George Daley has gained clout and connections in a long career as a stem cell researcher at Boston Children’s Hospital and Dean of Harvard Medical School.
He can choose to work on a lot of different things, and work with a lot of different people.
David Shaywitz
The implementation of emerging technologies requires front-line users to figure out what to do with the technology – how to adapt the technology to the problems users are actively trying to solve.
The most impactful use cases often are not immediately obvious – for example, Edison envisioned the phonograph would be predominantly used to record wills.
Moreover, effective adoption typically requires more than simply substituting new technology into processes built around legacy technology. For example, when factories first started using electric generators to replace steam power, there was minimal impact on productivity. It was only when the design of the factory was reimagined by entrepreneurs like Henry Ford (a redesign enabled by electricity) that the promised gains were realized.
It’s also important to consider what success looks like. PCR, an approach to amplifying often tiny amounts of DNA, was developed by Kary Mullis, who received the 1993 Nobel Prize in Chemistry for his efforts. Adopted relatively quickly, PCR enabled advances from disease detection (eg for COVID) to molecular engineering.
Yet if you look around medical labs today, you won’t find a “Department of PCR” or a “PCR Center of Excellence.” In a sense, the lack of such exceptionalism is a measure of PCR’s success and impact. Today, PCR is organically incorporated into the way science is done. It’s a tool, like the telescope and the microscope, that can be used to enhance our exploration of nature.
Today, medical researchers are actively exploring how to utilize AI. Rather than investing the methodology with spiritual or magical properties, it is increasingly recognized as a tool — a powerful tool if applied thoughtfully — that scientists are incorporating into their study of nature.
Alphafold, for example, is a deep learning tool that offers powerful predictions of 3D chemical structures based on the underlying amino acid sequence. It is already routinely, and appreciatively, utilized by structural biologists. It’s become a powerful new addition to the armamentarium.
Now that AI in healthcare has hopefully transitioned past both the peak of inflated (and truly extravagant) expectations as well as the trough of despair, we seem to have at last arrived at the point where savvy scientists are using AI as another technique to pursue their questions.
For these researchers, AI (like PCR, like microscopy) is a valuable means, a tool used to solve a meaningful problem; AI is not (like in too many breathless early publications) an exalted end, where the use of AI is celebrated, rather than any result it enabled, the “dancing bear” phenomenon I’ve described.
A recent paper, called to my attention by my long-time colleague Dr. Anthony Philippakis, a thoughtful physician-scientist and the chief data officer at the Broad Institute, offers an inspiring example of where AI in medicine may be headed.
The research he describes (and of which he’s a co-author) was led by MGH cardiologist Dr. Patrick Ellinor, who I first met when he was a cardiology and electrophysiology fellow at MGH, during the start of my medical training.
Patrick Ellinor
Ellinor and his colleagues were interested in understanding the basis of aortic aneurysms, dilations of the large blood vessel that can lead to sudden death. The identification of genes associated with aortic dilation could potentially guide the development of future medicines, while also enabling the identification of patients at risk.
Previous work had identified several extremely rare alleles that, if present, unquestionably contribute to the development of aneurysms. Yet most patients who develop aneurysms don’t have any of these alleles.
Other researchers conducted a genome-wide association study (GWAS) to identify genetic variations (single nucleotide polymorphisms, or SNPs) associated with aortic abnormalities based on data meticulously measured and recorded by echocardiography technicians; a dozen or so SNPs that could potentially contribute to disease were identified.
A talented member of Ellinor’s group, Dr. James Pirruccello, had another approach in mind. Pirruccello wanted to leverage the UK BioBank, a massive collection of deep genetic and extensive phenotypic data available to researchers for analysis. For example, cardiac MRI studies were available for about 40,000 subjects. This treasure trove of phenotypic data could be paired with the genetic data associated with participants in the U.K. database.
The elegance of Pirruccello’s approach was how he extracted the data he required from the MRI images. Manual annotation of 40,000 cMRI studies (each containing about 100 images) would be prohibitively demanding and expensive. Instead, Pirruccello trained an AI algorithm to assess aortic diameter, and, amazingly, he did so using a relatively small number of manually annotated images – 116 (92 in the initial training set, 24 in the validation set).
This approach was feasible because algorithms had previously been trained to do similar tasks. While millions of labeled images are required to train the algorithm initially, you need comparatively few to adapt an established AI algorithm to perform a similar task. This is the principle of “transfer learning.”
With the algorithm in place, Pirruccello was then able to turn it loose on the 40,000 or so cMRI images. The team was essentially converting a binary variable (aortic aneurysm: yes/no) into a continuous variable (aortic diameter). That enabled a more sensitive GWAS. Indeed, just focusing on the ascending aorta, Ellinor’s team identified 82 independent genetic regions (loci) of interest, 75 of these were novel. These loci could potentially shed light on the pathophysiology of aortic aneurysm.
These SNPs were then used to generate a “polygenic risk score”– an approach that seeks to integrate the risk contributed by a number of different SNPs, as I’ve discussed here; see also here). In turn, this measurement was used to analyze nearly 400,000 UK BioBank participants to see if it might help predict aortic aneurysms.
Remarkably, subjects with a genetic risk score in the top 10% were found to be twice as likely to develop aortic aneurysms as participants in the other 90% of the population. This type of approach, in theory, could be used to identify patients at higher risk of aortic aneurysm, and presumably help guide prevention strategies, as well as help select patients for future clinical studies. The genetic data might also help identify promising therapeutic targets.
There are many lessons from this approach, including the value of large integrated genetic/phenotypic databases, the power of GWAS analyses and its potential in target identification, and the promise of polygenic risk score assessments.
But the most exciting lessons here involve the intelligent incorporation of deep learning to “parameterize phenotype,” as Philippakis explains. The idea is to elicit an important continuous variable from a collection of images.
Significantly, Ellinor’s critical GWAS analysis, integrating genetics and phenotype, didn’t involve deep learning – just comparatively staid analytics that geneticists have been doing for two decades; the approach is at this point relatively routine.
Similarly, the polygenic risk score calculation didn’t involve deep learning.
And the research certainly didn’t involve someone asking Watson, Jeopardy-style, to think hard and come up with genes involved in aortic aneurysms.
What was clever was how the researchers leveraged AI to generate the input phenotype used in the GWAS analysis.
I hope and expect we’ll see more of these types of “organic applications” of AI as the approach becomes both less exotic and more accessible, and establishes itself as a powerful enabling tool for thoughtful medical scientists.
Luciano Santollani, PhD candidate, MIT; Stanford ’18
We’re in the middle of a cytokine renaissance.
One of the initial cancer immunotherapies, cytokines made their clinical debut over 30 years ago, with Interleukin-2 (IL-2) leading the charge. In the body, this small protein is known to activate and proliferate T cells, making it a naturally promising candidate for immunotherapy.
Jingyi Liu is a resident physician at Brigham and Women’s Hospital
Venture financing news has slowed down this summer, especially in the megadeal category of $100 million+ rounds.
Cambridge, Mass.-based CAMP4 Therapeutics is the latest to defy the trend.
CAMP4, a company targeting non-coding RNA to restore healthy protein expression, is today announcing a $100 million Series B led by Enavate Sciences, a portfolio company created by Jim Momtazee’s Patient Square Capital. Other participants included Gaingels, an LGBTQIA+/Allies investment syndicate, and existing investors 5AM Ventures, Polaris Partners, Northpond Ventures, Andreessen Horowitz, and The Kraft Group.
Vikas Goyal, former SVP, business development, Pandion Therapeutics (now part of Merck)
James Mutamba is the chief business officer of Waltham, Mass.-based Arrakis Therapeutics. It’s a biotech developing small molecules against RNA targets.
Arrakis struck its first major pharma partnership in 2020 with Roche. During the JP Morgan Healthcare Conference this past January, Arrakis announced another multi-target collaboration with Amgen to discover and develop small molecule RNA degraders, a new drug class which Arrakis calls nucleic acid targeting chimeras (NUTACs).
Arrakis’ and Amgen’s research teams are now working together to jointly design and characterize these novel NUTAC bifunctional compounds. For Arrakis, the partnership provided $75 million of upfront working capital, and expanded its platform capability for making small molecules against RNA. Amgen is getting the right to nominate a set of five initial targets and it has the option to nominate more. The deal is part of a pattern for Amgen, as it underscores the priority it has placed on drugs that specifically inhibit more than one target implicated in disease biology.
James Mutamba, chief business officer, Arrakis Therapeutics
Mutamba joined Arrakis on Dec. 6, 2021. Arrakis received the first draft of the agreement from Amgen that week. The deal was signed before Christmas Eve and announced two weeks later at the biggest healthcare investment and dealmaking event of the year.
Mutamba spoke with me recently about what it took to close such a broad and high-impact collaboration so quickly.
Why do partners come to Arrakis for access to your RNA platform?
Arrakis is building a broad platform that, given any RNA target, can figure out the structure of that RNA and develop a small molecule compound against that RNA. Building this kind of platform necessitates a lot of external resources, expertise, and insights. So as we build our platform, we are also out talking about our work. As folks hear about what we are doing, some have come to us and said, “Hey, we have a problem that Arrakis might be able to help with.” That is really what precipitated our collaboration with Amgen, as well as our earlier collaboration with Roche.
Arrakis is developing small molecules that bind to RNA. One way to leverage this is to target RNA’s intrinsic functions, and this is the focus of our partnership with Roche. This means inhibiting translation, changing splicing, modifying RNA stability, or other aspects of the RNA function. Another way is to look at extrinsic properties – can we use a binding event to force a function? One ‘extrinsic’ approach we are pursuing is our NUTAC platform for targeted RNA degradation. NUTACs are hetero-bifunctional small molecules – one side targets and binds RNA, the other side recruits a nuclease or other factor to eliminate the disease-causing RNA.
Why did Arrakis and Amgen want to work together?
We had done some early concepting and could keep working on NUTACs on our own. But, just like our partnership with Roche, we saw the potential to have a landmark NUTAC partnership to supercharge our efforts and more rapidly provide a foundation for us to build our capabilities. There is no better group to work with in the multispecific space than Amgen. They have deep expertise in both targeted degradation and induced-proximity degradation, as well as vast capabilities and competencies in the multispecific small molecule space. In addition to their technical expertise, they also have strategic goals and commitment to multispecific small molecules. And that’s an important piece in choosing the right partner. Is your partner committed to finding a way to make the collaboration and science work? Are they willing to work through any hardships?
We recognized that Amgen has a strong interest in proximity-induced drug approaches. Our NUTAC concept is akin to a PROTAC – an area in which by the way Ray Deshaies, SVP of Global Research at Amgen, is a leading expert. There’s a media interview Ray did on our deal where he explained that Amgen was looking across the RNA space seeking technologies to enable this kind of RNA degradation approach. They kicked the tires of a bunch of players in the space, and ultimately concluded that we were the right group to go with. My supposition is, again, that their decision to work with us is a testament to the breadth of our platform. At Arrakis, our proposition is ‘give us any RNA target and we’re able to tell you what structures are targetable and we can build binders.’ Amgen was bringing the drug function with the effector piece of the hetero-bifunctional molecule. So I suspect for them the focus was on which partner could best figure out the RNA binding.
