharma, particularly in the context of Vertex’s conviction that what’s required is pivotal insights from human beings, rather than more reductionist approaches that seek to garner primary insight from volumes of data derived from human cell lines cultured in a dish.
I wasn’t surprised that these two articles engaged TR readers given our shared passion for R&D. What I didn’t expect was the emphasis of the responses, both public (via social media, mostly on Bluesky, which seems to be the new home of BioTwitter) and privately.
Virtually all of the feedback I received boiled down to: in practice, Vertex isn’t doing anything different than what others are; they do solid science, and perhaps have been a bit lucky, so be careful not to be taken in by a tidy success narrative.
One Bluesky user wrote,
Say you have 200 small/med pharma companies, with 2-10 projects each. I think just random statistics, if you look over say one 10-year window you would expect one company to have a high success rate and that company would be lauded as highly superior.
Experienced drug hunter Jonathan Rosenblum suggested there was nothing distinctive about how Vertex pursued their sodium channel pain target vs how other companies approached this target, adding,
What I know of their process is – it’s not unique. They haven’t cracked some code that others haven’t. An excellent, science-driven company nonetheless.
Frank David
Industry veteran and advisor Frank S. David added,
In past 10y I’ve seen *nothing* unique about any pharma co’s R&D decision-making process. Maybe there were differences in past, but now, they’re all cousins of AZ’s 5Rs….Stories of “better” cos are post hoc rationalizations. (Note: the “5R” reference is to this paper and subsequent elaboration.)
In addition to noting the concerns about how Vertex’s approach deliberately overlooks important conditions, and is likely to increase risk in some areas (like new modalities) while decreasing risk in others, Frank David makes another, critically important observation:
Interesting to try to predict how much of VRTX R&D decision making is hard wired into co vs dependent on judgement of top execs. I bet a lot of it is the latter. (Ditto Regeneron.) So maybe the lesson for pharma is “hire R&D execs w/ good taste & give them tons of power”? (Good luck with that…)
In other words: perhaps Vertex is a company at the sweet spot with enough resources to try a range of ambitious programs, but small enough so that it’s still guided palpably by strong, smart scientific leadership.
The private feedback I received was essentially a collective eyeroll, as readers emphasized that virtually all biopharma R&D organizations seem to be preaching from the same hymnal, and assert they are pursuing a similar strategy.
Apparently, it’s only a matter of time before inspirational “Human Causal Biology” posters, suitable for display in your company’s cafeteria, will be available for sale from Successories.
Putting it all together, I can see three potential conclusions:
In trying to sort this out, it seems relevant to acknowledge several of my own biases.
I am incredibly partial to compelling science and compelling scientists. I also love the idea of biopharma companies led by science and scientists, rather than managers and metrics. I’ve found it incredibly sad to watch the status of R&D leaders within big pharmas decline over the course of my career, as their inevitable struggles to generate the next blockbuster (and the one after that) has often left them on the defensive, enmeshed with operational efficiency, process metrics and the latest re-org rather than delivering great science.
George Yancopoulos, president and chief scientist, Regeneron Pharmaceuticals
I’m also especially partial to the power of genetics (which I was drawn to and pursued in graduate school), and to the unique understanding that the study of the whole person provides (see here). When I joined DNAnexus as chief medical officer in 2014, I was motivated, in part, by the knowledge that DNAnexus had worked closely with Regeneron to develop the Regeneron Genetics Center, as I had always admired Regeneron’s George Yancopoulos (see here) and was an enthusiastic supporter of the Center’s ambition to integrate genetics and medical record data to guide scientific discovery.
In short, I am exquisitely set-up to buy into Vertex’s success narrative, and perhaps this is exactly what’s happening.
But if it’s true that really no R&D approach is better than any other, and it really is just throwing darts at the genome, then trying not to mess up the execution…I guess this is just a worldview I find myself unable to accept.
To make a difference, we need to find conviction around something, and I deeply believe we can leverage human causal biology to improve R&D.
I am also probably more optimistic about the opportunities to leverage powerful emerging technologies including AI than current Vertex leadership, although I share Vertex R&D head David Altshuler’s wariness about technology-first approaches.
