Oncodesign Precision Medicine (OPM) has submitted the protocol for its Phase 1b/2a clinical trial REVERT to Swiss authorities, marking a significant step forward in addressing treatment resistance in advanced melanoma. The study will evaluate OPM-101, a first-in-class RIPK2 inhibitor, in combination with pembrolizumab in patients who have developed resistance to anti-PD-1 therapies.
The protocol submission follows positive results from OPM-101's Phase 1 study in healthy volunteers completed in October 2024, which demonstrated a favorable safety profile and robust pharmacokinetic and pharmacodynamic properties.
Addressing a Critical Unmet Need
Melanoma represents a significant global health burden with approximately 325,000 new cases and more than 57,000 deaths annually. While immune checkpoint inhibitors (ICIs) like pembrolizumab have revolutionized treatment approaches, resistance remains a substantial challenge.
"Checkpoint inhibitors have revolutionized the management of melanoma. Despite high response rates in the advanced setting and clearly demonstrated long-term benefit, most patients progress under these treatments," explained Professor Olivier Michielin, Head of the Precision Oncology Service at Geneva University Hospitals, who will coordinate the study.
Approximately 40-60% of patients with advanced melanoma experience resistance or progression on ICI therapy, highlighting the urgent need for innovative approaches to overcome these limitations.
REVERT Trial Design and Objectives
The REVERT (RIPK2 for rEsistant and adVanced mElanoma tReatmenT) trial is designed as an international, multicenter, open-label study that will enroll approximately 45 patients across 10-13 sites in Switzerland, France, Italy, and Spain.
The study will proceed in two phases:
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Phase 1b: Will assess the safety of two doses of OPM-101 administered in combination with pembrolizumab in a minimum of 6 patients with advanced melanoma who have developed resistance to anti-PD-1 therapy. This phase will help determine the recommended dose for Phase 2a.
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Phase 2a: Will evaluate the efficacy of OPM-101 at the selected dose in approximately 35 patients, focusing on Disease Control Rate (DCR), safety, and key biomarkers associated with immune response.
Patients eligible for the trial include those who have developed resistance to treatment with anti-PD-1 alone or in combination therapies (except with anti-LAG-3). The study will assess the potential of OPM-101 to revert this resistance by resensitizing tumors to pembrolizumab and potentially reducing immune-related side effects such as colitis.
Mechanism of Action and Preclinical Evidence
OPM-101 is an orally administered RIPK2 inhibitor that has shown promising results in preclinical studies. In experimental cancer models, the addition of OPM-101 to anti-PD-1 antibody therapy significantly enhanced anti-tumor efficacy and promoted greater sensitivity to PD-1 blockade.
The OPM research team has demonstrated that OPM-101 works by enhancing tumor antigen presentation and recognition, associated with remodeling of CD8+ T cell infiltration into the tumor stroma. The drug has also shown significant antitumor activity as a monotherapy based on its immunomodulatory properties.
"OPM-101, our RIPK2 inhibitor, has the potential to increase the response rate and reduce the side effects of these ICIs. This is what we will be evaluating in this Phase 1b/2a study in melanoma," said Jan Hoflack, Scientific Director of Oncodesign Precision Medicine.
Study Timeline and Expectations
Phase 1b of the study is scheduled to begin by July 2025 in several hospitals in Switzerland, following the March 24, 2025 submission to Swiss regulatory authorities (Swissmedic) and Ethics Committees.
For Phase 2a, additional patients will be enrolled in centers across France, Italy, and Spain, with submissions for clinical trial authorization in these countries planned for the fourth quarter of 2025. The extension phase could start in the first quarter of 2026.
The study will measure efficacy based on imaging analysis after 12 and 24 weeks of treatment, defining the Disease Control Rate and Objective Response Rate. Additionally, circulating and tumor biomarkers of antitumor activity will be measured to document OPM-101's mechanism of action.
Completion of the entire Phase 1b/2a clinical trial is expected by the end of 2027.
Broader Implications and Company Strategy
Philippe Genne, Chairman and CEO of Oncodesign Precision Medicine, emphasized the strategic importance of this trial: "In parallel with phase 1 VS, which enabled us to build a solid foundation around the PK/PD relationship of OPM-101 in humans, we have explored the antitumor activity of our compound alone and in combination with an anti-PD1 in mice. These preclinical results, reinforced by many recent international publications, have convinced us of its major potential in oncology."
Beyond oncology applications, OPM is also exploring OPM-101's potential in treating chronic inflammatory bowel disease (IBD) and is seeking pharmaceutical partners for this indication.
OPM-101 is part of OPM's broader portfolio, which includes two other kinase inhibitors: OPM-201, which recently completed Phase I trials in healthy volunteers, and OPM-102, which is in preclinical development for oncology indications.
Professor Michielin highlighted the significance of the REVERT trial: "OPM's clinical trial is extremely important, as it addresses exactly this population for whom we lack therapeutic options. What's more, the prospect of being able to increase the efficacy of checkpoint inhibitors, while reducing toxicity, is of course extremely attractive and will be one of the hypotheses tested with OPM-101, as part of the study."
