On February 16, biopharma hit an extraordinary milestone. The US FDA accepted the first KRAS G12C inhibitor, sotorasib, for Priority Review. Once considered an undruggable target, we now anticipate the rapid approval of the first KRAS inhibitors offering patients new hope. In honor of this historic event, we want to share a few thoughts about the future of targeted oncology and where we are making investments at Canaan.
We want to fund new treatments that work
Our team is focused on how a new platform, target or modality will result in a broadly prescribed medicine that addresses an urgent need. Millions of cancer patients have benefited from precision medicines targeting abnormal HER2, EGFR, RAF, ALK, PARP, BTK, NTRK, FGFR, RET, ROS1, PARP, and beyond. Our own team members including Peter Farina, Paul Fonteyne, Julie Grant, Wende Hutton, Nina Kjellson, Nils Lonberg, and Tim Shannon have discovered, developed, commercialized or funded programs in targeted oncology. It gives us tremendous hope that 85% of new oncology approvals in the last five years were targeted agents and with 37% pre-selected against a driver mutation (BIO, Feb 2021). Targeted oncology is a productive strategy to advance outcomes for patients, which is why we are going to keep investing!
Novel tumor targets and dependencies
Tim Shannon’s investments offer a window into a next wave of cancer targets, including synthetic lethal interactions. At Vivace, Sofie Qiao and Len Post, have discovered the first TEAD inhibitor that allows the novel, high interest HIPPO-YAP pathway to be drugged. The new medicine is now being explored in a Phase 1 clinical trial that is enriched for patients with NF2 mutant tumors. YAP/TEAD is the transcriptional driver of various genetic aberrations, including inactivating mutations of the yet undrugged tumor suppressor NF2. Sofie and Len have a track-record in targeted oncology from their discovery at Lead Therapeutics of talazoparib, which is now commercialized as Talzenna® by Pfizer.
Under the leadership of Yujiro Hata and Michael Dillon who are building out a synthetic lethality platform at IDEAYA, the company is initiating a Phase 1 study of their MAT2A inhibitor in patients with MTAP gene deletion in their tumors, estimated to represent approximately 15% of all solid tumors. The company also has a PKC inhibitor in clinical development for unaddressed tumors harboring GNAQ or GNA11 mutations such as uveal melanoma. For each of these programs, the Phase 1 clinical trial designs are enriched for patients whose tumors are genetically defined as more likely to respond to the therapy. In our recently raised $800M fund, we will deploy capital to emerging precision oncology targets.
Transformational discovery methods and modalities unlock new pharmacology
While many targeted therapies offer impressive disease control as seen with EGFR inhibitors and BTK inhibitors, tumor evolution toward drug-resistance mutations is frequent and often predictable. Structural insights about the drivers of drug resistance is another theme we are focused on. We want to invest in compounds that work in resistant tumors or prevent mutations from emerging in the first place. Todd Harris and Daniel Bensen at Tyra captured Nina Kjellson’s attention by leveraging unusually rapid protein crystallography and medicinal chemistry methods to design and screen potent, highly-selective leads to distinct receptor tyrosine kinase isoforms and their emerging acquired resistance mutations. Tyra’s purpose-built compounds can offer second and third-line hope to patients with no other treatment alternatives while ultimately proving out best-in class profiles for optimal front-line treatment.
Novel modalities also offer another way to drug historically refractory tumors. Arvinas, which Canaan funded at the series A and where Tim was originally acting-CEO, has been the first to bring PROTACS and protein degradation to clinical development as a way to drug targets when classic protein inhibition is insufficient. This approach has recently demonstrated early evidence of clinical activity targeting androgen receptor and estrogen receptor driven prostate and breast cancer that was refractory to standard of care. The company also recently disclosed a preclinical pipeline of PROTAC therapies, all of which will follow a targeted, precision medicine development paradigm. We are investing in new methods in crystallography, modalities, and machine learning that unlock better medicines designed with a purpose.
Reimaging development and redefining patient populations
Beyond the biology and chemistry, new approaches to clinical development can accelerate and expand treatments for patients. The FDA is clearly inviting our industry to evolve how we design our oncology trials and to include overlooked populations. The approval of entrectinib and larotrectinib for patients over 12 years of age with NTRK fusions driven tumors – irrespective of original tissue – are extraordinary rays of hope for start-ups.
When incubating Day One, Julie Grant and Sam Blackman hypothesized that precision medicines could be brought to market faster for patients of all ages by leading with the unmet needs of children with cancer. This past fall, the FDA granted DAY101, an oral pan-RAF, Break Through Designation for the treatment of pediatric patients with advanced low-grade glioma harboring RAF alterations. With guidance from the FDA and EMA, the team at Day One, led by Jeremy Bender, leapt forward from Phase 1 into a global, single-arm, monotherapy, registration-enabling study of DAY101 for children and young adults with recurrent or progressive BRAF-altered low-grade gliomas. This week the team expanded the clinical stage pipeline by licensing two MEK inhibitors, pimasertib and MSC2015103B, from Merck KGaG. Pimasertib will be studied in combination with DAY101 in patients ≥12 years of age. Canaan’s investment team is searching for innovative teams that can redefined cancer populations by histology, molecular profile, tumor microenvironment or other factors in order to go faster and broader in the fight towards cures.
Reaching precision medicines’ full potential
Canaan’s healthcare team is primarily focused on biopharmaceutical investments. Yet, we know that the benefits of targeted therapy are only realized when physicians and patients are empowered with the best molecular information to select the optimal treatment. Actionable genetic alterations may be present in 40% of patients’ tumors but a far smaller proportion of patients (less than 15%) are eventually treated with a genotype matched drug (Malone et al., 2020). The reasons are many: tissue accessibility for testing, disparities in protocols by sites of care, and financial disincentives. The NCI estimates that 40% of Americans will be diagnosed with cancer during their lives. We all need to advocate for widespread molecular testing for earlier or better diagnosis at all sites of care, stronger insurance coverage and financial support to patients to scale targeted oncology more broadly. And continued partnership between patients, clinicians and the biopharmaceutical industry to bring forward more innovative medicines. Together we can make a difference.