On March 14, 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 full year and fourth quarter ended December 31, 2023 (Press release, Monte Rosa Therapeutics, MAR 14, 2024, View Source [SID1234641169]).

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"We made excellent pipeline and corporate progress during 2023 and early 2024, highlighted by the encouraging initial clinical results reported from our MRT-2359 Phase 1/2 study in October. We also continued to advance our VAV1-directed MGD, MRT-6160, for autoimmune diseases toward the clinic, and we progressed MRT-8102, a NEK7-directed MGD targeting IL-1b and the NLRP3 inflammasome, into IND-enabling studies. We are excited about the broad potential of MRT-2359 in MYC-driven cancers, as well as the opportunity that exists with both the VAV1 and NEK7 programs to address pathways of emerging clinical significance in systemic and neurological autoimmune and inflammatory diseases," said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics. "In addition, we entered into a strategic research collaboration with Roche to enable broader application of our technology. All combined, the terrific progress we made in the last 12 month highlights the uniqueness and differentiation of our approach and the strength of our ML/AI-driven QuEEN discovery engine. We look forward to building on that success with continued pipeline execution across multiple programs targeting substantial patient populations, and our anticipated cash runway into the first half of 2026 positions us well to do so."

2023 AND RECENT HIGHLIGHTS

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In October 2023, Monte Rosa announced interim clinical data from the Phase 1 dose escalation part of the ongoing Phase 1/2 clinical trial of MRT-2359 in MYC-driven solid tumors demonstrating tumor size reductions in heavily pretreated patients with biomarker-positive cancers and favorable pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles. Enrollment is ongoing in backfill cohorts at clinically active doses using a 5-days-on-drug, 9-days-off-drug schedule and in dose escalation cohorts using a 21-days-on, 7-days-off-drug schedule. The Company anticipates determining the recommended Phase 2 dose in Q2 2024, reporting updated Phase 1 study results thereafter, and initiating the Phase 2 portion of the study before year-end.
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In December 2023, Monte Rosa received U.S. Food & Drug Administration (FDA) Fast Track Designation for MRT-2359 for the treatment of patients with previously treated, metastatic small cell lung cancer (SCLC) with L-MYC or N-MYC expression. MRT-2359 previously received Fast Track designation from the FDA for the treatment of patients with previously treated, metastatic NSCLC with L-MYC or N-MYC expression.
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MRT-6160, a VAV1-targeting MGD designed to treat multiple systemic and neurological immunological and inflammatory diseases, is on track towards an anticipated Investigational New Drug (IND) application filing with the FDA in Q2 2024, and a Phase 1 single ascending dose/multiple ascending dose (SAD/MAD) study initiation in healthy volunteers in midyear 2024. The Company recently completed preclinical GLP toxicology studies in rats and non-human primates, demonstrating a highly favorable profile with no significant changes in peripheral immunophenotyping assessments.
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Monte Rosa recently announced the nomination of MRT-8102 as the first development candidate for its NEK7 program, targeting diseases driven by IL-1b and the NLRP3 inflammasome. MRT-8102 is an orally bioavailable MGD that has shown potent, selective, and durable degradation of NEK7 and near-complete reduction of IL-1b in a non-human primate model following ex vivo stimulation of whole blood. IND-enabling studies are ongoing, and an IND submission is anticipated in Q1 2025. The Company is also advancing other differentiated NEK7-directed MGDs.
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In October 2023, Monte Rosa entered into a strategic collaboration and licensing agreement with global healthcare leader Roche to discover and develop MGDs against targets in cancer and neurological diseases. Under the terms of the agreement, Monte Rosa Therapeutics received an upfront payment of $50 million and is eligible to receive future preclinical, clinical, commercial, and sales milestone payments that could exceed $2 billion, as well as tiered royalties. Roche has the option to expand the collaboration with an additional set of targets. If exercised, Monte Rosa would be eligible for an additional upfront payment of up to $28 million and potential preclinical, clinical, commercial, and sales milestones exceeding $1 billion, as well as tiered royalties.
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Edmund Dunn was recently promoted to Principal Accounting Officer. Edmund has more than 25 years of experience as a finance professional and has been with Monte Rosa since March of 2021. Andrew Funderburk was recently appointed as Senior Vice President, Head of Investor Relations and Strategic Finance. He was previously Managing Director at Kendall Investor Relations, LLC, and Managing Director and Partner at the healthcare and life sciences consulting firm Health Advances.

