iOnctura Initiates Phase I/II Trial Combining Roginolisib with Ruxolitinib for JAK Inhibitor-Resistant Myelofibrosis
核心洞察
iOnctura (搜索) has dosed the first patient in the HEMA-MED Phase I/II trial evaluating roginolisib plus ruxolitinib in myelofibrosis (搜索) patients unresponsive to JAK (搜索) inhibitors.
The dual-target approach combines PI3Kδ (搜索) and JAK (搜索) inhibition to address complementary disease mechanisms and potentially overcome JAK inhibitor resistance.
Non-clinical data presented at ASH demonstrate roginolisib monotherapy activity and synergistic anti-cancer effects when combined with JAK (搜索) inhibitors.
iOnctura (搜索), a clinical-stage biopharmaceutical company, has initiated dosing in its Phase I/II HEMA-MED clinical trial (NCT06887803) evaluating the combination of roginolisib, a PI3Kδ (搜索) inhibitor, with ruxolitinib in myelofibrosis (搜索) patients who are no longer responding to JAK (搜索) inhibitor therapy. The milestone represents a significant step toward addressing unmet medical needs for patients with this rare blood cancer who face diminishing therapeutic options.
Novel Dual-Target Approach
The HEMA-MED trial employs a dual-target strategy combining PI3Kδ (搜索) and JAK (搜索) inhibition to address complementary disease mechanisms in myelofibrosis (搜索). According to Dr. Michael Lahn, Chief Medical Officer of iOnctura (搜索), "Based on non-clinical data being presented at ASH, we anticipate that targeting both the PI3Kδ and JAK pathways could have a synergistic effect in MF — an approach that has previously eluded older generation PI3Kδ inhibitors because of their unfavorable tolerability profiles."
Overactivation of the PI3K-Akt signaling pathway contributes to cancer occurrence and progression, and in myelofibrosis (搜索), pathway activation represents a well-described mechanism of resistance to JAK (搜索) inhibition. Roginolisib's inhibition of this pathway may overcome treatment resistance and provide beneficial therapeutic effects.
Supporting Preclinical Evidence
New non-clinical data presented at the 67th American Society of Hematology Annual Meeting demonstrate roginolisib's monotherapy activity against myelofibrosis (搜索) cell lines and in vitro models of primary MF cells. The data show that roginolisib combined with JAK (搜索) inhibition using ruxolitinib or momelotinib exerts synergistic anti-cancer effects, supporting the rationale for the ongoing clinical trial.
Professor Alessandro Vannucchi, Principal Investigator of the HEMA-MED study and Professor of Hematology at the University of Florence, stated: "Myelofibrosis (搜索) patients often have suboptimal responses to ruxolitinib and/or acquire resistance over time. Roginolisib's intriguing mechanism of action and favorable toxicity profile position it as a compelling partner for ruxolitinib. By combining these agents, we could unlock more durable responses and redefine therapeutic expectations for this challenging rare disease."
Addressing Treatment Resistance
Myelofibrosis (搜索) is a rare myeloproliferative neoplasm characterized by activation and growth of mutated cells in the bone marrow, affecting approximately 0.5 cases per 100,000 individuals diagnosed globally per year. While JAK (搜索) inhibitors serve as a key treatment option that improves symptoms and quality of life, approximately half of patients discontinue therapy within three years due to disease progression, tolerability issues, adverse events, or death resulting from resistance to JAK therapy.
Trial Design and Objectives
The HEMA-MED trial is a prospective, multi-center, open-label Phase I/II single-arm study consisting of two parts. Part 1 will enroll 13 patients to assess the safety of combining roginolisib with ruxolitinib, while Part 2 will expand enrollment to 13 additional patients for a total of 26 participants to further evaluate the benefit-risk profile.
Beyond safety assessment, secondary endpoints include blood biomarker and spleen reduction responses, along with improvements in myelofibrosis (搜索)-related symptoms. Exploratory measures will evaluate endpoints associated with roginolisib's mechanism of action.
Roginolisib's Unique Profile
Roginolisib represents a first-in-class, non-ATP competitive, allosteric modulator of PI3Kδ (搜索) with a unique chemical structure and binding mode. This allosteric modulation approach promises clinical activity without the detrimental tolerability issues seen with previous generations of PI3Kδ inhibitors. The compound has demonstrated positive clinical signals in Phase I studies across solid tumor and hematological malignancies, including a doubling of overall survival compared to historical controls in uveal melanoma (搜索).
The HEMA-MED trial forms part of iOnctura (搜索)'s comprehensive development program for roginolisib, which includes ongoing Phase II studies in uveal melanoma (搜索) (OCULE-01), non-small cell lung cancer (搜索) (PULMO-01), and investigations in peripheral T-cell lymphoma (搜索) and chronic lymphocytic leukemia (搜索).