Monte Rosa Therapeutics (NASDAQ:GLUE) is preparing several clinical and regulatory milestones across its molecular glue degrader pipeline, Chief Medical Officer Filip Janku said during a session at TD Cowen’s Oncology Innovation Summit hosted by TD Cowen analyst Marc Frahm.
Janku described Monte Rosa as a pipeline company focused on oral small-molecule molecular glue degraders, with programs spanning oncology, inflammation and immunology. In oncology, he highlighted MRT-2359, an oral degrader of GSPT1, and a planned investigational new drug application for a cyclin E1 molecular glue degrader in the second half of the year.
GSPT1 Program Moving Toward Phase 2 in AR-Mutant Prostate Cancer
The program is being advanced after Monte Rosa observed what Janku called an “encouraging signal” in an expansion cohort of an early-stage trial. Among 15 evaluable patients presented at ASCO GU, five had AR mutations identified either through site genomic testing or testing conducted as part of the trial. Janku said all five had PSA responses, including two PSA90 responses.
Janku said there are currently no FDA-approved therapies specifically targeting AR-mutant prostate cancer. He said AR-mutant patients often respond less well, or do not respond, to AR-targeting agents with a hormone component. He suggested that a PSA response rate above 40% would be meaningful in this heavily pretreated population, while a rate above 50% would be “quite exciting.”
The planned Phase 2 trial will enroll only AR-mutant patients and use a two-stage design. Janku said the study could enroll up to 25 patients, but would stop early if the initial results did not meet predefined efficacy expectations. He said the company has not guided to when data from the Phase 2 study may be disclosed.
In the earlier expansion cohort, all patients were required to have RECIST-measurable disease. Among the five AR-mutant patients, Janku said two also had RECIST responses, while the remaining three showed at least some tumor shrinkage in data presented at ASCO GU. For the new Phase 2 study, Monte Rosa will not require all patients to have RECIST-measurable disease, though Janku said a significant proportion is expected to be RECIST evaluable.
Company Sees Broader Development Possibilities for MRT-2359
Janku said the AR-mutant population is the most promising signal observed so far, but not the only area of activity seen in prostate cancer. He said Monte Rosa has conducted work to understand the biology behind the signal and believes AR mutation may be a surrogate for tumors that remain highly dependent on AR signaling.
That could create development opportunities in earlier lines of prostate cancer treatment, where AR dependency may be more pronounced, he said. Janku also noted that four of the five AR-mutant patients in the early cohort had previously received Pluvicto, suggesting possible future development paths involving radioligand therapy combinations.
Cyclin E1 and CDK2 Programs Target Different Oncology Opportunities
Monte Rosa is also advancing a cyclin E1/CDK2 effort, with an IND expected in the second half of the year for a cyclin E1 molecular glue degrader. Janku said the company sees cyclin E1 degradation as potentially suited for single-agent targeted therapy in cancers with cyclin E1 amplification, with ovarian cancer as a key example.
By contrast, he described the CDK2 degrader as more likely to be developed in breast cancer in combination with CDK4 or CDK4/6 inhibitors and hormone therapy.
Janku said CDK2 inhibitors can face selectivity challenges because they bind to an ATP pocket conserved across the CDK family, which can translate into adverse events. He said Monte Rosa’s degrader approach differs because the molecules act through protein-to-protein interactions involving cereblon, the target protein and the glue.
For a cyclin E1-amplified ovarian cancer population that is platinum-failed or platinum-resistant, Janku said response rates above 30% to 35% in Phase 1 would be interesting, with response duration of more than six months viewed as meaningful.
Inflammation Pipeline Includes NEK7 and VAV1 Programs
Outside oncology, Janku discussed Monte Rosa’s NEK7 degrader MRT-8102, which targets the NLRP3 inflammasome pathway. The company previously reported proof-of-concept data in a C-reactive protein, or CRP, study in January. Janku said MRT-8102 showed CRP reductions comparable to IL-6 antibodies and described its potential as “best in class” in the NEK7/NLRP3 space.
He said a key differentiator for NEK7 degradation is the catalytic mechanism of molecular glues, which he said may allow comparable CRP reduction at relatively low doses compared with NLRP3 inhibitors. Monte Rosa is expanding its ASCVD risk-factor cohort by adding two additional dose levels with corresponding placebo arms after initial data looked strong, Janku said.
Janku also said the company expects to pursue Phase 2 work in gout and hidradenitis suppurativa. He said gout is attractive because its biology is strongly aligned with NLRP3 activity, while recent data in hidradenitis suppurativa have increased Monte Rosa’s conviction in targeting the IL-1 axis.
Monte Rosa’s VAV1 degrader, MRT-6160, has been licensed to Novartis. Janku said expectations include multiple Phase 2 trial initiations this year, consistent with the company’s guidance.
About Monte Rosa Therapeutics (NASDAQ:GLUE)
Monte Rosa Therapeutics is a biotechnology company focused on accelerating drug discovery through the integration of single-cell genomics and artificial intelligence. Founded in 2020 and headquartered in Cambridge, Massachusetts, the company has built a proprietary platform designed to identify novel therapeutic targets and optimize lead candidates for areas of high unmet medical need. By combining cutting-edge computational methods with comprehensive cellular profiling, Monte Rosa aims to streamline the preclinical development process and uncover insights into disease biology that might otherwise remain hidden.
The company’s main business activities center on using its AI-driven discovery engine to pursue programs in immuno-oncology and neuroscience.
