On December 5, 2024 Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, reported an update from its ongoing Phase 1/2 open-label, multicenter study of MRT-2359 in patients with MYC-driven solid tumors (Press release, Monte Rosa Therapeutics, DEC 5, 2024, View Source [SID1234648825]). MRT-2359 is an investigational, orally bioavailable, GSPT1-directed MGD discovered and developed by Monte Rosa Therapeutics.
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"These latest interim results from our ongoing Phase 1/2 study of MRT-2359 continue to indicate a favorable safety profile, and degradation of GSPT1 to desired levels in patients with heavily pretreated, solid tumors, including those that express high levels of MYC. Importantly, we believe the MRT-2359 safety profile supports further clinical development, with no signs of hypotension, cytokine release syndrome (CRS), or clinically significant hypocalcemia observed at any dose level and regimen, all of which have been reported as safety limitations of other GSPT1 degraders. We’re pleased to confirm the selection of 0.5 mg daily at a 21 days on, 7 days off drug dosing schedule as our recommended Phase 2 dose, a schedule that enables dosing of MRT-2359 more than twice as frequently per cycle as compared to the 5 days on, 9 days off regimen previously explored in our study and that we also believe to be more patient compliance-friendly," said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics. "Trial enrollment has been strong and we are working towards completing the biomarker and activity assessment of our monotherapy dose escalation study using the 21 days on, 7 days off schedule, including backfill cohorts. We have started safety assessments of MRT-2359 in combination with enzalutamide in previously treated metastatic prostate cancer patients as well as with fulvestrant in previously treated metastatic estrogen receptor-positive breast cancer patients. We look forward to providing an update on clinical data from the study as well as plans for potential expansion cohorts in the first quarter of next year."
Summary of Interim Data on Enrollment, Safety & Pharmacodynamics
Enrollment Highlights
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Patients have been dosed with MRT-2359 in 6 dose levels across two dosing schedules, namely a 5 days on, 9 days off drug (5/9) dosing schedule and a 21 days on, 7 days off drug (21/7) dosing schedule.
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The study has enrolled patients with a diverse set of tumor types, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), neuroendocrine (NE) tumors of the prostate, bladder and other organs of origin, androgen receptor-positive prostate cancer, and estrogen receptor-positive breast cancer.
Safety Highlights
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Using the 5/9 dosing schedule, doses of 0.5 mg and 1 mg per day were identified as having a generally favorable safety profile, while doses of 1.5 mg or higher were above the maximum tolerated dose (MTD) with thrombocytopenia being a dose limiting toxicity (DLT).
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Using the 21/7 schedule, both 0.5 and 0.75 mg were identified as having a generally favorable safety profile.
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0.5 mg using the 21/7 dose schedule was selected as the recommended phase 2 dose (RP2D) for any expansion cohorts of the Phase 1/2 study.
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Safety assessments of MRT-2359 in combination with enzalutamide in previously treated metastatic prostate cancer as well as with fulvestrant in previously treated metastatic estrogen receptor- positive breast cancer have been initiated.
Pharmacodynamic Highlights
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Pharmacodynamic effects were assessed utilizing mass spectrometry measurements of GSPT1 protein levels from paired tumor biopsies. The target levels of approximately 60% GSPT1 degradation were observed in tumor biopsies across all dose levels in relevant tumor types, supporting that the dose of 0.5 mg per day provides optimal degradation consistent with its designed activity based on preclinical studies.
Monte Rosa continues to collect and evaluate clinical results from the MRT-2359 Phase 1/2 study and expects to share updated data, including biomarker and activity data, in Q1 2025.
About MRT-2359
MRT-2359 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader (MGD) that induces the interaction between the E3 ubiquitin ligase component cereblon and the translation termination factor GSPT1, leading to the targeted degradation of GSPT1 protein. The MYC transcription factors (c‑MYC, L-MYC and N-MYC) are well-established drivers of human cancers that maintain high levels of protein translation, which is critical for uncontrolled cell proliferation and tumor growth. Preclinical studies have shown this addiction to MYC-induced protein translation creates a dependency on GSPT1. By inducing degradation of GSPT1, MRT-2359 is designed to exploit this vulnerability, disrupting the protein synthesis machinery, leading to anti-tumor activity in MYC-driven tumors.