How did your discussions with Amgen start and grow into this collaboration?
While we had a goal to ultimately find a good partner on NUTACs, we were not yet actively reaching out to potential partners. This collaboration started with an informal discussion between Ray Deshaies and Arrakis’ CEO Mike Gilman. Mike and Ray are both UC Berkeley alumni and were on campus together for a reunion. They started to talk and there was an alignment of vision that ultimately opened the door to this collaboration. And because of the strategic decisions we made early on to go after any RNA target, Arrakis was uniquely positioned to work on RNA degradation strategies compared to some of our peer RNA companies.
It was about a year from that initial discussion between Mike and Ray to when we executed the deal. Things really got serious when we came up with, what I like to call, our “peanut butter and jelly sandwich” concept. Arrakis is bringing the RNA binder to the table, and Amgen is bringing the effector molecule to recruit the degradation factor, and we will work together to develop those into hetero-bifunctional medicines.
Once that bifunctional concept came into view, we started putting the agreement together, including the workplan of who was responsible for which research efforts, and the budgets. We really know how to build the RNA binding piece. Amgen has the demonstrated expertise and interest in building hetero-bifunctional molecules. So a lot of the discussion was about how, working together, we and Amgen could do things sooner or faster or better than what we would have been able to do by ourselves.
This all went really quickly because we had alignment and a shared vision. From the first agreement draft to execution was three weeks. It is the fastest deal that I have ever worked on. Everyone was aligned on who would be doing what, and what was of interest to each party. There were snags here and there, which is true for most deals, but we quickly got over those because people had a very clear view of what success looked like. And we just pushed towards that.
How did you figure out the economics of the collaboration? Did you have any precedent deals or templates you could use as a starting point?
I would say there were more proxy deals we could look at, such as partnerships in the degrader space where one party brought the ubiquitination bait portion and another brought the targeting side. There were some macro guiding principles from those that we could learn from.
In parallel to working through who was going to do what part of the research plan, we also discussed how we each viewed the economics, and how we wanted to share and apportion downstream value upon successfully developing medicines.
Some of these discussions did have the risk to blow up the deal. There were 11th-hour issues that that needed to be worked through. But this is often the case during negotiations, right? Our teams at Arrakis and Amgen just had to step back and ask, “What is our larger goal here? Can we work around this issue?” And on some of the negotiation issues, both sides had to just prioritize what we actually needed to figure out how to get the technical work started and defer other issues that could be worked out in the future.
Going into your collaboration discussions with Amgen, how well did the two companies understand each other?
Both Arrakis and Amgen have done a really good job of telling the external world what we’re interested in and what our expertise areas are. From Arrakis’s side, we have rigorous publications speaking to the scientific community, for example on our PEARL-seq tool. There are also informal things we do. We post about our culture on social media and our website. Our CEO has a huge Twitter following and talks about everything from his guitars to our company. Our success at getting the word out has really been through utilizing a mix of the technical and informal channels available to us.
Of course, Amgen spent time under the hood to confirm we were the best partner with RNA binders. The main effort was on making sure both we and Amgen were thinking about the NUTAC application in the same way. I remember a technical discussion where both we and Amgen were presenting our proposed workplans – there were a lot of nodding heads and people bouncing ideas off of each other. And it became clear that our working together would be complementary. For our team, I think that meeting really cemented for us that Amgen was the right partner.
How did you approach your role in this BD process?
I joined Arrakis the first week of December 2021. Just a few days later, we received Amgen’s first draft of the agreement. This was a high priority for Amgen. They wanted to announce the deal at JPM 2022. Both teams were aligned that we did not want to work over Christmas. So the deal was actually executed on Christmas Eve at 6 pm.
The pressure was on to get the deal done fast. We needed a quarterback to manage the deal timeline. I stepped into this role to coordinate our discussions – which conversations needed to happen, who needed to be in the room, did it get scheduled, did our people actually have the bandwidth to work on it, can I make this process more frictionless? And then ultimately making sure what we discussed made its way back to Amgen and into the contract. We were parallel processing discussions across the overall agreement, the IP terms, the technical work plan and the program management team. There was a lot to coordinate.
There were also strategic things coming up. If Amgen asked for something, I was taking the lead on analyzing how that issue might affect our interests. And as things zigged and zagged, I was keeping an eye on what we were trying to achieve overall and making sure we were landing in an optimal place.
And I was definitely the hub of the discussions with Amgen. Formally, I was the one facilitating all the communications that were happening. Informally, I was also doing the work to understand what Amgen really wanted. For example, some term would appear in a draft which, as written, might have been problematic. I was the person able to go to the lead contact at Amgen and just say, “Hey, what’s the real ask? OK could we solve it like this instead?” And then I was able to come to the next drafting session with a real solution. Having those one-on-one conversations in a low-pressure way helped us get the deal over the finish line, and de-escalate issues that sometimes initially seemed like a hornet’s nest. Of course, there were also some issues that we had to escalate, but we tried to keep them to a minimum.
My counterpart was Chester Wong. who led the transaction from the Amgen side. Chester and I didn’t know each other before this deal and actually never met face-to-face, negotiating the entire deal by video. When we started, it felt like we were across the table from each other. By the end, after spending many late nights together, our relationship got much tighter. Discussions would veer off the deal to what we were watching on Netflix . . .
[laughs]
By the end we were all around the same table trying to figure out how to make the deal work. I remember one late night call with the IP folks from both teams, and in real time, we started writing the agreement together. There was none of the usual posturing you often get.
This was an all-hands-on-deck effort with Amgen. How did that impact everything else happening at Arrakis?
One thing is to just brutally triage what is and isn’t important. Amgen was right at the top of the list of priorities. Mike and everyone on the operational side was on board with that. Plus, we didn’t need to disrupt the entire organization over this. There were specific people from our senior research team who needed to weigh in with Amgen, and we just activated people from our side as and when needed. So we could keep running the business as usual. But sometimes I needed to get an hour of the research team’s time to get their input on the Amgen negotiation, and the team just had to pause whatever they were doing.
I had just been through a similarly complex, time-gated IPO process, so I quickly intuited the role I needed to play on this deal. I also had people around me who wanted and supported me to play that role. When I joined Arrakis, the team was very welcoming and gave me leeway to get the deal done.
Who were all the people around the table during these discussions to hammer out all the aspects of the deal?
We had multiple sub-groups who were parallel processing the discussions. The Arrakis team was literally exchanging notes at the end of every day to keep track of what was changing.
Our overarching BD team working on the actual agreement included me, our CEO Michael Gilman, and our Head of Legal, Erik Spek. Erik has a great IP background, as well, so he was really weighing in those considerations.
On the technical side, it was our CSO Jacques Dumas and our Chief Innovation Officer Jen Petter. They were taking the lead on reviewing the targets Amgen wanted to work on, even doing some early research to validate the ideas. Amgen also had a technical lead on their BD team, Duncan Huston-Paterson who was working closely with Ryan Potts, Executive Director and Head of Amgen’s Induced Proximity Platform.
And we also had our program management team, led by our SVP & Head of Operations, Heather Lounsbury. Heather’s team was instrumental in putting together the budgets and the timelines for the collaboration, and really mapping out what was required to bring this science over the finish line. One of Arrakis’ lessons from the Roche collaboration process was the value for coordination between the scientific and business discussions, so we also built this into the Amgen deal process.
All in all, it was an effort of working through all these facets of the collaboration and integrating all of them.
Now that you are in the collaboration, can you describe how it’s helping accelerate the NUTAC approach?
One way I think Amgen might help us is by learning the requirements for hetero-bifunctional small molecules. For example, how to consider the exit vectors from the RNA piece and therefore what the linker needs to look like. Amgen has also worked on the nuclease targeting side, which should enable us to put together that “peanut butter and jelly sandwich” much faster. So now we can work in parallel on the RNA binding piece, the linker piece, and the bait molecules.
Amgen is also nominating the targets for the collaboration. They know the biologies, likely have the assays in place, and know what success on those targets looks like.
And from a resource perspective, the funding Amgen is providing helps to finance the work and hire people to do our work even faster.
Ultimately, what’s also important is having a mature, seasoned, experienced partner help shape how we develop these NUTACs. We experienced this with Roche, as well. Where we are today, as a function of that partnership, is an order of magnitude difference. For example, with Roche we’ve industrialized our screening methods and run more than 40 high throughput screens and matured our approach to building RNA targeting molecules. So similarly with NUTACs, I think Amgen has the potential to help us mature how we think about hetero-bifunctional medicines.
How does this create more value for Arrakis?
Our collaboration with Amgen is initially focused on five targets. There’s undoubtedly more than five RNA targets one would want to degrade. All of that is open to us. That goes full circle back to our strategy to have landmark partnerships that helps us mature the platform. Yes, we give up value to a well circumscribed number of targets in the space, but then everything else is available to us. So we can work beyond the Amgen collaboration to build our capabilities and still retain value that we can build on.
The collaboration also definitely brought a new visibility to Arrakis. This deal made a splash at JPM, which is exciting for a preclinical deal. People across the biotech investor and business spectrum got interested and reached out to us. We were one of the few preclinical companies to present at the JPM conference this year
Shifting gears a bit, what have you learned about BD working on deals for so long now?
First is just my disposition, in any deal, to take nothing for granted. Until the money is in the bank, anything can go wrong. So foremost is just get stuff done, keep the trains running, be aggressive on the timelines, and just keep slogging away to get the deal done.
Second is to root out any sensitivities that might exist but aren’t being stated explicitly. It’s always navigating people. It’s what’s not being said that, in some cases, is more important.
What was surprising with Amgen was how fast we did it, and also what it takes to get it done that fast. I was blocking off whole portions of my days to do calls with Amgen, and also doing these calls at weird times. In some ways it was helpful to have the West Coast, East Coast time differential. We tried to set up cycle times where one group was working while the other was sleeping.
And we also built a really good relationship with Amgen’s deal team. I think that was because they were so strategically aligned with what we are trying to do and there was buy-in across the whole organization on their side. During meetings, we didn’t come into the room and pontificate or grandstand. Everything was solutions focused. We were very quickly just being transparent if something really was unacceptable. All in all, none of these are all that unusual. But when you bring all these pieces together, that’s the surprise. And I think because of our strategic alignment and the relationship we built, we were able to get over a lot of contract issues and other snags that otherwise could have become showstoppers.
What did I forget to ask you?