David Altshuler, executive vice president, chief scientific officer; Vertex Pharmaceuticals
In addition, I have seen how important organizational context and culture is for R&D. While nearly all big pharmas describe themselves as science-led, this often isn’t the lived reality. Even at large companies with the best R&D intentions, earnest ambitions tend to dissolve rapidly in a miasma of metrics, process, and power politics.
In contrast, mid-size companies (as I argued back in 2012, see here) with strong scientific leadership may well be the sweet spot for R&D, as exemplified most recently by Regeneron, Vertex, and Gilead while helmed by chemist John Martin.
In short: I choose to believe:
The folks at Nucleate, the global network for young scientific entrepreneurs, asked me a bunch of interesting questions.
I was the guest on the Nucleate Podcast. This was an hourlong interview which covered some turning points in my life. I also offered some commentary on the current state of biotech.
The co-hosts wrote:
In this episode, Sam Kessel and Anastasia Janas interview Luke Timmerman, an award-winning biotech journalist and founder of the Timmerman Report, as well as host of The Long Run Podcast. They explore Luke’s non-traditional background, his curiosity, and his openness to learning, which shaped his journey to becoming a prominent figure in the biotech space. Luke shares insights into his career, discussing his book Hood, the founding of the Timmerman Report, and his podcast. He also offers his perspective on the key qualities of biotech founders and VCs, the importance of diversity, and how to unlock individuals’ full potential. Additionally, Luke discusses his passion for mountaineering and how he combined it with his work, creating the Timmerman Traverse, a series of fundraising expeditions that have raised over $12M for causes such as cancer, poverty, and sickle cell disease.
Listen to the full episode wherever you like, or at the links below.
Timmerman Report launch party, Cambridge MA. Mar. 2015
David Shaywitz
Everybody reading this column knows that biopharma is a difficult business. Biology is unfathomably complicated and figuring out how to introduce something into the human body that does more good than harm is a fiendishly difficult challenge.
That’s why it’s important to recognize the occasional success. It reminds us what’s possible, and inspires us to think about how to achieve it more often (even as we consciously try to avoid the risk that Cass Sunstein highlights: selecting on the dependent variable and creating tidy post-hoc narratives around rare successes).
We’ll start with what still seems like an unimaginable achievement – the development of a therapy by Vertex Pharmaceuticals that effectively treats the vast majority of patients with cystic fibrosis.
We’ll then look at this achievement in the context of Vertex’s R&D strategy and consider how they are attempting to challenge (and hopefully defy) the distressingly low odds of drug development, and to demonstrate that, despite the concerns voiced by some wags, that maybe, just maybe, it is possible to “pick winners.”
First described by Columbia University pathologist Dorothy Hansine Andersen in 1938, cystic fibrosis is a heritable, autosomal recessive disease that affects approximately 40,000 people in the United States and 100,000 people globally. The disease is characterized by thick mucus secretions that logjam the airways in particular. Afflicted children are beset by constant coughing and lung infections. Until recently, most endured frequent hospitalizations and constant therapy, and had a median age of survival of around 30 years.
In 1989, the causative gene, CFTR, was (heroically) cloned by several research groups. That discovery prompted the next set of questions. Scientists wanted to know what the CFTR gene product actually did, and how disease mutations – including the most common CF mutation, called ΔF508 – affected the protein.
The story of the journey from CF gene to CF therapy, involving both academic researchers and industry scientists, is captured magnificently in a presentation offered by the key participants, as they accepted the 2023 Wiley Prize in Biomedical Science. The introduction and summary, by Richard Lifton, a geneticist and president of Rockefeller University, is superb.
(See also this excellent 2019 Stat piece by Matthew Herper and Adam Feuerstein.)
Michael Welsh, a physician-scientist at the University of Iowa who shared in the Wiley Prize, told the story of the first CF patient he saw when he was a third-year medical student.
We go in to see this little girl. She’s probably 7 or 8 years old. And as I watch her, she’s speaking in short sentences. She’s using her accessory muscles, respiration in her neck because she’s short of breath.
And as we talk, we find out that she has doesn’t have a normal life. She can’t go out and do the things that normal kids do. She’s spending much of her day with postural drainage, inhalation of aerosols. When she coughed, she had this foul sputum. I began to recognize the odor of Pseudomonas aeruginosa in the sputum.
