A powerful approach
We are leveraging the principle of synthetic lethality and the power and productivity of our discovery engine to discover and validate multiple novel targets each year. Our growing pipeline consists of discovery programs for genetically defined subsets of multiple cancers which have limited treatment options. Our pipeline is summarized in the table below:
Our first product candidate, TNG908, is a potent, selective, synthetic lethal, small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) – an enzyme whose activity is essential for cell survival. The challenge of non-synthetic lethal PRMT5 inhibitors in treating cancer is that they kill rapidly growing normal cells (such as bone marrow cells) almost as effectively as cancer cells.
To address this problem, we designed TNG908 to be selectively active in cancer cells that have a deletion of MTAP (synthetic lethal). In normal cells, MTAP encodes an enzyme that degrades 5′-deoxy-5′-methylthioadenosine (MTA), an intrinsic inhibitor of PRMT5. MTAP deletion results in marked accumulation of MTA in cancer cells, which causes partial PRMT5 inhibition, creating a differential vulnerability. However, the additional inhibition of PRMT5 by TNG908 is sufficient to cause cell death. In our preclinical studies, TNG908 has demonstrated 15-fold greater potency in MTAP-deleted cancer cells versus normal cells. This unique selectivity of TNG908 for MTAP-deleted cancer cells allows for the sustained inhibition of PRMT5 needed to induce tumor cell death while sparing normal cells, including bone marrow cells responsible for the dose-limiting toxicity of non-synthetic lethal PRMT5 inhibitors currently in clinical development.
MTAP-deletion occurs in approximately 10% to 15% of all human tumors, including many common cancers with high unmet need such as pancreatic cancer, squamous cell lung and esophageal cancer, creating a significant therapeutic opportunity for patients. We believe that the selectivity, potency, and robust preclinical PK/PD profile of TNG908 positions it as a potential best-in-class PRMT5 inhibitor. We plan to file an Investigational New Drug (IND) application for TNG908 in the fourth quarter of 2021 and initiate a Phase 1/2 clinical trial in the first half of 2022.
Our second product candidate has the potential to be a highly differentiated small molecule inhibitor of ubiquitin-specific protease 1, (USP1), a synthetic lethal target for BRCA1-mutant breast, ovarian and prostate cancer. We believe the market opportunity is comparable in size to approximately half of the patient population for PARP inhibitors. BRCA1 mutations are present in approximately 5% of breast cancer, 15% of ovarian cancer and 1% of prostate cancer. In vitro and in vivo preclinical data suggest USP1 inhibtors should be effective as single agents in PARP-naive and PARP-resistant cancers with a BRCA1 mutation. Our preclinical data further suggest that USP1 inhibition is synergistic with PARP inhibition, providing the potential for enhanced efficacy in BRCA1-mutant breast, ovarian and prostate cancer in combination with a PARP inhibitor. We anticipate filing an IND for this program in 2022.
Our third program is focused on reversing the immune evasion effects of tumor suppressor gene loss, in this case STK11 (serine-threonine kinase 11) loss-of-function, present in approximately 20% of non-small cell lung cancers. Using our target discovery platform, we identified STK11 as a tumor suppressor gene responsible for mediating cancer cell resistance to immunotherapy when inactivated, and identified a novel drug target (Target 3) that reverses this effect when inhibited in preclinical studies. We expect the clinical development plan for this inhibitor in STK11-mutant lung cancer to be the first to combine the power of genetic patient selection and checkpoint inhibitor therapy. We anticipate advancing a clinical candidate into IND-enabling studies in the second half of 2022 and filing an IND in 2023.
We aim to become a fully-integrated biotechnology company bringing transformative medicines to people with cancer. We believe strategic collaborations with pharma and other biotech companies can help us achieve this goal and deliver more innovative medicines to patients. Please reach out if you are interested in exploring ways to work together: firstname.lastname@example.org
Our global strategic collaboration with Gilead Sciences is focused on the discovery, development and commercialization of a pipeline of innovative targeted immune evasion therapies for patients with cancer. We are responsible for discovering and validating targets and for advancing select programs through clinical proof-of-concept. Gilead has options to worldwide rights on up to 15 of those targets. We retain the option to co-develop and co-promote the lead products for up to five of those programs in the U.S. with Gilead.
The collaboration, which was originally signed in 2018 and expanded in 2020, does not include our three lead programs. We retain all rights to those programs, along with the right to targets we have identified outside of the immune evasion space. We are committed to advancing the programs in our wholly owned pipeline into the clinic and beyond, as part of our mission to deliver the next generation of transformational targeted therapies to patients in need.
The Gilead logo is a trademark of Gilead Sciences, Inc.