On March 20, 2025 Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, reported a clinical update, business highlights, and financial results for the fourth quarter ended December 31, 2024 (Press release, Monte Rosa Therapeutics, MAR 20, 2025, View Source [SID1234651311]).
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"We continue to make excellent progress with our clinical and preclinical molecular glue degrader programs, targeting areas poorly addressed by conventional pharmaceutical approaches and with expansive therapeutic potential," said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics. "Today, we are pleased to report new clinical results from our two clinical programs. We believe the current results from our Phase 1 study of MRT-6160 are highly encouraging and demonstrate deep VAV1 degradation, biologically meaningful levels of ex vivo T and B cell functional inhibition, including inhibition of secretion of various cytokines following ex-vivo stimulation, and a highly favorable safety/tolerability profile. These data strengthen our conviction in the broad potential application of MRT-6160 as a novel treatment approach for immune-mediated diseases, and we look forward to rapidly advancing this program alongside our collaborators at Novartis."
Dr. Warmuth continued: "Our updated MRT-2359 results deepen our understanding of the drug’s clinical profile across several challenging-to-treat solid tumors. We have observed encouraging early signals of clinical response in heavily pretreated castration-resistant prostate cancer (CRPC), including a confirmed partial response and two patients with stable disease within the first three patients treated with MRT-2359/enzalutamide combination therapy. In light of these data, we plan to focus our ongoing MRT-2359 development efforts in CRPC, with the potential to expand this cohort to 20-30 patients, while deprioritizing other expansion arms except ER-positive breast cancer. We see CRPC as a hugely exciting opportunity for MRT-2359 with the added potential advantage for us of not having to identify biomarker positive patients, which would simplify our further clinical development. We expect to present further data from this program in the second half of the year. Furthermore, our early-stage pipeline is also making significant strides. Our NEK7 program is on track for an IND submission for MRT-8102 in the first half of this year, supported by GLP toxicology findings that demonstrate a considerable safety margin, with a more than 200-fold exposure margin over human efficacious doses in rats and non-human primates. We’re progressing our second generation, CNS-penetrant NEK7 program towards a 2026 IND submission and have released preclinical data demonstrating impressive levels of CNS activity in multiple species. Our ‘only-in-class’ CCNE1-directed MGD program represents a unique opportunity to directly target a previously undruggable but highly validated driver oncogene. Our AI/ML-powered QuEEN discovery engine has been highly productive, and we are advancing several programs as we seek to expand our portfolio of oral I&I drugs targeting pathways currently served only by injectable biologics or cell therapies."
RECENT HIGHLIGHTS
MRT-6160, VAV1-directed MGD for immune-mediated conditions
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Today, Monte Rosa announced clinical results from its MRT-6160 Phase 1, single ascending dose / multiple ascending dose (SAD/MAD) study. Details about the study, First-in-human Study of MRT-6160 in Healthy Subjects, can be found at clinicaltrials.gov under the identifier NCT06597799. The data presented includes the SAD portion of the study, which evaluated 5 dose cohorts, and the MAD portion of the study, which evaluated 3 dose cohorts. All cohorts were randomized and placebo controlled, and the study enrolled over 70 subjects in total. The study objectives were to evaluate safety and tolerability, pharmacokinetics, and pharmacodynamics, including VAV1 degradation and its impact on T and B cell function following ex vivo stimulation.
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Results demonstrated sustained, dose-dependent VAV1 degradation of greater than 90% in peripheral blood T cells after single and multiple dose administration. Similar results were observed in peripheral blood B cells. Sustained suppression of TCR-mediated T and B cell activation measured by CD69 was observed following single and multiple dose administration and ex vivo activation of whole blood. MRT-6160 also inhibited secretion of inflammatory cytokines, including IL-2, IFN-γ and IL-17A, by up to 99% from whole blood-derived T cells following ex vivo activation of TCR and demonstrated significant and sustained attenuation of IL-6 production across dose levels following B cell stimulation. The cytokine modulation profile observed in the clinical study closely aligned with preclinical studies that demonstrated the activity of MRT-6160 in various models of immune-mediated diseases.
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The administration of MRT-6160 was generally well-tolerated and there were no serious adverse effects observed. Treatment emergent adverse events were in general mild (82%) or moderate (18%) and self-limiting, and the overall frequency of treatment-related adverse effects was similar in the MRT-6160 and placebo groups.
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In summary, the current Phase 1 data and chronic toxicology package support a clear path into anticipated Phase 2 studies and broad potential applications in multiple immune-mediated diseases. Further development of MRT-6160 toward Phase 2 studies is ongoing, in collaboration with Novartis.
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In October, the Company announced a global exclusive development and commercialization license agreement with Novartis to advance VAV1 MGDs including MRT-6160. Under the terms of the agreement, Monte Rosa received a $150 million upfront payment. Monte Rosa is eligible to receive up to $2.1 billion in development, regulatory, and sales milestones, beginning upon initiation of Phase 2 studies, as well as tiered royalties on ex-U.S. net sales. Monte Rosa will co-fund any Phase 3 clinical development and will share any profits and losses associated with the manufacturing and commercialization of MRT-6160 in the U.S.