The hard part was when, after seeing her, we went to talk with the faculty, and we learned she might make it to the teens and she was not going to make it out of her teen years. That made a huge impression on me. It stuck with me all my life.
Welsh would go on to focus on the epithelial cells lining the airway, and, with colleagues, show (prior to the identification of the gene for CF) that “there was a problem in the airway with chloride getting out.”
Michael Welsh, professor of internal medicine; University of Iowa
After the CF gene was cloned — a prodigious effort — Welsh demonstrated that defective chloride permeability in cultured cells from patients could be restored with the introduction of the normal (“wildtype”) CF gene, but not with a mutant CF gene. This established a link between the genotype and the disease phenotype.
Welsh also conducted sophisticated patch-clamp studies to demonstrate that the CF gene encoded an ion channel; he was then able to dissect how different components of the channel worked and to understand how mutations disrupted the function.
For example, some mutations prevented the protein from ever being made; others prevented the protein from folding correctly while still others interfered with proper channel activity. The most common mutation, ΔF508, exhibited defects in both proper folding and channel opening.
A critical observation Welsh and his colleagues made was that the ΔF508 mutation was temperature sensitive, meaning that while it didn’t function at normal body temperature of 37 degrees Celsius, it did seem to function, somewhat, at lower temperatures, suggesting that if a medicine could duplicate this effect, then function might be restored.
The next set of speakers — Paul Negulescu, Sabine Hadida, and Fredrick Van Goor — described the ensuing stages of the journey — how industry translated this new knowledge of biology into an effective drug.
Paul Negulescu, senior vice president, Vertex Pharmaceuticals
Negulescu had been working at a San Diego-based startup called Aurora Biosciences. Aurora was founded in 1995 to develop and commercialize assays using reagents like the green fluorescent protein developed by co-founder (and future Nobel Laureate) Roger Y. Tsien.
In 2000, Aurora received a commitment from the Cystic Fibrosis Foundation to fund $47 million worth of work over five years. A year later, in 2001, Vertex Pharmaceuticals acquired Aurora Biosciences.
As Stat notes, it wasn’t clear if the nascent CF program was initially even on Vertex’s radar. But the funding commitment from the nonprofit CF Foundation contributed to Vertex’s decision to stick with the program rather than cut it.
A self-described “assay guy,” Negulescu approached the challenge of CF by seeking two types of molecules: “correctors,” addressing the protein folding defect, and “potentiators” seeking to restore channel function. The assay also relied on a Tsien reagent that responded to changes in membrane potential (so they could see if channel function was restored), and the temperature sensitive ΔF508 mutations described above.
Sabine Hadida, senior vice president, Vertex Pharmaceuticals, San Diego site head
Building on the initial hits was a chemist named Sabine Hadida, who described the herculean effort required to develop what would become a remarkably effective three-drug regimen. Development of the first component, a potentiator called ivacaftor, required the synthesis and evaluation of around 800 compounds; first generation correctors such as tezacaftor required synthesis of 3,000 compounds; second generation correctors (e.g. elexacaftor) required upwards of 25,000.
Subsequent work, as Fredrick Van Goor went on to describe, revealed that these molecules were unusual in several respects; they worked at a distance from the site of the causative mutation, and each bound the CFTR protein at a distinct site. These interactions all involved parts of the channel that were embedded within the lipid membrane, explaining why the resulting drugs exhibited properties that appeared to “bend” traditional rules.
Frederik Van Goor, vice president, Vertex Pharmaceuticals
The clinical impact of the Vertex effort has been extraordinary. The triple combination of ivacaftor, tezacaftor, and elexacaftor (Trikafta) was approved by the FDA in 2019. Patients on the triple-combo treatment are projected to live 72 years (or even longer, if the drug is started when the patient is younger than 18), according to data presented by Van Goor. This compares with an estimated lifespan of 38 years with the best standard of care without these new medicines. These patients also live far healthier lives.
This is a monumental advance for the 90 percent of CF patients who are eligible. (A different approach will be required for patients unable to manufacture the chloride channel in the first place, and Vertex is pursuing gene therapy-based solutions to address this critical need.)
