Novartis Strikes $2.25B Deal with Monte Rosa Therapeutics for VAV1-Targeting Molecular Glue Degrader MRT-6160 in Autoimmune Diseases

On October 28, molecular glue company Monte Rosa Therapeutics announced a global exclusive development and commercialization licensing agreement with Novartis to advance the development of molecular glue degraders (MGD) targeting VAV1, including the investigational therapy MRT-6160. Under the terms of the agreement, Novartis has agreed to pay Monte Rosa an upfront payment of $150 million. Starting from Phase II studies, Monte Rosa is also eligible to receive up to $2.1 billion in development, regulatory, and sales milestone payments, as well as tiered royalties on net sales outside the United States (totaling $2.25 billion, approximately RMB 16.045 billion).

Under the terms of the agreement, Novartis will obtain global exclusive rights for the development, manufacturing, and commercialization of MRT-6160 and other molecular glue degraders targeting VAV1, and will be responsible for all clinical development and commercialization efforts starting from Phase II clinical trials. Monte Rosa Therapeutics will be responsible for completing the ongoing Phase I clinical study, co-funding any Phase III clinical development, and will share in any profits and losses related to the manufacturing and commercialization of MRT-6160 in the United States.

Many human diseases are associated with abnormal protein function within cells. Currently, the primary pharmacological approach to treating these diseases is through small-molecule inhibitors. However, the number of protein targets that can be addressed by inhibitors is limited, restricted to those proteins with well-defined binding pockets (accounting for about 20%). The remaining proteins, lacking such binding pockets, are traditionally considered undruggable by small molecules.

Targeted protein degradation therapy can function without the need to tightly bind to sites that affect protein activity, allowing "undruggable" proteins to become new drug targets. At the same time, targeted protein degradation therapy can continuously induce rapid and efficient degradation of pathogenic proteins, greatly inhibiting the development of resistance in target proteins. Currently, the two most popular types of targeted protein degradation therapies are Proteolysis Targeting Chimeras (PROTAC) and Molecular Glue Degraders (MGD). Both mediate target protein degradation through the ubiquitin-proteasome pathway, but there are significant differences in their molecular design and mechanisms of action.

Monte Rosa Therapeutics believes that molecular glue degraders have more advantages compared to PROTAC, thus focusing on the research and development of molecular glue degraders, committed to treating diseases in immunology, inflammation, neurology, and genetics.Monte Rosa Therapeutics, Inc. was founded in 2018 and is headquartered in Basel, Switzerland. It was established by Professor Raj Chopra and Professor Ian Collins from The Institute of Cancer Research, UK, along with Versant Ventures, a healthcare venture capital firm. Academic co-founders Rajesh Chopra and Ian Collins are pioneers in the field of molecular glue degraders.

Monte Rosa Therapeutics has developed a proprietary protein degradation platform called QuEEN.(Quantitative and Engineered Elimination of Neosubstrates), capable of rapidly identifying protein targets and molecular glue degraders. The platform, through three key components—Degron encyclopedia, Proprietary MGD library, and Glueomics toolbox—continuously expands the range of new substrates and recruits these new substrates to additional E3 ligases, aiming to identify more therapeutically relevant proteins and bring them into the druggable target space, providing therapeutic solutions for previously considered undruggable or poorly targeted proteins.

Based on this platform, Monte Rosa Therapeutics has currently laid out eight product pipelines and has successively gained recognition from Roche and Novartis.

In October 2023, Monte Rosa Therapeutics and Roche entered into a strategic collaboration and licensing agreement to discover and develop molecular glue degraders targeting previously undruggable cancer and neurological disease targets.According to the terms of the agreement, Monte Rosa will receive an upfront payment of $50 million and is eligible for potential preclinical, clinical, commercialization, and sales milestone payments exceeding $2 billion, as well as tiered royalties. A year later, Monte Rosa has again gained recognition from a leading MNC, with the cumulative value of the two collaborations reaching approximately $4.3 billion. Monte Rosa has become the current "molecular glue star" in the eyes of MNCs.

