Ram Aiyar on Finding Deal Alignment Internally and Externally

Vikas Goyal, former SVP, business development, Pandion Therapeutics (now part of Merck)

Ram Aiyar is currently the CEO of Cambridge, Mass.-based Korro Bio, a company using RNA editing to treat genetic diseases, including Alpha-1 Antitrypsin Deficiency.

Before he took that job, he was a founder and executive vice president of corporate and business development at Corvidia Therapeutics. That company was acquired by Novo Nordisk in August 2020 for $725 million upfront, and $2.1 billion total.

The deal gave Novo access to ziltivekimab, a fully human monoclonal antibody with half-life extension technology, targeting the IL-6 ligand. The drug was in a Phase 2b trial in chronic kidney disease at the time of the acquisition, with plans to proceed into a global cardiovascular outcomes Phase 3 study. The Phase 2b data that drove the acquisition was published in The Lancet in May 2021.

Novo saw a large commercial opportunity in cardiovascular disease in chronic kidney disease patients, which would build on their existing insulin and GLP-1 driven diabetes franchise.

Aiyar spoke with me recently about that deal and some of the lessons learned.

Ram Aiyar, CEO, Korro Bio

Why did your team and board believe it was the right time to partner? Why was Novo the right partner to work with?

The science behind our drug was validated. The question was ‘did we have the money to bring ziltivekimab through approval?’ This would have required running a large cardiovascular outcome study that might cost between $300-500 million – and not to mention the investments required to support the commercial piece after that.

When you think about the likelihood of success and the amount of capital required to fully develop, we wanted to find a group that was committed to running that outcome study, and running it in a way that we thought would have a high likelihood of success.

Let’s leave money aside for a second. There were a couple of parties around the table during our acquisition. When we thought about how these companies might develop the drug themselves, we were very aligned with Novo on how we were approaching the unmet need for patients, and on how we would execute the drug development plans towards approval (assuming the science continued to play out).

There were other potential partners that wanted to go into larger patient populations. We agreed those trials could be done, but also believed conducting those trials could delay the approval and launch of ziltivekimab for CKD patients, where the unmet need was very high and where ziltivekimab’s mechanism had a very good chance of success. For example, Novartis’ CANTOS study with Paul Ridker [evaluating the anti IL-1ꞵ mAb canakinumab in patients with atherosclerosis] showed really differentiated benefit in patients with CKD. In just 1,800 patients over two years they showed a 50% mortality benefit.

Philosophically, Novo was aligned with our approach. Case in point, Novo has stuck to the timelines that we had put together back in 2020. To see large pharma move with that pace is so encouraging. I really believe the drug is in the hands of the right folks.

What was your role in building the relationship with Novo and ultimately closing the collaboration?

This is a team sport! We built our relationship with Novo over the course of three years. Initially, they were interested in one of our earlier programs which was going after acute pancreatitis. Those interactions built up a lot of goodwill. Over that time, Novo had strategic changes with new people coming in and a new desire to expand into cardiovascular disease. Our interactions shifted to ziltivekimab. We became deeply engaged on the drug’s science, where the drug needed to go, and the evidence that would be required to support approval.

I was on the frontline to a certain extent to set up those relationships – and managing a lot of back channel discussions to keep our companies aligned – but all of us played a role. Our CMO Michael Davidson played a big part in convincing Novo’s leadership of ziltivekimab’s therapeutic potential. Matt Devalaraja, our CSO and head of R&D who was responsible for all of our nonclinical, translational and CMC development, was key to convincing Novo the safety benefits our drug brought due to the low-dose and that we were at commercial stage manufacturing and ready for Phase 3. And during the final stages of the transaction, it was our CEO Marc de Garidel who played a role with Novo’s CEO [Lars Fruergaard Jørgensen] to ensure all the pieces tied together, and to remind Novo’s leadership that ziltivekimab’s had the potential to completely change Novo’s revenue trajectory.

How far into this 3-yr relationship building did you realize how serious Novo’s interest was?

I remember it very well – it was at the 2019 European Socety of Cardiology Congress [in Paris]. I knew we needed to get the right folks within Novo Nordisk educated, interested and engaged on ziltivekimab. We did two things. First, to at least start the conversation, I asked an old colleague [Marian Nakada at JJDC] who had previously worked with Novo’s head of CV [Karin Conde-Knape] to make a personal connection. At the same time, Michael [Davidson] and I reached out to one of Novo’s KOLs, [Dr. John Kastelein]. So there was this independent and positive reinforcement with Novo around the ESC Congress. That’s where the engagement really started and they got interested to dig deeper.

Over the next year as we generated more clinical data, that interest level just grew. I think we were on the top of their list for a year or so before we transacted.

It started with a small group of people at ESC 2019, but it very rapidly progressed to high level discussions with Novo’s leadership. There were maybe 10 people from Novo involved – their CSO [Mads Krogsgaard], Head of R&D [Marcus Schindler] their CV team, and the corresponding business development people. Zaki Salanti in Novo’s Search and Evaluation group led the scientific discussions. On the transactions side it was John McDonald, Novo’s head of business development.

In addition to the clinical data, what else drove Novo’s interest in partnering with you?

We had a pre-filled syringe in commercial scale manufacturing.

I think sometimes, especially with manufacturing, if a potential transaction could occur, companies may defer the investments and take a “minimal” path. We did not do that.

We started on CMC even in our Series A and that paid dividends for us. If there is any question you haven’t asked yet, it is where would I advise companies to invest early. We made a conscious investment in CMC. We were ready to go whether we were doing the study or a partner was doing it. Because if we didn’t do that, Novo wouldn’t have been able to start the outcomes study so rapidly. It would have taken a year or so of CMC work. And that would have had an impact on the transaction.

We had checked a lot of boxes for them. What was surprising for Novo was that Corvidia was a 15-person company. I remember when we went through diligence and transfer of CMC – they had 50 people on their side and we had literally 5. It was amazing to them that a 5 person team could do everything.

So you’ve got this really big clinical opportunity already with CKD, but then this even much larger opportunity with broader cardiovascular disease – how do you keep people’s eyes on the ball?

The Novo team was very pragmatic – they wanted to get the drug approved, they wanted to follow the strongest scientific evidence, and they wanted to start generating revenues. And CKD was a natural extension of Novo’s existing product mix of insulin and GLP-1 drugs for diabetes.

Diabetics are patients who have kidney and cardiovascular complications. 60% of CKD patients are diabetics.

When you think about the cardiometabolic unmet need from an anti-inflammatory standpoint, CKD really jumps out. And CKD is a very large clinical opportunity – it’s 3 million patients! And we had done enough commercial legwork on how we’d go to market, including looking at potential pricing strategies, to know that CKD was a very attractive business opportunity compared to other potential new drug opportunities.

As a small company, we made a conscious effort to provide the best benefit and long-term value to patients. There were some parties who got the huge potential across other cardiovascular indications and were only focused on that. But we were always clear about where we thought the data was strongest and where we wanted to take ziltivekimab in CKD.

We were lucky with Novo.

One, we had multiple parties at the table, including other potential industry partners and also potential investors. Novo had to at least offer us par value.

Two, we found a partner who really wanted ziltivekimab and is moving the drug like it’s their own child.

At one point, the CEO and CSO of Novo said that if Novo believes in this asset Novo should go after it and get the deal done. And so now we have the confidence that they will treat the drug well, develop it well, and turn it into a product. Even more than a year after the transaction, Lars [Novo’s CEO] mentions ziltivekimab and Corvidia in investor calls.

There’s an interesting aside here on how we approached indication selection internally. At one point in Corvidia’s history, we had considered going after anemia. But the clinical data said the mechanism could have huge benefit in CKD. And both indications would have been similar heavy lifts in terms of development costs and timelines. We as a team made a change in strategy in mid to early-2019 to follow where the data led us and committed to pursuing the cardiovascular outcomes in CKD patients. As a biotech, this decision was not for the faint of the heart, and [we were] fortunate to have the support of our board of directors.

We were in our Phase 2 is when COVID-19 was hitting. At the time, Actemra was being used off-label to treat COVID cytokine storm [Actemra (tocilizumab) is another mAb working in the IL-6 pathway, is already approved for multiple rheumatological diseases, and received an EUA for use in hospitalized COVID patients in June 2021].

The Corvidia team saw there may be an opportunity for us to approve ziltivekimab in a very rapid fashion for COVID, an indication that would not require a $400 million clinical outcomes study. But there was also a lot of frenzy about COVID at the time, and the Pfizer and Moderna vaccines were coming together. And we didn’t want to jeopardize access to ziltivekimab for CKD patients.

By the way, we were very transparent with Novo about all of this.

What other deal structures were being discussed? Did your team ever consider a co-development / co-commercialization structure?

There were some parties at the table who wanted to partner with us in Europe. But Marc had a lot of commercial experience and wanted us to be wary of slicing up the drug to multiple parties whose commercial interests may or may not be aligned in the future.

And we were pretty confident that we could get started with the Phase 3 study on our own. We had financing term sheets from investors that would have let us do this . . .

. . . wait, so Novo was competing against you raising more money and going it alone?

OK, that’s where the money part comes in. At the end of the day, when you compare a $725 million upfront cash vs a hypothetical $300+ million follow-on financing, it’s hard to ignore the tangible return that amount of capital would give our shareholders today.

Even when you’ve got access to the amount of capital you need with a nice premium on the valuation, you still have to ask the question about time to return for shareholders. Our investors had been in the company for 3-4 years already; if we kept going, how much longer would it take from here?

But yes, we had options and could say no to less attractive partnership proposals.

Any advice on how to say “no” to partners? How do you do that in a way that makes them come back with an even better offer?

Haha, that’s a good one. The balancing act is to not say “no” in an aggressive manner, to have real alternative options, and to be able to share your business situation. Most folks on the other side understand this. They wouldn’t even engage in a conversation if there was no possibility of a transaction. I think that’s also part of why it took a year plus to get here with Novo. The Novo team was really feeling us out to see where to even start the business discussion.

All of us understood that if we had done a follow-on financing, Corvidia’s valuation would significantly change. And all of us understood that we weren’t just talking about an upfront acquisition payment, we were also talking about a several hundred million dollar subsequent investment to develop ziltivekimab.

We were also transparent about how we would do the development, sharing data to help guide what pricing could be, and sharing tangible data on the relevant patient population. And we laid out for partners what we thought our worst case and upside scenarios could be, effectively setting expectations.

None of our discussions ever started at a super low-ball range, but the first offers were not the best offers. And if we did get a “low” offer, I actually spent time with the other party to explain why it was not a fair offer and to walk them through Corvidia’s perspective of the potential. If you as a company are not fully committed to a path from a patient population perspective, or not fully committed to getting the data to really support that potential, then you’re in no man’s land negotiating on opinion. By the time we launched our Phase 2b, we had all of that buttoned up.

And how did your team work out your own reservation price? How did you know what was “good enough”?

That can be hard. When there’s an interested party at the table, there can already be expectations on size of exit. As a management team, we’re in the middle aligning the interests between investors, the Board, and external parties.

What I found helpful was just laying out opportunities and risks – not necessarily putting probabilities – but just laying out the binary things that could go well or could go wrong, and then discussing with the team that we would be fine with either of those outcomes. So when you lay out the pros and cons, the opportunities and the costs, that plays itself out in terms of level-setting for everybody. And the question is an easier one at that point.

There was also an older partnership process that went through some negotiation dynamics. It was an earlier potential transaction with a separate company about 18 months before all of this with Novo, and before we had started our Phase 2b study. Corvidia had a diverse investor base including European investors, US investors, small investors, big investors, and even single LP investors.

There were some investors who were OK with lower exit numbers. There were others who, given the potential of the company, wanted more. Through that historical process, there was some level-setting in terms of what the market thought was reasonable, how Corvidia should approach a transaction, our valuation expectations, as well as an understanding of our investors’ range of intentions. So coming into the Novo discussion, there was already Board alignment about how we would move forward with a potential acquisition.

Another consideration for us was that we needed access to significant capital to fund the next cardiovascular outcomes study. Everybody loved the science, the product, and the team. But there was financing risk that would need to be removed off the table.

Should we go public? Did we need a step before that to support the IPO? We started a financing process about a potential Series C, and ended up with $350-400 million in term sheets. The Board was involved in all of those investor discussions about capital availability and the risks of running the clinical outcomes study. Let’s just say the valuation proposals from new investors were a tad bit lower than what we ultimately got in the acquisition.

I will say one thing, Vikas, outside of investors and the market, a very key alignment is internal team alignment. I cannot stress enough that it is critical the management team first knows what it wants to do. And then we can align with the other parties around the table. If there are disparate voices within the team about what to do or not to do, no matter where you end up in a negotiation, there is uncertainty. That was a learning for us in that previous transaction discussion. Some folks at Corvidia wanted to do it, others didn’t want to do it, and still other folks wanted to do something different. That also got clarified over time. If there is trust around the team, I don’t think that is necessarily a challenge. In Corvidia’s case, I truly believe that the four of us [Marc, Michael, Matt, and Ram] were tied at the hip. Sure, we had disparate opinions, but all opinions were heard and discussed, and we disagreed and committed.

In those last stages with Novo, how did the process go?

Over the year or so of our process with Novo, the drama was really around data, and that really came to a head when we were close to executing. They wanted, all of us wanted, to see what our Phase 2b data looked like. Any deal and its terms were contingent on that data. And this was during COVID [which was straining many clinical trial timelines]. Luckily, our clinical team was fantastic and we recruited faster than anticipated and got our data early. We were sharing data with Novo and other parties as the database lock came through. We were very factual about what we saw and what the safety and efficacy profile looked like. And we were fortunate that the data came out as we anticipated.

As our Phase 2b data came out, multiple parties got excited and came to the table trying to move fast. We hired a banker at the very last minute, first to have a buffer so the same information was exchanged with all parties, and to also ensure we had the right relationships around the table. And then it went very, very fast. We executed in about a week and a half.