Maybe a few parting thoughts on the road ahead. At Arrakis, we have the opportunity to replicate all of the novel modalities and progress that has happened on the protein side, except with RNA. Historically small molecules bind to a protein’s active site to change the behavior of that protein. That’s what our intrinsic partnership with Roche represents. The NUTAC partnership is a play on PROTACs. We’re now looking at irreversible inhibition or irreversible binders to RNA, which is similar to some of the covalent protein modifiers. Arrakis is sitting at the precipice of this large opportunity space, and there continues to be a desire at Arrakis to work with other partners to broaden our knowledge and enhance our scope and speed of developing new medicines. We are interested in doing more partnerships. I wouldn’t be doing my job if I didn’t put that plug in.
Luke Timmerman, founder & editor, Timmerman Report
Conferences are on midsummer break, and the weather’s warm. I’m going away for a couple weeks to Switzerland to climb the Matterhorn and the Eiger. Pictures to come.
I have a couple articles teed up for when I’m away. But for now, catch up on the highlights from this week in Frontpoints.
Today’s guest on The Long Run is Dr. Sanduk Ruit.
He is an ophthalmologist and the founder and executive director of the Tilganga Institute of Ophthalmology. The institute is in Kathmandu, Nepal.
Dr. Sanduk Ruit, founder, Tilganga Institute of Ophthalmology
Dr. Ruit has restored the eyesight of more than 130,000 people in Asia and Africa. He’s the pioneer of a small-incision form of cataract surgery. Not only was that a medical triumph, but he’s found a way to make the treatment accessible to many very poor people in Nepal and beyond. His institute has developed a way to manufacture its own intraocular lenses to insert in the eyes of patients, with the same quality of Western suppliers, and at a tiny fraction of the cost.
Dr. Ruit comes from a very poor and remote region of Nepal. He’s an inspiration in his home country, and has won more than 40 awards from governments and other institutions around the world. There’s a book about him called “The Barefoot Surgeon.”
I was fortunate to meet Dr. Ruit in Nepal this past spring. I was there with my team of 18 biotech executives for a trek to Everest Base Camp, in which we raised $1.3 million for research at the Fred Hutch Cancer Center.
While in Kathmandu, one of the trekkers, Jeff Huber, the former CEO of Grail, introduced me to Dr. Ruit and his amazing story. Jeff and I invited him to speak to our broader group. I’m glad, because Dr. Ruit’s work shows what a difference a talented and driven scientific entrepreneur can make. We were thinking a lot about how to make an impact for people in need, and Dr. Ruit really shows the way.
When he and his trainees do these eye surgeries, they are giving people their lives back, and relieving a major burden from whole families.
Now before we get started, a word from the sponsor of The Long Run.
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Now, please join me and Dr. Ruit on The Long Run.
David Shaywitz
Living in innovative domains like biomedical research requires an appreciation for the exceptional, the outlier. You might even argue that the goal of innovators – at least those who hope to see their ideas gain acceptance, or their inventions adopted – is to institutionalize the exceptional and make it routine.
In the Perez model of technology adoption, this is the basic difference between the “Installation Phase,” and the “Deployment Phase.” In the Installation Phase, the world tries to make sense of a new technology, and considers many possible expressions of it (rejecting most). In the Deployment Phase, the technology is widely adopted, becoming domesticated and routine.
Surviving and thriving in an innovation-oriented realm requires a distinctive mindset: the persistence and patience to search constantly for the exception..
At one level, of course, we understand the challenge: we know that most drug candidates don’t reach the market, that most startups fail, that most creative endeavors – music, literature, film – never leave an imprint on large numbers of people.
It’s also why many rational people prefer the comfort of more predictable domains, where consistency is both expected and prized.
The difference between exception-driven domains, ruled by the power law, and more predictable domains, governed by gaussian distributions, was also a central theme of Nassim Taleb’s The Black Swan – see here. Taleb termed these two worlds “Extremistan” and “Mediocristan.”
For those opting for innovation, for Extremistan, it’s easy to get discouraged and distracted by the median – especially after you’ve been pitched by the umpteenth unmoored AI startup or the latest vendor overpromising comprehensive distributed clinical trial capabilities, or forced yourself to remain awake through yet another dismal corporate visioning activity or ideation session.
Yet it’s critical to recall, as Stephen J. Gould famously explained, “the median isn’t the message.” Gould was diagnosed with a rare form of cancer, associated with a median survival time of eight months. While initially “stunned,” and “not, of course, overjoyed,” he was nevertheless able to recognize the possibility and promise of life on the far extreme of the distribution. Thanks to a deliberately positive attitude, exquisite medical care, and a lot of luck (not necessarily in that order), he lived another 20 years.
Colleagues who have thrived in innovative spaces seem to share Gould’s ability to locate the exception. Dr. Amy Abernethy, now at Verily, has long impressed me with her ability to identify the most hopeful outliers – ideas, people, organizations – however rare they might be.
The mindset is not to be confused with toxic positivity, which asserts that everything is just great; Abernethy, from what I can tell, has little trouble recognizing abundant mediocrity – but it doesn’t prevent her from also identifying and cultivating hints of unusual brilliance, wherever she might find it.
Similarly, I’ve always found myself involuntary drawn to the exceptional, and the most interesting. In organizations where most people are highly competent but just seeking to get their jobs done, I’ve consistently found the outliers, those with a slightly different perspective, and a more ambitious personal mission. The experience of connecting with an exceptional, perhaps overlooked innovator can turn a day of tedious, predictable meetings into one of discovery and promise.
Without question, in innovative spaces, it’s easy to get disillusioned. The hype is constant, and most innovation doesn’t pan out.
Nevertheless, to paraphrase Miracle Max from The Princess Bride (a movie that, as my friend and fellow Timmerman Report contributor Lisa Suennen has pointed out, may be the fount of all entrepreneurial wisdom), “there’s a big difference between ‘mostly crap’ and ‘all crap.’ ‘Mostly crap’ is slightly promising.”
And it’s this promise, however slight and elusive, that we need to celebrate, nurture, and relentlessly pursue.
As you wish.
Luke Timmerman, founder & editor, Timmerman Report
I was on the road for a few days for a Timmerman Traverse for Life Science Cares fundraising event in Kendall Square, followed by some climbing in the Teton Range of Wyoming. So this week’s Frontpoints rounds up highlights from a couple weeks.
Shehnaaz Suliman, CEO, ReCode Therapeutics
[Editor’s Note: this letter was drafted by female biotech leaders in response to the Supreme Court’s Dobbs decision. It was co-signed by more than 65 female biotech executives as of July 1. They’re listed at the end.]
Friends and colleagues, legislators and elected officials
We join the resounding millions in chorus to express our profound dismay and disappointment at the United States Supreme Court’s decision to strike down and ignore our fundamental rights as women to make personal reproductive health choices and for clinicians to practice evidence-based medicine without fear of reprisal.
Julia Owens, CEO, Ananke Therapeutics
It is a tragic moment in our history to see this blatant disregard for stare decisis and the repudiation of the will of the majority of the populace by the court’s conservative bloc. It negates the ability of medical practitioners that are best suited to provide care to vulnerable, pregnant women. It flagrantly ignores the physical, mental and financial consequences of carrying an unwanted pregnancy to term.
It is notable and discouraging that the decision comes at a time when our democracy bends under the heavy strain of partisanship.
Sheila Gujrathi, former CEO Gossamer Bio; board chair Ventyx Biosciences, ImmPACT Bio, ADARx Pharmaceuticals
By making such a cataclysmic decision, the Court demonstrated that America has become a country focused on special interests of the few rather than the interests of the majority. Whilst our nation was once conceived as a beacon of liberty for all, and an inclusive democracy and protector of fundamental human rights, this Court’s decision forces us to recognize the jolting reality that not all Americans are seen as equal.
Our right to be pregnant or unpregnant is a fundamental personal choice and civil liberty that should be safeguarded constitutionally. We believe in freedom of choice over our own bodies for all – but especially for women, underrepresented minorities, and LGBTQIA+ communities.
Abortion is reproductive healthcare. As doctors, scientists, innovators, caregivers, leaders and allies who are at the forefront of innovation in science and medicine for the benefit of patients and women around the world – we decry and denounce the decision by the Court.
We will not stand by silently. Our voices rise. We strongly dissent.
Shehnaaz Suliman, MD, MBA, M.Phil.
CEO ReCode Therapeutics
Julia Owens, PhD
CEO Ananke Therapeutics
Sheila Gujrathi, MD
Former CEO Gossamer Bio
Board Chair Ventyx Biosciences, ImmPACT Bio, ADARx Pharmaceuticals
Amy Burroughs
CEO Cleave Therapeutics
Wendye Robbins, MD
CEO Blade Therapeutics
Rene Russo
CEO Xilio Therapeutics
Hilary M Malone, PhD
CEO Certego Therapeutics
Leslie J Williams
CEO hC Bioscience
Rosana Kapeller MD, PhD
CEO ROME Therapeutics
Rekha Hemrajani
CEO Jiya Acquisition Corp.
Julie Anne Smith
ESCAPE Bio, Inc.
Aetna Wun Trombley, Ph.D.
CEO Lycia Therapeutics
Grace E. Colón, Ph.D.
CEO InCarda Therapeutics
Elizabeth Jeffords
CEO Iolyx Therapeutics
Alice Zhang
CEO, Verge Genomics
Angie You, PhD
Former CEO Amunix Pharmaceuticals, Board director Oric Pharmaceuticals and RayzeBio
Joanne D Kotz, PhD
CEO Jnana Therapeutics
Sabrina Martucci Johnson
CEO Daré Bioscience
Nancy Whiting, PharmD
CEO Recludix Pharma
June Lee, MD
Former CEO, Esker Therapeutics
Board Director at Tenaya Therapeutics, GenEdit, Cincor Pharma, Eledon Therapeutics
Kristen Fortney, PhD
CEO BioAge Labs
Yael Weiss MD PhD
CEO, Mahzi Therapeutics
Sevgi Gurkan, MD
Venture Partner, Orbimed
Sarah Boyce
CEO, Avidity Biosciences
Emily Drabant Conley, PhD
CEO Federation Bio
Board Director at Nuvalent, Medrio, and TMRW
Maria Soloveychik, PhD
CEO SyntheX
Kristine Ball
CEO Soteria Biotherapeutics
Samantha Truex
CEO, Upstream Bio
Kate Haviland
CEO Blueprint Medicines
Victoria Richon
Former CEO of Ribon Therapeutics
Ramani Varanasi
Former CEO, X-Biotix Therapeutics
Managing Director, ReVive
Daphne Koller, Ph.D.
CEO and Founder, insitro
Co-founder and former co-CEO, Coursera
Diala Ezzeddine, PhD
Former CEO, Xios Therapeutics
Ivana Liebisch
CEO Vigil Neuroscience
Catherine Stehman-Breen
CEO, Chroma Medicine
Alicia Levey, PhD
COO, Pionyr Immunotherapeutics
Mary Rozenman
CFO/CBO, Insitro
Susan B. Dillon
CEO Aro Biotherapeutics
JeenJoo Kang
CEO Appia Bio
Barbara Troupin, MD
Board Director, Equillium
Lisa Bowers
Former CEO, Rhia Ventures
CCO, Day One Bio
Charlene Liao, PhD
CEO Immune-Onc Therapeutics, Inc.