The key pipeline of the recent deal with Novartis, MRT-6160, is currently undergoing a Phase I clinical trial involving single ascending dose (SAD) and multiple ascending dose (MAD) studies in healthy volunteers for the treatment of immune-mediated diseases. MRT-6160 is an effective, highly selective, and orally bioavailable VAV1 degrader, where VAV1 is a key signaling protein downstream of T-cell and B-cell receptors. Preclinical studies have shown that the drug can deeply degrade VAV1, significantly reducing cytokine levels associated with immune-mediated diseases while showing no detectable impact on other proteins.

In preclinical models, MRT-6160 has demonstrated promising activity and has the potential to become a treatment option for various immune-mediated diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and dermatological conditions. The Phase I SAD/MAD study for MRT-6160 is currently ongoing, with clinical data expected to be available in the first quarter of 2025.

Data shows that the market for inhibitor-targeted drugs, which only target 20% of targetable sites, is worth $200 billion annually. If the remaining 80% of non-targetable sites could be utilized for drug development, the market potential would be immeasurable. Molecular glue degraders are the key to unlocking this "Pandora's box" with enormous market implications. This is also a major reason why large multinational corporations (MNCs) are relentlessly pursuing this field.

In this field, companies such as Pfizer, Eli Lilly, Sanofi, Novartis, Merck & Co., and Bayer have already entered the race. Since 2023, multinational corporations (MNCs) including Novartis, BMS, Roche, and Merck & Co. have successively reached collaborations on molecular glue technology platforms/projects with various emerging biotech companies, with a potential total transaction value exceeding tens of billions of US dollars.

Among them, Novartis has been actively pursuing mergers and acquisitions in the molecular glue degrader space, having already secured two major collaborations in this field this year. Its most recent acquisition was in April, when it entered into an exclusive strategic collaboration with Arvinas worth a total of $1.01 billion to jointly develop the oral PROTAC product ARV-766 for the treatment of metastatic castration-resistant prostate cancer (mCRPC), as well as a preclinical protein degradation therapy targeting AR-V7 for mCRPC.

In addition, in May this year, Takeda also announced a $1.2 billion agreement with Shanghai Dagu Biopharmaceuticals to develop novel molecular glue degraders for the treatment of oncology, neuroscience, and inflammatory diseases. According to the agreement, Dagu Biologics will use its GlueXplorer® platform to discover, validate, and optimize molecular glue degraders targeting specific disease targets selected by Takeda. Upon reaching certain progress milestones, these projects will be handed over to Takeda for further development and commercialization. Both parties may also choose to expand the scope of cooperation to include more targets. In addition, Takeda will make an equity investment in Dagu Biologics. Dagu Biologics will retain full ownership of its own pipeline.

In August, Eisai announced a collaboration agreement with Seed Therapeutic, a subsidiary of BeyondSpring Pharmaceuticals and a U.S.-based protein degradation company, to discover, develop, and commercialize novel molecular glue degraders for multiple undisclosed neurodegenerative and oncology targets. Under the terms of the agreement, Seed is eligible to receive up to $1.5 billion in upfront payments as well as preclinical, clinical, regulatory, and sales milestone payments, along with tiered royalties upon Eisai exercising its exclusive rights under the strategic research collaboration. Seed Therapeutic will lead preclinical discovery activities for selected targets, including the selection of E3 ligases and identification of molecular glue degraders, while Eisai will hold exclusive rights to develop and commercialize compounds arising from this partnership.

The reason why MNCs have unanimously bet on this field is essentially because, although molecular glues are highly ideal, the number of molecular glue degraders discovered so far remains very limited. Their discovery process is largely accidental, lacking systematic discovery and design strategies. Therefore, large pharmaceutical companies hope to bet on new technological platforms to accelerate the discovery of molecular glues.

Although the field of molecular glue degraders still faces numerous challenges, with the optimization of technology and the accumulation of research, the application scope of molecular glue degrader drugs will continue to expand, extending from oncology to multiple areas such as autoimmune diseases and neurodegenerative disorders. It is anticipated that, with the support of multinational corporations (MNCs), the field of molecular glue degraders will accelerate its development, bringing more accessible therapies to patients.