How did you create this situation with so many people ready for your data?

An important aspect there is that it takes 3 years to build competitive tension. You have to start with the relationship and then you’ve got to update people with everything going on along the way. There is no guarantee they are actually listening and interested. Strategies change any given moment in large pharmas. So a big part is keeping everyone informed – whether they like it or not. It seems like an obvious thing to just maintain relationships over time, but it’s under-appreciated in the industry.

As an aside, the data room is a great indicator of how many people are actually digging in and how interested they really are.


So now you’re CEO of Korro. What are the pro’s and con’s of being the BD person vs the CEO? What advice would you share?

One difference is the BD person is in a position to get overruled, no harm no foul. But the CEO, the buck 100% stops with them. At the end of the day, it’s the CEO’s judgment that the Board has to listen to or not.

Second, the BD person is in the middle between your team, the external party, and the Board. Because you’re just a conduit to ensure that everyone is aligned. That means you can do the market check – coming back and letting the team know what is going on outside. Usually, the BD person is alone in those market check discussions, so it gives you a buffer and room to play with business terms with the other side. And you can always be overruled and go back afterwards and play the “what do I know” card.

That said, some of the best interactions in my opinion were when you had both a scientific leader and a BD person together with the external party, to bridge those two topics. It’s also a good check for yourself, too. There were times where we would come back from meetings with different perspectives. There are things that my colleague caught, and there were things that I heard and they were different. It’s important to have that check.

Lot of times, folks internally may have drunk their own Kool-Aid. They’re so focused on doing the work. They don’t go out and see what’s happening externally. So the BD person will actually have to bring the scientific team members to the table to say “OK, here’s what others externally are doing and saying. Here’s the evidence to support their position. Should we do something different?” You’re not telling people what to do – you’re just opening up the window. Sometimes it’s an under-appreciated part of the BD job, but it is critical. Whether we like it or not, whether it’s on the science side or the finance side, the market is often right. We can go in a different direction than the market, but at least we need to know that perspective. You can’t just put your head down and do the work.


Biopharmas: Digitizing, But Not Quite Digital

David Shaywitz

What a difference two years makes.

In January 2020, I left my role as a senior partner at a corporate life-science venture fund to pursue my interest in what I recognized as a captivating frontier: the intersection of biopharma with emerging digital and data technology.

I set up an independent consultancy, and advised senior R&D executives in both large and small pharmas.  The need to understand digital technologies profoundly intensified with the arrival of the pandemic – as my co-authors and I documented in this National Academy of Medicine-sponsored analysis published earlier this year.

Our family moved from the Bay Area back to Boston in the summer of 2021. After a decade developing infectious disease medicines at Gilead, my wife became CEO of Allovir, a Cambridge-based public biotech company – a profoundly exciting opportunity.  In autumn of 2021, our three daughters – entering grades 7, 9, and 11 – each started the academic year in a new school. 

And in March 2022, I returned to the pharma company I left two years prior, in what feels like a tailor-made role, VP-Distinguished R&D Fellow, Data and Digital. The ambition: “to realize the future of biopharma through the thoughtful and pragmatic integration of rigorous biomedical science and emerging digital and data technologies.”

It’s been…busy.

Returning to the same company (albeit a different location) after a two-year hiatus is providing an unusual before-and-after view into the organization and the industry more generally: a lot has happened, and so much is different.

Office life: the new normal

As so many of us have discovered, the office has radically changed.  Most work is hybrid, and teams show up to the office several times a week (or less if someone is truly remote).  Moreover, many organizations, including ours, have adopted a “hoteling” system meaning that you don’t have your own office, or even your own cubicle.  In the morning, you plunk your stuff down at an available desk in your team’s designated “neighborhood,” and then you haul it away at the end of each day.

I’m not a huge fan of this approach; I like the idea of having a designated work area, which I can personalize; in my pre-pandemic life, I enjoyed stopping by my colleagues’ desks, seeing pictures of the families, knowing where to find them if I had a quick question.  It contributed to my sense of belonging and the feeling of community.  In contrast, I’m finding the flash-mob approach to office life less congenial – although our dog appreciates the extra attention he receives on the days I’m working from home.

Digital progress

Other changes I’ve noticed are surely for the better. Digital and data strategy has moved from the periphery of the organization to the core, as part of a CEO-driven digital transformation effort that seems to have really taken hold. There’s a sense of pragmatic possibility among the folks working on digital and data, driven by the palpable progress they’ve seen in a number of areas (like finally moving most compute from on-premise to the cloud, for example). 

The organization has also recruited – and retained – exceptional talent, which seems especially encouraging given the demand for these skills.

These efforts occur in the context of an industry that (as I’ve written in this space in the context of Novartis, AstraZeneca, and Lilly) is clearly making efforts to embrace digital, while also coming to terms with the challenges.

At a high level, it seems like what’s happening across the industry is what Jeanne Ross and her co-authors of Designed for Digital describe as “digitization,” which they distinguish from the higher-order ambition to develop and deliver digital offerings. 

As Ross and colleagues write:

“We distinguish these two potential impacts of digital technologies as the difference between digitized and digital. Digitizing with digital technologies involves enhancing business processes and operations with SMACIT [social, mobile, analytics, cloud, internet of things] and related technologies. For example, Internet of Things technologies can automate support of distributed equipment or operations; mobile computing can create a seamless employee experience; artificial intelligence can help automate repetitive administrative processes. The applications of digital technology can certainly benefit a company, but they digitize a company; they do not make it digital.”

The authors continue, “digitization enhances operational excellence; digital enhances the customer value proposition.” Digitization “is a prerequisite to digital transformation,” they argue, not equivalent to it.

This description of digitization seems like a perfect summary of what the industry is currently (and unevenly) attempting, an effort to improve operational efficiencies by leveraging the digital resources now available and routine in other industries.

Digital and COVID-19

As described by Pfizer CEO Albert Bourla in his captivating new book Moonshot, Pfizer’s ability to deliver a COVID-19 vaccine with such speed is attributable, at least in part, to an effort initiated prior to the pandemic to digitize operations. In the context of COVID-19, Bourla seems to have imbued the organization with a palpable, urgent, must-do culture (grounded on the premise that “time = lives”). By affording a common and up-to-date window into progress and problems, the digital dashboards enabled this culture by allowing the entire organization to align and focus. 

(It should be noted that, as this insightful 2021 McKinsey analysis points out, most of the 10-fold acceleration in vaccine development observed during the pandemic likely reflects the combination of enhanced regulatory engagement and extraordinary at-risk investment. Even so, the operational efficiencies – enabled by digitization – were also important.)

It will be interesting to see the extent to which biopharma can build on this success to further digitize, and rationalize/organize the many data flows within companies. Established biopharmas are notoriously siloed, as well as stitched together from years of successive acquisitions. This has a tendency to lead to kludged-together data solutions (see figure) that may get the job done, MacGyver-style, but are inefficient and result in missed learning opportunities.

In theory, digitally-native companies, such as Moderna, should start with an enormous advantage.  The ability of Moderna – a young company that entered the pandemic a fraction the size of Pfizer – to develop and deliver a novel vaccine in record time speaks to promise of such a foundation, as Iansiti and Lakhani argue in Competing in the Age of AI

Of course, it’s also easy to rationalize that COVID-19 was a special case, and that Moderna just happened to be in exactly the right spot at the right time. 

Hence question one: can digitally-native biotechs consistently beat pharmas at their own game?  Phrased differently, will the apparent operational efficiencies, and improved access to data (which can serve as the basis for further learnings, including those enabled by AI) enjoyed by digitally-native biotech companies represent a meaningful competitive advantage, or will experienced pharma giants manage, through selective digitization, to capture enough of the benefits to avoid disruption?

Question two, of course, is whether digitally-native biotechs – particularly those intent on building digital platforms – can potentially win at a different game, similar to how the iPhone beat Nokia; more on this later.

Lakhani, for his part, asserts that “traditional incumbent organizations have no choice but to embrace [a digital future].  Either you’re going to be competing against the platform or you’re going to be part of a platform that is going to be AI-first.”

Follow this space…

I am following progress in three areas with particular interest:

Future of evidence generation. This is a broad area that generally seeks a more complete understanding of and relationship with patient/participants, involving enhanced breadth (longitudinal data) and depth (e.g. wearables). It prioritizes both ease of participation (eg distributed/hybrid trials) and equity (diverse representation). For a phenomenal overview of this area by one of its leading lights, see this recent presentation by Dr. Amy Abernethy of Verily.

Getting beyond operational efficiency. Digital efforts to date in our industry and others have been most successful in the context of structured, high-volume data and repeatable activities. But in the big picture, what we need more than anything in biopharma are improved translational models – a way of figuring out if a molecule we put into people will actually work, and work safely. The failure rate of clinical development remains abysmal. While AI approaches are constantly hyped, the available data, as Andreas Bender eloquently discusses here, and as Derek Lowe has written here, appears to represent a poor fit for AI solutions.

Escalating security and privacy concerns. The potential insights associated with participant data are accompanied by profound responsibility for ensuring these data are managed appropriately, and always in accordance with the participant’s wishes; thus data stewardship has emerged as a critical pilar of all digital efforts. Add to this the increasing concerns related to bad actors. As FBI Director Robert Mueller said in 2012, “I am convinced that there are only two types of companies: those that have been hacked and those that will be. And even they are converging into one category: companies that have been hacked and will be hacked again.”

To these I might add a fourth topic, which could be called service-oriented architecture, but really boils down to the central premise of both the Ross book and the Iansiti and Lakhani book: will any biopharma embrace the radical digital transformation both sets of authors advocate, as captured in this figure:

The authors of both books emphasize the power of what they describe as a digital platform, constructed as shown at the right of the figure. 

Here’s the basic idea: in traditional firms, as Iansiti and Lakhani write (slightly paraphrased), the

“organization, data, and technology evolve into silos, with disparate retail focus areas largely contained in separate, disconnected units. Connections between silos are haphazard and often unpredictable, motivated by meeting immediate needs and fighting fires.”

A better approach, the authors contend, is to adopt a “modular, distributed structure” based on “a common set of building blocks that could be deployed to drive scale and scope.” At the heart of this approach is a “central, standardized set of services” and the ability to easily communicate through interfaces known as APIs. 

Consequently, “one of the seminal documents in the digital transformation of business,” according to Iansiti and Lakhani, might be a memo Jeff Bezos issued in 2002, in the early days of Amazon, mandating the use of this API-based approach throughout the company. While challenging to adopt, this approach is what ultimately enabled Amazon to scale so fast and so well.

In an industry that seems to be struggling even to digitize the information in narrow silos, such a transformation seems like a nearly impossibly heavy lift for established organizations. As Brian Bergstein has written in Technology Review, “the most common uses of AI have involved business processes that are siloed but nonetheless have abundant data.” Most work is happening within silos, not across them.

Most folks in pharma would love to do their existing jobs better, and struggle less to find and manage the data they currently need; but the idea of transforming the entire enterprise in hopes of facilitating the development of novel digital solutions may prove a prohibitively difficult sell, especially when their current objective – developing impactful new medicines — seems intrinsically worthy and consequential.

Besides, as Bergstein points out, the reports from the AI front are mixed, as “people in a wide range of industries say the technology is tricky to deploy. It can be costly. And the initial payoff is often modest.”  While he notes that technologists may be most interested in “What can the technology do,” the key question for companies is “How much will we benefit from investing in it?”

Transformation visionaries like Ross, Lakhani and their co-authors might suggest another question: “How much will you lose by not investing in disruptive technologies?” And they might suggest we speak to the good folks who used to work at Kodak and Nokia for perspective.


The Timmerman Traverse for Life Science Cares Is Back, Fighting Poverty

Luke Timmerman, founder & editor, Timmerman Report

The biotech community has plenty of people willing to work to support vulnerable members of our society.

This year, I’m doing what I can to again mobilize the biotech community to fight poverty.

I’m happy to announce the Timmerman Traverse for Life Science Cares.

It’s a Presidential Traverse hike set for Sept. 11-14, 2022.

This expedition builds on the success of the inaugural traverse, which raised $735,000 last year for the antipoverty work of Life Science Cares. This trip is a phenomenal way to give back, enjoy nature, and make lasting friendships.

“It was amazing to see leaders across our biotech industry come together to raise funds to help bridge the unfortunately real gap between the medicines we develop, and the patients and communities who need access to them,” said Vineeta Agarwala, general partner, Andreesen Horowitz, and a veteran of the Timmerman Traverse 2021.

Highlights of the Timmerman Traverse, 2021

This year, a new group of 20 biotech leaders will hit the trails of New Hampshire. Together, we’ll cover the beautiful 20-mile hike across the peaks of Mt. Washington, Mt. Adams, and Mt. Jefferson. It’s a physically demanding trek with 8,000 feet of elevation gain.

Each member of the team will have to be in shape. The weather can be harsh, so they’ll have to be prepared. They’ll also have to dedicate themselves to fundraising. Each person is committing to raise at least $25,000. Our team’s goal is $800,000.

This year, we’ll be expanding from Boston to raise money for all four communities where LSC has operations – Boston, San Francisco, San Diego and Philadelphia.

For those unfamiliar, Life Science Cares brings the biotech community together to support nonprofits that uplift the most vulnerable members of our society.

This means providing immediate basics like food and shelter. And it goes beyond that. LSC’s network of nonprofits also provide on-ramps to better life over the long term through education and job training.

I’m proud to support this work, and to leverage the biotech community to support it in a big way.

I’ve recruited a outstanding team for this mission.

Meet the Timmerman Traverse team for 2022 (and click on their name to support their Life Science Cares campaign.)

For sponsorship opportunities of this special event, talk to me at luke@timmermanreport.com and Emily Stanford at emily@lifesciencecares.org.

Let’s show what the biotech community is made of in 2022.

