At Canaan, we ask a key question when making decisions about our healthcare investments: Is this a transformative medical technology that will deliver irrefutable value, both to patients and the entire healthcare ecosystem? With that north star, we support biopharma companies that address an unmet medical need in an innovative way but importantly, we add another layer to the criteria: can this be done in a broadly applicable and scalable way?
That is precisely what the latest addition to Canaan’s portfolio, Arrakis Therapeutics, is setting out to do and I’m thrilled to have led their Series A financing and be on board for the journey.
Though conceptually I fully subscribed to the notion of drugging RNA since it was first introduced, we — at Canaan — had stayed on the sidelines because the only RNA-targeted drug format, oligonucleotides, has been fraught with challenges for both companies and patients. As investors, many of whom have worked in pharma in the past, we believe deeply that using readily scalable drug formats, such as our bread and butter small molecules and antibodies, is key to driving value for patients and the healthcare system as a whole.
This belief is reflected in our investment in CytomX Therapeutics (CTMX), a company that developed Probodies, which are masked monoclonal antibodies designed to address a critical limitation of many antibody therapies: therapeutic index. The promise of CytomX is that in the future, when a target that is expressed broadly throughout the body is identified, its true potential for disease modification will be realized because the drug will work only at the site of disease, saving the patient and physician from dose-limiting side effects.
Arvinas, another company in the Canaan portfolio, is also laser-focused on a transformative new approach this time using small molecules. Under its founder Craig Crews — a professor at my alma mater, Yale — Arvinas is pioneering protein degradation. Often, overactive disease-causing proteins outsmart drugs and become resistant to inhibition or are not amenable to inhibition in the first place. In that case, drug developers strive to shut the protein’s activity down but traditional inhibitor approaches are failing. Dr. Crews and the team at Arvinas are taking advantage of the cell’s existing quality control system to drag those proteins to the cell’s garbage disposal, where the protein is chewed up and flushed down the proverbial drain. When inhibition isn’t doing the trick now we can degrade drug targets! Targeted protein degradation is an innovative way to affect disease biology where classic approaches of inhibition fail us.
Given our focus on transformative new technologies using scalable drug formats, Arrakis’ story immediately resonated with me. As an investor, Arrakis’ unique application of small molecules was a beacon in a sea of pitches for complex therapeutic delivery systems, namely cell and gene therapies. Although I was instantly intrigued, I needed some convincing that RNA demonstrated the right properties to actually be drugged with small molecules. After spending several hours with Russell Petter and paying a visit to Anna Marie Pyle, one of Arrakis’ SAB members, I became a bona fide believer. In Dr. Pyle’s office at Yale, my colleague Tim Shannon and I looked at 3D images of RNA and were impressed by the similarity to protein structure. The power of using pharma friendly small molecules to modulate RNA function was readily apparent, similar to the way novel biology with protein degradation and tissue-specific monoclonal antibodies stood out with Arvinas and CytomX.
Considering that there are more than 200,000 known RNA transcripts and only about 20,000 possible proteins, Arrakis’ platform has the potential to make a whole new world of drug targets accessible. Not only could Arrakis possess the tools to affect new targets but it could also be the answer to old targets. What we currently know as “undruggable” — proteins that have not been amenable to classic protein-targeted small molecule or antibody approaches — could very well be druggable with Arrakis’ platform, which promises to stop disease-causing proteins before they’re even made. And the benefit to using small molecules is that these drugs will be orally available in traditional pills. That principle is distinct from all other RNA-targeting approaches and provides a key advantage for Arrakis.
Arrakis is helmed by an all-star team that is well positioned to realize the full potential of this technology. I believe deeply that Arrakis is going to transform biopharma drug discovery by boldly questioning the way we’ve approached drug discovery in the past and redefining the “druggable” target.