Sophia Yen, MD, MPH
CEO/Co-Founder
Pandia Health
Melita Sun Jung
Chief Business Officer, ShouTi
Siobhan Nolan Mangini
President & CFO, NGM Bio
Caryn McDowell
Chief Legal Officer, Cortexyme, Inc.
Lucinda Y. Quan
EVP, CBO & General Counsel, Aligos Therapeutics, Inc.
Suha Jhaveri
CBO and CCO, Leyden Labs
Christy Oliger
Board Director, Sierra Oncology, Reata, Replimune, Karyopharm
Yvonne Linney, PhD
COO Artificial Inc.
Christine O’ Brien
CEO, Tizona Therapeutics
Gisela A. Paulsen
COO, Oncocyte Corporation
Lori Lyons-Williams
CEO, a stealth biotech company
Karen LaRochelle
Venture Capital Advent Life Sci
Artax Biopharma CBO
Jodie Morrison
Venture Partner, Atlas Venture
Katherine Vega Stultz
President and CEO, Ocelot Bio
Katherine Bowdish
CEO , PIC Therapeutics
Patrice Milos
Board Director at 54gene, SeqLL, ProThera Bio
Sylvia McBrinn
Former CEO, Axerion Therapeutics
Director, BioAtla
Sarah Kurz
EVP, Partner Therapeutics
Lisa Iadicicco
Executive Director – WIB
Rosamond Deegan
CEO OMass Therapeutics
Linda Blackerby
CDIO, Informa PLC
Jennifer Petter
Founder and Chief Innovation Officer, Arrakis Therapeutics
Nerissa Kreher MD
CMO Entrada Therapeutics
Laura Lande-Diner
CBO Satellite Bio
Donna Higgins
CEO, The Higgins Group
Gail Maderis
CEO Antiva Biosciences
Rhonda Farnum
CBO, Theravance Biopharma
Clarissa Shen,
COO and Board Director, Q Bio
Lipid nanoparticles don’t get the glory. But these little packages have made it possible to deliver billions of mRNA COVID vaccines in people’s arms, saving millions of lives.
It’s been two decades of hard work. The strides ahead in delivery have fired imaginations of how to do even more.
Lisa Suennen
Matt Wilsey, CEO of Grace Science, once said, “You may have a plan set out for your career and your family, but life doesn’t always turn out that way…you have to make the most of it…turn the lemons into lemonade.”
It is a fitting description for a person who has made several shifts on a quest to cure a rare disease.
Matt started his career in politics. He then moved to Silicon Valley, and co-founded several tech companies, including Zazzle and CardSpring.
In 2013, he was on the precipice of selling the latter company to Twitter when his daughter, Grace, was diagnosed with NGLY1 Deficiency. She was three.
NGLY1 deficiency is a complex neurological syndrome in which the patient lacks an enzyme known as N-glycanase 1 (NGLY1). NGLY1 helps the body degrade mis-folded, malfunctioning proteins, a process essential for cell homeostasis. People with NGLY1 deficiency experience many physical challenges and tend to have relatively short life spans. There is no known cure.
Matt Wilsey, co-founder and CEO, Grace Science
Matt and his wife Kristen struggled to understand how to best care for Grace and to learn all they could about the disease. The body of evidence was thin. Only five people in the world were known to have NGLY1 Deficiency at that time. Things looked grim, but Matt and Kristen didn’t give in to despair. Rather, they scoured the world for knowledge that could help them understand what could be done for Grace and others like her.
Matt made a sharp turn in his career, moving from tech to medicine. He taught himself as much as he could about the genetic disorder and related diagnostic and treatment options and sought out scientists who could help him learn about rare genetic diseases. One thing he learned early on – there was a lot for scientists to learn about the biology of NGLY1, and that new knowledge offered some new hope for patients.
With a bias towards action, Matt and Kristen poured their heart and resources into the founding of the Grace Science Foundation, a non-profit focused on funding medical research that could facilitate a cure for NGLY1, and Matt volunteered as President of the organization. While they feared they would be too late to help Grace, they wanted to ensure that other families would not experience what their family was going through.
As Matt and Kristen sought funding for the Foundation, a key challenge was convincing donors that the organization could operate at the highest level of scientific validity given the backgrounds of the founders. Many asked Matt and Kristen, who had no formal scientific training, how they could possibly drive the kind of quality medical discovery that would be necessary.
They answered those questions and successfully raised donations to support the Foundation. They spent a relatively small portion of it to find as many of the people on earth that they could who also had the condition that Grace has. By 2022, they had identified 100 individuals around the world who were living with NGLY1 Deficiency.
In 2017, when approximately 40 affected families had been identified, the Grace Science Foundation brought 21 of the families together for a conference in Palo Alto, Calif. They commiserated, shared their day-to-day experiences of living with NGLY1, and took genetic tests that could be used to the benefit of all. This was the beginning of a tight-knit rare disease community, and a valuable resource on which to build knowledge about NGLY1 Deficiency.
Many of these patients and families had never been on an airplane or left their countries or states of origin, much less interacted with others who lived with the same condition.
As the research progressed, it became clear to Matt and Kristen that the Foundation needed to partner with a biotech company to get the science translated into a treatment.
An entrepreneur by heart, Matt wanted to start his own company. He set that idea aside for a while, as he suspected that an existing for-profit enterprise would be able to develop a drug faster. He tried to convince one of the rare disease companies to collaborate but was told that the disease was too rare and that a cure was too much of a long shot. Having been denied, the team at Grace Science Foundation set their sights on starting their own company.
Along the way, Matt reached out to Carolyn Bertozzi, Professor of Chemistry and Professor of Chemical & Systems Biology and Radiology at Stanford University. Bertozzi is also an entrepreneur, having co-founded Lycia Therapeutics and Palleon Pharmaceuticals among others. The Foundation funded a few projects in her lab and she and Matt had become friendly. When she heard about the biobank he had built and met Grace, she offered up some of her post-doctoral students to help.
Carolyn Bertozzi
When Matt suggested that a more targeted approach would be to start a company together, Bertozzi got excited. Through the collaboration with Grace Science Foundation, Bertozzi had already shown in her lab that it was possible to shut down or turn off the proteasome as a means of treating cancers such as multiple myeloma.
To advance the new enterprise, incorporated in 2017 and named Grace Science, LLC, the team realized they had to open the aperture of the work to attract a broader slate of investors who had an interest in both the social mission and financial returns, not just in helping Grace and those like her.
To date, the company has raised $54 million, mostly from high-net-worth individuals and family offices who are patient; these investors are focused not just on returns, but also on the ability to make a societal impact.
Having secured the capital they needed, the company hired and partnered with an experienced team of scientists and drug development experts. They started focusing on churning out lemonade.
It wasn’t easy. Gene therapy was still a nascent approach. But it seemed the best path for their work after realizing that gene therapy had the potential advantage of addressing the missing gene and restoring function in key tissues. Small molecule development would probably take longer, and likely had too many off-target effects. So, they set off down the path of developing a gene therapy for NGLY1 deficiency.
This particular shift was especially challenging, as an entirely new animal model had to be developed to test their lead drug candidates. They found a partner in Takeda Pharmaceuticals, which helped them establish a new rat model. After Grace Science tested 39 different gene therapy constructs in human cell lines and advanced the top two candidates through preclinical tests, the company was able to demonstrate that their lead candidate was safe and effective in rats.
Grace Science now has a lead drug candidate for NGLY1 Deficiency in the GMP manufacturing process and is hopeful the FDA will soon provide a “green light” to start a clinical trial.
While this was happening, another shift was in the works – Grace Science began expanding its orientation towards becoming a multi-product company. Because the science had potential value for treating cancer, consistent with Bertozzi’s earlier work, the company is now developing a small molecule drug for cancers that that can be treated through NGLY1 inhibition. So far, they have identified eight potential malignancies that are dependent on NGLY1. Grace Science is ramping up fast on these initiatives, securing lab space, hiring a dedicated team and speaking with potential partners.
Along the way, Matt says, he learned three critical things.
First, it’s essential for a company like his to have “more than one line in the water…as many as the budget will allow.” This raises the chances of success.
He also learned the importance of finding balance between micro and macro managing. He works hard to stay close to what’s important, giving his employees autonomy to do their work, but without over-delegating. For instance, he said, he and Kristen used to speak regularly to every family in the NGLY1 community but as the numbers grew, he realized it wasn’t sustainable. They now have a genetic counseling team that helps keep in touch with their patient community. But Matt and Kristen continue to find ways to stay personally connected with the families with whom they share so much hope.
Matt says that his third key learning has been the importance of hiring people who are truly excellent and empathetic. “It’s not just A+ operators that you need, it’s A+ people,” he said.
Considering the short timeline – just eight years from starting the nonprofit foundation – a lot has happened. The foundation raised money and built a patient and scientific network. That work gave rise to a company. The drug development enterprise now has a novel product candidate on track to enter a Phase I trial in early 2023. The company knows it still has much evolution and lemonade-making ahead, but the family’s optimism for Grace and those like her grows by the day.
Academia has a tradition of doing nothing, or next to nothing, to educate and encourage young people to learn about entrepreneurship.
But whether academia wants it or not, it’s coming. Young scientists are taking matters into their own hands, organizing themselves in many major research hubs.
Nucleate, the nonprofit providing free resources to empower a new generation of biotech entrepreneurs, is announcing today it is roughly doubling its network of regional chapters from 9 to 17. The new nodes will organize young scientists in some major US research centers – Ann Arbor, Atlanta, Boulder, Chicago, Seattle and Texas. The group is also expanding internationally to the UK and Switzerland.
Soufiane Aboulhouda, PhD student, Church Lab at the Wyss Institute of Harvard University; co-founder and co-president, Nucleate
“Nucleate has created a mechanism for connecting us all together,” said Soufiane Aboulhouda, a PhD student in the George Church Lab at the Wyss Institute of Harvard University. “We’re no longer limited to the Harvard or MIT peer network. Now I interact with people from all around the world.”
What the trainees want to learn about, and interact over, is all the stuff they don’t get from the lab, or from class. How to put together a business plan to build on the science. How to start a company. How to think about IP. How to find the right service providers. How to make a pitch to raise money. How to build a network of people with complementary skills to turn an idea into a reality.
“They want to learn, and they want to learn by doing,” says Oliver Dodd, a co-founder and co-president of Nucleate. He’s also a PhD student in the Church Lab, long known for its entrepreneurial bent.
The current crop of young leaders at Nucleate have assembled educational resources online for what it takes to start a company. They’ve tracked down skilled industry mentors like Peter Barrett of Atlas Venture, former Alnylam CEO John Maraganore, Mira Chaurushiya of Westlake Village Biopartners, Cami Samuels of Venrock and Peter Kolchinsky of RA Capital. Well-known scientific entrepreneurs like George Church at Harvard, Steve Quake at Stanford and Pam Silver at Harvard are also among the advisors.