Go to the Timmerman Traverse team page to donate today!




Regeneron Buys Checkmate, Bivalent Vaccine Progress, & a Fitting Acronym

Luke Timmerman, founder & editor, Timmerman Report

Clinical trialists are always trying to come up with catchy study titles. I’m not a big fan of these acronyms, and try to avoid using them. They’re often forgettable.

But this week I saw one that stood out as especially meaningful. Yale University researchers are running a new Long COVID study. It’s called – LISTEN.

It stands for Listen to Immune, Symptom and Treatment Experiences Now.

There’s certainly interest in what’s happening biologically with so many people — potentially millions — who are reporting some symptoms of Long COVID. Lead investigators Akiko Iwasaki and Harlan Krumholz appear to have a solid plan to collect data on the many potential contributing factors to this mysterious ailment — demographic, clinical, social, and environmental factors associated with health status.

Akiko Iwasaki, Professor of Immunobiology and Molecular, Cellular and Developmental Biology, Yale University; director of Center for Infection & Immunity, Yale School of Medicine

They’re collecting blood and saliva samples, and incorporating use of a health app called Kindred that is supposed to connect patients to each other’s experiences, to their own data, and to other potentially helpful studies.

This study, and others like it, could help point the way toward more effective prevention and treatment.

Equally important, though, is the sentiment around rebuilding public trust in science. We need to do a better job of listening to accomplish this goal.

It’s important that the research participants feel like they’re being listened to, that they’re being treated respectfully, and that they are part of helping solve the medical mystery. Studies like this point the way toward how to conduct rigorous scientific investigations with the kind of respectful, two-way street of engagement that participants want and deserve. We need studies like this to encourage more people to participate, and then to foster more confidence in the knowledge that results.

Many millions of people don’t trust what the scientific community has learned the past couple years about the pandemic. Especially during moments of maximum uncertainty, way too many people have turned to charlatans and other peddlers of misinformation for answers. Many people are vulnerable to these appeals because they feel like outsiders, like they’re not being listened to by The Establishment.

Some of this feeling is understandable, especially among people suffering from Long COVID, who haven’t been taken seriously enough by policymakers and the scientific community.

A little more careful listening could go a long way.

We might learn about the virus. We might also learn a bit about how to repair some of that torn social fabric. We need to do both of these things to get the scientific enterprise on a more sustainable footing, and to be better prepared for the next big thing.


This Week in Drug Pricing

How much do hospitals mark up the prices of cancer drugs they administer via infusion? How much do these prices vary from place to place? How often do they follow new federal rules on price transparency? Most people have no idea, and they would be shocked to learn the answers. Read about the eye-popping markups – between 120 percent and 630 percent — in in JAMA Internal Medicine.


Boston-based Sionna Therapeutics said it raised a $111 million Series B financing led by OrbiMed. The company is working on small molecules to fully restore function of the CFTR protein in cystic fibrosis patients. RA Capital, Atlas Venture and the CF Foundation also participated in the financing. Read RA Capital partner Josh Resnick’s piece on the opportunity to go beyond what Vertex has done in the past decade to transform the treatment of CF.

Somerville, Mass.-based Tessera Therapeutics said it raised more than $300 million in a Series C financing to advance its gene writing technology for drug discovery. Abu Dhabi Investment Authority; Alaska Permanent Fund Corporation; Altitude Life Science Ventures; ARTIS Ventures; Cormorant Asset Management and Tessera’s founder, Flagship Pioneering were among the investors.

Cambridge, Mass.-based Satellite Bio came out of stealth, saying it has raised $110 million in seed and Series A funds to make programmable cell therapies. aMoon Growth led the A round. Other investors include seed co-lead Lightspeed, aMoon Velocity, Polaris Partners and Polaris Innovation Fund. New Series A investors included Section 32, Catalio Capital Management and Waterman Ventures.

San Francisco-based Unlearn raised $50 million in a Series B financing. The company is working on a machine learning platform to help companies run randomized controlled trials with a higher probability of success, and with enrolling fewer patients. Insight Partners led with participation from new investor Radical Ventures, as well as all of the company’s existing investors including 8VC, DCVC, DCVC Bio and Mubadala Capital Ventures.

Denver-based Pathware raised $7 million to develop hardware and software for digital pathology, so it can go from the central lab to the point of care. UnityPoint Health Ventures and Level Eight Ventures co-led.

Emeryville, Calif.-based Octant said it raised $80 million in a Series B financing led by Catalio Capital Management. It’s using synthetic biology and chemistry to develop precision medicines. The company said it also established a Deep Mutational Scanning partnership with Bristol Myers Squibb, and hired Dean “Rick” Artis as its first Chief Scientific Officer. Feng Zhang also joined the Scientific Advisory Board.

Framingham, Mass.-based Alzheon, an Alzheimer’s drug developer, raised $50 million in a Series D financing.

Personnel File

Cambridge, Mass.-based eGenesis, an organ transplantation company, promoted Michael Curtis to CEO. He’s been president of R&D since 2020. Outgoing CEO Paul Sekhri will remain on the board of directors.

South San Francisco-based Twist Bioscience, the DNA synthesis company, promoted Tracey Mullen to senior vice president of operations, and Nimisha Srivastava to senior vice president of R&D. Patrick Weiss is stepping down as chief operating officer.

Cambridge, Mass.-based Evelo Biosciences, the developer of single-strain microbial therapies that can be given orally for inflammatory diseases, said it added John Maraganore and Tassos Gianakakos as strategic advisors. Maraganore is the former CEO of Alnylam Pharmaceuticals and Gianakakos is the former CEO of Myokardia.

Somerville, Mass.-based Finch Therapeutics, a developer of microbiome-based therapies, said it’s cutting its workforce by 20 percent.


Tarrytown, NY-based Regeneron Pharmaceuticals agreed to acquire Checkmate Pharmaceuticals, a cancer drug developer, for $10.50 a share, or $250 million. Checkmate is the developer of vidutolimod, a CpG-A oligodeoxynucleotide Toll-like receptor 9 (TLR9) agonist delivered in a virus-like particle to stimulate the innate immune system against cancer. Some market observers hoped that the acquisition might lift the biotech stock markets out of the doldrums, providing hope to the roughly 150 public companies that are now considered by investors to be essentially worthless. (See @bradloncar tweet).

New York-based Terran Biosciences said it licensed a pair of late-stage programs for Sanofi, and plans to develop them for neurological and psychiatric diseases. The assets weren’t disclosed, and neither were the financial terms.

AbbVie terminated its partnership with Sweden-based BioArctic. The companies had been working together since 2016 on antibodies directed against alpha-synuclein for Parkinson’s disease.

Waltham, Mass.-based Dragonfly Therapeutics said it expanded its research collaboration with AbbVie to work on immune-mediated diseases. AbbVie is getting the option to license multiple new candidates that use Dragonfly’s tri-specific NK cell engaging technology. Terms weren’t disclosed.

Data That Mattered

Amgen said it passed a Phase III trial with a biosimilar version of J&J’s ustekinumab (Stelara), an IL-23 antagonist for moderate to severe plaque psoriasis.

Moderna said its bivalent COVID vaccine candidate, designed to stimulate the immune system against mutations found in the Beta variant of concern, was able to elicit higher levels of neutralizing antibodies than the original vaccine formulation. The bivalent vaccine candidate appeared superior to the original against the Beta, Delta and Omicron variants one month after administration, the company said.

San Diego-based Arcturus Therapeutics said its self-amplifying mRNA vaccine candidate against COVID-19 delivered 55 percent vaccine efficacy against symptomatic COVID, and 95 percent efficacy against severe disease or death, in a study of 19,000 adults in Vietnam. Adverse events were similar between the vaccine and placebo groups, the company said. Arcturus said it’s planning a pivotal study of the vaccine candidate as a booster.

Ponte Vedra, Florida-based Orasis Pharmaceuticals said it met the primary and secondary endpoints of a Phase III trial that evaluated its eye drop for presbyopia – the loss of the ability to see items up close, a natural part of aging. The company said it plans to submit a New Drug Application to the FDA in the second half of 2022.

Science Policy
  • Better Ventilation Would Create a Healthier Workplace, but Companies Have to Invest. NPR / Kaiser Health News. Apr. 19. (Liz Szabo)
  • Now’s Not the Time to Dispense with COVID-19 Precautions. Washington Post. Apr. 20. (Lucky Tran and Oni Blackstock)
Annals of Manufacturing

Bothell, Wash.-based Seagen, the developer of antibody-drug conjugates for cancer, officially announced its plans to open a 270,000-square foot manufacturing facility in Everett, Wash. The company said the new facility will give it “greater control and flexibility over the production of its medicines to treat cancer.” I consider this to be a shrewd move for several reasons. (See my Frontpoints column, Feb. 2022, “Biotech’s Future Off the Beaten Path.”)

Novocure said it’s breaking ground on a new facility in Portsmouth, NH, which will house “a training and development center where partners from around the world can come to learn about Novocure’s Tumor Treating Fields (TTFields) cancer therapy.” NH Gov. Chris Sununu attended the ceremony.

Santa Monica, Calif.-based Kite Pharma received FDA clearance for a new cell therapy manufacturing facility in Frederick, Maryland. The company said it now has facilities in southern California, Amsterdam and Maryland. Kite said in a statement it has “the largest, dedicated in-house cell therapy manufacturing network in the world, spanning process development, vector manufacturing, clinical trial production and commercial product manufacturing.”

  • The Future of Early Cancer Detection. Nature Medicine. Apr. 19. (Rebecca Fitzgerald et al University of Cambridge)
  • Somatic mutation rates scale with lifespan across mammals. Nature. Apr. 13. (Alex Cagan et al Wellcome Sanger Institute)
  • The Challenge of Genetic Variants of Uncertain Clinical Significance. Annals of Internal Medicine. Apr. 19. (Wylie Burke et al University of Washington)
  • Development of a clinical polygenic risk score assay and reporting workflow. Nature Medicine. Apr. 18. (Matthew Lebo et al Mass General Brigham Personalized Medicine)
Science of SARS-CoV-2
  • The Evolution and Biology of SARS-CoV-2 Variants. Cold Spring Harbor Perspectives in Medicine. Apr. 20. (Amalio Telenti of VIR Biotechnology, Emma B. Hodcroft of University of Bern, Switzerland and David L. Robertson of MRC-University of Glasgow Center for Virus Research)
  • Intramuscular AZD442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19. NEJM. Apr. 20. (Myron Levin et al Provent Study Group). For people at increased risk of an inadequate response to vaccination or increased risk of exposure, AstraZeneca’s antibody cocktail (Evusheld) delivered a 77 percent relative risk reduction of coming down with symptomatic COVID, compared with placebo. Patients were followed six months. (AZ press release)
  • Increased Memory B Cell Potency and Breadth After a SARS-CoV-2 mRNA Boost. Nature. Apr. 21. (Paul Bieniasz & Michel Nussenzweig et al Rockefeller University)
  • Vaccine effectiveness against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha, Delta and Omicron SARS-CoV-2 variants: a nationwide Danish cohort study. MedRxiv. Apr. 20. (Christian Hansen et al Statens Serum Institut)
  • Admissions to a large tertiary care hospital and Omicron BA.1 and BA.2 SARS-CoV-2 PCR positivity: primary, contributing, or incidental COVID-19. MedRxiv. Apr. 18. (Juliette Severin et al University Medical Center Rotterdam, Netherlands)
  • Hospitalizations of Children Aged 5–11 Years with Laboratory-Confirmed COVID-19 — COVID-NET, 14 States, March 2020–February 2022. CDC Morbidity and Mortality Weekly Report. Apr. 19. (Dallas Shi et al CDC)
Science Features
  • Scientists Find No Benefit to Time-Restricted Eating. NYT. Apr. 20. (Gina Kolata)
A Word on Climb to Fight Cancer

Many of you saw social media announcements about my latest Climb to Fight Cancer campaign for the Fred Hutch Cancer Center.

I want to say thanks to everyone who contributed to this campaign. It was a huge success.

The 18-person team of biotech leaders reached Everest Base Camp in Nepal (elev. 17,600 feet) on Apr. 4. We raised $1.3 million for cancer research.

We enjoyed spectacular scenery in the world’s highest mountain range, the Himalayas.

We made new friendships on the trails.

We reveled in the culture of the Sherpa, the indigenous people of the Khumbu Valley famous for their strength at high altitude, and their generous spirit.

These trips are clearly resonating with many members of the biotech community. It was evident on the Kilimanjaro climb of 2019, on the Timmerman Traverse for Life Science Cares in 2021, and again on the Everest Base Camp trek of 2022.

I’m planning more expeditions. These trips mobilize the biotech community around good causes. I believe there’s tremendous potential for good work in the biotech community. I will continue finding ways to harness it.

For today, enjoy a few photos from the Everest Base Camp trek of 2022. Click on images to view at full size.

If you are interested in participating in a future expedition, or your company is interested in sponsoring one of these campaigns for cancer research or poverty relief, see me. luke@timmermanreport.com.


Microbiome-based Drug Development: Bernat Olle on The Long Run

Today’s guest on The Long Run is Bernat Olle.

Bernat is the CEO of Cambridge, Mass.-based Vedanta Biosciences. The company was founded in 2010 by Puretech Health, in collaboration with a handful of academic founders.

Bernat Olle, CEO, Vedanta Biosciences

At the time, the faster/cheaper tools of DNA sequencing were making it possible for immunologists and microbiologists to gain a much more fine-grained view of the complex interplay between microbes and the human immune system. Learning more about the multiple factors at work in health and disease promised to open up a treasure trove of new ideas for treatment and wellness.

Vedanta has been at this a long time, and is now at something of a turning point. It has completed a Phase II trial with a lead product candidate for the treatment of C.difficile infections. With its specifically-defined consortia of live bacteria, made into an oral therapy, Vedanta hopes to restore the microbial community balance needed to help ward off an invasion of C.diff microbes. The company has some data showing it can reduce the risk of recurrent C.diff infections, which can cause hospitalization and death. Its task is now to reproduce those findings in Phase III.

