On November 7, 2024 Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, reported business highlights and financial results for the third quarter that ended September 30, 2024 (Press release, Monte Rosa Therapeutics, NOV 7, 2024, View Source [SID1234647936]).

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"We continue to make significant progress towards pioneering the discovery and development of highly selective molecular glue degraders against paradigm-shifting targets. The recently announced global license agreement with Novartis to advance VAV1-directed MGDs for immune-related conditions marks a transformative milestone towards that goal," said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics. "We believe this agreement will accelerate and broaden the scope of clinical development of MRT-6160 across a spectrum of immune-mediated conditions while retaining substantial value for Monte Rosa. Moreover, the resources provided by this agreement are expected to meaningfully extend our cash runway and enable us to advance our pipeline to potential value-creating milestones and to further leverage our industry-leading QuEEN discovery engine to design and develop novel MGDs for previously undruggable targets across a variety of disease areas, including immunology and inflammation (I&I), cardiovascular, and metabolic diseases. We look forward to sharing initial clinical data from the ongoing Phase 1 study of MRT-6160 by Q1 2025."

Dr. Warmuth continued, "We have made significant progress advancing our second I&I program, MRT-8102, toward an expected IND application in the first half of 2025. Turning towards our oncology pipeline, we look forward to sharing updated clinical results from the Phase 1 dose escalation portion of the MRT-2359 study by year-end, and we’re pleased with the progress of our cell cycle portfolio, including the CDK2 and cyclin E1 programs, with both advancing towards development candidate nominations."

RECENT HIGHLIGHTS

MRT-2359, GSPT1-directed MGD for MYC-driven solid tumors

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Monte Rosa continues to evaluate MRT-2359 in a Phase 1/2 clinical trial in MYC-driven solid tumors (NCT05546268). In June 2024, the Company announced that it had obtained encouraging initial safety and pharmacodynamic data from the 0.5 mg dose using the 21 days on, 7 days off regimen. Monte Rosa continues to evaluate a higher 0.75 mg, 21 days on, 7 days off dose cohort.

MRT-6160, VAV1-directed MGD for immune-mediated conditions

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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, currently in Phase 1 clinical development for various immune-related conditions. Under the terms of the agreement, Novartis will obtain exclusive worldwide rights to develop, manufacture and commercialize MRT-6160 and other VAV1 MGDs and will be responsible for all clinical development and commercialization, starting with Phase 2 clinical studies. Monte Rosa remains responsible for completion of the ongoing Phase 1 clinical study of MRT-6160. Novartis has agreed to pay Monte Rosa $150 million upfront. 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. The agreement is subject to customary closing conditions including regulatory clearance.
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In August, Monte Rosa announced that the first participants had been dosed in an MRT-6160 Phase 1 single ascending dose/multiple ascending dose (SAD/MAD) study.

MRT-8102, NEK7-directed MGD for inflammatory diseases driven by IL-1β and the NLRP3 inflammasome

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In September, Monte Rosa presented preclinical data at the Inflammasome Summit demonstrating that its development candidate 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, is a potent, selective, and durable molecular glue degrader of NEK7. The data provide preclinical proof of concept that a NEK7 MGD leads to inhibition of the NLRP3 inflammasome and IL-1 release to reduce the effects of inflammation, supporting the potential to address central and peripheral inflammatory disorders.
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Monte Rosa expects to submit an IND application for MRT-8102 in H1 2025.

CDK2 and Cyclin E1-directed MGD programs

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In October, Monte Rosa 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 for the treatment of CCNE1-amplified solid tumors. The data demonstrated that Monte Rosa’s MGD degrades cyclin E1 with a high level of selectivity, sparing other closely related proteins, including other cyclins, and cyclin-dependent kinases (CDKs). The data also showed that a cyclin E1-directed MGD led to downstream pathway inhibition 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.
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Monte Rosa is progressing both its CDK2 and cyclin E1-directed MGD programs to development candidate nominations.

QuEEN (Quantitative and Engineered Elimination of Neosubstrates) discovery engine

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In October, Monte Rosa made a preprint available in BioRxiv entitled, "Mining the Cereblon Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition," which demonstrates a vast expansion of what had been considered druggable within the cereblon target space. Monte Rosa has identified more than 1,600 proteins predicted to be compatible with cereblon across diverse target classes that can potentially be targeted with molecular glue degraders.