ANTICIPATED UPCOMING MILESTONES

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Announce the recommended Phase 2 dose for the MRT-2359 Phase 1/2 study in Q2 2024 and report updated Phase 1 clinical results thereafter. Initiate the Phase 2 portion of the study before year-end. The Company is exploring Phase 2 expansion cohorts in high-prevalence c-MYC-driven tumors such as hormone receptor-positive breast cancer and prostate cancer, as well as tumor types and patient populations driven by L- and N-MYC including NSCLC, SCLC, and solid tumors with amplifications of L- and N-MYC.
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Submit an IND application for MRT-6160 in Q2 2024 and initiate a Phase 1 SAD/MAD study in healthy volunteers in mid-2024. Monte Rosa expects to subsequently initiate proof-of-concept studies in autoimmune diseases spanning gastroenterology, dermatology, rheumatology, and neurology indications.

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Submit an IND application for MRT-8102 in Q1 2025.
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Nominate a development candidate for the CDK2 preclinical program in 2024.

UPCOMING PRESENTATIONS

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Monte Rosa plans to present a poster at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting demonstrating that treatment with MRT-2359 resulted in marked tumor regressions in an AR-V7-expressing 22RV1 xenograft mouse model of c-MYC-driven prostate cancer associated with resistance to anti-androgen agents. The Company also plans to present at an educational session at AACR (Free AACR Whitepaper) on molecular glue degraders.

FOURTH QUARTER AND FULL YEAR 2023 FINANCIAL RESULTS

Research and Development (R&D) Expenses: R&D expenses for the fourth quarter of 2023 were $27.1 million, compared to $24.9 million for the fourth quarter of 2022, and $111.3 million for the year ended December 31, 2023, compared to $85.1 million for the year ended December 31, 2022. 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, the preparation of MRT-6160 to enter the clinic, and the continued development of the Company’s QuEEN discovery engine, and reflect increased personnel expense and external R&D costs including laboratory-related expenses to achieve these milestones. Non-cash stock-based compensation constituted $2.2 million of R&D expenses for Q4 2023, compared to $1.8 million in the same period in 2022, and $8.9 million and $5.6 million for the years ended December 31, 2023 and 2022, respectively.

General and Administrative (G&A) Expenses: G&A expenses for the fourth quarter of 2023 were $7.7 million compared to $7.6 million for the fourth quarter of 2022, and $32.0 million for the year ended December 31, 2023, compared to $27.3 million for the year ended December 31, 2022. 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 2023, compared to $1.6 million for the same period in 2022, and $7.7 million and $6.1 million for the years ended December 31, 2023 and 2022, respectively.

Net Loss: Net loss for the fourth quarter of 2023 was $33.3 million, compared to $30.8 million for the fourth quarter of 2022, and $135.4 million for the year ended December 31, 2023, compared to $108.5 million for the year ended December 31, 2022.

Cash Position and Financial Guidance: Cash, cash equivalents, restricted cash, and marketable securities as of December 31, 2023, were $237.0 million, compared to cash, cash equivalents, restricted cash, and marketable securities of $183.0 million as of September 30, 2023. The increase of $54 million was primarily related to the proceeds from the Roche collaboration and registered direct offering in Q4 2023.

The Company expects its cash and cash equivalents, including proceeds from the Roche collaboration, to be sufficient to fund planned operations and capital expenditures into the first half of 2026.

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 our in vitro 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. Moreover, VAV1-directed MGDs have shown promising activity in preclinical models of autoimmune diseases and thus have the potential to provide therapeutic benefits in multiple systemic and neurological autoimmune indications, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and dermatological disorders. Preclinical studies demonstrate MRT-6160 inhibits disease progression in in vivo autoimmunity models.

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-1b and the NLRP3 inflammasome. NEK7 has been shown to be required for NLRP3 inflammasome assembly, activation and IL-1b release both in vitro and in vivo. Aberrant NLRP3 inflammasome activation and the subsequent release of active IL-1b 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 potently, selectively, and durably degrades NEK7 and results in near-complete reductions of IL-1b models following ex vivo stimulation of whole blood. MRT-8102 has shown a favorable profile in non-GLP toxicology studies.