Discovering a New World of RNA-Targeted Medicines

February 27, 2017
Michael Gilman, PhD, CEO, Arrakis

So here we are. Nearly two years in the making, much of it focused, fastidious work by founder Jennifer Petter (of whom much more below), capped by an exhilarating and exhausting sprint to the finish by an outstanding team, Arrakis Therapeutics has now lifted off.

Today we announced a $38M Series A financing led by Colleen Cuffaro and her colleagues at Canaan Partners, joining founding investors Advent Life Science and Henri Termeer, and new believers Osage University Partners, Pfizer, and Celgene.

What’s it all about? If you’ve got some time on your hands, I refer you to the sneak preview of our thinking that I posted last week. Go ahead, read that. I’ll wait.

Meanwhile, for those seeking instant gratification, here’s the condensed version. Human biology is deep and vast, and it can go haywire in spectacular fashion—we call that disease. To treat disease effectively, we need to do two things. First, we need to understand the underlying biology, how it deviates in disease, and how to normalize it—in short, what buttons do we need to push to make things right. Second, we need to figure out how to push those buttons. Sometimes intervention requires lifestyle changes, sometimes surgery, but more often than not, we need a new drug. And if a drug can do the job, especially a safe and simple pill we can pop with our morning cereal, that’s usually the way to go.

Let’s pause for a moment to celebrate the magic that is medicinal chemistry, the science that gives us all those healing pills. It is a remarkable human achievement that we are able to design and fabricate custom chemicals that we can eat, that distribute throughout the body, find one (and often only one) protein, latch onto it and keep it from doing its thing. It’s a discipline that has saved lives and added countless years of happiness and productivity to our species.

Yet for all its power, medicinal chemistry can access only a small sliver of human biology, just a few hundred of the 20,000 or so proteins encoded in our genome and little if any of the biology performed by non-coding RNAs, of which there are perhaps 200,000. How can we overcome this limitation and unleash the awesome power of medicinal chemistry on new biology? Is it even a limitation at all? Or is the problem just our own feeble imagination? Can we reimagine small molecule drug discovery, re-architect the drug-discovery toolkit, and point it at RNA instead of protein?

That’s what we intend to do at Arrakis.

The back story

Jennifer Petter is a creative and charmingly iconoclastic chemist, whose wit is as incisive as her chemistry. We first worked together at Biogen in 1999 and during much of my tenure there as head of discovery research, she ran the small molecule drug discovery group. We both left Biogen in 2005, me to an interregnum during which I founded a fibrosis company called Stromedix, and Jennifer to Mersana Therapeutics. More importantly for this story, however, she soon arrived at another startup, Avila Therapeutics, where she stared down a medicinal chemistry challenge that conventional wisdom held to be impossible or at best ill-advised: Development of covalent drugs, compounds that act by irreversibly inactivating their target enzyme. One by one, Jennifer and her Avila colleagues picked off the long list of dearly held reasons why covalent drugs would never work and developed a series of novel drug candidates. In early 2012, Avila was acquired by Celgene. About two weeks later, Stromedix was acquired by Biogen.

We each joined our respective mother ship. I didn’t last terribly long—I was liberated after a year—but Jennifer persevered, eventually acquiring responsibility for the entire medicinal chemistry operation at Celgene. After three years at Celgene, Jennifer “retired.” But not to the golf course, or, more likely in her case, to breeding best-in-show collies. Instead, Jennifer prepared for her retirement by attending a Gordon Conference where, one fateful Thursday morning, she had a transformational experience listening to talks by Kevin Weeks of UNC and Matt Disney of Scripps on the prospects for drugging RNA with small molecules. Emboldened (or perhaps blinded) by her previous experience taking medicinal chemistry where the experts said it could never go, she figured, hell, I want to try to do this—intentionally and systematically.

And so she went to work. She discussed her ideas with another long-time (and ex-Biogen) colleague Roy Lobb, who directed her to their former Avila compatriot, Raj Parekh at Advent Life Sciences in London (Roy was a founder and Raj was on the board at Avila). Raj and his team were also working on putting together an RNA company and they decided to join forces with Jennifer. Alan Walts, a long-time Genzyme executive, now a venture partner at Advent, also got involved and brought in his long-time boss Henri Termeer. Together with Raj and the Advent team, Jennifer, Alan, and Henri founded Arrakis in October 2015.

