Optimal levels of degradation of GSPT1 in peripheral blood mononuclear cells and tumors observed at all doses, consistent with preclinical studies
Tumor size reductions observed in patients with biomarker-positive tumors
Safety profile supports further clinical development of MRT-2359
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BOSTON, Oct. 17, 2023 (GLOBE NEWSWIRE) -- Monte Rosa Therapeutics, a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today announced interim data from the Phase 1 dose escalation part of its ongoing Phase 1/2 open-label, multicenter study of MRT-2359 in patients with MYC-driven solid tumors, including lung cancers and high-grade neuroendocrine cancer. MRT-2359 is an investigational, orally bioavailable, GSPT1-directed MGD discovered by Monte Rosa Therapeutics. Cancers driven by MYC overexpression have been demonstrated to be dependent on GSPT1, creating a therapeutic opportunity.
Interim clinical data from the MRT-2359 study have demonstrated favorable tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in heavily pre-treated patients with lung cancers and high-grade neuroendocrine cancer. In addition, MRT-2359 has been observed to significantly reduce GSPT1 protein levels in patient tumors and has shown evidence of tumor size reductions, including partial responses, in heavily pretreated patients with biomarker-positive tumors. Monte Rosa is continuing with dose level and schedule optimization in this ongoing study.
"We're highly encouraged by the safety profile, the depth of pharmacodynamic modulation of GSPT1 in tumors, and even more so by the early evidence of anti-tumor activity of MRT-2359 in patients with biomarker-positive cancers," said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics. "We believe these results, the first ever to show clinical activity of a rationally designed molecular glue degrader in solid tumors, represent an important advance for the field and underscore the potential for MRT-2359 to benefit patients living with a variety of difficult-to-treat cancers. We are excited to learn more about the clinical profile of MRT-2359 in our ongoing Phase 1/2 clinical study, and early next year we plan to provide further clarity on the expected timing for the full Phase 1 data disclosure in 2024."
Summary of available study results:
- As of the analysis cutoff date of September 7, 2023, 21 patients had been dosed, with 15 of the 21 patients evaluable for efficacy.
- Optimal PD modulation of GSPT1 by MRT-2359 was observed at all dose levels, consistent with its designed activity based on preclinical studies. Following MRT-2359 dosing, approximately 60% reduction in GSPT1 protein expression was observed in peripheral blood mononuclear cells and tumor tissue biopsies. Similar levels of degradation were observed across all dose levels, suggesting saturated PD responses from 0.5 mg to 2 mg and supporting that pharmacodynamically, 0.5 mg is a fully active dose. The level of GSPT1 degradation observed was in line with the levels seen in preclinical studies that were associated with anti-tumor activity.
- Of the 15 evaluable patients that have been administered MRT-2359 across three dose cohorts (0.5 mg, 1 mg, and 2 mg in a 5 days on-drug, 9 days off-drug dosing schedule), six were identified as biomarker-positive in indicated tumor types, specifically N-MYC high non-small cell lung cancer (NSCLC) adenocarcinoma, L-/N-MYC high small cell lung cancer (SCLC), L-/N-MYC high-grade neuroendocrine tumors (prostate, bladder, and others) and neuroendocrine tumors of the lung.
- Clinical activity was seen across all dose levels. Of the six biomarker-positive patients, two achieved a partial response (PR), one confirmed and one unconfirmed, and one patient experienced durable stable disease (SD). Additionally, one patient who had an unevaluable biomarker status also experienced durable SD.
- The MRT-2359 safety profile supports further clinical development, with no signs of hypotension, cytokine release syndrome (CRS) or clinically significant ...