10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2024

Commission File Number 001-40522

Monte Rosa Therapeutics, Inc.

(Exact name of Registrant as specified in its Charter)

321 Harrison Avenue, Suite 900Boston, Massachusetts 02118

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (617) 949-2643

Securities registered pursuant to Section 12(b) of the Act:

Title of each class TradingSymbol(s) Name of each exchange on which registered

Common stock, par value $0.0001 per share GLUE The Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐ No ☒

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐ No ☒

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ NO ☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes ☒ NO ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). YES ☐ No☒

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant, based on the closing price of the shares of common stock on NASDAQ on June 30, 2024, was $199 million.

The number of shares of Registrant’s Common Stock outstanding as of March 17, 2025, was 61,509,821.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of registrant's definitive proxy statement for its annual meeting of shareholders to be filed within 120 days after the close of the registrant's fiscal year are incorporated by reference to into Part III of this annual report on Form 10-K.

Table of Contents

Page

PART I

Item 1. Business 1

Item 1A. Risk Factors 74

Item 1B. Unresolved Staff Comments 129

Item 1C. Cybersecurity 129

Item 2. Properties 129

Item 3. Legal Proceedings 130

Item 4. Mine Safety Disclosures 130

PART II

Item 6. [Reserved] 132

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 143

Item 8. Financial Statements and Supplementary Data 143

Item 9A. Controls and Procedures 144

Item 9B. Other Information 144

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 144

PART III

Item 10. Directors, Executive Officers and Corporate Governance 145

Item 11. Executive Compensation 151

Item 14. Principal Accountant Fees and Services 163

PART IV

Item 15. Exhibits and Financial Statement Schedules 165

SPECIAL NOTE REGARDING FORWARD LOOKING STATEMENTS

This Annual Report on Form 10-K, or Annual Report, contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, or the or the Securities Act, and Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act. All statements other than statements of historical facts contained in this Annual Report are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “may”, “will”, “should”, “expects”, “intends”, “plans”, “anticipates”, “believes”, “estimates”, “predicts”, “potential”, “continue” or the negative of these terms or other comparable terminology. These statements are not guarantees of future results or performance and involve substantial risks and uncertainties. Forward-looking statements in this Annual Report include, but are not limited to, statements about:

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the initiation, timing, progress, results, costs, and any expectations and/or predictions of success of our current and future research and development programs and preclinical studies, including our expectations for our molecular glue degraders, or MGDs, molecules, including our GSPT1-directed MGD MRT-2359, VAV1-directed MGD MRT-6160 our NEK7-directed MGDs, including MRT-8102, and our CDK2 and CCNE1 MGDs;

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the initiation, timing, progress, results, costs, and any expectations and/or predictions of success of our current and any future clinical trials, including our clinical trials for our GSPT1-directed MGD MRT-2359, VAV1-directed MGD MRT-6160, including statements regarding the nature of or the timing for when any results of any clinical trials will become available;

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our ability to continue to develop our proprietary discovery engines, called QuEENTM, and to expand our proteomics and translational medicine capabilities;

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the potential advantages of our discovery engine technology and product candidates;

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the extent to which our scientific approach and discovery engine technology may target proteins that have been considered undruggable or inadequately drugged;

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our plans to submit Investigational New Drug, or IND applications to the U.S. Food and Drug Administration, or the FDA for future product candidates;

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the potential benefits of strategic collaborations and our ability to enter into strategic collaborations with third parties who have the expertise to enable us to further develop our biological targets, product candidates and discovery engine technologies, including our agreement with Novartis AG, or Novartis, for MRT-6160 and our agreement with F. Hoffmann-La Roche Ltd., or Roche Basel, and Hoffmann-La Roche Inc., or Roche US, and together with Roche Basel referred herein as Roche;

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our ability to obtain and maintain regulatory approval of our product candidates;

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our ability to maintain and expand, including through third-party vendors, our library of MGDs;