During the pandemic times, they’ve poured their energy into community organizing of students across the country, which would not have been possible before Slack and Zoom and social media. The resources they put online for their members, like so much else online, are free. Even a long-anticipated two-day in-person summit in Boston Aug. 29-30 is free to members.
About 560 grad students and postdocs are active organizers, Aboulhouda said.
Campus culture usually says to keep your head down in the science, work hard, and maybe someday you can become a principal investigator.
That’s not realistic for most people, and hasn’t been for a long time.
Mira Chaurushiya, senior partner at Westlake Village Biopartners, said the Nucleate model reminds her of Biotech Connection Bay Area – a student-led group that’s been focused more on preparing students for careers in consulting. She’s been impressed with the combination of talent, drive, and humility from the founding Nucleate crew.
Mira Chaurushiya, senior partner, Westlake Village Biopartners
“I love it when PhD students and postdocs self-organize in a way that’s productive for the whole community,” Chaurushiya said. “Unsurprisingly, they are incredibly high achieving people. To go from a standing start to what they’ve achieved today is really impressive. I’ve found them very thoughtful and humble. There’s a sense of ‘we know what we don’t know.’”
John Maraganore added: “Nucleate is a remarkable organization of students and young entrepreneurs keen to advance new frontiers of medicine. I’m amazed with how this group has grown over the years, and I’m awed by their passion and energy. There’s so much potential for this group to continue to expand as a nexus for future leaders in our industry.”
One of the key challenges will be sustainability. Student-led groups naturally have high turnover as people graduate and get jobs. Part of the challenge will be to institutionalize some of Nucleate’s processes, and develop leadership succession plans at each chapter to keep the momentum going, Aboulhouda and Dodd said.
Diversity as a value is almost a given. Half of the active members are women or gender non-binary, one in four members are from underrepresented minority groups, and members come from 44 countries around the world. Increasing diversity is “one of our primary goals,” the organization says.
There is so much interest, Nucleate turned away a few local chapters that expressed interest in joining the model this time. The group had inquiries from students at about 30-40 campuses around the world for this round of expansion that ultimately included 9 new chapters. Nucleate wants to make sure it expands its donor base to support thoughtful expansion.
The group has hired its first full-time employee, a finance person, Aboulhouda said. The vision longer-term is to have a small professional staff that can do a lot of the day-to-day work of managing the organization, with volunteer students remaining in leadership. That way, Nucleate will maintain its street cred as a group run by students, for students. It’s important to keep a finger on the pulse, to stay close to what the students need, Dodd and Aboulhouda said.
Michael Retchin, PhD student, Memorial Sloan Kettering Cancer Center; EVP of strategy, Nucleate
Dodd and Aboulhouda both say they’ve been influenced by the experience in building Nucleate, and their “Plan A” is to work at a startup after getting their PhDs.
Michael Retchin, a PhD student at Memorial Sloan Kettering Cancer Center in New York and EVP of strategy for Nucleate, said something about the group’s influence that stuck with me for days.
The community that’s been created is providing something deep, something needed, and something missing from traditional graduate school experience. It’s both a supportive fellowship for entrepreneurs, and an outlet for personal growth.
“It’s like going from being blind to being able to see things,” Retchin said. “I can see possibilities for my own career that I didn’t see before. And no longer do I think of my career as being solely for myself. Now my career is something collective. It’s about how do we work together, how do we advance the science together in the next generation. It makes me thrilled to work on this.”
Roger Longman, chairman, Real Endpoints
More than 14,000 people attended the annual #BIO22 meeting in San Diego, meaning there are at least 14,000 versions of what happened. But unless you have the emotional intelligence of a rock, you felt the unease, if not outright panic, of an industry with a fast-evaporating cash runway.
No one really knows what to do about it. If they say they do, they’re lying.
The biotechnology industry depends on two major financing sources: investors and acquirers. The former, in general, invest in companies they hope will sooner or later be acquired; the latter in companies that create medicines of significant medical and commercial value.
One problem: whereas acquirers were willing to pay significant premiums for drugs which had proven their value in clinical trials, the acquirers apparently now want their targets to do more to prove commercial value too, often by launching and selling their drugs.
It’s a recent change. A good example: the difference between Novartis in 2019 being willing to pay $9.7 billion for The Medicines Co. and its almost-approved PCSK9 inhibitor inclisiran (now marketed as Leqvio) and Pfizer, two years later, paying $11.6 billion for BioHaven only after it had successfully launched the migraine medicine rimegepant (Nurtec). It’s why, I increasingly believe, we see more biotechs launching, or about to launch, their own drugs.
The implication for investors: they’ll have to wait longer for most of their exits; capital costs will increase; returns in too many cases will decrease. The implication for biotech C-suites: they’ll now have to get smart about something most really haven’t had to worry much about — actually selling drugs.
Earlier stage companies will need to show investors they recognize the hurdles in front of them, commercially speaking. They’ll need to show they have a sophisticated understanding of payer strategies, distribution, pricing and contracting analogs, and patient support services. Moreover, they will need to be able to crisply articulate why they will succeed in a market chockablock with competitors, whether that competition is direct or for overall budget dollars.
Later-stage companies will need management who have successfully brought products to market – and actually want to do it again. Those people aren’t common and they’re not cheap. And both early- and late-stage companies will need board members who have an intimate and contemporary — not decades-old — understanding of the commercial and reimbursement challenges products face today.
A few CEOs we met at BIO think they just need to sit tight. Trim their costs, sure – but no need to re-set the goalposts. The investment cycle, as it has before, will roll on, they believe, and valuations will rise to pre-crash levels. They may be right about valuations — though that’s not a bet I’d be willing to stake my company on. And it doesn’t mean that the valuation endpoints will be the same.
We firmly believe that the biotech industry has delivered – and will continue to deliver – extraordinary value to both society and investors. The science continues to astound. But the valuation markers have moved. While clinical and regulatory proof is still a must-have, there’s now a second hurdle: quarterly sales.
The question is how quickly, and how well, biotechs can prepare themselves to meet that challenge.
Amanda Banks, MD
On Friday night, after the Supreme Court’s decision to overturn Roe vs. Wade, my extended family gathered around my mother’s dining table. We were supposed to be there to celebrate my 18-year-old niece’s graduation from high school.
We ended up talking late into the night, discussing the implications of the Court’s majority opinion which will greatly restrict access to safe abortion services for millions of women in the US.
I found myself counseling every woman and girl of childbearing age around that table, some as young as 12, to get an IUD or implant placed now. And to stock up on Plan B, the emergency contraceptive pill, currently available over the counter. Do these things before they, too, become illegal.
We’ve seen this attack on women’s rights coming for a while, but it’s still shocking. When the Supreme Court’s draft opinion was leaked in May, I wrote about how, early in my career as a physician, I took care of a woman in the ICU who ultimately died after seeking abortion care from an unqualified provider.
There is no question that now, in a post-Roe world where abortion will be criminalized but not eliminated, there will be a sharp rise in avoidable deaths of pregnant women. This in a country where maternal death rates are already far higher than most developed nations in the world. Worldwide, 47,000 women die each year as a result of unsafe abortion and an estimated 5 million are hospitalized for the treatment of serious complications such as bleeding or infection, the International Federation of Gynecology and Obstetrics estimates.
This number is now set to rise.
The Supreme Court is showing no signs of holding back. Access to birth control could be next.
Justice Clarence Thomas, in a concurring opinion with the majority, wrote: “in future cases, we should reconsider all of this Court’s substantive due-process precedents, including Griswold, Lawrence, and Obergefell.”
Those last three names are references to landmark cases ensuring rights to contraception, gay rights, and same-sex marriage.
Let’s look at the implications of what it would mean to block access to safe, effective contraception.
The CDC estimates that between 2015–2017, 64.9%—or 46.9 million of the 72.2 million women aged 15–49 in the United States were using some form of contraception. Nearly all women use a contraceptive method in their lifetimes. The most effective methods, IUDs and implants, have a failure rate of 0.1% or lower (similar to vasectomy), making these methods far more effective and reliable than tubal ligation, birth control pills and condoms.
The majority opinion, in overturning Roe, prioritizes the rights of a potential life (the fetus) over an actual life (the pregnant woman), regardless of the quality of that actual life. By abandoning the notion of viability (24 weeks) and not explicitly addressing in the opinion the need for any exceptions to a ban on abortion, including for the health and life of the pregnant woman, one could take the Court’s logic one step further to conclude that anything that ends a potential life is therefore also illegal. The link between birth control and overturning Roe lies in how these devices and medicines work:
IUDs and commonly-used implants release progestin, either locally in the uterus, or systemically in the blood stream, respectively. They prevent pregnancy in three key ways: by thickening cervical mucous and preventing sperm from entering, by suppressing ovulation, and by endometrial thinning that prevents implantation of a fertilized egg.
And therein lies the rub: if life is defined as beginning at conception (fertilization), and anything that ends that “life” is illegal, it is easy to see how any contraceptive method that works by preventing implantation of a fertilized egg would be swept up into this net. There is a clear conceptual path to see how these birth control methods and Plan B would be outright banned in at least half the country.
As all rights currently protected under the 14th Amendment are re-examined, let’s take this framework a little further: If the existence of life is valued above the quality of life, whatever the cost or collateral damage, what is stopping these same forces from prohibiting a patient with cancer from refusing additional chemotherapy or surgery?
If that patient values quality over quantity of life, if that patient does not want to bear the toxicities of additional therapy and the attendant hospitalizations it might require, but prefers to live their remaining days at home with their family, does hospice care become illegal?
This may sound outlandish, but is it really? Half of the people in this country have just been stripped of that same right.
I am reminded of the story of Shirley Wheeler, the 8th child of a mother who died when she was 13 months old. Shirley was passed off to relatives by her alcoholic father, and at 16, was raped and became pregnant. She carried this pregnancy to term and delivered a baby that was raised by relatives. When she became pregnant again in her early 20s, she obtained an abortion which was illegal at the time. She was convicted on manslaughter charges in 1971 because she refused to disclose the names of clinicians who provided abortion services.
At 23, she was subject to 20 years in prison for this crime, but was instead sentenced to two years of probation by a judge in Florida. But there was a catch: she had to either “get married or go home” to North Carolina where she was born
Let that sink in for a minute. Get married or go home.
In the pre-Roe era, a sitting male judge told an adult woman that she could avoid prison by getting married or going home to her abusive family.
Why should we think the post-Roe era will be any different?
After imperfect but profound progress for women in the US over the last 50 years since Roe was passed, what kind of nation will we now allow this to become? This matters not just to the tens of millions of affected women, but to their families, healthcare in the US which is already buckling under the pressure of broken delivery systems, and to the biotech industry globally.
