Lirafugratinib

9.2-month median PFS in heavily pre-treated patients with PI3Kα -mutated, HR+/HER2- metastatic breast cancer at RP2D 33% ORR across all patients & 53% ORR in patients with kinase mutations at RP2D Favorable overall tolerability profile; at RP2D, only 2 patients discontinued treatment due to adverse events & only 1 patient experienced Grade 3 hyperglycemia Data support planned initiation of 2L pivotal study in 2025 Triplet combination with ribociclib expected to move into dose expansion in 1H 2025 & triplet combination with atirmociclib (CDK4) remains on track to start before year-end CAMBRIDGE, MA, USA I September 09, 2024 I Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, today announced positive interim data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα. The data showed that despite heavy pre-treatment, patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer who received RLY-2608 600mg BID + fulvestrant demonstrated clinically meaningful progression free survival (PFS). “These interim data suggest that by selectively targeting mutant PI3Kα, RLY-2608 has the potential to offer a level of benefit to patients that has not previously been possible with existing non-selective medicines, while also having significantly less toxicity,” said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. “We are very encouraged to see that RLY-2608 + fulvestrant led to clinically meaningful progression free survival in heavily pre-treated patients with PI3Kα-mutated, HR+, HER2- metastatic breast cancer. We will move quickly to share these data with regulators and align on the design of a pivotal study, which we anticipate starting in 2025.” ReDiscover – RLY-2608 First-in-Human Study RLY-2608 is currently being evaluated in ReDiscover, an ongoing first-in-human study, which was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of RLY-2608 alone, in combination with fulvestrant, and in combination with fulvestrant and ribociclib or atirmociclib (Pfizer’s selective CDK4 inhibitor). As of the August 12, 2024 interim data cut-off, the RLY-2608 + fulvestrant arm of the study had enrolled 118 patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer across all doses in both the dose escalation and dose expansion portions of the study, including 64 patients at the company’s recommended Phase 2 dose (RP2D) of 600mg BID (17 in dose escalation and 47 in dose expansion). Among these 64 patients, 31 had a kinase mutation and 33 had a non-kinase mutation. Twelve patients also had a PTEN or AKT co-mutation and were therefore excluded from the efficacy analysis, consistent with the currently proposed pivotal population. An abstract has been submitted for presentation at the San Antonio Breast Cancer Symposium, taking place December 10-13, 2024. Patients were Heavily Pre-Treated All patients across doses had received a significant level of prior therapy in the advanced setting, including at least one prior endocrine therapy and at least one prior CDK4/6 inhibitor. Among the 64 patients who received the RP2D: Promising Efficacy Data in Proposed Pivotal Population Among the 52 patients who received the RP2D and did not have a PTEN or AKT co-mutation: Maintained Meaningfully Differentiated Tolerability Profile RLY-2608 + fulvestrant was generally well tolerated in the 118 patients treated across all doses as of the data cut-off date. The overall tolerability profile consisted of mostly low-grade treatment-related adverse events (TRAEs) that were manageable and reversible. Safety outcomes were generally as expected across dose levels based on exposure and consistent with mutant-selective PI3Kα inhibition. Among the 64 patients who received the RP2D: Continued Progression of Front-Line Breast Cancer Regimens Two front-line triplet regimens are being progressed – one with the existing CDK4/6 standard-of-care ribociclib and one with Pfizer’s investigative selective-CDK4 inhibitor atirmociclib. Anticipated RLY-2608 Next Steps Lirafugratinib Update Portfolio Prioritization is a Continued Focus Wholly-Owned Portfolio Provides Strategic Flexibility for Cash Runway As of the end of the second quarter of 2024, cash, cash equivalents and investments were approximately $688 million, which the company expects to be sufficient to fund its current operating plan into the second half of 2026, assuming all current programs remain wholly owned and are fully prosecuted. About RLY-2608 RLY-2608 is the lead program in Relay Therapeutics’ efforts to discover and develop mutant selective inhibitors of PI3Kα, the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 14% of patients with solid tumors. RLY-2608 has the potential, if approved, to address more than 300,000 patients per year in the United States, one of the largest patient populations for a precision oncology medicine. Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. The Dynamo® platform enabled the discovery of RLY-2608, the first known allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor, designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608. RLY-2608 is currently being evaluated in a first-in-human trial designed to treat patients with advanced solid tumors with a PIK3CA (PI3Kα) mutation. For more information on RLY-2608, please visit here . About Relay Therapeutics Relay Therapeutics is a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies with the goal of bringing life-changing therapies to patients. As the first of a new breed of biotech created at the intersection of complementary techniques and technologies, Relay Therapeutics aims to push the boundaries of what’s possible in drug discovery. Its Dynamo® platform integrates an array of leading-edge computational and experimental approaches designed to drug protein targets that have previously been intractable or inadequately addressed. Relay Therapeutics’ initial focus is on enhancing small molecule therapeutic discovery in targeted oncology and genetic disease indications. For more information, please visit www.relaytx.com or follow us on Twitter . SOURCE: Relay Therapeutics

Relay Therapeutics plans to start a pivotal trial of RLY-2608 in second-line patients next year. Relay Therapeutics has beaten its survival goal in a first-in-human breast cancer study, positioning the biotech to move into a pivotal trial that could establish its candidate as a challenger to AstraZeneca’s Truqap.Ahead of the readout, Relay identified the 5.5-month progression-free survival (PFS) seen in a study of AstraZeneca’s Truqap as the benchmark for its trial. Monday, Relay reported a median PFS of 9.2 months in patients who received its PI3Kα inhibitor RLY-2608 in an early-phase trial. The biotech plans to start a pivotal study in 2025.Relay saw the PFS duration in 64 patients who received its recommended phase 2 dose in combination with Pfizer’s Faslodex. All patients had received at least one endocrine therapy and one CDK4/6 inhibitor, leading Relay to use a subgroup of the Truqap study as its benchmark. AstraZeneca didn’t limit enrollment in its trial to participants who had received a CDK4/6 inhibitor.Cross-trial comparisons can be unreliable, but the almost four-month difference between the PFS reported in the RLY-2608 and Truqap trials has encouraged Relay to advance its candidate. Talking at a Goldman Sachs event in June, Donald Bergstrom, M.D., Ph.D., president of R&D at Relay, said Truqap is the most likely comparator for a potential pivotal trial of RLY-2608. Peter Rahmer, Relay’s chief corporate development officer, added that he expected the RLY-2608 data to “be quite interpretable” against the benchmark set by Truqap. Rahmer said a “6-month PFS landmark analysis rate decently north of 50%” would give Relay confidence RLY-2608 could beat Truqap in a head-to-head study. Relay reported six and nine-month PFS of 64.1% and 60.1%, respectively. Truqap currently competes with Novartis’ Piqray for the market. The rate of grade 3 hyperglycemia is a factor that informs choices between the drugs. Seven of the 355 recipients of Truqap in a phase 3 trial had grade 3 hyperglycemia, resulting in a frequency of 2%. One-third of patients in a Piqray study had (PDF) a grade 3 or worse reaction.Relay reported one case of grade 3 hyperglycemia at its recommended phase 2 dose, suggesting its drug candidate could perform at least as well as Truqap on that front. Two patients discontinued treatment because of adverse events, one for grade 1 itching and one for grade 1 nausea and fatigue.Boosted by the data, Relay plans to start a pivotal trial of RLY-2608 in second-line patients next year. The biotech is also planning to advance work on triple combinations, which add Pfizer’s atirmociclib or Novartis’ Kisqali to the mix. Relay, which is seeking a partner for lirafugratinib after talking to the FDA, expects its cash runway to extend into the second half of 2026. Editor's note: This story was updated at 8 am on Sept. 9 to include data from Relay’s presentation.