Bernat has been a stalwart of the microbiome field over the past dozen years. He’s a Catalonian immigrant who made his way to MIT, and then to the biotech industry. He has an interesting personal journey, including a stint as a hockey player. He’s passionate about the role of immigration in making the US the world leader in biotech, and we discuss that briefly at the end.

Before we get started, here’s a word from the sponsor of The Long Run.


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Now, please join me and Bernat Olle on The Long Run.


Samantha Truex on How Getting Market Feedback Turned Into M&A for Padlock

Vikas Goyal, former SVP, business development, Pandion Therapeutics (now part of Merck)

Samantha Truex is the CEO of Upstream Bio, a stealthy developer of drugs for inflammatory diseases with $200 million in backing from a syndicate led by OrbiMed.

Before her newest venture, Sam had an impressive career as a business development executive, including as the chief business officer of Cambridge, Mass.-based Padlock Therapeutics. That company, a developer of Protein/Peptidyl Arginine Deiminase (PAD) inhibitors for autoimmune diseases, was acquired by Bristol Myers Squibb in March 2016.

Samantha Truex, CEO, Upstream Bio

The deal pre-empted Padlock’s trajectory as a growing start-up and provided investors with an unusually fast windfall return. Padlock secured a $150 million upfront payment, and was eligible for another $450 million in milestone payments.

The company was less than two years old, and had raised a $23 million Series A financing led by Atlas Venture.

With that deal now six years past, I asked Sam to talk about some of what happened behind the scenes.

Why were you pursuing a deal in the first place?

So the first point is that the deal didn’t need to happen. At the time, Padlock was a biotech focused on small molecule inhibitors of the PAD enzymes. We had the backing of excellent investors in our Series A, including Atlas Venture.We were well underway with investor discussions around a Series B which I felt quite confident could happen. Our pipeline was making great progress towards development candidate nomination in the next several months.

Given our stage, there was a clear choice facing us — should we start to build out Padlock to take our programs into the clinic, or should we partner with a larger company who could exploit the programs further than we might have on our own?

We spent a lot of time thinking about this. I really credit our investors and our management team, especially our CEO Mike Gilman, with taking a very thoughtful approach to deciding which pathway was best for us to pursue.

We had reached out to several partners to explore a collaboration. This fortunately generated quite a bit of interest and competition for our PAD inhibitors. There aren’t a lot of new and novel targets in the inflammation space and the PADs had high interest in industry. We ended up receiving term sheets from three different parties including BMS’ acquisition proposal.

Why did you end up partnering with BMS?

In fact, we had gotten quite far down the path with another company, let’s call it Company X, around a pretty different structure that included a meaningful upfront cash payment and equity investment, with an option to be acquired at the end of Ph1b. We really liked the team from Company X. They were thoughtful, creative, and really engaged on the potential to pursue PAD inhibitors in multiple clinical populations in parallel in Ph2 to de-risk the biology and try to benefit as many patients as possible. We had also spent a lot of time with them to work out the details of the research collaboration.

Behind the scenes, we were also having discussions with BMS.

Their approach was very different and much more transactional. They did not want to help grow Padlock, and wanted to pursue something more like a license where BMS would take the ball and run. For most of our BD process, this structure was not really that attractive to us and we were much more interested in the collaborative approach Company X was pursuing.

Along the way, though, we began to ask if there was some economic range whereby BMS’ proposal would be acceptable. Ultimately, we negotiated BMS to a very attractive deal range including $225M near term, of which $150M was upfront, with a total of $600M including downstream payments.

We also noted that, at least as of that time, Company X did have a track record of either renegotiating their option deals during the course of the collaboration, or not executing the options at all. As the small biotech in these types of option deals, you are beholden to the bigger company’s strategy shifts — do they decide to exit that research area, or do they end up partnering with a competitor program. So even if you achieve the technical milestones, you may not achieve the actual full goal of getting your medicine to patients. And in hindsight, Company X did end up having a major strategy change that might have impacted the outcome of our program.

What made Padlock’s program so attractive to industry? How did you convey Padlock’s innovation without giving away the “secret sauce”?

We knew that many companies had tried to develop chemical matter against the PAD enzymes and had failed. Padlock had made great progress on our chemistry and this was evident to all the parties around the table. We allowed extensive third-party chemistry diligence. We also executed an MTA with BMS so they could work with our compounds directly. This is always a little tricky to do if you have not run all of the assays the partners are going to conduct, but we felt confident that our compounds would perform well.

This was a great competitive process. How did you convey to the other parties that there was real competition?

Look I don’t make stuff up, I don’t lie, I don’t bluff, and I take the terms of CDAs very seriously. So in this case, Company X’s CDA was really broad and could be interpreted as covering even the existence of the CDA itself. So I ended up having to talk to BMS about the need for parties to move quickly, that there was a lot of energy in the process, and even sharing our decisions to focus on other strategic directions. And I could tell that several of the BMS team did not believe it was as competitive as it actually was. In fact, after the acquisition closed and I shared all of my company files, I distinctly remember exchanging  emails with my BD counterparts at BMS when they finally saw this almost fully-negotiated contract with Company X.

We also made it a point of being very responsive to all of the parties involved. One thing I note that Company X did not do was ask me if everything was still on track, if Padlock had any other considerations in the process, or if any changes to the deal structure might be worth exploring. Because we were so far down the path with Company X and the potential with BMS seemed low, we didn’t share that the competitive environment was changing when BMS came back to us. If Company X had asked us directly, we would have answered.  Since they did not ask, we waited until we had an acceptable M&A proposal from BMS before sharing that competitive reality with Company X.

They were quite unpleasantly surprised by this news. 

One can question whether we should have given them some more hints, but this was a critical business decision for Padlock with massive uncertainties along the way and two parallel confidential discussions progressing. There was no requirement for us to share our options and no exclusivity in place.

We preferred the Company X development plan, so we did give them a chance to pivot to an M&A structure with essentially the same financial investment. Ultimately, they wanted to stick with an option-based structure and didn’t make an M&A proposal.   We went with the BMS acquisition deal.

This kind of BD process is also a lot of work. How did you keep the Series B process going in parallel?

We just did a lot of work! This was definitely a time of a lot of work and not a lot of sleep. We kept building the company.We moved to bigger labs.We recruited additional senior team members.We scaled up manufacturing of our short-list development candidate leads.We were also talking to Series B investors.

As the BD person you’re bringing the team these proposals and sort of representing the outside world to your team. How did you balance that role with your responsibility as a senior member of the team to decide what was right for Padlock?

I was intimately involved with these important considerations and decisions. I tried to be as objective as possible in trying to evaluate what was best for all of our stakeholders — our patients, the investors, and the employees of the company. I give a lot of credit to Mike Gilman for involving me in this process.

We also spent a lot of time getting the senior R&D management team involved in these decisions, and helping them understand the implications on them personally because they were going to have to live with the collaboration or acquisition decision.

For example, would the scientists want to work for BMS? Would BMS want them to become employees? And because we were a small private company, we could really engage openly in these discussions with the team.

For most of the process, we really didn’t want to be bought. We turned down multiple proposals from BMS but when they came back with the economics we ultimately closed at, we were aligned it was the right deal to do. And the team was actually a little sad — we wanted to keep working together. But this was such a great return to our investors, we knew it was the right thing to do.

We also believed BMS was going to push this program aggressively. We suspected that BMS had learned a lot about the potential role of PAD inhibition in rheumatoid arthritis through their work on abatacept (Orencia). This was a company that was already set-up to immediately take the knowledge they already had and move with it. BMS was pretty different from the other companies around the table in this way.

In hindsight, would you do the deal again?

A lot of the original champions for our partnership at BMS have departed the company, presumably because of changes in strategic directions at BMS. Unfortunately, that is one of the inherent risks of transacting with a large pharma. So sometimes in retrospect I wonder if we should have kept going on our own until we got our own clinical data. And we’re now several years after Padlock’s acquisition closed, and BMS has still not disclosed a clinical stage PAD inhibitor.

But even knowing what I know now, I still think I would do this again.

First, I cannot honestly say that Padlock could have gotten these programs into the clinic if we had retained everything — I’m not privy to all of the data that BMS has generated since the acquisition. And frankly we got a substantial amount of value upfront and that was a great return to our investors at the time.

What did you learn from this process? What lessons would you share with your BD peers?

One thing I was really impressed with is how some of the pharmas approached us. As an example, early in our process Gilead brought multiple leaders from their R&D team all the way to the East Coast to meet with us. They talked to us about how interested they were in our work, and that they respected how we were approaching the science and wanted to hear from us how we would take the programs forward.

Second, I want to reiterate the importance of our not needing a deal.

I think it’s very important to always run a program as if you are the one who is going to take it all the way to market. You should never slow things down in anticipation of a deal.

First, if you slow things down it will actually hurt the momentum of any deal process. Second, partners will assume you desperately want to do a deal if you slow things down, which could hurt your valuation. And third, a deal is never done until it’s closed so you have to keep running it.

Finally, in my career, I think as interesting as the deals we do close are the deals we don’t close.

I’ve seen a lot of deals end up not closing, even some deals that were all the way through contracts. As leaders in our companies, it’s important we keep the focus on the future of the company and long-term value creation for both shareholders and patients. Even some deals with great upfronts and that would garner terrific press coverage I’ve ended up walking away from because they weren’t the right fit with the company’s goals. It’s easy to get caught up in getting a deal done, yet a deal is only a good deal if it accomplishes the long-term objectives of both companies entering into it.


Evidation: Finding Tailwinds For Pharma Companies, and Individual Patients

Lisa Suennen

Sailors know the concept of tacking. It’s an essential way of moving forward. Without tacking, the headwinds are too strong. The boat can go wildly off track, or stall. By steering from one direction to the other, in zigs and zags, it is possible to drive into the headwinds and make progress. Do it well, and you can gradually overtake an opposing force to reach the destination.

San Mateo, Calif.-based Evidation Health, Inc. has a long history of tacking, and it’s now maneuvered itself into position to perfectly match what the market wants. This is the well-known state of “product-market fit.” And when a company reaches this stage, the tailwinds begin to take over, helping push it even faster to the planned destination of market success.

Founded originally in 2012, the predecessor company to Evidation was called The Activity Exchange (TAE). TAE was founded early in the days of the digital health revolution, long before paths to health data monetization were clear. The company originally took data from consumer wearables and applied sophisticated predictive analytics to encourage wellness and drive patient behavior, particularly for employers and insurance companies. 

In many ways, that was the right product, but it entered the market at the wrong time. It was simply much too early for customers that were just beginning to think about the role that digital data might play in encouraging better health outcomes. As such, Evidation put its boat in the water at the precise moment that the oncoming wind was strongest.

When TAE merged with the newly formed Evidation in 2014, the company made its first tack. It shifted to help the emerging digital health companies demonstrate the value and validity of their products and interventions for pharma companies, payers, and other clients.

By helping digital upstarts develop an evidence base, they posited, all boats would rise. As it turned out, the digital health startups of that period didn’t have the funds to undertake the kind of sophisticated demonstrations of efficacy that Evidation sought to manage on their behalf for that demanding set of customers – pharmaceutical companies and health insurers.   

Many digital health companies of the time hit the rocks. But Evidation noticed something that led it to tack again — that the pharmaceutical companies were coming up the learning curve in digital health. They had both money and interest to invest in understanding patients’ experience when taking medications.

In response, Evidation redirected its efforts toward becoming a digital products Clinical Research Organization (CRO) of sorts. Evidation found a new angle, helping pharmaceutical companies sort through the burgeoning array of digital products to evaluate their validity and usefulness. With Evidation’s help, pharma companies, through a series of short post-market studies, began to see a more vivid and detailed picture of patient’s everyday lives as they interacted with newly marketed biopharmaceuticals.

Suddenly, Evidation was in position to provide pharmaceutical companies with new information that could help them with their sales and marketing campaigns.   

Each of these tacks was complex. That’s not just because of the business shifts required, but because there was uncertainty among leadership and, at times, a lack of unanimity on the Board as to whether the pharma market was really the right course to pursue.

At the time Evidation made this move, the idea of real-world evidence (RWE) was gaining currency in the pharma/biotech realm, especially as it related to Phase IV post-marketing surveillance studies of new drugs.But the market sent out some mixed signals that would, on occasion, tug the company back toward its wellness roots.

But Evidation fundamentally stayed on course. As it picked up steam, it began to recognize that its pharma insights business, as designed, wasn’t going to get them all the way to their target destination. 

Instead, the Evidation team was encountering more wind than waves, and that was keeping the business from growing to its full potential. Most of the pharma contracts were for short studies (3 month “catch and release studies” as Evidation internally referred to them) that did not produce a recurring revenue model or an ongoing relationship with customers and patients. Notably, pharma and biotech companies were also becoming far more curious and sophisticated about how data and data science could inform their business at a much more profound level.

It was time to tack again. 

Ultimately, the business set its course toward gathering and analyzing patient insights over extended periods of time (not just for short bursts), developing large condition-specific cohorts drawn from its proprietary patient network (the company has built a patient network of over 4.5 million individuals willing to participate in studies for minimal compensation). This has enabled pharmaceutical companies to engage in continual and continuous learning about patient experience through longitudinal engagement with large target populations.   

Evidation’s many large and mid-sized pharmaceutical and biotech clients can now continue to develop new queries and hypotheses to test and identify emerging trends over the course of a year or more to get a more holistic picture of what it’s like for people to live with various medical conditions and to take medications over the long term. At the same time, companies can satisfy patients’ hunger for education about how to best care for themselves by sharing information and personalized content, as well as relevant and individualized data with cohort participants.

