Dark Matter Blog

Following our pole star to a transformative collaboration

April 8th, 2020
by Michael Gilman, PhD
CEO, Arrakis

It is an axiom of effective navigation, on earth or water or in interstellar space, that you need a fixed point to guide you. A beacon that shines clearly, never changes, never moves. If you drift off course, it pulls you back, keeps you on track. Locking your eyes on the pole star is critically important when building a company, but never more so than when negotiating a significant collaboration like the one we announced today with our new colleagues at Roche.

Aim for the stars

If you’ve been with us for a while, you know that the Arrakis team set out several years ago to rebuild the small-molecule drug discovery toolkit, lovingly built over decades by thousands of talented scientists and engineers for tackling protein targets, and point it instead at RNA to create a new class of RNA-targeted small molecule medicines (rSMs). Our ambition was to unlock vast swaths of valuable biology inaccessible to medicine today because the proteins involved elude our reach. Most people, and in particular most investors we spoke to in those early days, thought we were nuts – that RNA lacked the structural and molecular complexity that medicinal chemistry exploits with such great effect for proteins. As his contemporaries told Columbus, we were going to sail ourselves right off the edge of the earth.

But Eminent Founder and CSO Jennifer Petter had several pole stars firmly fixed in her mind from the outset, and they’ve served as our beacons to this very day. One is that molecular recognition is purely a matter of physics and RNA has to play by the same rules. The second is that while it may be hard to achieve molecular recognition, it’s even harder to make a drug, which is to say a molecule that you can eat, that distributes throughout the body, and survives long enough to find its target. Consequently, we were going to stick to chemical space where we know real drugs live. Third, wherever possible we would use existing tools. We’d beat the hell out of them if we had to, but we’d avoid the challenges and uncertainties of pure invention if at all possible. Don’t set out for the stars with an unproven propulsion system.

Truth be told, it took us time to figure this out. On more than one occasion we found ourselves in dead ends and had to back out and re-establish our course. There were days when we seemed hopelessly lost. But, holding fast to Jen’s principles, we always found our way back. Finally, we cracked the code. We’ve now screened over two dozen human RNA targets and we’ve found hits for all of them. And we’re getting more expert at it all the time. We are bringing more sophisticated tools to bear on target identification – in particular, spotting segments of RNA where structure meets function. Our library improves with every screen, as we eliminate confounding binders (of which there are many in conventional compound collections) and enrich with RNA-friendly scaffolds. And as we’ve launched several internal discovery programs, we are learning the rules of molecular recognition for RNA; yes, the fundamental physical constants are the same, but RNA has mixed them up in fascinating, even wacky, ways; principles that feel hard-wired for protein targets just don’t hold for RNA. We have plenty more to learn, to be sure, but our team is fearless and resilient and our toolkit is powerful. Our destination is now in sight.

Destination: patients

This has been a thrilling journey for me personally. I’ve been a believer from the beginning, but I’d be lying if I said I didn’t have my doubts along the way. But those doubts are behind me now and the challenge I feel today – my own pole star – has changed. I believe there are more than a hundred medicines, powerful new therapies that can impact millions of lives, to be developed from our platform, and I want to see as many of them as possible find their way to patients. We all do. No matter how successful Arrakis is, how fast we grow, how much money we raise, we’ll never develop more than a tiny fraction of those medicines on our own. Instead of seeing two or three rSM medicines move into the clinic in the next few years, we want to see twenty or thirty. That’s now our pole star.

With that vision having crystallized in our minds, several conclusions quickly followed. First of all, there are plenty of targets to go around – no need to hoard them for ourselves; we can and should share target space with a dedicated partner. And once we reached that conclusion, we quickly recognized that we should share elements of our platform as well. That’s how we’ll get the greatest leverage from our science and turn it into as many medicines as possible. Consequently, we sought a strategic partner that could devote their own considerable skills and resources to realizing the fruits of the Arrakis platform.

We are thrilled to have found a fellow traveler in the Roche team. Roche is one of the strongest research and development organizations in our industry and they share our vision for dramatically expanding access to new molecular targets by developing drugs targeted directly at RNA. Roche scientists have compiled an exciting list of targets across all of their Disease Therapeutic Areas (DTAs). We will immediately get to work screening those targets. What is exciting about this collaboration is a commitment to share data and ideas from the very beginning. When we transfer programs to Roche, we’ll also transfer the tools and reagents they need to perform further work on RNA targets. By putting these programs and tools into Roche’s hands, we bring their talent, capabilities and capacity to bear on our pole star of maximizing the number of medicines from our platform, while preserving our own resources for own programs. Our goal is to fill Roche’s discovery pipeline with a new generation of first-in-class medicines and build our own pipeline at the same time.