Jennifer then recruited two former Biogen colleagues. Dan Koerwer, who held a number of business roles at Biogen, including running the research operations group when Jennifer and I were there, and worked most recently as Chief Business Officer at Bind Therapeutics, will be Chief Business Officer at Arrakis. Biologist extraordinaire Jim Barsoum, who spent sixteen years at Biogen before heading research at Synta and then taking the CSO job at RaNA Therapeutics, will head up biology for Arrakis. Jennifer also conscripted her former Avila/Celgene wingperson and ops whiz Heather Lounsbury to head our business and technical operations.

She also assembled an ace Scientific Advisory Board, chaired by Melissa Moore, then an HHMI Investigator at UMass Medical School and now CSO at Moderna, and including Anna Marie Pyle, an HHMI Investigator at Yale, Chris Burge of MIT and David Chenoweth from Penn.

I got involved completely accidentally, which is how these things often go. I bumped into Jennifer in late April 2016 at NGIN Workplace in Kendall Square when I was there for a board meeting of another company. We had only a moment to chat, but that moment was enough to derail my own retirement before it even got underway.

Today, we put in place another important piece—money!—as we add a strong, sophisticated, and supportive syndicate of investors to our team. We especially welcome Colleen and her colleagues at Canaan Partners, whose spirited and remarkably well-informed perspective on the challenges of drugging RNA catalyzed this financing. Of course, we thank our founding investors, Advent Life Sciences and Henri Termeer, for their unwavering support. And we welcome Osage University Partners and our new colleagues at Pfizer and Celgene to this great mission.

Mission possible

Arrakis has a simple but powerful vision: To extend small-molecule medicines into new realms of biology. We intend to do that by building on today’s sophisticated but entirely protein-focused drug discovery toolkit, massaging it as necessary to refocus it on discovering compounds that bind RNA.

We don’t think there’s magic required. We know, for example, that perfectly normal, street-legal (by which I mean Lipinski-compliant) small molecules can bind RNA. Many approved antibiotics do just that. More recently, functional screens have turned up compounds that exert their activity through RNA rather than protein. Novartis’s LMI070 acts specifically at the 5’-splice site of exon 7 of the SMN2 pre-mRNA to promote inclusion of that exon in the mature mRNA; it is currently being tested in patients with spinal muscular atrophy. Merck’s ribocil, selected for its effect on riboflavin metabolism in E. coli, acts by binding to a regulatory region in a bacterial mRNA. Clearly, there are RNA binders in our compound libraries. So far we’ve found them by accident. Why not go looking for them intentionally?

How are we building a platform that we can point at any RNA? We don’t think this requires magic either. We believe that many standard tools can be used unchanged—that’s certainly the early learning from our first screens. Other tools will need to be modified to handle RNA. Some tools will need to be invented from scratch to address unique opportunities and challenges presented by RNA.

One of our new tools is TRYST, which comprises ideas and bioinformatics algorithms to identify druggable structures in RNA, with particular focus on sites where we think we can interfere with mRNA translation. PEARL-seq is a chemical biology approach that allows us to interrogate compound binding to RNA in cells, to validate binding in an RNA’s natural habitat (for example, in complex with RNA-binding proteins), to map compound binding sites at nucleotide-level precision, and to understand the selectivity of our compounds in the face of tens of thousands of competing RNAs.

We’ve also begun to learn about the chemical space where RNA binders live. We already know there are plenty of RNA binders within Lipinski space and in standard compound libraries. But we know there are novel scaffolds too and are beginning to assemble chemical libraries of our own at Arrakis.

Clearly, we have a challenging mission ahead of us. No doubt we will make a few mid-course corrections along the way. But challenging is not the same as impossible. The Arrakis team has been at the business of drug discovery for a long time, longer than some of us would care to admit, and we’ve all internalized our fair share of dogma along the way. But not this one. We believe in the power of medicinal chemistry to deliver an entirely new class of medicines to patients by harnessing the considerable biology of RNA.

And it all begins today. Please come back often as we report on our adventure.

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