As Stat notes, by 2008, Vertex’s CF efforts had gained enough momentum that, in the words of former Vertex CEO Josh Boger, he “couldn’t stop the program if I tried,” even though it “remained a sideshow” for “management and its investors.”
The CF program could still have been killed when Vertex faced a moment of crisis in the early 2010s. The company’s sole marketed drug, a hepatitis C therapy marketed as Incivek, was successful at first, then quickly rendered obsolete by more effective competitors.
Things came to a head at a 2012 board meeting led by CEO Jeff Leiden and attended by David Altshuler, a distinguished physician-scientist and geneticist at the Broad Institute who had joined the board of directors. (He would leave the Broad to join Vertex as head of R&D several years later, in 2015.)
As Leiden saw it, Vertex had three options:
(A) Push forward with hepatitis C;
(B) Try to get acquired by someone who could then sort out next steps; or
(C) Shift the company’s focus to the still relatively early-stage CF program.
Leiden recommended Option C. The board agreed, and Vertex would go on to deliver remarkable medicines with the power to transform the lives of CF patients (at least those patients eligible for, and with access to these medicines).
The Vertex CF story is actually the (extended) introduction to the R&D strategy topic I want to discuss: has Vertex identified a way to “pick winners?”
David Altshuler, executive vice president, chief scientific officer; Vertex Pharmaceuticals
For context, we can turn to a fascinating talk Altshuler presented earlier this summer, and available here; many of the same points are summarized here and here, and amplified in this 2023 interview with Endpoints reporter Andrew Dunn, and in this 2024 profile by Michael Gibney.
Altshuler starts his talk by describing the challenges of R&D so familiar to readers of this column, emphasizing our limited understanding of human biology, and the challenge of predicting the impact of interventions. He then outlines Vertex’s R&D strategy, which is to limit the company’s focus, in an unusually rigorous fashion, to “causal human biology” – that is, “targets that have been validated in humans as playing a causal role in human disease.” He has described this as “targeted conviction.”
This often, but not always, involves human genomics.
Vertex also strives to be modality agnostic, similar to the concept of matching therapeutic modality to mechanism thoughtfully articulated and passionately advocated by Bristol-Meyer-Squibb CSO Robert Plenge. Plenge is another champion of the use of causal human biology and a former Altshuler post-doc (see this piece about applying human genetics to drug discovery that Altshuler, Plenge, and former President of Merck Research Laboratories Ed Scolnick penned in 2013).
The willingness to embrace any relevant modality or target reflects Altshuler’s belief that there isn’t a playbook for drug discovery – rather, “each disease has unique causal human biology, and cracking this biology presents a central challenge in the discovery of a novel therapeutic.”
Readers will recognize an echo of former Pixar CEO Ed Catmull’s view that there isn’t a formula for successful films, and creative teams have to start from scratch each time.”
Altshuler says Vertex also seeks to “choose programs where there exist or we can invent highly predictive in vitro assays based on primary human cells, and early biomarkers that predict long-term success.” Finally, he explains, Vertex strives to “select opportunities where the clinical and regulatory path enables efficient assessment of therapeutic potential and to potential approval.”
Altshuler contrasts this approach with many other biopharma companies, who he says tend to organize around a platform (like CRISPR or RNAi), a therapeutic area like cancer or neuroscience, or a “me too” fast follow approach. He suggests this represents commercial strategy more than a science strategy.
The heart of the Vertex approach is focused on data from people, not animal models (or AI models, for that matter).
He contends, “You can have a high success rate if you’re willing to go after human biology. It’s actually the not going after human biology that is the biggest problem in biotherapeutics.”
Altshuler cites not only the clinical success of their CF regimen, but also the recent FDA approval of their ex-vivo gene therapy program to treat sickle cell disease and beta thalassemia (by using CRISPR to excise a repressor of fetal hemoglobin); positive phase 3 data from a pain program strongly informed by human genetic insights; positive phase 2 data in a kidney disease program focused on the inhibition of the APOL1 protein; and encouraging early results from a program driven by my former post-doc mentor Doug Melton focused on transplanting pancreatic beta cells (generated by differentiating stem cells) into patients with type 1 diabetes.
