On September 26, 2024 Mural Oncology plc (Nasdaq: MURA), a clinical-stage immuno-oncology company developing novel, investigational engineered cytokine therapies designed to address areas of unmet need for patients with a variety of cancers, reported that it will host a virtual Investor Day today beginning at 10 a.m. ET (Press release, Mural Oncology, SEP 26, 2024, View Source [SID1234646879]). Mural leadership will provide new clinical insight into the trial design, statistical assumptions, and progress of the company’s late-stage trials of nemvaleukin.
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"Mural has the most advanced IL-2 program currently in development and we have made significant progress this year. We have a great deal of conviction around nemvaleukin, which is engineered to unlock the efficacy potential of high dose IL-2 for more patients, and we are pleased to share more details around our study designs and assumptions during today’s Investor Day," said Caroline Loew, Ph.D., CEO of Mural Oncology. "There has also been significant interest in our IL-18 program and we announced today that we plan to submit an IND to the FDA for this program in Q4 2025. Together we believe these programs have the potential to be the next wave of much needed treatment options for cancer patients."
ARTISTRY-7:
ARTISTRY-7 is a potentially registrational phase 3 trial comparing the combination of nemvaleukin and pembrolizumab versus investigator’s choice single agent chemotherapy in heavily pre-treated patients with platinum-resistant ovarian cancer (PROC), with a primary endpoint of overall survival (OS). Secondary endpoints include progression free survival, overall response rate, disease control rate, duration of response, time to response, CA-125 response, and treatment emergent adverse events. This four-arm trial also contains two smaller monotherapy arms to assess contribution of components.
PROC is an area of high unmet need, with few effective treatment options and poor survival. Nemvaleukin for the treatment of PROC has received Food & Drug Administration (FDA) Fast Track Designation.
Enrollment is complete, with a total of 456 patients (versus 448 planned), and approximately 187 patients in each of the two experimental arms.
Futility analyses are complete for both monotherapy arms:
Pembrolizumab (arm 2):
Predetermined analysis criteria were based on Keynote-100 trial, where single agent pembrolizumab was evaluated in 376 patients with PROC with a response rate of 8%.
Futility in this arm of ARTISTRY-7 was defined as fewer than two confirmed complete or partial responses in the first 12 patients enrolled.
This arm was closed to further enrollment for futility in August 2023 after enrolling 27 patients.
Nemvaleukin (arm 3):
Predetermined futility criteria were based on two historical phase 2 trials using different doses and schedules of aldesleukin, an approved high-dose IL-2, that showed consistent response rates of approximately 25%, including some patients with durable complete responses.1
Futility criteria for this nemvaleukin single arm required at least one patient among the first 24 enrolled to achieve an objective response or stable disease for at least three months to continue enrollment.
The nemvaleukin single arm met this threshold to continue and ultimately enrolled 55 patients.
No statistical comparisons will be performed on the pembrolizumab and nemvaleukin monotherapy arms; all analyses of these two arms will be descriptive.
ARTISTRY-7 Overall Survival Expectations and Rationale
Based on benchmarking against prior phase 3 trials in PROC, which had different eligibility criteria regarding the number of prior therapies, and the eligibility criteria of ARTISTRY-7 which allow for up to five prior lines of therapy in the platinum-resistant or refractory setting, protocol assumptions are:
A median Overall Survival (OS) of 10 months for the chemotherapy control arm.
A median OS of 14.3 months for the nemvaleukin plus pembrolizumab experimental arm.
ARTISTRY-7 Events and Statistics:
Protocol specific interim analysis for OS will occur at 75% of OS events (~215 of 286 total OS events).
Cumulative alpha spend at interim analysis is 1-sided, 0.0096.
Maximum hazard ratio for success at the interim analysis is 0.727 (a 27.3% reduction in the risk of death), assuming exactly 215 OS events.
ARTISTRY-7 Timing:
With enrollment complete, the OS events required for interim analysis are estimated to occur by late Q4 2024 or early Q1 2025.
Mural expects the interim analysis data readout to be available in late Q1 or early Q2 2025.
If the hazard ratio meets the bar for success, the study will be declared positive and the company will plan to file a Biologics License Application (BLA) in 2025.
If the target hazard ratio is not met, the company may decide to continue to final analysis at approximately 286 OS events, or it may decide to terminate the study.
ARTISTRY-6, Cohort 2:
ARTISTRY-6 cohort 2 is a potentially registrational single arm study of single agent nemvaleukin in patients with unresectable or metastatic mucosal melanoma. The trial’s primary endpoint is overall response rate evaluated per RECIST 1.1 by an independent central radiology review. Secondary endpoints include duration of response, time to response, disease control rate, progression-free survival, and safety.
Mucosal melanoma is a rare subtype of melanoma with poor prognosis and currently no approved treatment options. Nemvaleukin for the treatment of mucosal melanoma has received both FDA Fast Track Designation and Orphan Drug Designation.
Enrollment in this study is complete with 92 patients enrolled.
ARTISTRY-6, Cohort 2 Response Rate Assumptions and Rationale:
The target response rate is 25%. At this target, the lower bound of the 95% confidence interval will exceed a 15% response rate.
Mural believes that in this rare and highly aggressive tumor with poor outcomes even in the first line setting, demonstrating durable responses with a response rate of 20-25% would be meaningful for patients, and would support a discussion with the FDA regarding a potential BLA submission and potential accelerated approval.
A potential accelerated approval would require confirmatory evidence to be agreed with and later submitted to the FDA for conversion to a regular approval. Discussions with FDA on a potential confirmatory evidence package are ongoing.
ARTISTRY-6 Timing:
The primary analysis will occur when all patients have a minimum follow-up of at least six months. In order to ensure adequate follow-up on all patients, Mural anticipates that the top-line readout will occur in the second quarter of 2025.
Potential accelerated approval with confirmatory evidence to be later submitted for conversion to regular approval.
Regulatory filing may be deferred if the ARTISTRY-7 study continues to final analysis, pending the final outcome.
Mural Oncology’s IL-18 Program:
Mural plans to nominate a development candidate for its IL-18 program by the end of 2024 and intends to submit an Investigational New Drug (IND) Application to the FDA in Q4 2025.
Mural Investor Day Webcast Details:
Mural’s management team will be joined by three clinicians on the webcast to discuss the treatment landscape for PROC and mucosal melanoma, as well as nemvaleukin’s clinical proof of concept data.
The live webcast will begin at 10 a.m. followed by a Question & Answer session. To join the webcast, please visit View Source
A replay of the webcast will be available shortly after the conclusion of the meeting.