MRT-2359, GSPT1-directed MGD for MYC-driven solid tumors
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Today, Monte Rosa provided updated clinical results in its evaluation of safety, pharmacodynamics and clinical activity of MRT-2359 in various tumor types. Details about the study, Study of Oral MRT-2359 in Selected Cancer Patients, can be found at clinicaltrials.gov under the identifier NCT05546268.
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A total of 59 patients were dosed with MRT-2359 monotherapy at 6 dose levels across two dose schedules, 5 days on / 9 days off drug and 21 days on / 7 days off drug. Using the 5/9 dosing schedule, doses of 0.5 mg and 1 mg per day were generally well tolerated with mostly low-grade adverse events (AEs), while doses of 1.5 mg or higher were above the maximum tolerated dose (MTD) with thrombocytopenia being a dose-limiting toxicity (DLT). Using the 21/7 schedule, both the 0.5 and 0.75 mg doses were generally well tolerated with mostly low-grade AEs observed. The 0.5 mg dose using the 21/7 dose schedule was selected as the recommended phase 2 dose (RP2D). Optimal degradation (based on optimal PD modulation in preclinical studies) of approximately 60% was achieved in biomarker L-/N-MYC high tumor samples, as assessed by targeted mass spectrometry.
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While MRT-2359 demonstrated signals of activity in the dose escalation cohorts, the frequency of tumors expressing high levels of L-MYC or N-MYC in study patients was lower than expected compared to preclinical data across target populations, including non-small cell lung cancer (NCSLC), small cell lung cancer (SCLC), and high grade neuroendocrine (HG NE) tumors, resulting in lower than expected identification of biomarker-positive patients. Monte Rosa has determined this lower-than-expected biomarker positivity rate to be insufficient to support further development in lung cancers and neuroendocrine tumors through expansions cohorts. As such, the Company does not plan to conduct further studies in these indications and open the respective expansion cohorts. In summary, L-MYC and N-MYC expression in tumor tissue obtained at baseline or known L-MYC or N-MYC amplification in the absence of tissue was available in 48 patients. Of these, 37 patients were evaluable for response per RECIST 1.1. Of 13 patients determined to be biomarker positive, there was 1 confirmed partial response (PR), and 4 patients with stable disease (SD), for a disease control rate (DCR) of 38%. Of 24 biomarker negative patients (low L-MYC and N-MYC expression), there was 1 unconfirmed PR and 3 patients with SD, for a DCR of 17%.
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Evaluation of MRT-2359 activity in castration-resistant prostate cancer (CRPC) patients resistant to AR therapy, a patient group characterized by widespread expression of c-MYC, demonstrated encouraging early signals of clinical response, including a confirmed RECIST response, in the ongoing Phase 1/2 study. MRT-2359 is being dosed at 0.5 mg per day with a 21 days on drug, 7 days off drug dosing schedule, in combination with enzalutamide, a standard of care therapy for CRPC. As of a data cutoff of March 10, 2025, three CRPC patients were evaluable per RECIST 1.1 criteria. One patient had a confirmed partial response (tumor shrinkage of -57%) and two patients had stable disease. All 3 patients had mutations typically associated with resistance to AR antagonists including enzalutamide. PSA response was available for 2 patients showing 1 PSA response (-90%) in the patient with a confirmed PR. The safety profile observed has been generally favorable, with one case of grade 3 stomatitis being the only AE over grade 2. The Company is continuing to enroll and evaluate patients with CRPC, with the potential to expand enrollment to 20-30 patients if a positive efficacy signal continues to be observed, and expects to present additional results in H2 2025. The Company believes that the lack of need for biomarker-based patient selection in CRPC due to the widespread expression of c-MYC in this tumor type will facilitate future clinical development.
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The Company is continuing to enroll and evaluate patients with HR+ breast cancer and expects to present additional results for this cohort in H2 2025.
NEK7-directed MGDs for inflammatory and CNS diseases driven by IL-1β and the NLRP3 inflammasome
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Monte Rosa has successfully completed GLP tox studies for MRT-8102, a first-in-class NEK7-directed MGD for the treatment of inflammatory diseases driven by interleukin-1β (IL-1β) and the NLRP3 inflammasome, supporting a considerable safety margin. The no observed adverse effect level (NOAEL) was the highest dose tested, specifically 150 mg/kg/day in rats and 100 mg/kg/day in cynomolgus monkeys (cynos). The study demonstrated a greater than 200-fold exposure margin over the projected human efficacious dose in both species. No MRT-8102 related clinical signs, no changes in immunophenotyping (studied in cynos only), and no gross or clinical pathology findings were observed at any dose level.
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The Company is on track to submit an IND application for MRT-8102 in H1 2025. Following the IND submission, Monte Rosa plans to initiate a Phase 1 healthy volunteer study, and Phase 1 proof-of-concept studies in individuals with high levels of C-reactive protein (CRP) and in individuals with pericarditis. The Company is also evaluating future Phase 2 proof-of-concept studies in gout, pseudogout (calcium pyrophosphate deposition disease), and osteoarthritis.
