On November 7, 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 three poster presentations at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), taking place November 6-10, 2024 in Houston (Press release, Mural Oncology, NOV 7, 2024, View Source [SID1234647937]).

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Data presented from the ARTISTRY-3 clinical trial of Mural’s lead candidate, nemvaleukin alfa (nemvaleukin), showed tumor site-specific pharmacodynamic activity and immune activation in patients with ovarian cancer and mucosal melanoma. In addition, Mural presented preclinical data from its interleukin (IL)-12 and IL-18 programs that supported the company’s unique protein engineering capabilities to overcome shortcomings associated with cytokines.

"To date, nemvaleukin, as both a single agent and in combination with PD-1, has shown durable antitumor activities with manageable safety profile in an outpatient setting. In order to make nemvaleukin treatment administration more convenient for both patients and providers, we initiated the ARTISTRY-3 clinical trial to evaluate the effects of a less frequent IV dosing schedule," said Sarina Piha-Paul, MD, Associate Professor, Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and senior author of the ARTISTRY-3 poster. "The data from ARTISTRY-3 reveal that less frequent IV dosing of nemvaleukin demonstrated tumor-site immune activation dominated by cytolytic effector NK cells and CD8+ T cells and further support the mechanism of action of nemvaleukin."

The details for the presentations are as follows, and all posters are available at muraloncology.com/publications.

Tumor microenvironment pharmacodynamic effect of nemvaleukin less frequent intravenous dosing in multiple solid tumors: results from the phase 1/2 ARTISTRY-3 study (Friday, Nov. 8: Abstract #217)
Nemvaleukin is a novel, engineered fusion protein designed to leverage antitumor effects of the IL-2 pathway while mitigating the hallmark toxicities that have historically limited its use. ARTISTRY-3, a phase 1/2 study, evaluated less frequent intravenous (LFIV) dosing of nemvaleukin in advanced solid tumors.

Paired biopsies were available from 8 patients across the three different dosing schedules of nemvaleukin (Schedule 1: dosing on day 1; Schedule 2: dosing on days 1 and 8; Schedule 3: dosing on days 1 and 4).

Collectively, LFIV nemvaleukin demonstrated tumor-site-specific pharmacodynamic activity and immune activation. Nemvaleukin treatment increased cytolytic NK and CD8 T cell densities in the tumor microenvironment. Density ratios of CD8 and NK cells relative to immune-suppressive Tregs were also favorable for the nemvaleukin LFIV regimen. The results were seen in biopsies from both mucosal melanoma and ovarian cancer tumors, supporting the hypothesis that nemvaleukin has the potential to recruit cytolytic effectors to poorly immunogenic tumor sites.

Mural is currently running two late-stage, potentially registrational trials in platinum-resistant ovarian cancer (ARTISTRY-7) and mucosal melanoma (ARTISTRY-6, cohort 2), with data readouts expected in late Q1/early Q2 2025 and Q2 2025, respectively.

Preclinical efficacy and immune activity of half-life extended IL-18 fusion proteins resistant to IL-18BP suppression (Saturday, Nov. 9: Abstract #1340)
IL-18 is a potent immune-stimulating cytokine, but it is limited by IL-18 binding protein (IL-18BP), a secreted high-affinity decoy receptor that neutralizes IL-18, thus limiting its activity over time. Mural’s protein engineering aims to address the shortcomings of native IL-18 in two ways. First through the introduction of mutations designed to minimally impact the native structure while eliminating binding to IL-18BP. Secondly, by extending the half-life of IL-18BP via fusion to a protein scaffold to increase the cytokine’s exposure, allowing for sustained immune stimulation.

In preclinical models, a weekly dosing regimen in mice provided durable immune responses and tumor growth inhibition. These mouse ortholog variants demonstrated resistance to IL-18BP and increased half-life, with durable expansion of immune-stimulating NK and CD8 T cells.

These studies support pursuit of IND-enabling studies for first-in-human clinical trials. 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.

Modulation of IL-12p70 exposure and activity following sequential administration of tumor targeted self-assembling split IL-12 subunits (Saturday, Nov. 9: Abstract #1300)
IL-12p70 is a potent stimulator of the immune system with profound anti-tumor activity but very poor tolerability. Mural is developing an innovative approach to mitigate that toxicity by creating inactive split IL-12 subunits (IL-12p35 and IL-12p40) and assembling functional IL-12p70 predominantly in the tumor and tumor microenvironment.

In murine models, increasing the interval time between subunit injections or reducing the dose level of the second subunit effectively modulated serum drug concentration while maintaining IL-12 levels in the tumor. Pharmacokinetics and pharmacodynamics were also assessed in non-human primates, where the inactive subunits were assembled and formed functional IL-12p70 in the periphery.

Together, these data suggest Mural’s novel approach may unlock the potential of IL-12p70 as a therapeutic by mitigating the toxicity associated with systemic administration.

Mural plans to nominate a development candidate for its IL-12 program by the end of 2024.