As leaders in life sciences, we must take action now, before it is too late:
Leverage our talent pool to create new solutions. Leaders in our industry are already talking about creating solutions to match women to needed and available services, streamline travel and obtain financial support. They may also match qualified providers and other volunteers to clinics with staffing shortages.
Make contraceptive and reproductive health devices, services and medicines free to those without the ability to pay, and more accessible to everyone. Manufacturers of IUDs, implants, Plan B emergency contraception, and medicines that safely induce abortion in the early weeks of pregnancy must partner with providers and other stakeholders to make these options available to any woman who needs them. This is particularly important if we consider the possibility of future legislation limiting Medicaid coverage for birth control and related medicines.
Implement policies to support affected women. Provide paid time off and financial support for any employee who needs to travel to obtain reproductive healthcare that is banned in the state where they live.
Withdraw investment in states where bans continue. Do not set up operations in these states. Move headquarters if necessary. Venture capitalists should add a “social impact” parameter to their investment decisions.
Contribute to equity by showing your opposition to the Supreme Court’s action, and by continuing to diversify C Suites and Boards. As an industry we’ve made strides to become more representative and diverse in our leadership. It matters now more than ever. Don’t be silent. Take a position.
I grieve for our nation in my own particular way, with my experience as a doctor, a mom, a daughter all coloring my lens. Those of us who are angry and feeling helpless will rally — together with like-minded, dedicated, incredible people across our industry — to do what we do best: solve hard problems in ways that make people’s lives better and healthier.
We’ve been knocked back, but make no mistake, this doesn’t stop here.
Luke Timmerman, founder & editor, Timmerman Report
Sometimes doing the right thing requires sacrifice.
Other times, the right thing for human health can also be a shrewd business move.
That was the intriguing result of a study on the returns sponsors can expect from decentralized trials. The study relied on data from Medable and the Tufts Center for the Study of Drug Development. Results were presented this week at the Drug Information Association meeting, and are being prepared for a peer-reviewed paper.
The early results are eye-opening.
Companies that incorporated decentralized trial technology into their protocols – things like eConsent, remote monitoring, local labs, wearables and telemedicine visits to reduce in-person trips to the clinical site – saw a 5-fold return on investment in Phase II trials, and a 13-fold return in Phase III trials.
What it means in practical terms is that a $2 million upfront investment can be expected to translate into $10 million in savings in a Phase II trial. A $3 million upfront investment should deliver $39 million in savings in Phase III.
Biotech companies ought to take notice. That’s real money. Learning how to incorporate the new tools into clinical development also promises to make it easier for patients to enroll in clinical trials, for underrepresented diverse populations to get engaged, and to ultimately make medicines more accessible for the people who need them.
Pamela Tenaerts, chief scientific officer, Medable
“We need a lot more hard, systematically researched metrics on what decentralized trial technologies do for clinical trials,” said Pam Tenaerts, chief scientific officer of Medable. “A lot of methods we use in clinical trials hardly have evidence at all on whether they work or not. If people are going to spend money on something there has to be a reason… we can see it’s not only the right thing to do for patients, it’s a good business thing to do.”
With this analysis, researchers wanted to know from an expected Net Present Valuation perspective whether the technologies are worth adopting.
The pandemic provided a forcing function. Many companies saw their trials go on hold in early 2020, and had to get serious about learning to use the new tools if they wanted to stay on budget and schedule.
The data do have some caveats. There was a small sample size, with data compiled from 54 companies using decentralized trial technologies from 2020-2022. A larger dataset, with more time for follow-up, could shed light on more nuanced questions such as which decentralized technologies provide better returns than others, Tenaerts said. It would be good to know whether a certain technology is more useful for oncology, or neurology or some other indication, she added.
Getting the data is a good first step. Seeing these technologies pay off in the real world is encouraging.
We know the problem well. Way too many people find it too difficult to enroll in trials. It takes too long. It costs too much. It filters out many low-income people and people of color who can’t take a whole day off of work for repeated clinical visits three hours from home.
Many of us have become numb to these barriers to participation. We accept them as business as usual. This status quo is like sand in the gears of biomedical progress. It slows the whole machine down, and corrodes the enterprise. We often don’t get results from clinical trials that are representative of what we can expect in the real world.
The biotech community is capable of amazing leaps ahead when pressed into action. The community can pool more data to get better answers on best practices to make clinical trials more accurate, more representative, and more easily accessible to everyone. It would be a great way to help people see we’re living in the biotech century, and everyone stands to gain.
TR has long advocated for much bigger investment in basic biomedical research, as a catalyst for biotech industry development, regional economic development, and national competitive advantage. Investing in basic research is one of the best things the federal government can do, as we saw with far-sighted US government bets on the Human Genome Project, the Internet, GPS and many more foundations of knowledge that industry was able build upon. That’s why I was excited to see the US House of Representatives vote overwhelmingly to embrace this vision of what government can do at its best to advance health and economic development.
The House voted 336-85 in favor of a bill (HR 5585) to create the Advanced Research Projects Agency-Health (ARPA-H). It’s modeled after the Defense Advanced Research Projects Agency (DARPA), which invests in bold, futuristic research ideas, rather than the more incremental approaches that require some data already, and are often favored by the more traditionally conservative study sections at the National Institutes of Health. Reps. Diana DeGette (D-Colo.) and Rep. Fred Upton (R-Mich.) worked together to champion this bill, much like they did the 21st Century Cures Act. Side note: the legislation overwhelmingly passed the House without the presence of Eric Lander, the president’s former science advisor who championed the creation of this daring new agency, but who had to resign amid reports of toxic, bullying office behavior.
Cambridge, Mass.-based DEM Biopharma raised $70 million in financing to target ‘don’t eat me’ and ‘eat me’ signals on cancer cells and macrophage cells. Longwood Fund and Alta Partners led.
Boston-based Carbon Biosciences raised $38 million in a Series A financing led by Agent Capital. The company, founded by Longwood Fund, is working on parvovirus-based delivery for gene therapies. The hope is that it will enable larger genetic payloads to be delivered to targets.
Menlo Park, Calif.-based MyOme raised $23 million in a Series B financing led by Healthcare Venture Partners. The company does clinical whole genome analysis, helping families assess risk of inherited diseases. Sequoia Capital, Foresite Capital and Founders Fund participated.
Alameda, Calif.-based Magnetic Insight, an imaging diagnostics company, raised $17 million in a Series B financing. Celesta Capital led, and existing investors 5AM Ventures and Sand Hill Angels participated.
Burnaby, British Columbia-based Xenon Pharmaceuticals raised $250 million in a public offering at $30.50 a share. Earlier in the week, it released subgroup analysis from a Phase II trial for an anti-seizure drug candidate.
Beijing-based Therorna raised $42 million in a Series A financing to develop circular RNA therapies.
Moderna reported some more encouraging news for its bivalent COVID vaccine candidate that’s designed to stimulate the immune system against the original SARS-2 virus and the Omicron variant. The bivalent vaccine boosted neutralizing antibody concentrations by 5-fold against the BA.4 and BA.5 subvariants now spreading and causing re-infections. Moderna CEO Stephane Bancel said the company plans to start supplying the bivalent vaccine in August, to give people the opportunity to get a booster vaccine before the anticipated surge in cases likely to come this fall. See data published June 22 in the New England Journal of Medicine on the Omicron subvariants.
Cambridge, Mass.-based Scholar Rock reported 24-month follow-up data for patients in a Phase II study of its drug candidate apitegromab for type 2 and 3 spinal muscular atrophy. Researchers reported sustained improvement in motor function for patients who can’t walk, and that results were a bit better at 24 months than at 12 months. Based on the Phase II results, CEO Nagesh Mahanthappa said Scholar Rock is “urgently enrolling” patients in an ongoing Phase III trial.
Carlsbad, Calif.-based Ionis Pharmaceuticals and its partner, AstraZeneca, reported on positive interim results from a Phase III study of eplontersen for patients with hereditary tranthyretin-mediated amyloidosis with polyneuropathy. The drug is an antisense medicine, given by an autoinjector, and which is designed to inhibit production of the TTR protein at the root of the disease. Researchers said the drug reduced the amount of TTR in the bloodstream, and met its goal on a neuropathy clinical measurement. Ionis and AZ plan to submit the data to regulators. The drug will be a competitor to Alnylam’s subcutaneous RNAi medicine, vitrusiran (Amvuttra). The Alnylam drug was approved by the FDA 10 days ago.
Bothell, Wash.-based Athira Pharma said its lead drug candidate for Alzheimer’s disease, fosgonimeton, failed to hit the primary endpoint in a Phase II proof-of-concept study. The study was designed to measure a biomarker, change in ERP P300 latency.
Palo Alto, Calif.-based BridgeBio Pharma reported encouraging early data for its AAV-based gene therapy for Canavan disease, an ultra-rare and fatal disease. Researchers evaluating the first two patients saw significant decreases in a key biomarker, N-acetylaspartate (NAA), in the urine, the cerebrospinal fluid, and brain tissue as seen by Magnetic Resonance Spectroscopy scans. No serious adverse events were reported in the first two patients, the company said.
Mark Cuban’s Cost Plus Drug Company could save Medicare about $3.6 billion in one year with the discounted prices it obtained for 109 generic medicines through this February, according to researchers writing in the Annals of Internal Medicine. Since this involved a reality-TV show billionaire who’s a household name, it generated a lot of free media publicity for the Cuban Cost Plus Drug Company. There’s nothing wrong with negotiating for discounts on generic medicines, cutting out the middlemen, and making it simple and easy for people to purchase their meds at the lowest price. But I get a sinking feeling when reading articles like this in the WSJ that make Cuban look like a hero riding to the rescue of US healthcare, standing up for the little guy against those greedy monsters in the pharmaceutical industry. We should beware of billionaires who say they come to us bearing gifts for the masses, but may have something else in mind altogether. Like a Presidential campaign.
I’d feel better if this “Cost Plus Company” was run by talented operators behind the scenes, not a celebrity frontman. See my previous coverage (Frontpoints, Jan. 2022).
Newark, Calif.-based Ultima Genomics, the well-financed startup aspiring to sequence whole genomes for as little as $100, said it formed a long-term supply agreement with Madison, Wis.-based Exact Sciences. Exact, the maker of the noninvasive Cologuard screening test for colorectal cancer, agreed to invest in Ultima, and become an early-access customer for its next-gen sequencing technology. Driving down the costs of sequencing is especially important for high-volume clinical applications like cancer screening, minimal residual disease assessment, and recurrence monitoring, Exact CEO Kevin Conroy said in a statement.
Pfizer agreed to invest $95 million in France-based Valneva, and alter a few terms of its 2020 license agreement, to support the development of a vaccine for Lyme disease. Pfizer plans to start a Phase III trial of VLA15, a protein subunit vaccine candidate, in the third quarter of 2022.