Christine Lemke, co-founder and co-CEO, Evidation

It’s early going on this course, but the coordinates appear to be correct.  As Co-Founder and Co-CEO Christine Lemke noted, “It’s fascinating to see how many use cases come out of the woodwork as you watch the population for longer periods. Trends over time are profound and many could not have been anticipated.”

Evidation and its biopharma clients have been experimenting, for example, with large cohorts of patients who opted in to allow programs to track possible signs of emerging illness. By monitoring certain vital signs, it has been possible to see subtle fluctuations that could portend signs of flu or COVID-19. When identified, the patients are engaged to take tests for both conditions, an action they deeply appreciate. Interestingly, this may send Evidation heading full circle to its original customer roots as the company identifies ways of predicting and preventing illness.

For now, Evidation is running with the pharma sector. 

With its many zigs and zags, the big learning for Evidation has been importance of staying nimble, noting it’s much harder to tack with 300 team members than 30.  

“Being ahead of the market is hard and being first is not always best,” Lemke says. “Sharks survive because they keep moving. We realized along the way that we were never going to have perfect info or judgment, so we must always watch how the wind is blowing and just keep going.”


Structural Biology-Driven Drug Discovery: Ray Stevens on The Long Run

Today’s guest on the Long Run is Ray Stevens.

Ray is the CEO of ShouTi. It’s a company that uses advanced structural biology technologies like cryo-EM images, and computational techniques, to discover small molecule drugs. The idea is to come up with orally available medicines that can build off the biological insights gained from protein or peptide drugs, but replace them with a less expensive and more convenient oral small molecule.

Ray Stevens, CEO, ShouTi

ShouTi has operations in San Francisco and Shanghai, making it a hybrid Chinese-and-American company. The company raised a $100 million Series B financing in October.

Ray comes to this position with a long and distinguished track record in structural biology. Ray was a professor at USC, Scripps Research, and UC Berkeley. He played a role in Syrrx, which was acquired by Takeda, and later co-founded Receptos – a company acquired by Celgene for $7.2 billion. The main asset there was ozanimod. It’s an oral small molecule agonist aimed at a G-protein coupled receptor target. It’s now marketed by Bristol Myers Squibb as Zeposia for the treatment of multiple sclerosis and ulcerative colitis.

In this conversation, we talk about Ray’s journey through academia and industry, the technologies that are enabling important advances in small molecule drug discovery, and a bit on what it’s like to run a company that tries to bridge the gap between the US and China.

Now please join me and Ray Stevens on The Long Run.


Aiming High, With a Team

Luke Timmerman, founder & editor, Timmerman Report

Climbing Mt. Everest changed my life. The world’s highest mountain required digging deep — physically, mentally, emotionally.

That was four years ago.

That original climb was a success, raising $340,000 for cancer research at the Fred Hutchinson Cancer Research Center. But what came next meant more. The climb opened my mind to new ways of making a contribution, in addition to biotech journalism.

The expeditions that followed have become bigger. More impactful and more enduring.

I’m returning to the Himalayas this month. This time, it will be with a team of 18 people I recruited to trek to Everest Base Camp, elevation 17,600 feet. Before hitting the trails of Nepal, we have worked together to raise more than $1 million for cancer research at the Fred Hutch. We could exceed $1.2 million before it’s all done.

I’m proud of this team and what it has accomplished for science.

It’s been a long and hard road the past two years for everyone. I can hardly imagine what it has been like for my Sherpa friends.

I will cry tears of joy and gratitude when we meet in Kathmandu. Hugs are on the first team meeting agenda.

Luke Timmerman with Everest guide Jangbu Sherpa at Everest Base Camp. 2018

The people of Nepal are poor in material terms, yet so generous and grateful in spirit. Going back, and giving back, is one way to make a positive contribution.

We will be meeting with researchers from the Kathmandu Cancer Center. We will be learning from people in the villages. We will enjoy the mountain scenery, savor warm cups of tea, and form meaningful relationships on the trail. More good things are bound to emerge.

Expect things to be quiet at Timmerman Report the next couple weeks. I plan to be mostly off the grid, with a few brief team updates from Nepal. By mid-April, I’ll be back.

Thanks to all the TR readers. Your outpouring of comments about the 7th anniversary of TR were heartwarming. Many of you have contributed to my campaigns for Fred Hutch and Life Science Cares. A few of you have participated. Some of you may want to participate someday. There will be time to discuss all of that later.

Tumultuous things are happening in the world. But one thing I learned four years ago is that in difficult moments, people are capable of more than they realize. Sometimes a kind word, or a sincere expression of confidence, is all it takes to provide people with the spark.

When we commit to a cause larger than ourselves, and when we show faith in others, amazing things can result.

Let’s keep lifting up the people around us.


Data That Mattered

Gilead Sciences released underwhelming top-line Phase III clinical results for sacituzumab govitecan-hziy (Trodelvy), in metastatic HER2-negative breast cancer patients. The company issued a mealy-mouthed and detail-light press release which said it hit the primary endpoint of Progression-Free Survival, and that the study was powered to show a 30 percent reduction on PFS, but that only a trend toward benefit on Overall Survival was seen. These were sick patients previously treated with CDK4/6 inhibitors, but still. That’s not great news, especially for a key asset obtained in a $21 billion acquisition of Immunomedics. Baird analyst Brian Skorney summed it up well: “Although not a failure, we think this top line release indicates that the opportunity in HR+/HER2- breast cancer is likely to be constrained, as the benefit seen may not be enough to drive utilization vs. the cheap generic chemos Trodelvy was compared to in this study.” Gilead followed up its tepid clinical results by cutting 114 jobs in the former Immunomedics unit it acquired, and reallocating some resources for manufacturing in Southern California. The series of missteps at Gilead has been jarring of late, and has prompted some analysts to wonder about the state of the company under CEO Daniel O’Day. See Matt Herper’s take in STAT.

France-based Valneva, a vaccine developer, reported positive Phase III results with a single-shot, live-attenuated vaccine candidate against chikungunya virus. The data from a study of more than 4,000 subjects showed protective levels of neutralizing antibodies were observed in 98.9 percent of subjects on the vaccine after one month, and 96.3 percent of vaccine recipients after six months. The company said it plans to seek FDA approval before the end of June. If approved, this would be the first vaccine against this mosquito-borne illness that sickens millions of people around the world.


San Diego-based Illumina, the market leader in DNA sequencing, continues to struggle with antitrust regulators. This week, Reuters, citing people familiar with the matter, reported that European Union regulators are still unsatisfied and yet to approve of the company’s plan to acquire Grail for $8 billion. The acquisition would allow Illumina to expand globally into the emerging market of early cancer detection powered by DNA sequencing technology.

Cambridge, Mass.-based Voyager Therapeutics pocketed $54 million upfront from Novartis in an option agreement. The deal gives Novartis the option to license novel AAV capsids to use in gene therapies against three targets of the Central Nervous System, and potentially two more targets in the future.

San Francisco-based Cellevolve struck a partnership with Seattle Children’s Therapeutics, a venture from Seattle Children’s Hospital.

Derrell Porter, founder and CEO, Cellevolve

Cellevolve will bring its expertise in development and commercial strategy for cell therapies to the table, while Seattle Children’s Therapeutics brings its GMP CAR-T cell therapy manufacturing capability and lentiviral vector manufacturing capability for cell therapies. The organizations will collaborate on three pediatric cell therapy programs for malignancies of the Central Nervous System. Michael Jensen, a Seattle Children’s researcher and co-founder of Juno Therapeutics and Umoja Biopharma, has agreed to serve as chair of Cellevolve’s Scientific Advisory Board. (Listen to Cellevolve founder and CEO Derrell Porter on The Long Run podcast, Feb. 2022)

Our Shared Humanity

  • ‘Something is off here’: Black biotech entrepreneurs still struggle for funding as the industry pledges to diversify. STAT. Mar. 4. (Jonathan Wosen)
  • Orcas doctor to climb to Mount Everest Base Camp in campaign to raise $1m for cancer research. The Orcas Island Sounder. Mar. 9. (Colleen Smith)
  • Unclouded Judgment. NEJM. Mar. 9. (Lisa Rosenbaum)

Science Features

  • The Coronavirus’s Next Move. The Atlantic. Mar. 9. (Katherine Wu)
  • Vaccinating Kids Has Never Been Easy. The Atlantic. Mar. 10. (Sarah Zhang)


  • Tumor-Infiltrating T cells. A Portrait. NEJM. Mar. 10. (David Braun and Catherine Wu)
  • Distinct biological ages of organs and systems identified from a multi-omics study. Cell. Mar. 8. (Chao Nie et al BGI Shenzhen)

Science of SARS-CoV-2

  • Whole genome sequencing reveals host factors underlying critical Covid-19. Nature. Mar. 7. (Mark Caulfield, Kenneth Baillie et al Genomics England)
  • The changing epidemiology of SARS-CoV-2. Science. Mar. 10. (Natalie Dean et al Emory University)
  • The immunology and immunopathology of COVID-19. Science. Mar. 10. (Akiko Iwasaki et al Yale University).
  • Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody. Cell. Mar. 9. (Cheng Li et al Shanghai Institute of Infectious Disease)
  • Resistance mutations after sotrovimab use. NEJM. Mar. 9. (Rebecca Rocket et al University of Sydney, Australia)
  • Immunogenicity and Reactogenicity of Vaccine Boosters after Ad26.COV2.S Priming. NEJM. Mar. 10. (SWITCH Research Group)
  • Boosters protect against SARS-CoV-2 infections in young adults during an Omicron-predominant period. MedRxiv. Mar. 9. (Peter Frazier et al Cornell University)

Science Policy


Moderna announced its near-term global health strategy. It includes a commitment to advance vaccine candidates against 15 pathogens considered to be risks to global health, as determined by the World Health Organization (WHO) and Coalition for Epidemic Preparedness Innovations (CEPI). The company reached an agreement with the US government to build its first mRNA vaccine factory on the African continent in Kenya. It agreed to an open platform for researchers to gain access to its technology against emerging or neglected diseases. And the company agreed not to enforce its IP in 92 low to middle income countries.

Personnel File

Morphosys closed the Cambridge, Mass.-based R&D center it obtained through the acquisition of Constellation Pharmaceuticals. It’s consolidating work in Germany. (Endpoints News)

Cambridge, Mass.-based Alnylam Pharmaceuticals promoted Kevin Fitzgerald from senior vice president and chief scientific officer to executive vice president and chief scientific officer of research. He’s been with the RNA interference drug developer for 18 years.

Seattle-based Adaptive Biotechnologies hired Tycho Peterson as chief financial officer. He’s a former JP Morgan analyst. The company said it’s also cutting 12 percent of its workforce.

Waltham, Mass.-based Affinia Therapeutics, a developer of AAV gene therapies, said it’s added Diana Brainard to its board of directors. She’s the CEO of AlloVir.

Cambridge, Mass.-based Bluebird Bio said in a regulatory filing that Gina Consylman, the chief financial officer, is resigning on Apr. 3. Jason Cole, the chief business officer, will serve as the company’s primary financial officer. A few days earlier, in its 10-K, the company issued a warning to investors that it has doubt about its ability to continue as a “going concern” as it runs low on cash.


San Diego and Research Triangle Park, NC-based Creyon Bio came out of stealth with a $40 million Series A financing. It’s working on using AI to develop custom oligonucleotide therapies. DCVC Bio and Lux Capital co-led.

Concord, Mass.-based Adiso Therapeutics, backed by Morningside Ventures, announced its debut. The 25-person company is working on small molecules and single-strain live biotherapeutics for the treatment of ulcerative colitis and C. difficile infections.

Venrock led a $20 million Series B financing in San Francisco-based SmithRx, an aspiring new pharmacy benefits manager (PBM). The idea, according to Axios, is to use algorithms to help employers find “lower-priced medications based on pharmacy distribution, clinical management, rebates and special programs.”

Vancouver, BC-based Solve FSHD was founded with $100 million from Lululemon founder Chip Wilson, who suffers from facioscapulohumeral muscular dystrophy type 2.

Mountain View, Calif.-based DNAnexus raised $200 million in a deal led by Blackstone Growth to support its platform for using multi-omics data to advance precision medicine. Terms of the deal weren’t disclosed, even whether it’s equity, debt, or some combination of the two. Northpond Ventures, GV, Perceptive Advisors, Innovatus Capital Partners, and Foresite Capital joined the round.

Regulatory Action

Seattle-based Alpine Immune Sciences said the FDA placed a partial clinical hold after a patient died in the NEON-2 clinical trial that is evaluating its drug candidate davoceticept in combination with Merck’s pembrolizumab (Keytruda) for advanced cancers. The company said the death was attributed to cardiogenic shock. The treating physicians thought it was “likely related to immune-mediated myocarditis, or possibly infection,” Alpine said. The partial hold doesn’t affect Alpine’s NEON-1 trial, which evaluates its drug candidate as a monotherapy.   


Good news.


Praveen Tipirneni on Watching Out for Sleeper Deals

Vikas Goyal, former SVP, business development, Pandion Therapeutics (now part of Merck)

[Editor’s Note: this is part of series of interviews with business development executives about some of the surprises, subtleties, and human aspects of biotech dealmaking.]

Praveen Tipirneni is a physician by training, but more than anything it was his work in business development that put him in position to become the CEO of a publicly-traded biotech company – Waltham, Mass.-based Morphic Therapeutic.

Before Morphic, Tipirneni spent 13 years at Cubist Pharmaceuticals. He was senior vice president of corporate development and global strategy in 2015 when Cubist was acquired by Merck for $9.5 billion. At the time, Cubist was best known for marketing the antibiotic daptomycin (Cubicin).

But there were other assets in the pipeline. In this interview, Tipirneni recalls another deal – Cubist’s 2009 acquisition of Calixa Therapeutics — that helped set the table for the ultimate big deal with Merck.

Let’s start with the punchline. What is your advice for your biotech BD peers out there?

My advice is to not underestimate what is possible, to not underestimate the future importance of a deal. Sometimes it’s those sleeper deals that turn out to become important. The important deals are not always the one you expect or predict.

Praveen Tipirneni, CEO, Morphic Therapeutic

So what deal are we going to talk about today?

Cubist’s acquisition of Calixa Therapeutics in 2009. Calixa were in Phase 2 at the time with a cool new anti-pseudomonal cephalosporin. Calixa was backed by Domain Associates and had a very credible antibiotics team.

That drug ultimately became Zerbaxa (ceftolozane). With Cubicin later in its lifecycle, ceftolozane had the potential to be the critical driver of Cubist’s future growth. And, ultimately, this drug became one of the assets that Merck really wanted when they acquired Cubist in 2014.

What was your role in Cubist’s acquisition of Calixa?

Do you know the baseball term Wins Above Replacement? Honestly, anybody on the technical side at Cubist could have done the Calixa deal. It was an antibiotic right up our alley. My value add was getting the deal closed.

We were almost at the end of the process. All the major terms had been negotiated; the diligence was mostly done. But then this accounting issue came up. It was December and I was literally on a ladder putting up the Christmas tree talking to Rick Orr, COO at Calixa.

There had been some very recent changes in the 409A accounting rules. Back then, there were no third-party advisors for 409A equity valuations and start-ups basically did it internally. Cubist’s diligence suggested that Calixa may have underestimated the 409A tax liability. With the risk of penalties and fines, Cubist’s accounting firms were using terms like “unlimited” liability and this very technical accounting issue got elevated all the way to our Board.

What was the deal risk? What did you do?

Cubist ended up requesting a very large escrow as part of the M&A agreement to address the 409A tax risk. And Calixa was having a very hard time accepting this escrow term.

This totally could have tanked the deal.

First the 409A analysis was a highly technical issue and both sides thought our analyses were right. Second, the acquisition had milestone-based earn outs which was still novel at the time and there were uncertainties about how to handle the accounting for those future payments. And third, the emotions and egos were so high there was no way senior management was going to meet halfway and compromise on the issue.

The deal had been going nowhere for days until the negotiation got delegated down to me on the Cubist side and Rick at Calixa. Rick was concerned that if Calixa accepted the escrow and closed the acquisition, post the deal there would be no one left to represent Calixa’s interests and Cubist could interpret the escrow however we wanted.

So there I was on the Christmas tree. I was only VP of Business Development back then and I ended up being really honest with Rick. I told him, “I’m not a decision maker for this issue, Rick. What I can do is personally commit to you that I will represent Calixa’s side after the acquisition.”

Was there a lot of pressure at Cubist to close this deal? What about on Calixa’s side?

Yes, I think both sides really did want to do the deal.

To set the stage for the Calixa acquisition, you have to look back at their predecessor company Cerexa. Calixa spun out of Cerexa in 2007. Cubist had really wanted to acquire Cerexa and we ended up bidding to our full financial capacity. The Cubist team all thought we had won the auction, but literally in the last week Forest Laboratories came out of nowhere and bid way above us. I felt totally burned.

So with that backdrop, we’re now looking at Calixa wondering if we were about to lose to Forest again. And I also think the Calixa team remembered us from the Cerexa interactions and wanted to do the deal with us.

It sounds like you really needed to advocate for Calixa’s side to get this deal closed. You were negotiating with Calixa, but also with our own colleagues and tax advisors at Cubist. Would you do it all over again?

Obviously this product was very important for Cubist. After the deal closed, we started working through the formal tax analysis. And, of course, the escrow issues all worked out in the end. And to this day, I really believe Rick and the Calixa team were right and that our advisors were overestimating the tax risks.

But I don’t know if I would do this all again.

There was no need for a BD person to be involved in this tax escrow analysis. And there was zero upside to me acting so smart on this issue. We literally had multiple major accounting firms including Price Waterhouse, Ernst & Young, and Coopers & Lybrand advising us – this was one of those nightmare scenarios where we had conference calls with 50+ people. But there I was reading the tax laws myself and questioning the work of our accounting firms. These guys were all so mad at me.

Before this deal, there had been a chance I might have gotten a shot at the CFO job at Cubist. I’m pretty sure all of this 409A stuff cost me that job (though in retrospect, that turned out to be a good thing).

You mentioned ceftolozane became a driver for Cubist’s ultimate acquisition by Merck. How so?

So first, Zerbaxa (ceftolozane) was going to be a big next product for Cubist. Merck was very interested in the drug.

Second, it also tied into a subsequent deal we did in 2013. Calixa had originally licensed ceftolozane from Eisai (which then became Astellas). The license terms were good for Calixa, but they had to leave Japan and several other Asia geographies with Astellas. It remained an ongoing annoyance that we didn’t have full global rights. And I could tell our CEO, Mike Bonney, really wanted the Japan rights back.

We were just 6 months away from Ph3 trial results, and our BD team wanted to wait until the clinical data readout before approaching Astellas. I kind of agreed with the BD team but I figured I’d give it a shot. I was able to get the full global rights from Astellas for $25 million.

Maybe it was a coincidence, but right after we got the global rights from Astellas was when we started getting really serious engagement with Merck. Hence my advice to my BD colleagues is to never underestimate what may be possible.


The Globally Integrated Biotech Is Down, But Not Out

Alex Harding, MD. Entrepreneur in Residence, Atlas Venture; internal medicine physician, MGH

“What else can you do? The entire isolation of Russia. Nowadays we see real solidarity of the whole world to cancel or stop any economic, cultural, technological, financial connections with Russia and we urge the same from the Drug Discovery community.”

This was the message on Mar. 5 from Andrey Tolmachov, founder and CEO of Enamine Ltd., a Ukrainian chemistry services provider, to his clients in the biopharma industry.

Tolmachov’s words reflect the dire situation in Ukraine, a country under attack from the Russian army, and fighting to preserve its existence as an independent nation. His words also reflect powerful economic ties between Enamine and the drug discovery industry.

Andrey Tomalchev, CEO, Enamine

As reported by Jason Mast at Endpoints, Enamine has become a dominant supplier of chemical building blocks and gigantic chemical libraries that can be used by biopharma companies to conduct high-throughput drug screens. In its facilities in Kyiv, Enamine has enormous banks of freezers containing millions of compounds that cannot readily be obtained anywhere else in the world.

Tolmachov’s appeal, then, is not solely an emotional appeal. Numerous companies, including powerful large pharma companies, have a strong economic incentive to see Ukraine, and Enamine, pull through this war intact. Perhaps those incentives will make those companies more likely to heed Tolmachov’s words and exert economic pressure on Russia to back down.

Such dependence upon a single company based in a mid-sized emerging country is a case study on the opportunities and pitfalls of the globalized business model that has emerged in the biopharma industry over the past 10-15 years.

The vision behind this model was that companies headquartered in one location could tap into resources from diverse geographic regions, exploiting cost of living differences and strong regional expertise to obtain quick and cheap services, all while maintaining flexibility to expand and contract services rapidly depending on scientific and business needs.

That vision has taken a beating over the past two years. The war in Ukraine is only the latest example of a major geopolitical crisis to strain the globalized biopharma business model.

Pandemic Lockdowns

The biggest stressor, of course, has been the COVID-19 pandemic. Early in the pandemic, when most of China went into lockdown, biopharma companies’ work at key Chinese service providers, including WuXi AppTec, Pharmaron, and ChemPartner, and others, ground to a halt.

Just as companies scrambled to shift those services to service providers in the US and Western Europe, the virus spread globally, leading to rolling lockdowns throughout much of the world. For the past two years, managing a global network of vendors has turned into a global game of whack-a-mole as different cities and countries have gone through unpredictable pandemic restrictions that have contributed to various business interruptions and delays.

Stalled Supply Chains

Next came the supply chain crisis. Globalized companies rely upon fast shipments between facilities. A biopharma may hire one company in Asia to produce an experimental molecule, another company in Europe to perform in vitro characterizations of that molecule, and a third company in the US to study the molecule in an animal model of a certain disease.

The drug discovery process is iterative; anywhere from a few dozen to a few thousand molecules may be made and tested in a variety of in vitro and in vivo studies before a specific molecule is chosen to enter clinical trials. Even a one-week delay in shipping between two sites that gets multiplied many times over during a drug discovery campaign can dramatically delay a company’s timeline to begin clinical trials.

Crippled Service Providers

Now, the Ukraine crisis has brought another stressor to the globalized biopharma business model. Enamine is no longer able to fulfill any orders from its Ukrainian facilities. While Enamine has a few facilities outside of Ukraine, including one site in New Jersey, those sites are small compared to the Kyiv headquarters and cannot perform the full range of services that were performed in Kyiv.

Beyond the preclinical services that Enamine focuses on, clinical trials are also under threat. Hundreds of clinical trials were active in Ukraine at the start of the war. Some trials are dependent on Ukrainian sites to enroll a large percentage of their overall patient quotas. Most of those sites have surely stopped enrolling new patients, and many patients who were already participating in a trial have probably been forced to discontinue prematurely because of the war.

What Now?

With all the stresses to the globalized model over the past two years, it is natural to consider reverting to an entirely local and in-sourced approach to drug development. Rather than working with companies across the globe to manufacture compounds, test them preclinically, and study them in clinical trials, one could imagine building internal facilities and hiring scientists to conduct all the work of drug discovery and development within one biopharma company based here in the US. Clinical trials could all be run in-country as well.

In light of all the challenges that have arisen over the past two years, wouldn’t an “in-sourced and localized” model be safer and more efficient than the globalized model?

Absolutely not.

For one thing, it isn’t possible to internalize all the capabilities that outsourced providers offer. Enamine, for example, offers millions of compounds that can be ordered off the shelf and billions of compounds that can be synthesized on demand. No small or mid-sized biotech could dream of developing such a capability internally. Enamine has spent 30 years building up this capability.

What’s more, even if a biopharma company could build those capabilities internally in a city like Cambridge, MA or San Francisco, CA, they would likely sacrifice quality in doing so. While those cities harbor an exceptional concentration of biotech companies, they do not hold a monopoly on scientific talent. There are excellent scientists in China, India, Ukraine, and elsewhere that companies can work with, who would be unavailable to a company that insisted on working exclusively with scientists based in Cambridge or the Bay Area.

Last, we should not assume that the US and Western European countries are not themselves vulnerable to crisis. If anything, the past two years have demonstrated that we are all vulnerable, whether it be to a pandemic or even a war. A flexible, globalized model will be more resilient in the long run than one dependent on any single location.

A More Robust Globalized Model

Rather than abandoning globalization, the biopharma industry should seek a more robust network of global service providers. Companies should partner with multiple service providers in diverse geographic regions so that if one company or one country shuts down, another service provider in another region will be able to pick up the slack. Companies should get contracts in place before they need them, and those contracts should allow services to flexibly expand and contract.

Biopharma companies should also assess their supply networks for weaknesses. Wherever possible, companies should avoid relying on a single supplier for a crucial service or material. In some cases, it may be necessary to maintain a stockpile of a material that is subject to shortages or that only one vendor can provide.

Taking these measures will preserve the advantages of the globalized biopharma business model—flexibility, affordability, and quality—while making the model more resilient to unforeseeable macroeconomic and geopolitical events like those that have occurred in the past two years.

For Enamine, all we can do now is follow Andrey Tolmachov’s advice and push for a Russian withdrawal. For our industry, for the future, we can build an improved globalized model that benefits from the capabilities of excellent companies like Enamine, and does so in a more resilient, sustainable manner.


SARS-CoV-2: Where Did It Come From and Where Does It Go Next?

Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University

We are once again in a period of pandemic optimism — June 2021 redux. I hope this is justified, but I am reminded of the “fool me once, fool me twice” saying.  

Over the past few weeks there have been four papers that examine viral infection dynamics between animals and humans — animal to human and back again (Zoonosis) that should provide a dose of caution in this otherwise optimistic moment.

The origin of SARS-CoV-2 has been hotly debated and politicized for the past two years. Origins matter – they define epidemic dynamics, and possible future variant directions. When we know where an epidemic comes from, we can better prepare for the next one.

Two papers from Michael Worobey’s team at University of Arizona (and collaborators) have been released that are compelling (although based on limited early pandemic sequence data). This latest research provides the most compelling evidence yet that the virus originated from the Wuhan Wet Market (not the Wuhan Virology Institute). One examines the genetics (phylogenetics) of the earliest cases, the other, their geographic spread.


The bottom line: the first cases clearly occurred in the wet market, presumptively via intermediate hosts known to be traded there, from a long-term animal reservoir in wild Horseshoe bats.

We have known for some time that human to animal outbreaks of SARS-CoV-2 have occurred: e.g. Danish farmed mink in 2020, and in 2022, domestic hamsters in Hong Kong. A paper from Canada documents the first (and so far, only) completed loop (human to deer and back to human). A very intriguing paper from the Journal of Genetics and Genomics in December 2021 makes the case that Omicron’s enormous number of mutations was caused by a long period evolving in mice before jumping back to humans. 

Very big and surprising variant jumps can occur when a virus completes a human to animal and back to human roundtrip. All four of these papers underline the importance of animal susceptibility and surveillance if we are to understand which novel variants may evolve in humans after the Omicron wave. 

Of course, all the hypotheses presented, however compelling, are probabilistic based on currently available data – as new evidence emerges these can change. Nevertheless, we are at a point of knowing a lot more than we did just one year ago.