ANTICIPATED MILESTONES

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Announce the recommended Phase 2 dose and data from the Phase 1 dose escalation portion of the MRT-2359 Phase 1/2 study including safety, biomarker data, and clinical activity before the end of 2024. The Company also expects to provide guidance on Phase 2 expansion cohorts before year-end.
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Report initial data from the Phase 1 SAD/MAD study of MRT-6160 in healthy volunteers by Q1 2025. The Phase 1 study of MRT-6160 is designed to provide early insights into safety, pharmacokinetics, VAV1 protein degradation, and key downstream pharmacodynamic markers including CD69, IL-2, IL-6, and IL-17.
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Submit an IND application for MRT-8102 in H1 2025.
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Nominate a CDK2 program development candidate before year-end 2024.

UPCOMING INVESTOR CONFERENCES

Monte Rosa management will participate in the following investor conferences:

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Guggenheim Securities Healthcare Innovation Conference (Boston, Mass.) – Markus Warmuth, M.D., Chief Executive Officer, to participate in a fireside chat, November 11, 2024, at 3:30 p.m. EST.
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Jefferies London Healthcare Conference (London, UK) – November 19, 2024.

A webcast of the fireside chat will be accessible via the "Events & Presentations" section of Monte Rosa’s website at ir.monterosatx.com, and an archived version will be made available for 30 days following the presentation.

THIRD QUARTER 2024 FINANCIAL RESULTS

Collaboration revenue: Collaboration revenue for the third quarter of 2024 was $9.2 million. Collaboration revenue represents revenue recorded under the Roche license and collaboration agreement. No collaboration revenue was recognized during the same period in 2023.

Research and Development (R&D) expenses: R&D expenses for the third quarter of 2024 were $27.6 million, compared to $28.3 million during the same period in 2023. R&D expenses 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, 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 $2.6 million of R&D expenses for Q3 2024, compared to $2.3 million in the same period in 2023.

General and Administrative (G&A) expenses: G&A expenses for the third quarter of 2024 were $8.1 million compared to $8.7 million during the same period in 2023. G&A expenses included non-cash stock-based compensation of $1.6 million for the third quarter of 2024, compared to $2.2 million for the same period in 2023.

Net loss: Net loss for the third quarter of 2024 was $23.9 million, compared to $30.3 million for the second quarter of 2024.

Cash position and financial guidance: Cash, cash equivalents, restricted cash, and marketable securities as of September 30, 2024, were $247.1 million, compared to cash, cash equivalents, restricted cash, and marketable securities of $267.1 million as of June 30, 2024. The end of Q3 cash position does not include the recently announced $150 million upfront payment due from Novartis, subject to customary closing conditions including regulatory clearance.

Based on current cash, cash equivalents, restricted cash, marketable securities, and the anticipated $150 million upfront payment due from Novartis, the Company expects its cash and cash equivalents to be sufficient to fund planned operations and capital expenditures into 2028.

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.

About MRT-6160

MRT-6160 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader of VAV1, which in preclinical studies has shown deep degradation of its target with no detectable effects on other proteins. VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T- and B-cell receptors. VAV1 expression is restricted to blood and immune cells, including T and B cells. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor-mediated activity. This modulation is evident both in vitro and in vivo, demonstrated by a significant decrease in cytokine secretion, proteins vital for maintaining autoimmune diseases. MRT-6160 has shown promising activity in preclinical models of multiple immune-mediated conditions. Under the terms of an agreement announced in October 2024, Novartis will obtain exclusive worldwide rights to develop, manufacture and commercialize MRT-6160 and other VAV1 MGDs, subject to customary closing conditions including regulatory clearance.

About MRT-8102

MRT-8102 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader (MGD) that targets NEK7 for the treatment of inflammatory diseases driven by IL-1β and the NLRP3 inflammasome. NEK7 has been shown to be required for NLRP3 inflammasome assembly, activation and IL-1β release both in vitro and in vivo. Aberrant NLRP3 inflammasome activation and the subsequent release of active IL-1β and interleukin-18 (IL-18) has been implicated in multiple inflammatory disorders, including gout, cardiovascular disease, neurologic disorders including Parkinson’s disease and Alzheimer’s disease, ocular disease, diabetes, obesity, and liver disease. In a non-human primate model, MRT-8102 was shown to potently, selectively, and durably degrade NEK7, and resulted in near-complete reductions of IL-1β models following ex vivo stimulation of whole blood. MRT-8102 has shown a favorable profile in non-GLP toxicology studies.