Resilience in the face of the unexpected

Those of you who have participated in designing and negotiating collaborations of this magnitude – of any magnitude, honestly – know that it’s grueling work. It requires clarity of mission, relentless focus, deep reservoirs of energy, and a surprising amount of empathy. It’s not just about what you want or need. You have to figure out what your partner needs as well. This process of mutual discovery and memorializing the shared vision for the collaboration in words (nearly fifty thousand in this case, each one carefully parsed and scrutinized) takes months. And it’s not without its challenging moments.

Then try doing that during a global pandemic.

I’ll spare you the full tick-tock. But as you might imagine, the face-to-face sessions that lubricate relationships and facilitate negotiation simply couldn’t happen. As late as mid-March, the Roche deal team was still planning to fly to Boston for three days of face-to-face negotiation. Instead, we negotiated by video – and we got pretty good at it. Indeed, as both teams transitioned to working from home, we saw into one another’s kitchens, living rooms, and home offices. Business attire disappeared in favor of T-shirts and hoodies. It brought unexpected intimacy to a process that would otherwise play out in lavish but sterile law-firm conference rooms. Remember when I said empathy is key to getting a deal done? Not that I recommend pandemic negotiation as a strategy, but I truly believe the circumstances helped us see one another as people and helped get this deal done.

Great credit is due to the Roche deal team, who had their own pole star in clear sight throughout. They were fantastic colleagues during this process, clear with their communication and expectations, pragmatic and constructive during negotiation, never in doubt about the importance of this collaboration to both parties. All of that, of course, bodes well for a productive long-term relationship.

Our expedition continues – in unusual times

Now the real work begins. Yet we find ourselves at home, our lab silent and empty. How do we hit the ground running on this transformative collaboration and make good on our shared goal of creating dozens of new medicines for patients?

We are not alone in facing this challenge, of course. And, honestly, our problems pale compared to the trials faced health care workers on the front lines of this pandemic. We have the luxury of staying home; that’s not exactly hazardous work.

Like most companies in our area, we sent our non-lab employees home a few weeks ago and shortly thereafter began an orderly process of shutting down the lab. Today everyone’s working from home except for occasional visits to top off liquid nitrogen freezers and keep the NMR alive. The good news is that plenty of work can continue even with our own lab dormant. Our Chinese CROs are back online and doing synthetic chemistry at a pre-pandemic pace. We have transferred some cell assays to China, so that ironically some things are actually going faster now. Previously, compounds were shipped here (in at least two steps) for assay; now they’re being tested in the same facility in which they’re made. Much of our work is computational and that, of course, continues at full speed.

So I’m not so worried about keeping experiments going. Rather I’m focused on holding the organization together, keeping our team connected and engaged, consolidating our culture so that it’s robust and ready to absorb the substantial growth Arrakis will experience in the next year or so. The massive scope of the Roche collaboration requires that we more than double our headcount in the next year or so. That would be challenging under the best of circumstances in the hyper-competitive hiring environment in Boston. But now, with people hunkered down at home and worried about their health and safety and that of friends and family? When candidates, hiring managers, and potential colleagues can’t meet and talk face to face? So, like everyone else, we’re becoming adept at video interviews and have actually hired a half dozen new scientists in just the last two or three weeks. Last week we had our first virtual onboarding of a new employee. We’re staying connected and we’re getting to know each other’s kids and pets on video. And we’re flexing our “resilience” muscles – great exercise for anyone in the long game of drug development.

Our collaboration with Roche comes at an important time. Businesses of all stripes face challenges in this crisis. We’re lucky. Our relationship with Roche gives us the ability to focus on our science and delivering the first rSMs to patients. For that, I am deeply grateful. Meanwhile, the world fights its way through a massive crisis. It’s easy to feel helpless in the face of chaos, which is why it is ever more important to hold your pole star in sight. For now, I look forward to seeing my Arrakis and new Roche colleagues in person when we come out the other side of this crisis. Thinking of a North Star theme for our collaboration kickoff celebration.

Photo Credit:  A. Duro/ESO

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