But before digging in and summarizing conclusions and implications, there are five virus principles worth remembering (see Viral Phylodynamics for details and examples): 

  • the mutations that create novel variants occur regularly and randomly on a virus-specific clock. Generally, the bigger a pathogen’s genome the slower they happen;
  • variant evolution only happens in small steps. If jumps look big, it is only because we missed the “middle of the movie”. Both Delta and Omicron are significantly different from their ancestral variants; 
  • every host species has a unique mutational and immunological “evolutionary fingerprint” creating a pattern that can be traced to a specific species; 
  • fitness creates winners: increased transmissibility is the key to relative fitness early on in a fast-growing epidemic in an immune naïve population (i.e. SARS-CoV-2 2020-21) but immune evasion becomes dominant over time as immunity adapts (i.e. SARS-CoV-2 in 2022, when prior infection, vaccination, therapies are more widespread); 
  • there is no general fitness incentive for breakthrough infections to become less severe over time (e.g. HIV, Polio, Smallpox, Measles, Hepatitis C are as pathological as ever), except when a disease has an extremely high and rapid death rate (e.g. Bubonic plague, Ebola, Rabies). In those cases, new outbreaks require re-emergence from resistant species or individuals.

Geography is compelling that animal to human cross-over happened initially in the Wuhan Wet Market. Early cases were strongly concentrated in and around it, and primarily within the section dedicated to live animals. 

The Viral Institute lab leak conspiracy theory was initially supported by a now-debunked false claim that the furin cleavage site of the virus genome showed signs of human engineering. Beyond that, there were two popular scenarios: a lab accident infected one or a few workers; or a more extreme version in which the release was intentional. 

The latter scenario is simply ludicrous. No sound malevolent plan would involve release of a virus in the same city or country where it had been developed. The former, though is certainly possible — accidents do occur. If that had happened, the geographic infection pattern would be very different — highly centered around the few exposed individuals and those who care for them. That was the case in an Ebola-like MVD virus lab contamination event in Frankfurt and Marburg in 1967. The reluctance of the Institute to release detailed records is an unforced error that has hampered disposing of this scenario conclusively, but there is simply no positive evidence for it.

Genomic (phylogenetic) evidence is a more complex, but equally compelling, argument for wet market origins. The paper concludes that at least five separate animal-to-human viral introductions likely occurred, of which two became established (lineage A and B) while 3 (or more) failed.  

A consistent challenge to the wet market theory is that no specific intermediate host animal has yet been found to be the bridge from wild bats to the wet market to humans.

At first, the leading suspect was the Pangolin, but a China CDC investigation found no Pangolins had been present in the market in late 2019.

China CDC launched an extensive testing program in January and February 2020, the full details of which have only recently been published: 457 samples from 188 animals of 18 species underwent RTqPCR testing; followed by a further 80,000 animal samples from across China. No SARS-CoV-2 was found in any of them. Surfaces in and around the market were swabbed for virus, and 73 of 923 environmental samples reported positive. 7 of these were subsequently sequenced, revealing that all were from the human contamination (earliest clinical cases of Wuhan-Hu-1), therefore shedding no light on the “missing intermediate host” mystery.

Testing techniques in 2020 were primitive by 2022 standards (and methods still not disclosed) and this likely led to this critical lack of evidence. Knowledge of the virus was very limited at the time, and testing was performed too late to have a chance to detect crossover events that must have happened months earlier, back in November and December 2019.

The most “likely to transmit” market animals were long gone by the time testing was done. The chain of transmission was broken by the market closing Jan. 1, 2020, no live animals were available to test; no serology that would have detected past infection was performed.

In a wider nationwide program (80,000 tests), the animals tested were from what we now know to be from uninfected regions; animals not then susceptible to the SARS-CoV-2 variant circulating at the time (e.g. chicken, cattle); and/or of animals butchered before the emergence of SARS-CoV-2.

Every species (including humans) that any virus inhabits presents unique mutational and immune pressures (a species-specific mutational fingerprint). All virus, e.g. SARS-CoV-2, then develop variants consistent with these unique pressures. When the virus then reappears back in humans, large mutational jumps appear to have occurred, but only because all the intermediate small steps were hidden out of sight in an animal host.

This pattern of repeated jumps between animals and humans is very similar to what happened in prior outbreaks of SARS-CoV-1 and MERS-CoV. More stable established virus types (e.g. influenza) show an incremental year-to-year evolutionary pattern, interspersed by less frequent big mutational jumps caused by cross-over from non-human avian or swine sources.

We can expect more and more of these cross-over events (animal to human) in the future since humans, not bats, are now the largest animal reservoir of SARS-CoV-2 and are frequently in contact with susceptible wild and domesticated animals. As of January 2022, 29 different species have been found to be infected with a human form of SARS-CoV-2. For example, 40 percent of free range deer tested in Michigan in 2021 were found infected with human SARS-CoV-2.  

Of course, this works both ways: mouse was immune to the initial Wuhan strain, but as SARS-CoV-2 evolved in humans, a strain that could infect mouse (Beta) emerged in early 2021. Beta made only limited headway in humans, but in wild mouse a hidden epidemic occurred, during which Omicron was likely incubated: the types of mutations seen in initial Omicron (B.1.1.529) bear a mouse fingerprint on their evolution.


This is one hypothesis that could account for the enormous difference between Omicron and the prior human variant, Delta. Only the initial (B.1.1.529) Omicron has a mouse fingerprint, subsequent mutations to Omicron (BA.1, BA.2, BA.3) are consistent with typical in-human evolution, as expected. 

There are other hypotheses for the novel and extensive mutational profile of Omicron, but all require a sustained period (3-6 months) of hidden mutational evolution. Three primary possibilities: a different non-human host; a single human host with long term chronic SARS-CoV-2 infection (e.g. an immunocompromised individual); or an isolated community of humans where the virus could mutate unobserved.

To conclude, we have only a limited and hence inadequate history of the earliest SARS-CoV-2/human relationship to rely upon to predict the future. The one thing we know for sure is that SARS-CoV-2 is not yet finished with us.

We must remember that this is the third time at bat for the virus. But unlike baseball, there is no “three strikes and you’re out” rule.

The Achilles heel of SARS-CoV-1 in 2002-2003 was early detection of fever concurrent with transmissibility. A decade later; MERS-CoV had a high fatality rate but only limited transmissibility in humans and animals (mostly camels).  

SARS-CoV-2 hit a winning formula: hidden early transmissibility, now universal human exposure, and widespread non-human susceptibility. 

The 4,000 year history of human airborne disease transmission is one of repeated “surprises” encountering ignorance and confusion. After the past two years we have developed extraordinary (although of course incomplete) knowledge of disease processes, genomic surveillance, physical protections, diagnostics, vaccination, and therapeutics. We need to concentrate our resources on preparedness plans that reflect our growing knowledge of this wily virus.

Ignorance is no longer a valid excuse. We must not allow this foundation to erode through wishful thinking and neglect.


Peacetime vs Wartime CEO: A Useful Lens for Transformative Leaders?

David Shaywitz

As biotech execs cope with challenging market conditions (the XBI biotech index is off about 50% from its high of February 2021), I found myself revising a now-classic 2011 essay by venture capitalist Ben Horowitz of Andreessen-Horowitz, arguing that extremely challenging times require very different management skills, and a different leadership style. 

He describes and contrasts the approaches of what he calls “peacetime” CEOs and “wartime” CEOs (an admittedly uncomfortable analogy during these harrowing days of actual war in Ukraine).

Peacetime, Horowitz says, “means those times when a company has a large advantage vs. the competition in its core market, and its market is growing. In times of peace, the company can focus on expanding the market and reinforcing the company’s strengths.”

Ben Horowitz

Under these circumstances, he continues, company leaders “must maximize and broaden the current opportunity,” and “employ techniques to encourage broad-based creativity and contribution across a diverse set of possible objectives.” According to Horowitz, Google’s Eric Schmidt and Cisco’s John Chambers were both examples of good peacetime CEOs.

When a company is facing an “imminent existential threat,” Horowitz writes, a very different, more directive, style of leadership is required, an approach historically embodied by CEOs such as Intel’s Andy Grove, Apple’s Steve Jobs, and Google’s Larry Page.

Horowitz presents some of the ways he says peacetime and wartime CEOs are different, including:

  • “Peacetime CEO knows that proper protocol leads to winning. Wartime CEO violates protocol in order to win.
  • Peacetime CEO thinks of the competition as other ships in a big ocean that may never engage. Wartime CEO thinks the competition is sneaking into her house and trying to kidnap her children.
  • Peacetime CEO strives to tolerate deviations from the plan when coupled with effort and creativity.  Wartime CEO is completely intolerant.
  • Peacetime CEO does not raise her voice. Wartime CEO rarely speaks in a normal tone.
  • Peacetime CEO works to minimize conflict. Wartime CEO heightens the contradictions.”

Learning how to manage through wartime is especially difficult, Horowitz contends, since “management books tend to be written by management consultants who study successful companies during their times of peace,” and thus are largely irrelevant during times of existential stress.

Finally, Horowitz notes that it’s possible “but hard” for a single individual to be both a brilliant peacetime and wartime CEO, since the demands are so different.  “Mastering both wartime and peacetime skill sets,” he says, “means understanding the many rules of management and knowing when to follow them and when to violate them.”

* * *

This lens of wartime vs peacetime leadership may also provide a way of thinking about the challenge of “brilliant jerks,” a topic I’ve discussed at TR, in context of the pursuit of ethical hypergrowth as suggested by Reid Hoffman in Masters of Scale, and elsewhere, in the context of visionary geneticist Eric Lander’s recent resignation from his cabinet-level role at the White House. See also this important meditation by New York Times technology writer Shira Ovide.

Eric Lander

In some ways, what Horowitz is arguing is that when you’re facing corporate extinction, leaders don’t have time for what some might consider “social niceties.” Worse: attending to such “niceties” can actually distract leaders and organizations, and interfere with focused execution.

This argument raises at least two important questions:

First, is Horowitz right? 

Does wartime require leaders to become, for lack of a better phrase, deliberate a**holes – a necessary, temporary sacrifice so that the company can survive? 

Or are there other models of leadership – even under wartime conditions – that would enable a company to productively mobilize, yet continue to respect peacetime values like inclusion and civility, which of course many would argue represent foundational “table stakes” rather than social niceties. 

Examples of leaders who managed through existential threats without adopting the approaches Horowitz advocates would contribute significantly to this discussion – far more than pious, feel-good advice voluminously offered by those far removed from the wartime arena, like the management book authors Horowitz derides.

The second question raised by the wartime/peacetime CEO model is whether this construct offers either an excuse for, or at least an explanation of, many of the examples of bad leadership behavior we’ve seen? 

In other words, wouldn’t many CEOs who’ve been called out for bad behavior, such as Travis Kalanick, the former CEO of Uber, and Elon Musk, argue that they view every day as a life-or-death struggle for their business, and that this mindset is what drives them to advance their vision relentlessly forward?  After all, if you’re trying to grow and establish a radically new business in an unforgiving world, might not you plausibly view this as requiring, inherently, a “wartime” mindset?

A number of particularly visionary, highly successful academics I know also seem to view their work in a similar fashion – they see themselves as struggling to gain traction for their ideas, and to shift paradigms, in a world that’s reflexively skeptical if not outright antagonistic. Battling against these steep odds every day often leads to adoption of many “wartime” characteristics.

Beyond what might be called the “self-deception” of visionary leaders who see themselves as perpetually at war, we must also acknowledge the possibility – perhaps even ubiquity — of deliberate malevolent deception.  After all, invoking exigent circumstances and life-or-death stakes to justify self-serving, typically autocratic behavior is a tried-and-true political approach that we’ve seen more than our share of in recent years.

Bottom Line:

Managing a business through an existential crisis represents a formidable challenge for executives.  One approach is to revert to what feels like our most primitive, reptilian instincts in order to persevere. 

A critical question we now struggle with is whether this represents an adaptive if distasteful response, or whether it reflects our least imaginative instincts, our failure to lean into some of the values we earnestly champion and appropriately extol during peace. 

Also unclear: can we prevent mindset creep, and the tendency for many business leaders — particularly visionary startup entrepreneurs — to view themselves as continuously at war, justifying the confrontational attitude Horowitz describes?

Finally, channeling Ovide: is it possible that the ready adoption of a wartime business mindset is an essential quality that defines and enables the most transformative entrepreneurs — as well those who are the most reviled? Should we embrace this trait as vital, or seek to temper it because of the dangers it can pose when unconstrained? How can we best live with these contradictions?

Now it’s your turn!  TR welcomes reader contributions: is the wartime vs peacetime lens a useful construct for biotech leaders and visionaries? Are there particular biotech leaders that you would characterize as a striking example of either a “peacetime” or “wartime” CEO?  Are there leaders who have successfully managed an organization through an existential crisis without resorting to “wartime” behavior?  Let us know. luke@timmermanreport.com.


Biotech Takes a Stand

Luke Timmerman, founder & editor, Timmerman Report

Not long ago, biotech leaders steered clear of commenting on the issues of the day. Politics was limited to certain vested interests like drug pricing, science funding, and FDA regulation.

Then came COVID-19 and the racial justice reckoning.

Staring these terrible things in the face, people began to think more about their roles in the workplace, and in the community. The aperture widened. We are redefining what it means to be a scientific citizen.

Now we have a Russian dictator starting a war against a sovereign and democratic Ukraine. The Russian leader is issuing threats reminiscent of the old Soviet empire. He has some of the world’s most powerful weapons – nuclear, cyber, and psychological infowar tools to destabilize Western democracies from within. He’s ruthless. Political opponents or journalists who dare to report uncomfortable truths get poisoned, jailed, or killed.

Staying neutral isn’t an option. This is a serious threat to the world order.

Citizens need to pay attention, and think carefully about what’s happening, how it affects us, and what we can do.

In a globalized, hyper-networked world, it’s not just all about Putin and Zelensky and Biden and Macron. Millions of people making millions of decisions each day can each play a part. Even if it’s as small and simple as choosing what to tweet or not tweet, what we spend money on and what we don’t, we are each contributing.

It’s heartening to see biotech leadership that understands. They don’t want to be part of a generation that said nothing and did nothing when it counts. They don’t want to appease, or worse, help support the rise of a monstrous regime.

