The Book of Nimbus

Posted April 27th, 2023 by Jeb Keiper, in Drug discovery, From The Trenches, Leadership, Portfolio news, Strategy

By Jeb Keiper, CEO of Nimbus Therapeutics, as part of the From The Trenches feature of LifeSciVC


Nimbus Therapeutics began 14 years ago.  The premise at the time was that putting computational chemistry in the primary position for new molecule ideation would upend the drug discovery paradigm.  It did just that.  Three best-in-class molecules in the clinic, over $400 million invested and over $4 billion returned to equity holders, all while focused on our mission to design breakthrough medicines for patients. 

Fourteen years on, this corporate experiment has gone far beyond the initial idea, and has established an R&D engine more effective than most big pharma R&D groups at producing best-in-class small molecules against targets that matter in human disease biology.  Throughout that time Nimbus has not just built functional capabilities and continued adopting technological innovation, but importantly has worked tirelessly to establish strong cross-functional and interdisciplinary ties that bind discovery and development into a more cohesive, more effective R&D engine.  Much of our success springs from being nimble and pragmatic on the journey: by optimizing areas we know work well and adapting to ever-changing landscapes in the capital markets, therapeutics spaces, and laws and regulations (e.g., IRA).

The Book of Nimbus is still being written, but its arc over the years already shows the shape of what I believe to be Nimbus’ mark on our industry: as an R&D powerhouse with the potential to repeatedly create breakthrough medicines for patients.

 Chapter 1 – An Unreasonable Idea

The year was 2009.  Barack Obama had just been sworn in as the 44th president.  The automotive industry just received an $81 billion bailout from the federal government, and unemployment sat at 10% (the highest in 25 years).  Michael Jackson died, Slumdog Millionaire won the Oscar for Best Picture, and meanwhile Bruce Booth of Atlas Venture and Ramy Farid, CEO of Schrödinger, began work on a very unreasonable idea.  It was the beginnings of Project Troubled Water, Inc.: set up a “virtual project team,” leverage Schrödinger scientists to lead computational chemistry, and do all the wet work at CROs.  Invest $10 million to get 5 development candidates in 2 years.  Unreasonable indeed.

The five development candidates in two years became one development candidate in five years.  The cost went from $10 million to $50 million, inclusive of investments in the platform and broader pipeline.  In those respects, one might look at Nimbus’ first chapter as a failure, but they’d be wrong.  Because the other thing that happened was the creation of an incredible discovery engine that entirely changed the small molecule drug discovery paradigm.  Those years of hard work forged the unique project style that coupled computational chemistry leadership with battle-tested medicinal chemists, biologists who are subject matter experts on the target, and CROs and academic collaborators that fueled an unprecedented “DMTA” engine:  Design a molecule on a computer, Make the molecule at a CRO, Test the molecule in a proprietary bespoke biological screening cascade for the target, and Analyze the resulting data, which would then feed the design phase of the next iteration.  Blood, sweat, and tears poured into the establishment and optimization of this framework.  High science led the vanguard of the work, yet behind the scenes a novel business structure was developed simultaneously, the LLC structure.  The LLC structure at Nimbus is more than just a holding company framework; it is an intricate, well-planned set of agreements, accounting methods, and governance operations procedures that allowed the Nimbus discovery engine to flourish.  Long-time Nimbi extraordinaire Holly Whittemore perfected this approach alongside the amazing counsel at Goodwin, notably Bill Collins, Mitch Bloom, Dan Karelitz, and many others.

By the time Chapter 1 was nearing its end, Project Troubled Water, then Nimbus Discovery, became Nimbus Therapeutics as we took a further step to forward integrate into clinical development.  Having partnered our lead IRAK4 asset with Genentech (which ultimately failed to progress), Nimbus entered the clinic with our allosteric inhibitor of acetyl-CoA carboxylase (ACC) in healthy volunteers, with plans to begin a Phase 2 in NASH.  Our ACC inhibitor, now named firsocostat, remains first-in-class, and is in a Phase 2b study in severe NASH patients run by Gilead, who acquired the program in 2016.