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Monte Rosa has generated preclinical data with a second-generation NEK7-directed MGD optimized for CNS penetration. The compound has demonstrated potent systemic and CNS NEK7 degradation in cynos, and substantial reductions of inflammatory cytokines in an LPS-induced murine model of neuroinflammation. IND submission is expected in 2026.
Cyclin E1 and CDK2-directed MGD programs for treatment of solid tumors
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Monte Rosa continues to advance its cyclin E1 (CCNE1)- and CDK2-directed MGD programs for the treatment of CCNE1-amplified solid tumors and ER+ breast cancer. The company is benchmarking MGD molecules for both programs against each other in multiple preclinical models to determine the optimal MGD to advance to IND submission, which is expected in 2026.
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In December, at the 2024 San Antonio Breast Cancer Symposium, the Company presented preclinical data on the potential of its highly selective cyclin-dependent kinase 2 (CDK2)-directed molecular glue degrader to treat HR-positive/HER2-negative breast cancer. Data demonstrated deep tumor regression in preclinical models of HR-positive/HER2-negative breast cancer when combined with either a CDK4/6 inhibitor or a CDK4/6 inhibitor and endocrine therapy.
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In October, the Company presented preclinical data at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on the potential of its cyclin E1 (CCNE1)-directed MGDs, demonstrating that Monte Rosa MGDs degrade cyclin E1 with a high level of selectivity and induced tumor growth suppression and regression preferentially in CCNE1-amplified and over-expressing tumor cell lines and xenograft models. Cyclin E1 MGDs may represent a potential novel therapeutic approach by directly and selectively targeting a frequently amplified non-enzymatic driver oncogene relevant in multiple solid tumors.
QuEEN (Quantitative and Engineered Elimination of Neosubstrates) discovery engine
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Monte Rosa is advancing novel discovery programs for immunology and inflammation targets that the Company believes have the potential for highly differentiated, oral MGDs degrading undruggable targets in critical I&I pathways. These may include programs with the potential to improve upon the clinical profile of cell therapies such as CAR-T or biologics such as FcRn inhibitors.
ANTICIPATED UPCOMING MILESTONES AND DEVELOPMENT PRIORITIES
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Continue advancement of MRT-6160 through Phase 2 initiation, in collaboration with Novartis.
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Share additional MRT-2359 Phase 1/2 study data in CRPC patients resistant to AR therapy in H2 2025.
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Submit an IND application for MRT-8102 in H1 2025.
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Submit an IND application for the second generation NEK7-directed MGD with enhanced CNS penetration in 2026.
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Submit an IND application for a CDK2 and/or cyclin E1-directed MGD in 2026.
FOURTH QUARTER AND FULL YEAR 2024 FINANCIAL RESULTS
Collaboration revenue: Collaboration revenue for the fourth quarter of 2024 was $60.6 million and $75.6 million for the year ended December 31, 2024. The Company did not record collaboration revenue in 2023. Collaboration revenue represents amounts earned from our collaboration and license agreements with Roche and Novartis.
Research and Development (R&D) Expenses: R&D expenses for the fourth quarter of 2024 were $38.9 million, compared to $27.1 million for the fourth quarter of 2023, and $121.6 million for the year ended December 31, 2024, compared to $111.3 million for the year ended December 31, 2023. These increases were driven by the successful achievement of key milestones in our R&D organization, including the continuation of the MRT-2359 clinical study, the progression and growth of our preclinical pipeline, including research performed in connection with our collaboration with Roche, the advancement of MRT-6160 to enter the clinic, and the continued development of the Company’s QuEEN discovery engine. Non-cash stock-based compensation constituted $2.7 million of R&D expenses for Q4 2024, compared to $2.2 million in the same period in 2023, and $10.6 million and $8.9 million for the years ended December 31, 2024 and 2023, respectively.
General and Administrative (G&A) Expenses: G&A expenses for the fourth quarter of 2024 were $8.8 million compared to $7.7 million for the fourth quarter of 2023, and $35.2 million for the year ended December 31, 2024, compared to $32.0 million for the year ended December 31, 2023. The increase in G&A expenses was a result of increased headcount and expenses in support of the Company’s growth and operations. G&A expenses included non-cash stock-based compensation of $1.8 million for the fourth quarter of 2024 and 2023, and $7.5 million and $7.7 million for the years ended December 31, 2024 and 2023, respectively.
Net Income (Loss): Net income for the fourth quarter of 2024 was $13.4 million, compared to a net loss of $33.3 million for the fourth quarter of 2023, and net losses of $72.7 million for the year ended December 31, 2024, compared to $135.4 million for the year ended December 31, 2023.
Cash Position and Financial Guidance: Cash, cash equivalents, restricted cash, and marketable securities as of December 31, 2024, were $377 million, compared to cash, cash equivalents, restricted cash, and marketable securities of $247.1 million as of September 30, 2024. The increase of $129.9 million was primarily related to upfront payment received from Novartis in connection with our license agreement.
Based on current cash, cash equivalents, restricted cash, marketable securities, the Company expects its cash and cash equivalents to be sufficient to fund planned operations and capital expenditures into 2028.