On September 9, 2024 Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, reported positive interim data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα (Press release, Relay Therapeutics, SEP 9, 2024, View Source [SID1234646442]). 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).

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"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:

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45% of patients (n=29) had received two or more prior lines of therapy
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52% of patients (n=33) had received a prior selective estrogen-receptor degrader (SERD), such as fulvestrant or a novel SERD
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25% of patients (n=16) had received chemotherapy or an ADC
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59% percent of patients (n=38) had visceral metastases
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34% of patients (n=22) had a BMI of at least 30 and/or HbA1c of at least 5.7%

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:

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Median PFS was 9.2 months across all mutations and 10.3 months among patients with kinase mutations
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Clinical benefit rate (CBR) was 57% across all patients (20 of 35 CBR-evaluable patients; CBR defined as the proportion of patients with complete response, partial response or stable disease for at least 24 weeks)
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Among the 30 patients with measurable disease, one third achieved a partial response (PR) (33% objective response rate, ORR; n=10; 8 confirmed, 1 confirmed post data cut-off date, 1 unconfirmed in an ongoing patient)
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Nearly three quarters of patients experienced tumor reductions (73%; n=22)
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Among the 15 patients with measurable disease who had a kinase mutation, more than half achieved a PR (53% ORR; n=8; 7 confirmed, 1 confirmed post data cut-off date)
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Median follow-up was 7.5 months

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:

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The low rate of TRAE-related dose modifications allowed for 95% median dose intensity
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Only two patients discontinued treatment due to TRAEs (Grade 1 pruritis; Grade 1 nausea, loss of appetite)
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The majority of hyperglycemia was Grade 1; only one patient experienced Grade 3 hyperglycemia; no Grade 4-5 hyperglycemia
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Only 25% of patients experienced a Grade 3 TRAE; no Grade 4-5 TRAEs

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.

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RLY-2608 + ribociclib + fulvestrant dose escalation portion of the ReDiscover study is currently testing biologically active doses of RLY-2608
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On track to identify a dose of RLY-2608 that is combinable with full-dose ribociclib
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Initial safety data expected in the fourth quarter of 2024
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Expect to initiate dose expansion cohort(s) in first half of 2025
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RLY-2608 + atirmociclib + fulvestrant triplet on track for initiation by the end of 2024

Anticipated RLY-2608 Next Steps

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Doublet – Breast Cancer:
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Initiate 2L pivotal study of RLY-2608 + fulvestrant in 2025, pending regulatory discussions
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Triplets – Breast Cancer:
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Report initial safety data for RLY-2608 + ribociclib + fulvestrant in the fourth quarter of 2024
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Initiate RLY-2608 + ribociclib + fulvestrant triplet dose expansion cohort(s) in the first half of 2025
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Initiate RLY-2608 + atirmociclib (CDK4) + fulvestrant triplet by the end of 2024
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Monotherapy – Solid Tumors:
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Initiate RLY-2608 monotherapy solid tumor dose expansion cohort(s) by the end of 2024
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Monotherapy – Vascular Malformations:
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Initiate vascular malformations study in the first quarter of 2025

Lirafugratinib Update

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Updated FGFR2 fusion tumor agnostic data, which have generally stayed consistent with the October 2023 disclosure, will be presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place October 23-25, 2024
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The company met with the FDA regarding the lirafugratinib regulatory path. The FDA suggested that the company first file a new drug application (NDA) in cholangiocarcinoma, followed by a tumor agnostic supplemental NDA for FGFR2 fusions with data from more patients and more follow up
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The company plans to seek a global commercialization partner for lirafugratinib in order to maintain focus on the remainder of the portfolio

Portfolio Prioritization is a Continued Focus

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The company continues to advance high-value next-generation programs:
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Fabry disease: clinical start anticipated in the second half of 2025
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NRAS: clinical start anticipated in the second half of 2025
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Ongoing streamlining of the research organization

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.

Conference Call Information

Relay Therapeutics will host a conference call and live webcast today, Monday, September 9, 2024, at 8:00 a.m. ET. Registration and dial-in for the conference call may be accessed on Relay Therapeutics’ website under Events in the News & Events section through the following link: View Source An archived replay of the webcast will be available following the event.

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.