For further reading about Nimbus’ first chapter, many an excellent blog has been written about those formative days.  Check out:

Chapter 2 – Building an Integrated Approach

It was 2016, we had sold our lead asset to Gilead, and we had no idea what exactly was going to happen next.  The transaction in 2016 was also the first true biotech “exit” of a holding company/single asset that would return capital to investors and employees – like a true M&A – but preserve the rest of the portfolio and the Nimbus business model. Miraculously, everyone came back to work the next day, week, month, and it truly felt like a new adventure as we knew we were charting a course not many previously had. The transition had its challenges though: we had begun working in clinical development, hired staff, and now were reset to an early-stage preclinical company.  All our resources in chapter 1 had begun funneling to the lead program, and with only $67 million raised over 7 years, Nimbus was not exactly “robust” at an enterprise-level.  We had just 22 people by the end of that year, 15% of the company having departed following the Gilead deal.

At that time the Nimbus Board discussed the next chapter of our company.  The first thought was to never raise money again; become a perpetual motion machine.  We kept 5% of the Gilead deal proceeds in 2016 in the hopes we could span our way to a next BD deal in our pipeline – and we did!  In 2017 we formed a classic Celgene option deal with our two most advanced programs, TYK2 and STING.  Nimbus retained full ownership and control of the programs in exchange for funding and pre-programmed exits of $400 million each for Phase 1b data in a few years.

That created a conundrum.  With the two lead programs effectively pre-sold, what would the rest of Nimbus do?  Would we wind down and exit, or chart some different path?  That critical strategic discussion led to some fundamental changes in Nimbus, changes that ultimately laid the groundwork for amazing success in chapter 2.

The year was 2018, and the Board at Nimbus had agreed with our plan to re-invest in discovery and build out our internal pipeline.  The successful computational powerhouse DMTA cycle we had built could broaden applications across more targets.  And in that new pipeline, our goal was to identify “The One” (I personally cannot help but think of Keanu Reeves’ character Neo, from the Matrix movies).  “The One” was a molecule that we would forward-integrate further around, which would be the nucleus to crystallize our clinical development organization.  The strategic shift spawned our mission statement at Nimbus:  We design breakthrough medicines.  It also led to a $65 million equity financing to kickstart pipeline creation.  Little did we know that “The One” would be a molecule we already had in our hands, our allosteric TYK2 inhibitor….

This direction and change in strategy fomented uncertainty, which led to inevitable turnover.  Nine years in at that point, we saw 25% of the Nimbi depart that year, including our first CEO, Don Nicholson, and I am humbled the Board asked me to step in as Nimbus’ next CEO.  Having said farewell earlier to our founding CSO, Rosana Kapeller, my first step was to rebuild the fundamental high science foundation of the company.  I turned to my good friend and former colleague, Peter Tummino, then VP, Global Head of Lead Discovery at Janssen, to be our next CSO.  Over the next four years, the science at Nimbus flourished, and with it, the reputation for excellence grew. We became the magnet for top talent that Nimbus is now known for, attracting such amazing scientists as Christine Loh, Scott Edmondson, Mark Cartwright, and so many more, too many to name, but all of whom deserve my most humble thanks for joining on this mission to design breakthrough medicines for patients.

In the middle of chapter 2, the most dramatic wrinkle then occurred.  It was January 3rd, 2019, and BMS just announced that they were acquiring Celgene.  I remember learning of this from Holly Whittemore, as I cheerfully greeted her with “Happy New Year” on my first day back to the office.  She replied, “Hey, did you see this?” and swiveled her monitor to show me the news.  After I picked my lower jaw up off the floor, I said 30 seconds later “We are going to keep our TYK2 program.”  Celgene had signed up for the option deal with Nimbus in 2017 to access our (hoped-for at the time) best-in-class allosteric TYK2 inhibitor to compete with their rival BMS’ TYK2 inhibitor (which today is known as Sotyktu).  BMS had just begun Phase 3 trials of their agent, which was likely to be successful — as we now know it was.