Jeremy Levin, CEO, Ovid Therapeutics

Meg Alexander and Jeremy Levin of Ovid Therapeutics, Paul Hastings of Nkarta Therapeutics, Peter Kolchinsky of RA Capital Management, Ted Love of Global Blood Therapeutics, and John Maraganore, the former CEO of Alnylam Pharmaceuticals, co-authored a forceful piece about the Russian invasion on Feb. 26 on Medium.

The open letter called for business leaders to disengage from Russian interests in a few clear ways:

  • Cease investment in Russian companies and new investment within the borders of Russia
  • Reject investment from Russian funds
  • Halt collaboration or service agreements with Russian companies
  • Except for food and medicines, halt trade in goods with Russian companies

All of these actions should remain in effect, the authors wrote, until “the restoration of peace and democracy in a sovereign Ukraine.”

Peter Kolchinsky, managing partner, RA Capital

One week later, more than 680 people have signed on. Many more are spreading the word through social media. More people are feeling the pressure to use their voices, use their power, to stand up for people halfway around the world who are facing terrible attacks.

By now, many in biotech have heard of Enamine, the contract research organization in Ukraine that is a trusted partner to many companies. It’s already close to home.

If Mr. Putin is able to extend his sphere of influence further into Eastern Europe, we’ll hear about many more trusted partners who suddenly find themselves no longer so free and secure.

Government leaders have their role to play. But so do we.

We aren’t helpless and voiceless. One person alone may not make much of a difference, but when we activate our networks, when we make business decisions on moral grounds and shut off the flow of money and goods, those actions send ripple effects.

John Maraganore, former CEO, Alnylam Pharmaceuticals

The US is the beating heart of biotech, but we don’t do this work alone. Great science bubbles up from all around the world. Contract development and manufacturing firms have something to contribute from all corners of the globe. Clinical research sites are almost everywhere. Patients are everywhere.

If we’ve learned one thing the past couple years, it should be that the biopharma industry is a strategic asset to the US and is a beacon of hope to the world. This industry doesn’t thrive here by accident — it’s here in large part because of our historic systems of free enterprise and democracy. Because of our laws and spirit and traditions.

The world counts on the US to hold it together, to be a serious country, to maintain our resilience. We need all that to deliver groundbreaking science and lifesaving products.

Ted Love, CEO, Global Blood Therapeutics

America hasn’t always lived up to its founding ideals. But we continually strive to form a more perfect union. We can course correct, regain our balance. We still have the rule of law, the Bill of Rights, free elections and freedom of speech.

We should remember that it’s our job to use these gifts wisely, and to pass them on to the next generation. When we operate within the laws and norms of our system, we can be at our optimistic best. We can see far out, think big, and make long-term investments. It’s what has always drawn tremendous immigrants here, and continues to draw them here.

An authoritarian state like Russia can’t say these things.

I’m thankful that the US biotech industry has a generation of leaders who are willing to stand up for our ideals. I hope to see this good fight continue. It may require some sacrifice, whether in the form of clinical trial delays, lost deals, or higher prices for oil or gas. Or maybe worse. It might be the start of a long, hard confrontation.

Paul Hastings, CEO, Nkarta Therapeutics

Some things are more important than next quarter’s earnings, or the fleeting price of a gallon of gas.

We need to rediscover a certain steeliness in our national character. We need to rediscover an ability to focus on what’s important, and not allow ourselves to be distracted.

It will be difficult. But we have to defend a way of life that’s worth defending.  


Data That Mattered

Cambridge, Mass.-based Intellia Therapeutics and its partner, Regeneron Pharmaceuticals, reported follow-up data that show deep and sustained efficacy with in vivo gene editing for patients with transthyretin amyloidosis. The companies showed that this CRISPR gene editing technique could bring down serum TTR levels by 52 percent at the tiniest dose tested, and 93 percent among the 6 patients on the high dose – still a very small 1 mg/kg. The drug is getting to the liver, and it’s doing its edit safely — there were no clinically significant liver findings observed. It’s big news for the field, and sets the stage for single-infusion in vivo gene editing in many indications, because it has some practical advantages over ex vivo gene editing. Whether TTR amyloidosis will be the ideal first indication for CRISPR therapies is still an open question – I’m not sure it makes sense (TR coverage, July 2021).


San Diego and Suzhou, China-based Adagene struck partnership with Sanofi on masked monoclonal and bispecific antibody drug candidates for cancer. Sanofi is paying $17.5 million upfront, and will get the ability to advance two development candidates, with an option for two more. This partnership comes a few months after Sanofi agreed to acquire Amunix Pharmaceuticals for $1 billion upfront. Amunix was also developing masking technology to assist bispecifics against cancer.

Cambridge, Mass.-based Blueprint Medicines, the developer of precision cancer drugs, agreed to pay $20 million upfront to New York-based Proteovant Therapeutics to gain access to its targeted protein degrader drug discovery platform. The companies will work together on targets, and plan to advance two protein degrader development candidates.

AbbVie agreed to acquire Syndesi Therapeutics, a neuroscience drug developer. AbbVie is paying $130 million upfront, and getting ahold of a lead small molecule drug candidate in Phase I development to enhance synaptic efficiency. Synaptic dysfunction is believed to underlie the cognitive impairment seen in multiple neuropsychiatric and neurodegenerative disorders. If the drug pans out, Syndesi shareholders could collect another $870 million in milestone payments.

AstraZeneca’s rare disease unit, Alexion, agreed to pay $30 million upfront to Neurimmune. It’s for the right to develop a monoclonal antibody program to treat transthyretin amyloidosis cardiomyopathy.


San Francisco-based Rondo Therapeutics raised $67 million in a Series A financing co-led by Red Tree Venture Capital and Canaan Partners. The company is working on bispecific antibody T-cell engagers for solid tumors. It’s led by an entrepreneurial pair responsible for TeneoBio, a bispecifics-for-liquid-tumors company that was acquired last year by Amgen for $900 million upfront. (TR coverage).

Cambridge, Mass.-based Atlas Venture said it raised $450 million for Fund XIII. The firm didn’t announce any strategic or partner changes – just more investment in platforms and asset-centric biotech companies. Since 2015, when the biotech and tech investing sides of Atlas went their separate ways, the new biotech-only Atlas has raised over $2 billion and has created and/or invested in over 50 biotech companies.

San Francisco-based Foresite Capital said it raised $173 million to invest in companies it forms through Foresite Labs. This cash is in addition to the firm’s $969 million Fund V.

A team of eight Howard Hughes Medical Institute investigators at the University of Washington and Fred Hutchinson Cancer Research Center secured a three-year $15 million HHMI grant to work on ways to track, prevent, and treat COVID-19 as it moves into an endemic state. The team includes Jesse Bloom, Trevor Bedford, Harmit Malik and Erick Matsen at Fred Hutch and David Baker, Joseph Mougous, Jay Shendure and David Veesler at UW.

Cambridge, Mass.-based NextRNA Therapeutics secured $46.8 million in a Series A financing led by Cobro Ventures and Lightchain Capital. It’s working on medicines directed at non-coding RNA targets.

Cambridge, Mass.-based Flagship Pioneering announced the debut of Vesalius Therapeutics, with a $75 million commitment. The company is focusing on common illnesses, and using machine learning to assist with drug discovery. Vesalius says its platform uses “proprietary patient-derived experimental systems that it uses to screen and characterize drug candidates to restore circuits to healthy functioning.”

Boston-based Selux Diagnostics raised $50 million in a Series C financing. It’s working on diagnostics for infectious diseases, to help doctors better select precision antibiotics quickly.

Cambridge, Mass.-based hC Bioscience raised $24 million in a Series A financing to develop engineered tRNA therapies to address protein dysfunction. Arch Venture Partners, Takeda Ventures, and 8VC participated.

Princeton, NJ-based ArrePath said it raised $20 million in seed funding to advance its work on anti-infective drugs that will work against microbes that resist current therapies. Boehringer Ingelheim Venture Fund, Insight Partners, and Innospark Ventures co-led. Lloyd Payne, formerly EVP of anti-infectives at Evotec, joined as CEO.

London-based Epsilogen raised $41 million in a Series B financing to develop IgE antibodies for cancer. Novartis Venture Fund led.

Personnel File

Julie Gerberding will be the new CEO of the Foundation for the National Institutes of Health, starting May 16. She is currently Chief Patient Officer and Executive Vice President, Population Health & Sustainability at Merck.

South San Francisco-based Graphite Bio, a gene editing company, hired Alethia Young as chief financial officer. She was previously a biotech analyst with Cantor Fitzgerald. (TR coverage of Graphite, Sept. 2020)

Canada-based Amplitude Ventures hired Ali Tehrani, the co-founder and former CEO of Vancouver, BC-based Zymeworks, as a venture partner.

Merck hired Aileen Pangan, as vice president and therapeutic area head for immunology, global dlinical development, effective March 1. She previously worked at AbbVie.

Cambridge, Mass.-based Synlogic hired Michael Jensen as chief financial officer.

Needham, Mass.-based Candel Therapeutics, the developer of oncolytic virus therapies for cancer, hired Seshu Tyagarajan as chief technical and development officer.

  • The burden of rare protein-truncating genetic variants on human lifespan. Nature Aging. Mar. 3. (Jimmy Liu et al Biogen)
  • Lipidomic risk scores are independent of polygenic risk scores and can predict incidence of diabetes and cardiovascular disease in a large population cohort. PLoS Biology. Mar. 3. (Chris Lauber et al Institute for Experimental Virology, Hanover, Germany)
Science of SARS-CoV-2
  • Assessment of Clinical Effectiveness of BNT162b2 COVID-19 Vaccine in US Adolescents. JAMA Network Open. Mar. 3. (Carlos Oliveira et al Yale School of Medicine)
  • Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nature Genetics. Mar. 3 (Manuel Ferreira et al Regeneron Genetics Center)
  • Recurrent SARS-CoV-2 Mutations in Immunodeficient Patients. MedRxiv. Mar. 2. (Sam Wilkinson et al University of Birmingham, UK)
  • Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant. NEJM. Mar. 2. (UK Health Security Agency)
  • Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and signs of neurodegeneration: a prospective cross-sectional study. MedRxiv. Mar. 2. (Manina Etter et al University Hospital Basel)
  • SARS-CoV-2 emergence very likely resulted from at least two zoonotic events. Zenodo. Feb. 26. (Jonathan Pekar et al UCSD)
  • The Huanan market was the epicenter of SARS-CoV-2 emergence. Zenodo. Feb. 26. (Michael Worobey et al University of Arizona)
Science Policy
  • National COVID-19 Preparedness Plan. March 2022. White House. (96-page PDF document).
  • CVS, Walgreens, Walmart part of Biden’s Test-to-Treat COVID-19 program. Marketwatch. Mar. 3. (Jaimy Lee)
  • Tim Kaine introduces bill to research and combat long covid, after suffering it himself. Washington Post. Mar. 2. (Meagan Flynn)
Science Features
  • The Biden Administration Killed America’s Collective Pandemic Approach. The Atlantic. Mar. 2. (Katherine Wu)
  • CRISPR Might Actually Live Up to Its Immense Hype. Bloomberg Opinion. Mar. 1. (Lisa Jarvis)
  • Arthritis drug reduces mortality in severe COVID-19, huge clinical trial finds. Science. Mar. 3. (Kai Kupferschmidt)
Legal Corner

UC Berkeley lost the high-profile patent case over CRISPR technology, which meant it was also a loss for Intellia Therapeutics and CRISPR Therapeutics – the companies that took a license from UC Berkeley. That decision by the US Patent and Trademark Office was a victory to the Broad Institute and its licensee, Editas Medicine. What fewer may have noticed is that UC Berkeley’s patent was upheld by the European Patent Office. (San Jose Mercury News)

Regulatory Action

Janssen Pharmaceutical and its partner, Legend Biotech, won FDA clearance for cilta-cel (Carvykti), a new cell therapy for cancer directed at the BCMA antigen overexpressed in multiple myeloma patients. The treatment was approved on the basis of a Phase III trial which showed a remarkable 98 percent overall response rate among heavily pre-treated patients, including a 78 percent Complete Response rate. The new treatment will now compete with a BCMA-directed cell therapy from Bristol Myers Squibb (Abecma).

Seattle-based CTI Biopharma secured FDA approval for pacritinib (Vonjo), a JAK inhibitor, as a new treatment for high-risk primary or secondary myelofibrosis.

Newton, Mass.-based Karyopharm Therapeutics said that it plans to start a new Phase III clinical trial of its experimental drug selinexor for advanced or recurrent endometrial cancer. The decision comes after the FDA told the company that its existing Phase III study results are unlikely to be enough to support a supplemental New Drug Application, which the company had been planning to submit.

Belgium-based Celyad Oncology voluntarily placed a clinical trial on hold for its experimental CAR-T cell therapy being tested in combo with Merck’s pembrolizumab (Keytruda) after learning of two deaths with similar pulmonary findings. The company said it’s investigating the nature of the deaths and in discussions with regulators.

Somerville, Mass.-based Finch Therapeutics said the FDA placed its Phase III clinical trial for a C.difficile treatment on hold, over concerns that donor-derived microbiome therapies could potentially spread the SARS-CoV-2 virus.

The FDA issued a Clinical Hold to Gilead Sciences until it can resolve the issue with glass fragments showing up in vials of lenacapavir, a long-acting treatment being evaluated against HIV-1.

The FDA rejected an application from Plano, Tex.-based Reata Pharmaceuticals to market bardoxolone for kidney disease caused by Alport Syndrome.


Our healthcare system is way too costly, but it’s also way too complex. We need not only to make things more affordable, but more simple, if we want to improve access. The President spoke about making tests and antiviral treatments available at pharmacies. It’s showing an instinct for simple problem solving. Of course, it takes work behind the scenes to make things appear simple on the surface, as Eric Topol notes.