Durham, NC-based Precision Biosciences secured $75 million upfront through a deal with Novartis, in which the big company will get access to its technology to enable in vivo gene editing for the treatment of beta-thalassemia and sickle cell disease. Precision quickly followed up the partnership news with a $50 million stock offering at $1.39 a share.
Boston-based Radius Health agreed to be acquired by Gurnet Point Capital and Patient Square Capital in a deal valued at about $890 million. The company’s lead drug is for reducing the risk of fractures in postmenopausal women with osteoporosis.
Waltham, Mass.-based Morphic Therapeutic, the developer of small molecule drugs against integrin targets, said that AbbVie walked away from a collaboration that began in 2018.
Belgium-based Galapagos agreed to acquire CellPoint for 125 million Euros upfront, and AboundBio for $14 million. The deals are intended to strengthen Galapagos’ cell therapy capabilities.
AbbVie secured FDA approval for risankizumab-rzaa (Skyrizi), an IL-23 inhibitor, for moderate to severe Crohn’s disease.
The FDA ordered Juul Labs to pull its e-cigarette products off the US market. The products have long been marketed to teens. It’s a rare and tough public health enforcement action on the part of the FDA under Commissioner Robert Califf. (FDA statement).
The FDA approved Merck’s 15-valent conjugate vaccine (Vaxneuvance) for pneumococcal infections in infants and children.
Novartis secured FDA clearance to sell the combo of dabrafenib and trametinib (Tafinlar + Mekinist) for adult and pediatric patients with BRAF V600E mutations, regardless of the tumor’s tissue of origin. See Novartis R&D chief Jay Bradner’s comment on how cancer is moving to targeted therapies based on precision molecular definitions such as this.
Watertown, Mass.-based Enanta Pharmaceuticals sued Pfizer for patent infringement. The case involves nirmaltrevir (Paxlovid), the antiviral treatment for COVID. Baird analyst Brian Skorney said the case appears to have some merit.
President Biden nominated Arati Prabhakar to be his science advisor. She’s an engineer and physicist by training who previously led DARPA in the Obama Administration. Her Cabinet-level position requires Senate confirmation.
Chirfi Guindo, chief marketing officer, Merck Human Health
Merck said Chirfi Guindo will lead marketing for Merck Human Health, starting July 1. He will report to CEO Rob Davis. Guindo was previously executive vice president and head of global product strategy and commercialization at Biogen.
Baltimore-based Delfi Diagnostics added Jacob van Naarden to its board of directors. He’s a senior vice president at Eli Lilly and CEO of Loxo@Lilly.
Cambridge, UK and New York-based Artios, the developer of small molecules aimed at DNA damage response, added Samantha Truex to its board of directors. She’s the CEO of Upstream Bio.
Cambridge, Mass.-based Oncorus, a viral immunotherapy company focused on cancer, added Doug Fambrough, former CEO of Dicerna Pharmaceuticals, to its board of directors.
San Diego-based Iconovir, an oncolytic virus therapy developer, added William Kaelin to its board of directors. He’s a scientist at Dana-Farber Cancer Institute and a Nobel Laureate.
Real Estate
Regeneron Pharmaceuticals broke ground on a $1.8 billion expansion of its campus in Tarrytown, New York. Gov. Kathy Hochul said in a statement the company has pledged to create 1,000 jobs at the facility over the next five years.
Takeda Pharmaceuticals signed a 15-year lease in Cambridge, Mass. on 600,000 square feet in R&D and office space. The facility is at 585 Third Street, walking distance from major research universities, startups, venture capital, mid-to-large companies, and more skilled consultants and service providers than you can shake a stick at, as my grandmother used to say.
Moderna said it’s building a new mRNA vaccine manufacturing facility in the UK, with the goal of turning out new vaccines in 100 days. The UK has also agreed to purchase 60 million doses of Moderna’s COVID vaccine for booster campaigns in 2022 and 2023. Moderna also has plans for an mRNA vaccine manufacturing facility in Kenya.
Today’s guest on The Long Run is Ivana Magovcevic-Liebisch
She is the CEO of Cambridge, Mass.-based Vigil Neuroscience.
Ivana Magovcevic-Liebisch, president and CEO, Vigil Neuroscience
The story starts with Amgen. The big biotech made a strategic decision to get out of neuroscience in 2019. That meant a couple of drug programs targeting TREM2 came up for sale.
One is a monoclonal antibody, and the other is a small molecule. They are aimed at a neuro-inflammation target on microglia cells, and it has been implicated in genome-wide association studies for rare neurological diseases, and for larger indications like Parkinson’s and Alzheimer’s.
Atlas Venture, which has a longstanding relationship with Amgen as a limited partner in its funds, sought to in-license the programs – which it thought had potential in a small, focused, asset-centric startup.
That’s where Ivana and Vigil Neuroscience enter the picture. She’s an experienced executive, with stops at Dyax, Teva, and Ipsen along the way. She’s been through some ups and downs in the early days of Vigil – venture financings, an IPO, a bearish stock market, and a partial clinical hold while the company and FDA discuss dose ranges with its lead monoclonal antibody for a rare disease called ALSP.
I saw Ivana speak at a recent conference about the importance of building a strong team and culture to navigate through a downturn. I think she has some valuable perspective for managing in these times.
Now before we get started, a word from the sponsor of The Long Run.
Calgary is home to more than 120 life sciences companies, from emerging startups to established firms. With this critical mass of research, technical talent and expertise, the city is an active hub for life sciences innovation.
Technologies homegrown in Calgary are changing the face of healthcare. Syantra is revolutionizing breast cancer detection using artificial intelligence-derived algorithms. NanoTess is harnessing the power of nanotechnology to tackle chronic wounds and skin conditions. And this is only the beginning. Calgary’s life sciences sector is projected to spend $428 million on digital transformation by 2024.
If you’re a bright mind or bright company solving global health challenges, Calgary is the place for you.
Take a closer look at why at calgarylifesciences.com
Now, please join me and Ivana on The Long Run.
Vikas Goyal, former SVP, business development, Pandion Therapeutics (now part of Merck)
UK-based Kymab made headlines back in January 2021. Sanofi agreed to acquire the antibody drug developer for $1.1 billion upfront, plus $350 million in potential milestones.
The main attraction for Sanofi was KY1005, a monoclonal antibody targeting OX40L, a regulator of the immune system. Five months before the deal, Kymab announced it hit both primary endpoints of a Phase 2a trial of patients with moderate to severe atopic dermatitis that wasn’t responding to topical corticosteroids.
Sanofi, in its official statement, mentioned its interest in an ICOS-agonist antibody in clinical development for cancer, along with Kymab’s broader capabilities in antibody drug discovery.
I spoke recently with Brandon Lewis, the former head of corporate strategy at Kymab, on the dynamics that were at work in this transaction.
Brandon Lewis, former head of corporate strategy, Kymab
Why was this deal the right thing to do?
We realized that in order to give KY1005 the best chance of success we needed a committed partner with deep intellectual and financial resources focused in immunology. Sanofi presented the opportunity to collaborate. Sanofi has a great share of voice with patients and physicians plus an incredible amount of knowledge about the potential in dermatological diseases and beyond for the OX40-Ligand (OX40L) pathway. And they saw how our molecule could have application across multiple dermatology indications and certain autoimmune disorders.
At that moment in time, it was becoming increasingly clear that there were only so many R&D teams that had the wherewithal, capacity, and interest to drive the bus through this tiny little window to see what could happen for patients. And after many years with both of our lead molecules advancing on promising trajectories, we felt our lead OX40L molecule KY1005 deserved that, as did our immuno-oncology program KY1044 (an ICOS agonist antibody).
As we began to see some early open label clinical activity for KY1044 and recognizing the evolving competitive landscape in immuno-oncology in general, along with the opportunity to pursue both mono and combo therapy paths, we believed it would be hard for an emerging drug development company to do both programs properly and at pace by ourselves.
Several potential partnerships were available, offered, discussed.A few entered negotiations. Nigel Clark (Kymab’s SVP of Business Development, now CBO at Nucleome) is an incredible dealmaker with a unique business acumen. The parties varied from dermatology-specific companies, a few regional partners, as well as a few large pharma / large biotech companies that saw elements of KY1005’s potential but not the same breadth of potential that we saw. Of course, there was a range of opinions on how KY1005 should be priced, and whether to stick with dermatology or go broader.
We ultimately wanted a partner with the necessary enthusiasm, interest and knowledge of the space. And so that led us back to the folks at Sanofi. They had reviewed everything in the space. And had become category leaders in immuno-dermatology, which is classically a difficult space to gain adoption with new therapeutic interventions. Plus, dermatology practices have unique economic incentives regarding interventions. Even great drugs have to compete with things like microsurgery, Mohs, and cryotherapy. To get that share in dermatology, we knew we had to work with a committed company that had an established presence with both patients and physicians to launch another new therapy with a novel mechanism of action.
What drove the timeline for your acquisition? Why did this happen in January 2021?
In 2017, Kymab had four therapeutic areas and a large research and translational footprint of 150 people, plus a burgeoning clinical development organization. And the company had just raised its last equity financing in 2016.
ASCO 2017 had been incredibly exciting, and the world went mad for immune oncology. We had our first two presentations on our ICOS program at SITC in November 2017 where there was a lot of excitement with combination checkpoint inhibition at that moment. So strategically the plan was to raise a modest amount of capital, take KY1005 and KY1044 into Ph1 studies and get some early clinical data, with KY1044 as the lead focus. We had also recruited Dr. Sonia Quaratino as our Chief Medical Officer to lead the clinical development of both programs. She joined us from Novartis and is brilliant at translational clinical development. She is an immunologist with very strong oncology development experience.
Fast forward to ASCO 2018. The highly anticipated results for IDO landed awkwardly and theICOS data presented by others in the field was going to require a lot of additional interpretation. On Day 1 of ASCO the palpable enthusiasm in the audience quickly turned to concerns and questions . We had not yet presented any human clinical results from KY1044, but now we had to respond to the market’s collective confusion about the target and emerging questions around clinical development trials for combination therapy. This again, presented a considerable communications challenge to overcome and required a new approach to establishing KY1044’s target product profile.
So now we are in the summer of 2018 post an enthusiastic American Academy of Dermatology (AAD) in February and let’s say a more somber ASCO. We had already achieved some incredible preclinical in vivo data in acute and chronic Graft-versus-Host Disease (GvHD) models with our OX40L antibody, KY1005, in some challenging primate models run by Leslie Kean (then at Seattle Children’s now at Boston Children’s) which we published in Science Translational Medicine. In this model, we had a striking survival benefit. And when we examined the treated animals at the end of the study, it looked like we were resetting these activated T cells back to a homeostatic state. So, we realized we had an incredibly potent molecule that was doing the biology that we wanted it to do.
It is crucial to choose the most appropriate setting that will showcase a molecule’s full potential or shortcomings in the clinic. Atopic dermatitis provided this for KY1005. There was a clear biological rationale supported by a strong and growing body of research that published in 2012 identifying the presence of OX40L in atopic dermatitis lesions.
