Grey Wolf Therapeutics Unveils Initial GRWD5769 Data at 2024 ASCO Meeting

Grey Wolf Therapeutics, a clinical-stage biotechnology firm, revealed promising preliminary results from its ongoing Phase 1/2 trial of GRWD5769, an investigational ERAP1 inhibitor, at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. This study marks a significant milestone by demonstrating, for the first time, the modulation of the human immunopeptidome with therapeutic intent, providing clinical proof-of-mechanism.

The trial's initial findings from the repeat dosing monotherapy module showed that GRWD5769 was well tolerated across all four dose levels administered. The results indicated dose-dependent target engagement through escalating oral doses of GRWD5769. These findings suggest that the candidate, designed to modulate antigen presentation in immuno-oncology, might allow T cells to identify new targets on tumor cells, thereby initiating novel anti-tumor responses.

Dr. Tom Lillie, Chief Medical Officer of Grey Wolf Therapeutics, expressed optimism about the results, highlighting their significance in validating the company’s antigen modulation strategy. He emphasized that the trial has shown GRWD5769 to have a promising tolerability profile, with some patients achieving stable disease and continuing treatment for nearly a year. This positive outcome has recently led to the initiation of combination dosing with GRWD5769 and cemiplimab, and there are plans to expand the cohorts shortly.

Grey Wolf's innovative approach in immuno-oncology involves using a proprietary antigen modulation technique to expose novel cancer antigens on the surface of tumor cells. This is achieved through oral administration of an ERAP1 or ERAP2 inhibitor, crucial proteins in the antigen presentation pathway. The inhibition strategy aims to trigger a de novo T cell response against tumors and avoid T-cell exhaustion, addressing two significant resistance mechanisms in current immuno-oncology therapies.

The ongoing EMITT-1 (ERAP Mediated Immunopeptide Targeting Trial – 1) Phase 1/2 clinical trial is structured as a multi-part, multi-arm open-label study. It is designed to assess the safety, tolerability, preliminary efficacy, and pharmacokinetics of GRWD5769 alone and in combination with Regeneron's PD-1 inhibitor Libtayo® (cemiplimab) in patients with various solid tumor types.

Key points from the EMITT-1 trial presented at ASCO include:
1. GRWD5769 demonstrated tolerability and predictable pharmacokinetics with repeat oral administration across all dose cohorts, up to 200 mg BID.
2. The study observed dose-dependent target engagement, evidenced by modulation of the immunopeptidome.
3. Clinical proof-of-mechanism was established, confirming the mechanistic effects of ERAP1 inhibition as seen in preclinical models.
4. Initial efficacy assessments showed that several patients achieved stable disease, with some undergoing treatment for nearly a year.

The trial's dose escalation phase continues as the company aims to determine the recommended Phase 2 dose for GRWD5769. Additionally, the company has initiated dosing in the first cohort combining GRWD5769 with immune checkpoint inhibition and is expanding the trial to include more tumor types.

Grey Wolf Therapeutics is a UK and Australia-based biotech firm pioneering a unique therapeutic approach with its antigen modulation platform. The company's lead candidate, GRWD5769, is an oral ERAP1 inhibitor showing promise in eliciting a robust immune response against tumors. A second ERAP1 inhibitor, GRWD0715, is under preclinical development for autoimmune disease treatment. The company is also exploring ERAP2 drug discovery and targeting novel ERAP1 inhibitor-generated cancer antigens with therapies such as soluble T cell receptor (TCR) and TCR mimic bispecifics.