To be sure, Altshuler is not suggesting Vertex has come up with an infallible formula but argues their approach might be able to significantly improve the probability of success.
I’m not only attracted to Altshuler’s strategy, but (together with Nassim Taleb) have also advocated for it.
As Taleb and I wrote in the Financial Times in 2008:
The next-generation pharma company will create a lean, agile organisation able to capture, consider and rapidly develop the best scientific ideas in a wide range of disease areas and aggressively guide these towards the clinic. Small market size will not deter their pursuit of promising drugs with a clear and comparatively inexpensive path to clinical development; their ideal portfolio will consist of an extensive collection of such molecules, cheap options that may offer unexpected benefit to patients and provide disproportionately large returns to investors.
There are important caveats. FDA approval doesn’t always equate to commercial success and focusing on specialized products at extremely high prices can be tremendously challenging (particularly in the current political environment). That can be the case even if the value to the patient and the healthcare system is exceptional.
(For now, at least, investors seem to like what they are seeing. The company’s stock is near its all-time high, and the current market cap is north of $120B – ahead of Gilead Sciences, whose transformative hepatitis C products compelled Vertex to focus elsewhere).
Furthermore, while remaining agnostic about modality does maximize optionality, this approach may underestimate the difficulty of utilizing an emerging technology, where many of the details are still being worked out; presumably Vertex is hedging their risk in these areas by partnering with platform companies like CRISPR Therapeutics and Moderna.
Another key limitation – which Altshuler acknowledges – is that the human causal biology approach (“our quest to go where causal biology demands”), as Vertex applies it, will only work in conditions for which there are compelling data; it’s essentially like looking only where the (causal) light is.
Even so, the idea of leaning into causal human biology, as Vertex is, seems intuitive and increasingly supported by data. Why doesn’t everyone adopt the Vertex approach?
Two responses spring to mind.
First, large pharma organizations are invariably guided by market size projections and are perhaps unlikely to embrace the specialized markets Vertex tends to focus on.
But this is unlikely the whole answer.
What I really think is happening is something similar to what we’re seeing in tech, where every tech company claims it’s embracing AI, whether it’s OpenAI actually pursuing artificial general intelligence or the many entrepreneur wannabes creating a “glut of scam companies that are little more than wrappers on OpenAI’s GPT tech,” as one Hacker News commenter aptly observed.
In biopharma, as BioCentury astutely noted, and as many readers have probably experienced, “casual human biology” is all the rage.
“Expectations are rising for researchers to show newly proposed drug targets have a causal role in driving or preventing disease,” writes BioCentury’s Karen Tkach Tuzman, adding that there’s a “mandate to provide proof of causal human biology for novel targets.”
Tuzman continues,
The phrase is on the lips of research heads and early-stage investors, who use it to mean that a target or pathway plays a role in causing or preventing a human disease, such that modulating it will cause an intended effect in patients. Its rise has paralleled a shift in which the traditional strategy of proposing target hypotheses based on animal studies is taking a back seat to human-first approaches.
What’s more, AI approaches, as BioCentury also notes, increasingly seek to provide computational insight into networks and relationships, quantify causality, and increase probabilities of success.
In theory, this suggests we’re likely to see a marked increase in translational success, but in practice, what actually seems to be happening across the industry is that “human causal biology” is invoked almost universally to justify any given approach to any given target.
I don’t think there’s a single program in biopharma R&D that doesn’t have a “causal human biology” narrative to which they can point.
My sense is that Altshuler and Vertex have far more stringent criteria for “causal human biology” than most others, and place particular emphasis on primary insights from human beings rather than what J.S. Haldane called “scraps and fragments” of people (a patient-centric framework Joe Martin, Denny Ausiello, and I advocated here in 2000). This deliberately high bar may contribute to Vertex’s apparently high success rate.
By analogy, I’d point to the example of Danaher and its rigorous application of the principle of “kaizen” – continuous improvement. While most every company claims to embrace kaizen, I don’t know of an organization that is more rigorous about it than Danaher, or, over time, more successful. Vertex is as serious about causal human biology as Danaher is about kaizen – a commitment that may be associated with achieving better than expected performance.
The hope, of course, is that:
