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Bill Lundberg, CEO, Merus; former CSO, CRISPR Therapeutics
A little more than 10 years have passed since the discovery of CRISPR gene editing. It’s been a whirlwind development for science and medicine. We are now on the cusp of seeing the first medicine based on this powerful technology win approval from regulators in the US and Europe.
It’s exagamglogene autotemcel (exa-cel), a cell therapy developed by CRISPR Therapeutics and in partnership with Vertex Pharmaceuticals. The treatment is made when a patient’s blood is withdrawn, hematopoietic stem cells are isolated in the lab, they are gene-edited to produce high levels of fetal hemoglobin, and then the edited cells are re-infused back into the patient.
These engineered cells, after a single shot, have been shown to successfully produce enough fetal hemoglobin-expressing and oxygen-carrying red blood cells to effectively cure patients with sickle-cell disease and transfusion-dependent beta-thalassemia. Vertex and CRISPR Therapeutics have completed their application for FDA approval.
This is a landmark achievement for the biotech history books. It’s both a meaningful treatment for patients with no good options, and it’s a testimony to our industry’s capacity to turn basic science into life-changing medicines.
I was there in the early days as the first US-based employee and chief scientific officer of CRISPR Therapeutics. Let me tell you a bit about how this medicine came to be, along with some lessons that we learned along the way.
We opened our first lab in Boston in 2015. Within three years, we filed to begin our first clinical trials in Europe for CTX-001, now called exa-cel. CRISPR Therapeutics raised a $25 million Series A financing from Versant Ventures in April 2014. One year later, we raised a $29 million Series B financing from that included Vertex, SR One, Celgene, and Bayer.
We had resources, but not unlimited resources. We had to think about where to start with a technology that could potentially change any gene in the genome, or could potentially treat any one of hundreds of different diseases.
The first big decision was about where to concentrate our valuable time and energy. We couldn’t afford to be distracted, or risk spreading ourselves too thin.
We chose initially to pursue sickle cell disease and transfusion-dependent beta-thalassemia. This was a logical place to start.
Every patient with sickle cell disease has the exact same molecular change. Every patient has the same clinical manifestations of rigid, sticky, and misshapen red blood cells that can clump together and damage the lining of blood vessels, and organs. Every patient suffers from terrible pain crises that end up requiring emergency medical care. Every patient has respiratory problems. Fatigue is a constant battle. Patients suffer terribly for years, and they die too soon.
We knew that while patients endure a variety of symptoms, we had a chance to take them all out if we could deliver a single, elegant edit to those blood-forming stem cells. (The related disease beta-thalassemia, with similar rationale and evaluation of therapeutic approaches is not discussed further here).
By National Human Genome Research Institute (NHGRI) Creative Commons license.
We also knew that if we went down this path, we could find out quickly in the lab if we were wrong. Biomarkers of disease and treatment efficacy – both short-term and long-term – could be easily obtained from a blood draw. And we wouldn’t have to wait for a long-term follow-up study to tell us if the biological edit caused an improvement in the clinical outcomes that matter most.
The genetic defect, as alluded to above, is in the hematopoietic system, from which cells can be removed, studied, manipulated (gene edited), and returned to the patient. Several gene therapy companies that came before us already established processes that were well-understood. Perhaps equally important, we knew that sickle cell disease was severe enough that doctors and patients would consider trying out a brand-new technology to treat it, even though that naturally meant taking on some unknown risks.
Once settling on sickle cell disease and beta-thalassemia as our top priorities, we then had to think as clearly as possible about the questions to ask. The first and most obvious one was:
One option was to correct the genetic defect itself in the beta-globin gene, by using CRISPR to “knock-in” the correct code. However, we found early on that such a gene correction approach was less efficient than other approaches described below, and we were concerned we may not be able to correct enough of the cells to treat the disease. The CRISPR edits also cause gene disruption, which might knock out beta-globin function and cause thalassemia major, making the patients worse.
This strategy wasn’t worth the risk, and we dropped it quickly.
Before spending too much time and money in the lab, it helped a great deal to work with experts in the field and dig deeply into the literature. We went back to re-read a seminal finding published back in 1948, by Janet Watson, a pediatrician in New York. She observed that infants with sickle cell disease hadn’t yet developed symptoms and proposed that this was related to the protective effects of a fetal form of hemoglobin in the blood at birth.
Remarkably, the infants Watson studied only developed symptoms 6-9 months after birth, when the adult beta globin gene, or the sickle globin variant in patients, was fully expressed. In 1955, scientists found that some adult patients had only mild symptoms. These patients were no longer infants, but they appeared to have a persistent expression of an “alkali resistant” form of hemoglobin known as fetal hemoglobin, which was responsible for ameliorating symptoms. Later studies confirmed that increased levels of fetal hemoglobin is associated with reduced clinical manifestations, and acute pain episodes.
These observations decades ago made it clear: If scientists could spur more expression of fetal hemoglobin in adults, either through gene therapy or gene editing, it could make a big impact against the disease. There are now many reported inherited variations in gene sequences that are known to cause long-lasting expression of fetal hemoglobin into adulthood. Perhaps re-creating one of these rare variants in cells from a patient could ameliorate disease. Importantly, prior work by others had validated this approach, including in mouse models here and here.
Another approach was suggested by genome-wide association studies here, here and here that identified more commonly occurring variations in different genes that had more modest effects. These led to a series of remarkable discoveries, essential for our later work: the BCL11A gene is a master regulator of fetal hemoglobin. Removing it alone — a single factor — from the red blood cell compartment leads to high fetal hemoglobin and cures sickle cell disease in a mouse model; and ultimately identifying the critical sequences in the BCL11A gene that controls its function in the red blood cell compartment, called an erythroid enhancer.
Perhaps we could aim our CRISPR gene editing efforts at BCL11A or other targets identified by genome wide studies, to cause high levels of fetal hemoglobin and cure sickle cell disease. At CRISPR Therapeutics, we extensively evaluated in the laboratory these two approaches: re-creating variants associated with hereditary persistence, and disrupting sequences identified by the genome wide association studies and subsequent BCL11A studies. We were also guided by important concurrent work from multiple academic laboratories also pursuing similar approaches, for example here, here and here.
As we evaluated different potential approaches, we needed to keep asking ourselves the most pertinent questions.
We intended to edit the hematopoietic stem cell, which gives rise to the disease-causing red blood cells. The ‘edited’ hematopoietic stem cell contains the genetic code to produce both the fetal hemoglobin that would be protective, and the defective sickle hemoglobin that is the source of so many problems.
But here’s where we were fortunate: fetal hemoglobin is extremely potent in overcoming the toxic effects of sickle hemoglobin. As little as 25-30% fetal hemoglobin appears protective, slowing down by 10,000-fold the sickling process of hemoglobin polymerization in the low oxygen state that causes symptoms. That provides ample time for the red blood cell to circulate back to the oxygen-rich lungs, to prevent the onset of sickling.
We were also fortunate that not all red blood cells in a patient had to be corrected to reduce or prevent the worst symptoms – the vaso-occlusive crises that often send patients to the Emergency Department. Only two-thirds of the red blood cells in a patient need to be of the healthy and non-sickling type to dramatically reduce the risk of stroke, as shown in studies of blood transfusion therapy.
We also realized that far less than two-thirds of the hematopoietic stem cells that give rise to red blood cells actually needed to be corrected, because these blood cells that are protected from sickling will last longer in circulation and accumulate over time. As little as 20-25% correction of the precursor hematopoietic stem cells could give rise to this important two-thirds blood cell threshold, based on computer models and experiments in mice.
Remarkably, these predictions matched the observations here, here and here from rare patients who carried a mix of both healthy donor cells from transplantation and also some of their original, disease-associated cells.
This was an important signal to us. The bar wasn’t impossibly high.
Once we settled on our strategy for gene editing, and we had an idea of the threshold we needed to clear, we had to ask ourselves the same question over and over in different ways —
We presented our initial results at the American Society of Hematology annual meetings in 2016 and 2017, where we demonstrated 80% editing efficiency of the hematopoietic stem cells – far greater than the 25% needed. The process we invented delivered greater than 30% fetal hemoglobin expression. These values met or exceeded our goals, and, together with other foundational work from academia supporting our approach, encouraged us to move forward into the clinic with the lead candidate CTX-001 (now exa-cel), which uses CRISPR gene editing to disrupt the erythroid enhancer of the BCL11A gene.
It can be easy to get immersed in the details of the biology or new technology or only focus on the efficacy measures. But we had to remain rooted in the most basic question of all —
The body produces an estimated 2-3 million red blood cells per second. With the nature of our edit, it had to be safe, precise, and it had to persist. We would only find out the answers to these questions in clinical trials.
We wondered why the intended change we were making with our gene editing had never been observed in a patient, despite the evolution of hundreds of other naturally occurring genetic variations that both increased fetal hemoglobin in patients and reduced their symptoms. Might our particular edit have some other negative effects that we had not yet uncovered? We knew that loss of BCL11A function outside of the red cell compartment had other negative effects, shown here and here.
In contrast, our approach with CTX-001 limits the BCL11A disruption specifically to the red blood cell lineage. We didn’t have direct validation from human genetics to lean back on, to give us confidence that it would be safe. However, extensive foundational academic work — for example here and here — and our own preclinical experiments were critical in providing further support for our approach.
Early on, concerns had been raised in the scientific community about the potential for ‘off-target’ effects elsewhere in the genome with CRISPR gene editing. At ASH 2017, we addressed this concern directly. The specific guide RNA (site for editing) we selected showed no evidence of off-target activity in a deep evaluation of thousands of potential off-target sites, and the edited cells still functioned normally.
Furthermore, there was no evidence of clonal (precancerous) growth and no evidence of cancer formation in the standard Good Laboratory Practice (GLP) toxicology studies. The cumulative body of evidence to that point supported our decision to go to the clinic with CTX-001.
From the start we were faced with the question:
When we began, it was unclear how best to apply this new CRISPR gene editing approach. Should the Cas9 nuclease component be delivered as protein or encoded in RNA or DNA? Should we use separate CRISPR and TRACR RNA fragments — as occurs naturally in bacteria — or use a concatenated single guide RNA? Should RNA be synthesized or transcribed? Or contain bases that are chemically modified? Introduced into the cell by transfection, viral transduction or electroporation? Which source was best for starting and in-process materials? How to establish GLP materials and methods? How to bring experimental-grade processes up to Good Manufacturing Practice (GMP) standards?
Our research and process development teams urgently evaluated different variables and suppliers to assess and determine the optimal approach; we relied, as much as possible, on well-established methods and providers for obtaining, managing, manipulating and evaluating hematopoietic stem cells; for process development and manufacturing; and iterating through variations at scale with GLP-like materials and under GMP-like conditions where necessary. This was about reducing as many variables as possible, over time, to keep focused on the immediate problem at hand: to invent a CRISPR gene editing process for patients that was effective, robust and reliable.
We also wondered:
Like other early entrants, we faced considerable scientific and public concern about the ethical and societal consequences of human gene editing. Much of the concern centered on heritable modifications to the germ line, in which changes could be passed on future generations, with no turning back.
This concern about “editing humanity” or “designer babies” led some to call for a total ban on human gene editing for therapeutic purposes. That would derail or delay not only our own progress and ability to finance our company, but also the efforts of the entire field. We all had to address it thoughtfully.
We engaged consultants and obtained an evaluation from the ethicists and clinicians at the Stanford Center for Biomedical Ethics. Together with another gene editing company, we met with the White House Office of Science and Technology Policy as well as members of Congress and staff on Capitol Hill to both educate and learn.
We participated in the first International Summit on Human Gene Editing at the National Academies of Sciences, Engineering and Medicine in December 2015. We published a peer-reviewed position paper recommending that CRISPR gene editing for therapeutic approaches should “treat the patient, not [modify] the germline.” We were hoping to build broad support for somatic (non-heritable) gene editing of the kind we were developing in CTX-001.
We did not know whether the regulatory landscape for CRISPR gene editing would be permissive. We relied on established FDA Guidance and EMA Guideline documents and precedents as much as possible. We engaged extensively with consultants and sought early advice from national health authorities. We formed partnerships with clinical trialists and clinicians with deep experience in genetics, pathophysiology, disease management, and transplantation medicine.
With this support, we developed clinical protocols that incorporated the appropriate patient selection, treatment plans, endpoints and evaluation, and biomarkers and thresholds for success. We worked hard to ensure that our clinical plans continued to be aligned with regulatory guidance, guidelines and precedent.
The rapid development of exa-cel, from opening our labs in 2015 to first clinical trial application in Europe in 2017, could only have been possible through the dedication, hard work and focus of the teams at CRISPR Therapeutics, with the help and support of our partner Vertex, the deep knowledge and expertise of our many collaborators, and the foundational understanding of red cell biology and disease pathogenesis built over the past 70 years, summarized here.
The impact on patients with sickle cell disease has been remarkable. As of Dec 2022, all 31 sickle cell disease patients treated with exa-cel remain free of transfusions or vaso-occlusive crises.
Rarely in our careers are we given the opportunity to bring a brand-new technology, in this case CRISPR gene editing, to an important and well-understood medical need. We are all grateful to be able to contribute to this landmark achievement, the first CRISPR gene editing medicine.
This article is adapted from a talk given at the 80th birthday symposium in honor of MIT professor Robert Weinberg.
David Shaywitz
In 1935, Astounding Science — the premier science fiction magazine of the day, and perhaps ever — published “Proxima Centauri.” It was a short story envisioning an encounter between a voyaging earth spacecraft and a ship from a nearby star system. 
Written by Murray Leinster (William Fitzgerald Jenkins), the tale features the original use of the phrase “first contact” in science fiction. Think Close Encounters of the Third Kind, or perhaps more appropriately the “To Serve Man” episode of The Twilight Zone, since Leinster’s aliens turn out to be carnivorous plants who quickly develop (as alien plants often do) a taste for human flesh.
“First contact” is also the phrase Microsoft’s head of research Peter Lee selects to describe his initial encounter with GPT-4, in The AI Revolution in Medicine: GPT-4 and Beyond, the engaging and timely new book he’s co-authored with Harvard physician-scientist and
AI researcher Zak Kohane and journalist Carey Goldberg, documenting the trio’s early experience with this emerging, intriguing technology.
Lee’s phrase seems apt. When I asked GPT-4 to provide the first paragraph of a blog post on the subject, written in the style of The New Yorker, it responded:
The phrase “first contact” conjures up images of flying saucers and green men, of awe and wonder, of fear and loathing. It is the ultimate fantasy—or nightmare—of humanity’s encounter with the alien Other. But what if the Other is not from another planet, but from another machine? What if the first contact we are about to make is not with a distant civilization, but with a new form of artificial intelligence that surpasses our own in linguistic prowess and creativity? This is the prospect that looms over us as we await the arrival of GPT-4, the latest and most advanced iteration of a technology that can generate coherent and convincing texts on any topic, given only a few words or sentences as input….
GPT-4 even provides a cogent opinion on the popularity of “first contact” stories in science fiction, suggesting it may reflect the interplay of curiosity, fear, hope, and imagination.
Lee and Kohane have worked on AI their entire careers – yet neither seemed prepared for their encounter with GPT-4. Both described losing sleep as they contemplated the implications of what they describe as an “alien intelligence” with whom they each formed a “relationship.” Both are struck by its capabilities,yet acknowledge its limitations.
Lee describes GPT-4 as “at once both smarter and dumber than any person you’ve ever met.” He is particularly captivated by its ability to “imagine emotions and perhaps even empathize with people.”
Lee and his colleagues also present a series of specific, formalized challenges to GPT-4, examining its common-sense understanding, its moral judgement, and even its ability to navigate “theory of the mind” tests, exploring GPT-4’s ability to intuit what others might be thinking. The performance of the technology was extraordinary, Lee reports.
Responding to one question involving two roommates who shared a cat that was moved from one place to another when one roommate left the apartment, GPT-4 not only correctly anticipated the likely reaction of each roommate, but even offered an opinion on what the cat in the scenario might be thinking – namely that the two roommates were “very rude and confusing because they keep moving it from one place to another without asking.”
As discussed in my last column, Kohane was especially impressed by the GPT-4’s clinical reasoning skills, and by the way it approached complex medical cases and suggested reasonable next steps. On the other hand, GPT-4 would also make some fairly basic mistakes (especially involving math), and would often confidently assert it was correct even when it demonstrably was not.
Having established GPT-4’s bona fides, Lee, Kohane, and Goldberg devote the balance of their text to a question that even the technology itself might struggle with: how do you solve a problem like GPT-4? Each of the three authors seems focused on slightly different aspects of the challenge.
Lee appears especially preoccupied with the underlying existential question of what GPT-4 is, and whether at some level it can “understand” and “empathize.” He seems consumed by GPT-4’s capabilities, particularly since so many of these, “were not programmed by humans. Instead, they emerged into existence – sometimes unexpectedly – as its neural network grew.”
He continues, “how on earth can it be that the next-word prediction can possibly do… all the things that we’ve seen…unfortunately, we simply do not know the answer to this question.”
Kohane seems hopeful the technology can be used as a partner or co-pilot for healthcare providers, reducing burnout, administrative burden, and medical error, while allowing providers to practice at the top of their license. He delights in the possibility of physicians able to focus once more on the complex reasoning and human relationships that had first attracted so many of us to the profession.
Carey Goldberg
Projecting forward, Kohane imagines a next-generation large language model, fancifully called “Dr. One-With-Everything,” encompassing “protein structure, other basic biological databases (like gene regulation and human genetic variation), preclinical studies, and the design and conduct of clinical trials.”
This model, Kohane suggests, “will be likely the central intellectual tool for biomedical research by the mid-2030’s.”
Goldberg, meanwhile, offers the most pragmatic and in some sense relatable perspective on how GPT-4 will be used. She recognizes that “because GPT-4 appears to be such an extraordinary tool for mining humanity’s store of medical information, there’s no question members of the public will want to use it that way – a lot.”
Already, Goldberg writes:
“health-related web searches are second only to porn searches, by some counts. Surveys find roughly three-quarters of American adults look for health information online. It’s not hard to predict a massive migration from WebMD and old-style search to new large language models that let patients have a back-and forth for as long as they want with an AI that can analyze personal medical information and seems almost medically omniscient.”
Moreover, she adds, patients want this capability now. While awaiting access to GPT-4, she writes, “My ‘everypatient’ emotion has tended to be impatience. Sure, I get the risks of hallucinations and other little-understood distortion, but I’ve still felt mainly the AI-delay frustration of people on the waiting list for chatGPT: ‘I get it – it’s not perfect. I’ll manage – just give me access!’”
The promise of democratizing this powerful technology is easy to appreciate. As Microsoft AI expert Karmel Allison tells Goldberg, “If the internet and the mobile age were about putting information in the hands of everyone across the planet, the AI age is about putting intelligence into the hands of everyone across the planet.”
Karmel Allison
At the same time, the co-authors all recognize that there are clearly risks involved in deploying this powerful technology. Kohane, for example, asserts “GPT-4 cannot be used in medical settings without direct human supervision.”
Kohane and Goldberg also suggest that this is the “moment for broad, thoughtful consideration of how to ensure maximal safety and also maximal access,” and emphasize the need for “guardrails to keep patients as safe as possible.” But they also recognize it’s a “tricky balance,” adding:
“those safety measures must not mean that the great advantages that we document in this book end up unavailable to many who could benefit from them. One of the most exciting aspects of this moment is that the new AI could accelerate healthcare in a direction that is better for patients, all patients, and for providers as well — if they have access.”
None of the co-authors seem to seriously contemplate pausing ongoing work in generative AI – as Elon Musk and others have recently proposed.
Kevin Scott
Collectively, the authors’ perspective seems well-summarized by Microsoft Chief Technology Officer Kevin Scott, who tells Goldberg, “The technology will exist. It will have an enormous amount of possibility. I think it will be incredibly useful and powerful. And then society has to choose how it’s going to use it.”
It’s a thrilling future to envision, to anticipate, and (as many of us hope) to help create.
Unless, of course, the technology breaks away, and chooses how it’s going to use us.
How To Serve Man? It was a cookbook.
Vikas Goyal, Managing Partner, Trekk Venture Partners
Jan Skvarka isn’t a household name in biotech. Maybe he should be.
Skvarka was previously the CEO of Trillium Therapeutics, where he led a remarkable turnaround of the Canadian small cap biotech into a leading immune oncology player. Trillium had a market capitalization of $16 million when he started. Over the next two years, he led it to a $2.26 billion acquisition by Pfizer.
The acquisition gave Pfizer access to TTI-622 and TTI-621, two potentially best-in-class CD47 inhibitors now in development for multiple cancer indications, and a team of more than 50 expert drug developers.
Prior to Trillium, Jan had a long career as a strategy consultant at Bain & Co, an experience that would help him in many ways during Trillium. He is currently the executive chairman of DEM Biopharma, and a board member of Zentalis Pharmaceuticals and Monte Rosa Therapeutics.
Jan Skvarka, former CEO, Trillium Therapeutics
Jan spoke with me about why he is so excited about the CD47 mechanism, the situation when he joined Trillium, and how he approached the strategy, culture, and vision for the company.
I have always been fascinated by the success of T cell checkpoint inhibitors. It’s one of the biggest success stories in the history of medicine, delivering cancer cures, winning the Nobel Prize, and soon to be the largest drug class ever.
But, T cell checkpoint inhibitors engage only the adaptive arm of the immune system, and typical response rates are about 20-40 percent. My aspiration was to help create a novel checkpoint inhibitor therapy that would target the innate arm of the immune system, and – ultimately – in combination with T cell checkpoint therapies, to have a complete immunotherapy regimen that engages both arms of the immune system, and would challenge chemotherapy as a frontline approach in cancer
[When I joined Trillium in 2019,] CD47 was arguably the most promising innate immune system checkpoint inhibitor in clinical development. Trillium had two CD47 blockers with promising safety profiles and monotherapy activity.
Importantly, the molecules did not bind red blood cells and hence didn’t cause anemia, a major potential liability with some of the other CD47 targeted approaches in development. Trillium’s lead molecule also had stellar monotherapy activity, with over 90 percent of cutaneous T cell lymphoma (CTCL) patients showing lesion improvement within three weeks of treatment in an ongoing Phase 1 study.
Trillium had a great core executive team in Canada, comprised of CSO Bob Uger, CTO Penka Petrova and CFO James Parsons. They were highly capable in their respective functions, smart, loyal and dedicated.
But the company was facing numerous challenges.
One, the company’s lead program was intratumoral treatment of CTCL. Neither the delivery route nor the indication had any commercial legs. So this was an ironic situation — the clinical data was incredibly strong, but strategically the program had little commercial potential, and as such no appeal to partners or investors.
Operationally, the phase 1 study was stuck in its fifth year of crawling patient enrollment.
On the financial side, the stock price was down from a high of $30 to $0.40 per share. There was almost a complete exodus of quality investors save for NEA. We were only a few months of cash away from hitting Going Concern, and the company was about to be delisted from NASDAQ.
Nevertheless, the scientific foundation was there. And with this foundation, and the core executive team, I felt we had a shot at rebuilding.
Given the challenging situation, I spent about six months on a diligence of the underlying science and Trillium’s assets. I wanted to be sure my conviction in the scientific foundation was solid.
I also wanted to be sure I was aligned with the board on what to do.
So I wrote a memo before I joined, outlining: (1) my analysis of the situation, (2) strategic options, and (3) plan and hypothesis for how to proceed. I presented the memo to chairman Bob Kirkman and, with his support, spoke to every member of Trillium’s Board. Once we had alignment, I was in.
It would end up being a two-year journey which I describe in three stages.
Stage one I’ll call the Emergency Room, stage two was Transformation, and stage three was The Build Out.
Stage one, the Emergency Room, took the first three months – the fourth quarter of 2019. We approached the situation like a patient in an ER, when you have to stop the bleeding. First, to address the cash burn, we had to lay off 40 percent of the staff. Second, we had a complete reset of strategy — we discontinued the lead intratumoral CTCL program and refocused on the intravenous route while prioritizing larger hematologic indications and solid tumors.
We also decided to resurrect the backup molecule, TTI-622, which would eventually become the molecule that drove Pfizer’s interest. By the way, I also believe that this decisiveness and speed helped us later rebuild investor confidence.
Stage two, the Transformation, took about 15 months, spanning 2020 and the first quarter of 2021. It was a lot of systematic blocking and tackling, touching every single aspect of the company.
On the people side, six out of eight board members and five out of eight executive team members, including myself, joined as part of the turnaround. We created a world class SAB and six indication-specific Key Opinion Leader panels.
We moved the headquarters from Canada to the US (Cambridge, Mass.), and transitioned from a foreign to a domestic filer. We raised $300 million across two rounds. We secured an equity deal with Pfizer for $25 million and added their chief scientific officer of oncology, Jeff Settleman, to our scientific advisory board.
At the first signs of COVID, we bought two years of manufacturing capacity in advance, a critical decision that helped us execute clinical studies without any delays.
On the clinical development side, we accelerated patient enrollment despite COVID, completed Phase 1 studies, declared recommended Phase 2 doses, and – critically – showed best-in-class monotherapy activity with intravenous delivery, and strong tox profiles.
We also did a lot of work in the trenches with investors. This was a turnaround and we needed to rebuild confidence. We had over 400 investor meetings in 2020! We recruited Paul Walker and Ali Behbahani from NEA to our board, which sent a strong signal to the investor community. And even with magrolimab’s good data at ASH 2019, it was only with our significant effort to communicate our new strategy that we got any read-through benefit.
In April 2021, we entered Stage three, The Build-out. With money in the bank, board and executive teams in place, and two molecules with class-leading monotherapy activity, we launched a broad Phase 2 program with nine clinical studies across multiple indications in both hematologic malignancies and solid tumors, while doubling the size of the organization within the next year.
The initial $25 million Pfizer investment was not about the money – it was about validating our work, building relationships, and getting access to Jeff’s expertise.
Let me step back to January 2020, just as we exited the “ER”. At that time, we announced a new strategy transitioning TTI-621 from intratumoral to intravenous delivery, and from CTCL to larger hematological malignancies.
A few months later that year, our back-up program TTI-622 started showing strong monotherapy activity with a very good tox profile, while TTI-621 was experiencing thrombocytopenia issues. We made a strategic decision to transition the strategy a second time, making TTI-622 our new lead program while deprioritizing TTI-621. I was worried about how this new transition would be perceived by investors.
The Pfizer equity investment gave us an important validation for the shift to TTI-622. On Sept. 8, 2020, at 4 pm, we announced the new data for TTI-622. Two hours later, at 6pm, we announced the Pfizer deal. The day after, we announced we were going to do a public fundraising offering. Then on Sept. 10, we closed the round for $150 million.
At this time, with Phase 1 studies of both TTI-621 and 622 ongoing, we weren’t looking for a partner. We were in a great place to continue building the data and building the company, and we had high confidence in our assets. However, come May 2021 and the stock price started coming down, partly due to the markets getting nervous about biotech, and partly due to some retail investors selling out of their Trillium positions.
I approached John DeYoung, Pfizer’s head of business development for oncology, to ask if Pfizer would consider another $25 million equity investment, given that we had generated [substantial additional] Phase 1 data since Pfizer’s initial investment in September 2020. John said “let us have a look at the data” and Pfizer started the diligence. While they were looking at the updated Phase 1 results, Phase 2 data started coming in, including from some very tough multiple myeloma and AML patients, two indications of strategic interest to Pfizer.
It was at this point that Pfizer shifted their interest from a simple equity investment to a full buy-out.
I’m not a believer in lengthy meetings about culture and putting lots of buzzwords on the wall. Buzzwords are cheap – after all, even Enron had “Integrity” engraved on their headquarters entrance wall. I think culture is shaped organically through how we make decisions, who we recruit, and how we treat employees. It has to be with respect, transparency and honesty, while always keeping patient impact in mind.
It is critical to have a vision and be crystal clear about the company’s direction. And not just clarity about who you are. It’s also equally important to be clear about who you are not. Without this clarity, companies and executives get distracted, they get pulled in different directions.
The toughest part of my time at Trillium was Stage one, the emergency room. Turnaround situations require decisive leadership and speed. There is no room for hesitation. You cannot procrastinate. Maybe you can still pay severances if you move today, but if you prolong things six months the company could run out of cash. And the team is deflated and maybe considering moving on to other opportunities – so staff are already anxious to hear where we are heading. So, we did these changes with speed, balanced with respect and transparency.
It was this respect and transparency with our staff that allowed us to rehire several laid-off employees once we were stabilized.
Trust is key. Don’t oversell, always be honest and transparent. In our case, Pfizer had about 150 people on the due diligence, and they turned over every stone. So, if there are any problems, just be transparent about them, disclose them upfront, as you don’t want them to come up later in the diligence and then play defense.
That’s a great question. I believe there are two parts to it – relationships that contributed to our success at Trillium, and relationships that were formative to who I am as a person and an executive.
On the Trillium part, we had a truly outstanding team. In addition to my Canadian executives who I mentioned before, we later added Ingmar Bruns, a talented, brilliant chief medical officer; Lisa Fiering, an excellent human resources executive; Ben Looker, an outstanding general counsel; and Rose Harrison who thoughtfully led our strategy efforts.
Paolo Pucci, our lead director, masterfully guided the board through its M&A considerations and was always there for me as a great coach and mentor. Jason Fenton of Cowen (now with Oppenheimer) played a critical role in our fundraising efforts, especially at a time when no other banker would have touched Trillium. Eric Tokat of Centerview was much more than just our M&A banker – he was also a true advisor who guided several of our major strategy and BD decisions even before we were an actual M&A candidate.
I would be remiss not to mention also the Pfizer oncology leadership team – Jeff Settleman, Oncology CSO, who as our SAB member greatly contributed to some of our most critical clinical development decisions; Chris Boshoff, oncology chief development officer, who did a phenomenal job at pre-merger integration and squarely deserves the credit for achieving a 100 percent acceptance rate of the Trillium staff who were offered to continue with Pfizer after the acquisition; and John DeYoung, oncology BD head, a master communicator and someone who just gets things done.
Beyond Trillium, I have been incredibly lucky to have great mentors who took personal interest in me, helped me grow as an executive, and navigated me in many tricky situations. In particular, I owe enormous debt to three people who I worked with as a CEO of Tal Medical prior to Trillium – Steve Paul, Tal co-founder and Board chair, former head of R&D at Lilly, who coached me in my transition from a Bain consultant to a life sciences CEO; John Abele, Tal senior advisor, co-founder and former chair of Boston Scientific, who taught me how to build industry relationships and manage people; and Bob Langer, co-founder of Tal’s parent company PureTech and MIT professor, who helped me navigate several complex business and career situations.
Last but not least, I’d like to mention Chuck Farkas, senior partner at Bain & Company, under whose thoughtful mentorship I grew from a fresh MBA grad to one of the lead life sciences partners at Bain. It is my aspiration to help other life sciences executives by passing on the knowledge I learned from these great individuals.
Luke Timmerman, founder & editor, Timmerman Report
The next biotech team adventure is here.
I’m thrilled to announce the Timmerman Traverse for Life Science Cares 2023.
We’re on a mission to raise $1 million. We’re giving it all back to the most vulnerable people in the communities where we live and work.
This trip involves shared sacrifice. We will cover 20+ miles and gain 8,000 feet of net elevation on the Presidential Traverse in New Hampshire. The expedition is set for Aug. 20-23, 2023.
Sweat will be involved. Legs will be tired. The weather may get rough. Teammates will need to lend each other a hand.
The difficulty is what makes it so meaningful. Over the past two years, this initiative has raised a combined $1.7 million to fight poverty.
Awareness of Life Science Cares and its outstanding network of community nonprofits is on the rise. Relationships among scientists, executives and investors have been forged on the trails. Sometimes these relationships translate into new professional and business opportunities.
The Life Science Cares network is brimming with excellent nonprofits who are entrepreneurial problem-solvers. Some provide basics like food and shelter. Others concentrate on on-ramps to a better life in the long term, through science education and job training. They are smart, caring, inspirational, resilient people.
Our resources are concentrated in biotech industry clusters — Boston, San Francisco, San Diego, Philadelphia, and New York.
Everyone who goes on this expedition must raise a minimum of $25,000. Many raise more. Each hiker has his or her personal reasons for stepping up to the challenge. I encourage you to look over their personal statements and donate to their campaigns on JustGiving.org.
Corporate sponsorship opportunities for this year’s Timmerman Traverse for Life Science Cares are available. See Mathias Vialva mathias@lifesciencecares.org for more information. If you are interested in joining the hike, see me. luke@timmermanreport.com.
These trips are a wonderful way to enjoy nature, get fit, give back, and make new friends.
Biotech entrepreneurs can do amazing things when focused on a tough challenge.
Let’s roll up our sleeves and fight poverty together.
Luke
See what alumni of the Timmerman Traverse have to say:
“We started as industry colleagues with an aligned philanthropic goal. We finished as friends, deeply connected through an experience none of us will ever forget and all of us will work to rekindle in our lives.” — Reid Huber, partner, Third Rock Ventures
On the top of Mt Clay, there are no hierarchies, job titles, favored sons, or favored daughters. You are driven by your personal grit, your fellow climbers, and the beauty and challenges in front of you. We climbed for ourselves, we climbed for each other, but most importantly we climbed for the community being served by Life Science Cares. It was a bond we will never lose.” — Dave Melville, founder and CEO, The Bowdoin Group
It was amazing to see leaders across our biotech industry come together to raise funds to help bridge the unfortunately real gap between the medicines we develop, and the patients and communities who need access to them.” – Vineeta Agarwala, general partner, Andreesen Horowitz
Members of the Timmerman Traverse for Life Science Cares 2022. At Crawford Notch.
Today’s guest on The Long Run is Eric Dobmeier.
Eric is the CEO of Seattle-based Chinook Therapeutics.
Eric Dobmeier, CEO, Chinook Therapeutics
Chinook is seeking to develop drugs for kidney diseases. About 10 percent of people on Earth are estimated to have some degree of chronic kidney disease. It ranges from mild forms all the way through end-stage renal disease that requires dialysis. America spends $130 billion a year on managing and treating kidney disease.
The therapeutic options are pretty limited. Chinook is developing a Phase III drug candidate, atrasentan, for IgA nephropathy – a disease of localized inflammation in the kidneys. That’s a small molecule. It also has an antibody drug candidate for IgA nephropathy in Phase II, aimed against a target called APRIL.
The founding thesis of the company was to use some of the tools of precision medicine – which have successfully changed the way many types of cancer are treated. That vision hasn’t exactly materialized yet. But the FDA has shown some willingness to consider surrogate endpoints, biomarkers, that make clinical trials a bit more practical to run. Kidney disease has become more attractive for drug developers who have to look at the time and expense required, and probability of success of various disease categories, before deciding where to invest.
During a biotech financial downturn, Chinook finds itself in the fortunate position of having late-stage clinical assets that will deliver meaningful data readouts within the next year.
Eric comes to this opportunity after a long career on the business side of biotech. Eric, a lawyer by training, made his way from basic contracts to more strategic business development, and eventually other functions – investor relations, communications, manufacturing, and corporate strategy. He was there 15 years, as the company grew into the leading maker of antibody-drug conjugates for cancer. Seagen has now agreed to be acquired by Pfizer for $43 billion.
Eric’s had quite a career already, and he’s an area with a lot of patient need, and a lot of potential for biotech to help people live better lives.
And now for a word from the sponsor of The Long Run.
Occam Global is an international professional services firm focusing on executive recruitment, organizational development and board construction. The firm’s clientele emphasize intensely purposeful and broadly accomplished entrepreneurs and visionary investors in the Life Sciences. Occam Global augments such extraordinary and committed individuals in building high performing executive teams and assembling appropriate governance structures. Occam serves such opportune sectors as gene/cell therapy, neuroscience, gene editing, the intersection of AI and Machine Learning and drug discovery and development.
Now, please join me and Eric Dobmeier on The Long Run.
David Shaywitz
Biopharma, like the rest of the world, appears to be on the threshold of profound, technology-induced change. Incredible advances in artificial intelligence, manifested most recently in GPT-4, are here.
This technology, Ezra Klein explains in the New York Times, “changes everything.” Bill Gates describes it as “the most important advance in technology since the graphical user interface,” and declares, “the age of AI has begun.” Similarly, Times columnist Thomas Friedman argues:
“This is a Promethean moment we’ve entered — one of those moments in history when certain new tools, ways of thinking or energy sources are introduced that are such a departure and advance on what existed before that you can’t just change one thing, you have to change everything. That is, how you create, how you compete, how you collaborate, how you work, how you learn, how you govern and, yes, how you cheat, commit crimes and fight wars.”
At an entrepreneurship salon at Harvard this week, I discussed GPT-4 with Dr. Zak Kohane, Chair of the Department of Biomedical Informatics at Harvard University (disclosure: I’m a lecturer in the department), and Editor-in-Chief of the soon-to-be-launched NEJM-AI.
Kohane received early access to GPT-4. He has just completed a book, The AI Revolution in Medicine: GPT-4 and Beyond, to be published in mid-April, about the impact of emerging AI technology on healthcare. I read an advanced, draft copy of the book. Kohane’s co-authors are Peter Lee, Corporate Vice President and Head of Microsoft Research, and Carey Goldberg, a distinguished journalist.
From both the book and the salon, the three most striking features of GPT-4 seem to be:
How did GPT-4 impress Kohane? For starters, it performs spectacularly on standardized exams like the medical boards, and seems to be able to reason thoughtfully, Kohane says.
Zak Kohane
For example, we discussed the ability of GPT-4 to respond to an apparent paradox that Kohane says stumps the vast majority of the non-physician data scientists. The question: why is a low white blood cell count between midnight and 8 am associated with far worse outcomes than a low count between 8am and 4 pm?
GPT-4’s top suggestion, Kohane says, was the correct answer: the issue isn’t so much the low blood count but rather the existence of a blood draw in the middle of the night. That signals the patient is experiencing some sort of medical crisis.
GPT-4 can also provide sophisticated differential diagnoses, Kohane says, and suggest relevant next steps.
He posed GPT-4 a question from his own specialty, pediatric endocrinology:
“I gave it a very complicated case of ambiguous genitalia that I was actually called for once back in my training. And it’s able to go through everything from the clinical presentation to the molecular biology. It had a disagreement with me and was able to cogently disagree with me, and it was also able to articulate concerns for the parents of this child and for the future engagement of the child in that discussion. So, on the surface it’s acting like one of the most sensitive, socially aware doctors I’ve ever met. But we have no guarantee that it is such.”
The ability of GPT-4 to engage in such a human-like fashion is one of the most striking, and disarming, characteristics of the technology. Many who engage with GPT-4 over time describe the sense of developing a close relationship with it, in a fashion that can feel dislocating. Kohane, Lee, Friedman and others all describing losing sleep after spending time with GPT-4. They are overwhelmed, it seems, by the power and possibility of what they’ve experienced.
“GPT-4’s abilities to do math, engage in conversation, write computer programs, tell jokes, and more were not programmed by humans,” wrote Lee, of Microsoft Research. These capacities emerged unexpectedly, he wrote, “as its neural network grew.“
Peter Lee, Corporate Vice President,
Microsoft Research
This creates what Lee calls a “very big problem.” He writes: “Because we don’t understand where GPT-4’s capabilities in math, programming, and reasoning come from, we don’t have a good way of understanding when, why and how it makes mistakes or fails….”
The implications are dizzying. As Kohane writes, “I realized we had met an alien agent and it seemed to know a lot about us, but at the moment, I could not decide if it should be given the keys to our planet or sealed in a bunker until we figured it out.”
Some AI experts, like University of Toronto professor and author Avi Goldfarb, said the AI technologies will serve as a democratizing force in healthcare. He suggests, in a podcast interview with Patrick O’Shaughnessy, it will be able to “automate diagnosis,” with the consequence of “upskilling” the “millions of medical professionals” like nurses and pharmacists. The consequence, he suggests, is that:
“There’s hundreds of thousands of doctors in the U.S. and their special skill in diagnosis is going to go away. They’ll have to retool and figure out how to deal with that. But there’s millions of other medical professionals who are now going to be able to do their jobs much better, be more productive. And that upskilling provides a lot of what we see as the hope and opportunity for AI.”
I asked Kohane about this, and (to my surprise) he seemed to largely agree, albeit with a slightly different framing. He notes that we have a crisis resulting from a shortage of primary care doctors. Massachusetts (as the Boston Globe has recently reported) is being hit particularly hard. While we may have an idealized view of how the best primary care doctors can treat patients, Kohane argues, this is generally not the lived reality, and suggests that a nurse practitioner or physician assistant, coupled with AI, could generally offer a higher level of care for patients than a typical primary care doctor without AI. Given the shortage of trained medical professionals, AI can help improve the quality and quantity of available care.
It’s also clear that patients will have access – and, through Bing (which works with GPT-4 when accessed from Microsoft’s Edge browser), already have access – to this knowledge and information.
Many patients and caregivers are eager for this capability, as Goldberg writes in the book. The problem is that GPT-4 (like surgeons and Harvard grads) tends to be frequently correct but rarely in doubt. It still suffers from the problem of “hallucinations,” making up information that sounds plausible but isn’t accurate. Like humans suffering from the Dunning-Kruger Effect, it can insist that it’s correct, when it’s wrong. I saw that when GPT-4 tried to persuade me that Goose, not Merlin, uttered the line “That MIG really screwed him up,” in the original Top Gun.
For now, everyone seems to acknowledge the hallucination problem, and call for “human in the loop” approaches. But what happens as we gain more confidence in GPT-4 and, motivated by both convenience and cost, are increasingly tempted to take the human out of the loop?
What seems clear is that we are truly experiencing what economist Carlota Perez has described (see here) as the “irruption phase” of emerging technology. We recognize that there’s something promising and incredibly exciting, and now everyone is trying to figure out what to make of it, and how to apply it.
These days, it feels like every healthtech person I know who hasn’t started their own VC fund (as noted here) is either starting their own health+AI company or writing a book about health+AI, and in some cases both. Microsoft Office programs are about to be boosted by GPT-4. Other companies, such as the regulatory intelligence company Vivpro – are already offering GPT-powered tools. Every consultancy is offering executives frameworks and navigation guides to the new technology.
The truth, of course, is that no one has any idea how things are going to evolve. The pharma company of the future, the healthcare system of the future, the payor of the future, perhaps even the FDA of the future: all are likely to be profoundly changed by technologies like GPT-4.
The technology will likely first arrive as incremental, point solutions, says Goldfarb, of the University of Toronto. Eventually, however, the real productivity gains arise from more fundamental change. The classic example here, as I’ve discussed, and as Goldfarb also cites, is that dropping electric generators into factories built around steam power didn’t have much impact. But reconceptualizing the structure of factories from the ground up, in a fashion enabled by electricity, was transformative.
As Microsoft AI expert Sebastien Bubeck observes in Kohane’s book, “GPT-4 has randomized the future. There is now a thick fog even just one year into the future.”
What an amazing, terrifying, thrilling, and hopeful time to be alive. For those of us in medicine and biomedical science: what an opportunity, and profound responsibility, to be in the arena, actively shaping the future we hope to create and aspire to inhabit.
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.
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 Ryan Watts.
Ryan is the co-founder and CEO of South San Francisco-based Denali Therapeutics.
Ryan Watts, co-founder and CEO, Denali Therapeutics
Denali is one of the prominent development-stage biotech companies working on treatments for neurodegenerative diseases. It has a pipeline with seven drug candidates in clinical development. It’s developing small molecules and large molecules against a range of neurodegenerative diseases that includes rare diseases such as Hunter Syndrome and ALS, as well as more common maladies such Alzheimer’s disease and Parkinson’s.
Ryan is a scientist by training. He did his PhD at Stanford University and spent the first part of his career running labs at Genentech. He joined with former Genentech colleagues Alex Schuth and Marc Tessier-Lavigne to co-found Denali in 2015. The company secured a Series A financing of $217 million – which was big then, and is still big now. The company doesn’t yet have any products on the market, but it has amassed $1.34 billion in cash as of the end of 2022, and has established a broad base of support for its R&D through partnerships with Sanofi, Biogen, and Takeda Pharmaceuticals.
This is a wide-ranging conversation that includes Ryan’s path into biotech and neuroscience, some of the classic challenges of the field, and reasons why he’s optimistic that significant progress is coming to neuroscience R&D.
And now for a word from the sponsor of The Long Run.
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Now, please join me and Ryan Watts 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.
Chris Garabedian, chairman and CEO, Xontogeny
There has been much debate about the biotech workplace in the aftermath of pandemic disruptions.
Employers and employees are all thinking about how and to what extent companies should enable and support remote-based work. People are discussing the advantages and disadvantages of remote work, especially in terms of the effect on productivity and creativity.
This matters in biotech. The goal of the industry is to discover, develop and manufacture products for patients. Two of those three activities — wet-lab discovery and manufacturing — require a specialized physical space. Much of this work has been outsourced and takes place far from headquarters. Many biotech office workers rarely, if ever, step foot into the wet labs or manufacturing facilities, even if those functions are in the same building.
The nostalgia for pre-Covid office culture must die. Some biotech leaders, including John Maraganore (TR, Jan. 24, 2023), argue that having management and employees working together in person is essential to a company’s ability to be productive, creative, and competitive.
I disagree. This is a notion that should fade away.
The Fourth Industrial Revolution, which includes the blurring of the physical and digital worlds with increasingly smarter and connected technologies that allow us to intimately communicate with an expanded network of people ever further away from us geographically, has arrived. Those clinging to work practices established in the Third Industrial Revolution are swimming against the current of an inevitable change in corporate culture and talent management. Companies that embrace this change will have a sustainable competitive advantage.
It is important to take a long view of how technology has profoundly changed our behaviors in how we live, learn and work over the last 200 years, especially over the past 50 years.
No one questions that we are designed to be social creatures and we long for interaction with others from the moment we leave our mother’s womb. Throughout most of history, we have established strong relationships with our immediate and extended families and forged friendships and work relationships with people nearby.
The last two centuries brought technological change to transportation and communications. These developments changed the nature of commerce, how and where we worked, and our personal and professional identities and lifestyles.
Although sea vessels were used by the Egyptians and Mesopotamians thousands of years ago, most relied on horses and camels to connect with others for socialization and commerce. It was not until the 19th and 20th centuries that we saw the invention of the steam locomotive (1812), the first automobile (1886) and the first airplane (1903) which became available to the masses, at least in wealthier developed countries, decades later.
While the invention of the Gutenberg printing press in the 15th Century is credited as one of the greatest inventions in history, it was not until the last 175 years that we saw the widespread proliferation of interpersonal communication tools. It started with the telegraph (1844) and telephone (1876), and continued with the mobile telephone (1973). These communication tools enabled us to reach and interact with others who lived great distances away.
The more profound impact on our socialization, culture, identity and sense of community came with the advent of radio and television. Although these were one-way passive forms of communication, these media allowed us to become familiar with those that were not in close physical contact with us.
This passive form of communications technology has exploded into an interactive lollapalooza over the last 30 years with the internet, social media, VOIP, texting and messaging apps. When Covid hit, it brought another change, forcing everyone in business to use Zoom and similar video conference platforms.
We discovered some things. It was now possible to have a productive meeting, with internal colleagues or external collaborators, that went well beyond the audio-only conference calls of the past.
Before COVID, the arguments for remote-based and hybrid work over traditional office culture were largely theoretical. But now we have run the experiment.
Consider the following advantages:
While no one is suggesting the choice between old office culture and remote-based work is black and white, as each has their pros and cons, I believe the balance is more favorably weighted toward decentralizing work that that can be done anywhere.
My job requires leading investments across dozens of companies, serving on Boards of Directors, and having a presence at conferences and industry events.
It might sound shocking, but it is no exaggeration to say that the move to video meetings allowed me to be 2 to 3 times more productive than in the pre-Covid era.
In 2018 and 2019, I spent over 200 nights in hotels. That translated into countless hours on trains and planes (often with spotty or unworkable WiFi) and the often unproductive time Uber-ing to the airport, waiting at the gate, Uber-ing to a hotel, and waiting in line to check in. At the end of this typical slog, I’d realize I wasted an entire day, often to attend a 90-minute in-person meeting or to be part of a 60-minute panel at a conference.
While I often would be able to stay on top of my emails or dial into a few critical conference calls, it would have been easier to manage if I were consistently in front of a computer, on video, with no concerns about a good WiFi signal.
On prolonged trips in the pre-Covid era, was not uncommon for me to have no or limited meaningful interactions with my employees. Since Zoom became a mainstay, I now have more routine daily interactions with my employees. I have experienced more team engagement, not less.
Several years before Covid lockdowns forced the new way of working, I founded my company, Xontogeny, with a simple concept: good science and entrepreneurs were found in institutions and geographies all over the country – not just in the top biotech hubs of Boston/Cambridge and the San Francisco Bay Area. Our industry needed a better way to assist these companies by providing operational and strategic support remotely.
The model has worked. We have successfully supported more than a dozen seed investments, which often require weekly interactions. Almost none of those meetings take place in-person. Our seed investment companies are located in Philadelphia, Chicago, San Diego, Research Triangle Park, NC and our first collaboration was with a company in Blacksburg, Virginia. The Xontogeny team covers even more territory through investments out of our Perceptive Xontogeny Venture Funds (an investment vehicle of Perceptive Advisors).
As investors, we keep tabs on our companies largely through quarterly board meetings. With over 20 investments, simply participating in board meetings translates to a big time commitment. If we were required to attend four board meetings per year in-person for every company, it would be almost impossible because of the required travel.
In-person board meetings can be especially inefficient. For example, to justify flying 6 to 8 board members from various distances, the meeting agendas are often extended to 6 to 7 hours (e.g., 8:00am-2:00pm). Many directors have to depart early to catch their Uber back to the airport to get home so they are not forced to take a red-eye back to the East Coast.
Contrast this experience of dialing into a Zoom link for 3 to 4 hours. It’s now possible to fit two or three board meetings into a day. In the last three years, no board meeting I’ve attended virtually has needed more than four hours. More often than not, they end early, without anyone ever feeling there was insufficient time to cover the necessary topics. This increased efficiency frees up time for me to do other valuable things, like meet with employees.
Requests for in-person attendance at conferences are back in full-swing, but I already long for the Covid era where I was able to attend multiple conferences within a couple weeks, or even in the same week.
At one Netherlands-focused virtual conference, I was able to engage with dozens of scientists and entrepreneurs. The following week, I attended a similar virtual conference focused on Copenhagen. Each of these conferences took up less than a couple of hours on my calendar, but led to numerous follow-ups on email, many pitch decks shared, and subsequent one-on-one Zoom meetings.
The results were just as good, if not better, than if I had spent a lot of extra time and money to attend in person. The same could be said the for the JP Morgan Healthcare Conference. I stopped attending in 2020, and have found ways to be just as productive, if not moreso, by working in the virtual office.
Biotech has historically taken root in geographic hubs because they have an abundance of drug development talent. San Francisco, Boston, New York/New Jersey have been traditional leaders, thanks to their many excellent academic institutions. But it’s also true that many outstanding scientific entrepreneurs are scattered across the United States (and throughout the world). An increasing pool of experienced industry talent prefers to live outside the main biotech hubs, and many can’t be enticed to move back.
Employers, myself included, have had to choose between losing star employees or adopting a more flexible remote-based model. I prefer to choose keeping star employees, and offering a more flexible, remote workplace. Young employees are especially interested in the flexible, remote work offerings. Any company that wants to recruit and retain this group of workers should be paying close attention.
The argument for how the younger generation will suffer in their careers if they don’t experience the same in-office facetime with their managers or CEOs strikes me as empty. They are getting more facetime, virtually, and more opportunities to contribute, display their creativity and convey the fruits of their work to managers. In this new virtual, geographically-agnostic biotech community, I’ve met more people, and established more meaningful relationships, than during any three-year period of my career.
These last 18 months have been a challenging time for the vast majority of early-stage biotech companies. Management teams are finding it difficult to close financings, are asked to shelve programs and focus on one or two core activities to conserve cash. Layoffs are a weekly occurrence.
Our industry is constantly under pressure to be smarter about R&D productivity and careful with investor dollars. Cutting back on unnecessary leases, and embracing the remote workplace, is one way to be a good steward of capital and extend the company runway.
Of course, there are still good reasons to maintain some physical space, even for the office workers. There will remain employees who prefer the go into the office and management teams that prefer office culture and will demand all employees report to the office 3 or 4 days per week. I don’t begrudge those that choose to offer this alternative working environment. There are many workers that prefer to get more of their social needs and personal identity through daily in-person work interactions. Many of us have formed our closest friendships, met romantic partners or found our spouses through the workplace.
In speaking to many colleagues, it seems that for every one of those individuals that prefer to have an in-person office setting, there are as many or more that prefer to spend more time at home with their partner or spouse, to see their children more often, or to visit aging parents. Some prefer to use their extra time to indulge their desire to travel. All this can be done while being a productive employee with just as much opportunity to impress the boss, take on new assignments, and advance one’s career.
It is time to embrace the future of remote work or ‘very’ flexible hybrid models as we embark on the Fourth Industrial Revolution. We can work together more efficiently, productively and, yes, creatively.
These new communication tools bring us all closer together. Rather than go back to an old way of working, let’s put more energy into determining how to optimize this new hybrid/remote model so we can get better at our fundamental work – discovery, development and manufacturing of new products for patients
If all goes well, we’ll see benefits extend far beyond what we’ve seen in these last three years.
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 David Hallal.
David is the CEO of Waltham, Mass.-based ElevateBio.
David Hallal, chairman and CEO, ElevateBio
ElevateBio describes itself as a technology-driven company for cell therapies. It has pulled together gene editing tools, induced pluripotent stem cells, and various viral vectors necessary to modify cells to fight cancer or treat other diseases.
David co-founded ElevateBio in 2017 with Mitchell Finer, the president of R&D, and Vikas Sinha, the chief financial officer. They saw a big bang moment in cell therapy, as hundreds of companies were being formed around the time of FDA approval of CD19-directed CAR-T therapies for cancer from Novartis and Kite Pharma. They saw many of these companies weren’t fully formed, and had a piece of technology here or there, but not the whole toolkit. Many of these companies were going to struggle to raise the cash needed to invest in needed facilities, and they were likely to need help from partners to refine their processes if they were ever going to do complex manufacturing at scale.
ElevateBio raised $150 million in a Series A financing in May 2019. It has used the money, and more that came later, to invest a lot in facilities and people with know-how to run them. The business is something of a hybrid animal. It uses its technology, people and facilities to make cell therapies under contract for other companies. You could call that traditional contract manufacturing. But this isn’t exactly a ho-hum service provider with relatively flat profit margins. It seeks to further leverage its technology and entrepreneurial people by investing in companies with upside potential, such as AlloVir, Abata Therapeutics, Life Edit Therapeutics and a startup from the lab of George Daley, the prominent stem cell researcher at Boston Children’s Hospital and Dean of Harvard Medical School.
David came to this moment – the beginning of a cell and gene therapy wave – after a long career in more traditional biotech. He was CEO of Alexion Pharmaceuticals, the rare disease company that was eventually acquired by AstraZeneca. He came up on the commercial side of the business, including key early career stops at Amgen, Biogen and OSI Eyetech.
This episode was recorded in person at the JP Morgan Healthcare Conference in San Francisco. Biotech history buffs will especially enjoy the first half, where he talks about what pharmaceutical sales was like and what it was like to work at Amgen in the early days.
Now, please join me and David Hallal on The Long Run.
David Shaywitz
The success or failure of many technology platforms — including in particular health tech platforms — rests with a largely obscure role of outsized importance: the “solutions engineer.”
The role itself goes by many names. Back when I was at DNAnexus in the mid-2010s, this role was called “Solutions Scientist.” Others call it “Forward-Deployed Engineer” or “Embedded Analyst.”
Whatever the title, the solutions engineer (SE) is a technology or data expert who embeds within an organization that’s trying to figure out how to make a new technology platform work. The SE functions as an on-site super tech-support specialist who helps the customer use the technology and get as much value from it as possible. While the SE doesn’t need to reside in the customer’s organization, the SE must inhabit the customer’s challenges and workflow — and having a desk (real or virtual) within the customer’s team can help.
Richard Daly, CEO, DNAnexus
“In a high velocity health information technology environment such as we are in,” says DNAnexus CEO Richard Daly, the SE is the “key person” for both selling and service, because “they get inside the customer’s skin, co-own the problem, and fit the solution to the customer need.”
At the same time – and arguably, this is the most critical aspect – the SE also develops a richly nuanced understanding of the needs of the customer and is able to provide this intelligence back to the product manager and the rest of the engineering team, so that the platform can be evolved to more effectively meet the needs (and future needs) of the customer, and presumably other future customers.
In serving as a “key transmission point” for both customer and tech company, Daly notes, the SE “improves product development and fit-to-market.”
Moreover, Daly adds, since “customers in the health tech market are scaling,” which introduces its own set of challenges, a well-functioning team of SE’s can “draw on industry and other customer experiences, in a way syndicating industry-wide knowledge, and ensuring continuing fit as the customer evolves.”
SEs come in different flavors, says Dr. Amy Abernethy, President of Product Development and Chief Medical Officer of Verily.
“The type of SE depends on the type of tech itself. Sometimes the tech is purely software, in which case you need someone fluent in the intersection of software development and customer needs. Sometimes the tech developer is supporting mostly data products, in which case the SE looks more like an embedded analyst who has data empathy, an understanding of customer analytic needs, and a sense of the possible from a data perspective. In pharma, the tech product is becoming increasingly more a combo of software and data, and the SE needs to be able to blend both of these skills.”
A lot of the thinking here comes back to the advice offered by Lean Startup author and entrepreneurship guru Steve Blank, who emphasized the need for the technology developers to spend as much time as possible with actual customers, to ensure that the needs the developers have prioritized are actually the same needs customers face.
In this context, SE roles provide the opportunity for essential fine tuning; after all, if a tech platform wasn’t in the ballpark, the SE would never have been given the opportunity to engage with a customer in the first place, and certainly wouldn’t be in the privileged position to go work on a customer’s team.
The most successful SE’s exhibit an authentic interest in the customer’s business – they are innately, intensely curious about the work the customer is doing, and the problems the customer is trying to solve. A high EQ SE can become an enormously valuable member of the customer’s team, a critical resource that enables them to function better and achieve more.
At the same time, it is absolutely critical that the SE is not regarded as simply as an implementation specialist, someone who gets a team up and running on a new system. Rather, the most significant opportunity the SE affords is to provide an inquisitive and adaptable technology team with a sense of what is and isn’t working well, and how the technology could more effectively meet customer needs. If the technology team isn’t thirsty for and responsive to this feedback, a valuable opportunity is lost.
The need for SEs applies not only to technology companies who are developing platforms, but also, in biopharmas, to internal technology teams as well. Indeed, because of the abiding, largely unbridged differences between the seemingly immiscible cultures of life-science trained drug developers, and engineering-oriented technologists, effective communication and shared understanding can be a challenge, as I’ve discussed here and here.
Amy Abernethy, president of product development and chief medical officer, Verily
In this context, Dr. Abernethy points out, SE’s can “help with ‘lingua franca,’ translating terms between customers and developers.”
Adds Dr. Abernethy, “This task is also becoming more important within the tech and pharma companies themselves as we see a confluence of actions/capabilities across teams within the companies. Building lingua franca will be a key accelerant across the industry and the SE can help.”
In large biopharmas, it’s common for technology teams, after a highly-structured, well-intentioned needs-gathering exercise, to put their heads down and set up developing and deploying a technology solution.
Afterwards, there’s often little rejoicing. Tech teams tend to grumble about how their brilliant technology is not being efficiently utilized, inevitably calling for more “change management,” while customers routinely complain that their most important needs are (still) not being met. It’s not uncommon to hear technology teams push for mandates that compel customers to use the new technology – an effort that’s received about as well as you might expect. What’s worse, this pattern seems to repeat all the time – it feels like the rule, not the exception.
In many cases, a critical missing link is an SE role – a person with “amphipathic” qualities embedded inside the customer teams to help apply and troubleshoot the technology, and (critically!) to provide ongoing granular feedback to the tech teams about how the tech could evolve to meet customer needs more effectively.
Success critically requires both curiosity and a commitment to continuous iteration on the part of tech teams. These teams must want to deeply understand customer challenges, and ideally begin to viscerally understand what the customers are trying to do, the problems the customers are trying to solve. At least as importantly, the tech teams must also see the relationship with their customers as a constant, on-going dialog. This can be particularly challenging in biopharma when technology teams are often more accustomed to obtaining and then building towards a set of fixed specifications.
There’s another complicating factor: many customers — especially within biopharmas — may not be all that clear on what they initially want from technology, or understand what might (or might not) be possible. This understanding can evolve and sharpen over time, particularly when catalyzed by a skilled SE, and enabled by a tech organization that’s driven to constantly refine the product on offer.
As technology plays a more central role in healthcare and biopharma, the role of the SE is likely to evolve accordingly. As Dr. Abernethy observes, “The technologies that are being developed are more and more informed by our understanding of underlying biology and/or data/implementation elements from clinical care. I wouldn’t be surprised if the phenotype of the solutions engineer of the future has a bit more science or clinical knowledge built in, and the job descriptions will similarly become more sophisticated.”
Perhaps reflecting her previous experience as Deputy Commissioner of the FDA, Dr. Abernethy adds:
“The SE may also need to generally understand the implications and requirements of many different regulatory paradigms. We see this right now, because sometimes the SE looks like a person who understands computational biology and software engineering, sometimes looks like a person who understands clinical and EHR data coupled with the needs of outcomes researchers delivering a dataset for a regulatory filing, and sometimes looks like a person who understands when a product crosses over the line to being regulated clinical decision support.”
Phrased differently, the SE role reflects and embodies the need for constant dialog and evolutionary refinement between those developing digital, data, and technology offerings, and those who hope to leverage these powerful but still unformed or unfinished capabilities.
A key gap in technology deployment, particularly in biopharmas, is the space between what technology teams develop and what customers actually want and need. A skilled solution engineer (SE) can bridge this gap and serve as a bidirectional translator, helping customers more effectively utilize the technology, and guiding technology teams to create improved solutions. Success requires not only a skilled SE, but also a curious and adaptable technology team driven to elicit, understand, and respond to customer needs – even (especially) when these needs are difficult for the customer to articulate.
Today’s guest on The Long Run is Joanne Smith-Farrell.
Joanne is the CEO of Cambridge, Mass.-based Be Biopharma.
Joanne Smith-Farrell, CEO, Be Biopharma
Many listeners of this show are familiar with the explosion of activity in cell therapy. Engineered T cell therapies have delivered extraordinary results for people with certain types of cancer. The success in these personalized T cell therapies, which get modified outside the body and re-infused, has inspired all kinds of academic and industrial work in engineering other cell types as cancer fighters, such as NK cells. Many others are seeking ways to make off-the-shelf, or so-called allogeneic cell therapies, that can be administered to patients much more cheaply and easily in clinics around the world.
What you don’t hear as much about is engineered B-cell therapies. This other arm of the adaptive immune system has been challenging for scientists to work with. This is the work Be Biopharma is setting out to do. It seeks to create engineered B cell therapies for cancer and rare diseases, which can be given off-the-shelf to any patient, and be given via repeat doses over time, without the need for toxic preconditioning regimens that are required by today’s cell therapies.
Joanne came to lead this startup in 2021 from Bluebird Bio, where she was chief operating officer and head of the company’s oncology business unit.
Joanne passion for biopharmaceutical R&D shines through in this conversation. She has a personal story here that reveals a lot about her outlook on life.
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