The initial interactions with BMS were pragmatic and sensible.  Following the close of the BMS deal, the Nimbus TYK2 option was allowed to persist as a backup option, should the BMS TYK2 drug fail in Phase 3.  During the year-of-Covid, 2020, we slowly started our Phase 1 program with our TYK2 candidate while BMS slogged through Phase 3.  Then came 2021, the most consequential, and tumultuous, year in the Book of Nimbus thus far.  It was a period of dramatic activity, much of it well-documented in the public domain, but thankfully all resolved by January of 2022.  In the end, after a rollercoaster of legal ups and downs, we settled out of court, leaving Nimbus sole ownership of its TYK2 program.

Throughout this period of interacting with BMS, litigation attorneys, and the FTC, Nimbus was fortunate to find investors who believed in our team, our science, and our conviction that we had a sound strategy that did not rely on a binary outcome of whether we won or lost litigation. We were fortunate to raise $225 million to power TYK2, as well as the rest of our pipeline, including the clinical start of our HPK1 inhibitor program in cancer patients.  That funding enabled the two Phase 2b trials of our TYK2 program, one in psoriasis and one in psoriatic arthritis.

In 2022, with sole ownership of our lead asset, Nimbus began seriously considering an initial public offering after 13 years of private operation.  Our CFO, Ian Sanderson, had joined to lead us through that transition, and instead his experience and expertise led us through finding private funding at the start of a very turbulent period in the public capital markets.  By mid-summer 2022, the market sentiment was downright sour, and Nimbus was running low on the cash needed to power up our programs. In true Nimbus fashion, we did continue to keep all our options on the table, and the BD team at Nimbus had been in constant communication since 2019 with all key pharma partners that would entertain talks about our TYK2 program. Our Phase 2b study was wrapping up and we expected data in Q4; meanwhile, on every investor’s mind was the expected approval of BMS’ TYK2 inhibitor in September.  Nearly 90% of investors and physicians had predicted that BMS would get a black box warning on Sotyktu, since TYK2 was a JAK family member, even though Sotyktu was super selective against the other JAKs.  When the approval finally arrived at 11pm on the PDUFA date with no black box, suddenly, allosteric TYK2s were a new class of medicines for psoriasis with potential in many autoimmune diseases.

Shortly after the Sotyktu approval, our 260 patient Phase 2b study read out.  The data, ultimately unveiled at AAD in March 2023, were stunning: biological efficacy rivaling IL-17 and IL-23 with an oral small molecule, and possessing a safety profile at least as benign as BMS’ Sotyktu.  Our long-time clinical development lead, Bhaskar Srivastava, an M.D. Ph.D. dermatologist, could not contain his excitement.  He delivered one of the most well designed and executed studies in the field and deserves enormous credit for developing a medicine with such profound potential for so many patients.

In the frenetic weeks that followed the unblinding of the study, our Chief Business Officer, Abbas Kazimi, was on center stage, building a team including the excellent advice of Phil Ross at J.P. Morgan and wise counsel of Sarah Solomon at Goodwin.  The pharma relationships Nimbus had established allowed diligence teams to engage efficiently and move past the first point of an interaction – trust. Our small team was able to support multiple major pharmaceutical companies plowing through diligence, not just withstanding the onslaught but in fact delivering a data package of Phase 3-ready quality.  The bidding was fast and furious, and ultimately the incredible team at Takeda, led by CEO Christoph Weber and R&D Head Andy Plump, became the most compelling group dedicated to taking our program forward to patients, which we announced on December 13, 2022.  We could not be more thrilled with their leadership and commitment, and we closed the deal by February of 2023.

For further reading about Nimbus’ second chapter, many excellent blogs were written about this period.  Check out:

Chapter 3 – Establishing a Legacy R&D Institution

This blog is being written as we turn the page to chapter 3, however the groundwork began with long-range planning almost a year ago.  We had scenarios for every eventuality for the TYK2 data, partnering interest, and the financing environment.  With that said, we knew if we were successful in psoriasis, the implications would require a large multinational company to create the value of global registrations in multiple indications.  Given the value of established infrastructure in pharma, it was clear that an M&A acquisition of our TYK2 subsidiary was likely.