Despite the biology associated with OX40/OX40L axis there was still limited human clinical proof-of-concept for these mechanisms at that time back in 2017. Roche-Genentech had earlier published very nice data in transplant, but they moved forward in asthma where the studies did not produce the intended results. We had been evaluating the potential intervention in atopic disorders and skin diseases where the literature supported the biological rationale to target the OX40/OX40L axis. In the first quarter of 2018 the first in human study of KY1005’s safety and tolerability was nearly completed and we were incredibly optimistic. After this readout, our optimism matured to excitement as KY1005’s properties and drug-like attributes became further substantiated. Sonia and I headed to AAD in February 2018 in San Diego with this preliminary knowledge of KY1005 and a busy schedule of meetings with key opinion leaders and principal investigators, to further refine our thoughts around the Phase 2a study design in patients with atopic dermatitis given what we understood about KY1005’s proposed mechanism of action. There was a lot of excitement in the medical dermatology space.[Regeneron and Sanofi’s] Dupixent [an IL-4 and IL-13 inhibitor for atopic dermatitis] had begun to catch its stride and there were many companies presenting “small” signal seeking studies around blunting the immune response in atopic disease.
If you recall, until now, the OX40/OX40L checkpoint axis was primarily being investigated as another immuno-oncology approach and had limited success. These approaches were trying to agonize the [T-effector cells] Teffs and dampen the [T-regulatory cells] Tregs. KY1005 is designed to do the opposite by working to restore a more normal balance of these cell subsets. This is what we investigated in the acute GvHD animal models. This presented a real hurdle when educating the Street that our intervention was in autoimmune diseases not immuno-oncology and KY1044 was doing the opposite targeting ICOS pathway in immuno-oncology.
A company then named Glenmark (now Ichnos) was presenting on an open label uncontrolled data with its anti-OX40 antibody in atopic dermatitis. It was a small dataset, but it provided additional encouragement for the pathway and its clinical rationale. However, there are always risk and rewards with making apples and oranges comparisons. When interacting with external stakeholders there is never enough time to get through the whole story in most 1×1’s, and even more to actually do a proper deep dive on why you selected the optimal molecule .
Sonia and her team were working hard on the filing for the KY1005 study in atopic dermatitis patients.We were convinced KY1005 and its emerging therapeutic profile would have a meaningful benefit, there was a clear unmet need to offer better therapies than topical steroids, and we saw potential to be one of the first to market.
The classical development challenges remained, working through the atopic dermatitis clinical trial designs, dealing with inter site variability and patient recruitment. We worked hard and worked fast to get the trial done. And of course, the competitive landscape in atopic dermatitis evolved. We saw data from Anaptys, Equillium, Dermira, and others. And all of a sudden, we were 6th or 7th in line with KY1005.
We also had two new targets progressing to development candidate stage and were facing the decision to shift resources from discovery to development. Our discovery team was continuing to find cool new things to work on. And our development organization was trying to push INDs and CTAs forward.
In 2019 we had recruited a great new CEO Simon Sturge and he brought a new level of large pharma and biotech experience, along with corporate discipline and a commercial strategic focus to the Company. Biotech companies are constantly looking for funding and so we were always evaluating a variety of options, including, but not limited to, a possible IPO.
Later in the summer during a series of non-deal roadshows meeting investors in the US we were hit with a “black swan event” of the Woodford funds. It had been one of our largest investors after our 2016 Series C. And in the background we were also dealing with an ongoing patent challenge to some of our platform patents.
Drug development is incredibly hard, but there are so many other seen and unforeseen obstacles that will emerge and have to be overcome. I mean every time we got through one door . . . But the company persevered. Our investors and board remained very supportive of us continuing to build the company and refine the story. And we were executing nicely on both our lead clinical programs..
Now move forward to 2020 and our OX40L program is looking really promising. There was no question we had a competitive advantage on dosing schedule, durability of response, and on our impact on the immune axis. Meanwhile other biological mechanisms had not achieved the clinical success many were hoping for, and although the JAKs efficacy results were encouraging, long-term safety questions would need to be understood. And in 2020 we also got some favorable patent decisions in the US and UK.
So now there was no question this could be a successful drug. The question became, would a small company like Kymab turn KY1005 into a category killer? And could we keep up the pace to move forward much more aggressively? We were at a crossroads and the timing was right to work with Sanofi.
How important was the US Patent Trial and Appeal Board’s decision in all of this?
It was really our own data trailblazing the role of OX40L inhibition in atopic dermatitis that drove all of this. The patent issues were not at the core of it. I think this was a distraction that you don’t want to have as an operator and executive. It would have been a constant battle to get people to focus on what the Company is doing. If I was sitting on the other side of the table, this kind of issue is also an easy way for a partner to change their risk matrices in their models, because at the end of the day this is about getting to a number.
And just for context, David Chiswell (Executive Chairman, scientific advisor, and former CEO of Kymab) and I worked closely together during the early days of Cambridge Antibody’s corporate affairs and development during the early clinical translation of D2E7, which ultimately became Humira. At the time, the investment world was consistently telling us that “we don’t need another TNF-alpha inhibitor because we already had Enbrel and Remicade, they are effective and appear to be disease modifying”. And so we had some personal experience with how external dynamics can affect a young company. You have to follow the data and be confident in the collective work of your teams or you will get lost in the “noise”. Obviously, this is much easier said than done.
How did the deal process go?
We were fortunate to have many options available to us in parallel. We had a broad process that started north of 40 companies. About half of those guys went to the next room. And several of those went to letters of intent that we reviewed with our advisors and investors. Across those proposals we had a version of each path forward. We had a capital markets solution that would let us do a lot on our own, a partnership proposal that was more-or-less a traditional 50/50 collaboration, and a partnership proposal that would have seen us building a global clinical organization and us taking KY1005 all the way to Ph3 ready.
But you know how it goes. In the middle of this, we got a call late one night, and suddenly teams are working through the holidays to get a deal done with Sanofi. Sanofi had been watching the Company intimately for a long time, and their scientists and clinical teams had been huge advocates for our OX40L program. And when Paul Hudson, CEO of Sanofi, took over and started doing the deals like the acquisition of Synthorx, that opened a window for us in a very different way across our ICOS and other oncology programs. And now Sanofi offered a way for us to properly resource all our programs.
Why did you take the $1.1 billion? How did you get comfortable that was the right price? Why not $700 million or $3 billion?
Ha, through many painful hours of splitting hairs and ongoing market analysis conducted by our business development and finance teams internally before the process was even kicked off. There was no question our OX40L was targeting a very large market opportunity, and out of everybody Sanofi uniquely understood the size of the market given their commercial presence.
And look, some other partners may have been getting to larger cumulative payments in their respective models, but the structures were such that the real payments may never have happened.
And on the capital markets side, we had enough investor feedback to estimate how much money we could likely raise and at what terms.
How did you manage all this activity?
We had an incredibly strong and dedicated internal team along with a deep bench of experienced advisors as is required with these endeavors. Personally, I thought we should either take it all the way on our own and raise enough money to do that or take an option that removes the risk and would not be dilutive to our existing shareholders.
As for me, I’m sitting inside the company as an external corporate development person, so I liaise with all my key stakeholders internally. And of course, looking across this incredibly productive platform, which is generating multiple leads for development candidate consideration, how can you ensure everyone gets the resources needed for each respective program and also align them with our strategic corporate development objectives and also balance with the resources actually available to you. We were still a young biotech, we didn’t have the evolved and established portfolio management and resource allocation expertise of more mature development companies.
There was a lot to manage. It was a lot like a chess game where we had keep thinking three steps ahead. Because every time we didn’t think ahead something would surprise us. It was not easy and I’m so proud of our team. Nigel only had 3.5 people in his business development team. It was only me and Anne Hyland (Kymab’s CFO) in the external facing finance function. And for a big chunk of this critical time, the CEO role was transitioning from David to Simon.
Why do a whole company sale? Why not a co-development collaboration on the atopic dermatitis program or a cancer partnership?
All these paths were considered at different times. We didn’t set out to sell the company.
This all really happened over the course of four years. When I joined Kymab, it was obvious to us that we had a great potential in our platform to generate antibodies to otherwise refractory targets and to achieve high biological function with those antibodies. Kymab had developed great tools to probe the immune system, identify antibodies, and create very focused and evolved biological libraries to design functional attributes of our antibodies in a way that had not historically been done for biologics.
We were working in infectious disease and had a collaboration with the Gates Foundation, we had a hematological focus with our BMP6 and matriptase programs (now licensed to RallyBio) and then of course we also had immunology and immuno-oncology. The breadth of our platform was so robust, that there was a real challenge as we began to grow into a clinical stage company. It’s not easy to develop relationships with PIs and have deep knowledge across all those areas.
And when we looked at the intellectual and financial capital needs to bring our two clinical programs and our growing preclinical pipeline through Ph2 proof-of-concept, it was going to require raising multiple hundreds of millions of dollars. So, in addition to a broad range of partnership pathways, we also aggressively and simultaneously explored several capital market solutions whether that was IPO in the US or locally in the UK, a mezzanine round, and even SPACs and reverse mergers. We believed it might be difficult to raise that amount of capital given our business strategy cut across so many therapeutic areas, but we were far enough along in these discussions to know the capital was available.
We were really at a crossroads. And like many companies, it started to become clear that our lead program was driving a lot of the perceived equity value. We could have put several strategic puzzle pieces together and come out with a mosaic.
With Sanofi we found a single partner with interest in immunology, oncology, hematology, infectious disease, and in antibody platforms. And through the acquisition by Sanofi, we found a business solution to help build and resource Kymab’s drugs and platform through one transaction as opposed to a less certain series of 4+ different transactions.
Luke Timmerman, founder & editor, Timmerman Report
The market is in bear territory. A recession could be on the way. That’s what the economists say.
Sometimes the investment world, and the wider world, respond positively to fundamental progress. Sometimes the world shrugs off the good news, or never even notices at all.
Many of my interactions at BIO were with executives who had hangdog looks. They look like they’ve been through the wringer. They’re working hard. Some of them have real accomplishments that aren’t being recognized. That doesn’t feel great.
Then again, there were a lot of people obviously happy to be meeting again in person in San Diego. It’s restorative. The human side of biotech needs some care and attention after all the tribulations of the past two and a half years. We need colleagues, peers, friends, family to lean on.
Some amazing things are happening. There are seasoned management teams who have seen downturns before. Quite a few companies raised cash when times were good, and with some careful management, will be able to weather the storm even if lasts a couple years. The strongest companies will be able to lean on the cultural bonds they’ve established — the cohesion, and the driving sense of purpose that comes from working on meaningful solutions to interesting, challenging biomedical problems.
These things may not always garner much attention. They may not be easy to see. But they are happening.
Read about some of those things in Frontpoints.