We therefore have had some time in which to contemplate what this next act for Nimbus holds. Although we are just now at the beginning stages of the great journey to come over the coming years, many of the formative pieces are now in place — just as our TYK2 program was at the time of Nimbus’ last inflection point.  Our clinical-stage HPK1 inhibitor is now progressing into expansion trials in solid tumors, while a crafted pipeline of opportunities, including what we would consider a disruptive medicine in the autoimmune field, heads toward the clinic next year.  While our expertise in immunology and oncology is strong, we also have depth in metabolic disorders, and have a fabulous collaboration with Eli Lilly on AMPK activators, along with earlier programs in discovery.

And excitingly, we are better positioned than at any point in our history to navigate what comes next. Our investments throughout chapter 2 have built an organization with an even wider skillset, from discovery through to clinical execution, and deeper disease area expertise than ever before. Key to Nimbus’ third chapter will be Chief Medical Officer Nathalie Franchimont, who joined us from Biogen late last year to lead our Development organization, building upon our foundations of quality, operations, and execution.  Nathalie, Peter Tummino and Bhaskar Srivastava are building out our early clinical and translational biology expertise, while at the same time we are investing in our computational capabilities, tackling tough targets like transmembrane GPCRs in our discovery pipeline.  As the winds of change in our industry keep blowing strong, the flexibility and optionality of the Nimbus structure remain a key competitive advantage that has contributed to this enterprise’s longevity.

Transitions are not easy times, though, and as was the case in our move to chapter 2, we’ve needed to navigate turnover and figure out a way to realign and reorganize the Nimbi while preserving our diversity and special sauce, a task that has been led with care and grace by our Chief People Officer, Erin Cowhig.  Reorganizations are never a pleasant task, and it has led to some tough choices, where we have needed to bid farewell to some excellent Nimbi simply because their roles were not going to be essential to this next chapter.  We thank them for their service and are committed to their safe landings, as they join the ranks of amazingly successful alumni from Nimbus.  We’re proud of the small but growing Nimbus diaspora, a testament to how special a place Nimbus has become.  Elsewhere in the industry we see biotechs who emulate our corporate structure, our computational engine, or our approach to deal-making (or all 3!).  Awesome.  We must be doing something right.  If Nimbus is able to help shape the industry approach, give a better shot to making therapeutics that help patients, then we have multiplied our impact many times beyond our four walls.

Nimbus is committed to the notion that “small is beautiful” in drug R&D: breakthrough small molecules designed by a small expert team.  We have built hard-earned capabilities in both discovery and development, and will continue to build on those in chapter 3.  Our mission remains the same: We design breakthrough medicines.  Our objective in dollars and cents terms is to again shoot for the moon, to become again a multi-billion-dollar biotech.  But our ambition is far greater than that.  Nimbus has an opportunity to build a legacy R&D institution.  A paradigm of excellence in small molecule drug discovery and development.  Chapter 3 will take some time to evolve as the pages are just being written, but we are blessed with an ideal combination of functional skills, established quality processes, and enough hungry, “unreasonable” individuals who drive us to become more than we ever thought we could be.




Teamwork.  It is all teamwork.  There is no single hero or function that has been essential, yet without everyone we could not have come this far: our alumni; our collaborators across many companies, professional groups, and at academic institutions; the patients in our clinical trials, their physicians and families; our investors who have put over $400 million into Nimbus over the years; our Board and senior advisors; our industry colleagues; and of course the active Nimbi and their families. I’d also like to acknowledge Bruce Booth, Abbas Kazimi, and Lisa Raffensperger who all contributed to this blog.

This entry was posted in Drug discovery, From The Trenches, Leadership, Portfolio news, Strategy and tagged , . Bookmark the permalink.