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our ability to manufacture, including through third-party manufacturers, our product candidates for preclinical use, future clinical trials and commercial use, if approved;

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our ability to commercialize our product candidates, including our ability to establish sales, marketing and distribution capabilities for our product candidates;

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the rate and degree of market acceptance of our product candidates;

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the size and growth potential of the markets for our product candidates, and our ability to serve those markets;

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our ability to establish and maintain intellectual property rights covering our current and future product candidates and technologies;

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the implementation of our business model and strategic plans for our business, product candidates, and technology;

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estimates of our future expenses, revenues, capital requirements, and our needs for additional financing;

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our expected use of proceeds from sales of our common stock in "at-the-market" offerings and other offerings, and the period over which such proceeds, together with existing cash, will be sufficient to meet our operating needs;

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our ability to obtain funding for our operations necessary to complete further development and commercialization of our product candidates;

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our financial performance;

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developments in laws and regulations in the United States, or the U.S., and foreign countries;

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the success of competing therapies that are or may become available;

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our ability to attract and retain key scientific or management personnel;

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the effect of global economic uncertainty and financial market volatility caused by economic effects of rising inflation and interest rates, global health crises, geopolitical events, changes in international trade relationships and military conflicts on any of the foregoing or other aspects of our business or operations; and

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other risks and uncertainties, including those listed under Item 1A, “Risk Factors.”

Any forward-looking statements in this Annual Report reflect our current views with respect to future events and with respect to our future financial performance, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by these forward-looking statements. Factors that may cause actual results to differ materially from current expectations include, among other things, those described under Item 1A, “Risk Factors” and elsewhere in this Annual Report. Given these uncertainties, you should not place undue reliance on these forward-looking statements.

All of our forward-looking statements are as of the date of this Annual Report only. In each case, actual results may differ materially from such forward-looking information. We can give no assurance that such expectations or forward-looking statements will prove to be correct. An occurrence of or any material adverse change in one or more of the risk factors or risks and uncertainties referred to in this Annual Report or included in our other public disclosures or our other periodic reports or other documents or filings filed with or furnished to the Securities and Exchange Commission, or the SEC, could materially and adversely affect our business, prospects, financial condition and results of operations. Except as required by law, we do not undertake or plan to update or revise any such forward-looking statements to reflect actual results, changes in plans, assumptions, estimates or projections or other circumstances affecting such forward-looking statements occurring after the date of this Annual Report, even if such results, changes or circumstances make it clear that any forward-looking information will not be realized. Any public statements or disclosures by us following this Annual Report that modify or impact any of the forward-looking statements contained in this Annual Report will be deemed to modify or supersede such statements in this Annual Report.

We may from time to time provide estimates, projections and other information concerning our industry, the general business environment, and the markets for certain diseases, including estimates regarding the potential size of those markets and the estimated incidence and prevalence of certain medical conditions. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties, and actual events, circumstances or numbers, including actual disease prevalence rates and market size, may differ materially from the information reflected in this Annual Report. Unless otherwise expressly stated, we obtained this industry, business information, market data, prevalence information and other data from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data, and similar sources, in some cases applying our own assumptions and analysis that may, in the future, prove not to have been accurate.

TRADEMARKS

Solely for convenience, our trademarks and trade names in this report are sometimes referred to without the ® and TM symbols, but such references should not be construed as any indicator that we will not assert, to the fullest extent under applicable law, our rights thereto.

iii

SUMMARY OF RISK FACTORS ASSOCIATED WITH OUR BUSINESS

Our business is subject to numerous material and other risks and uncertainties that you should be aware of in evaluating our business. These risks are described more fully in Part II, “Item 1A—Risk Factors,” and include, but are not limited to, the following:

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We are a biotechnology company with a limited operating history and have not generated any revenue to date from drug sales and may never become profitable.

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We have incurred significant operating losses since our inception and anticipate that we will incur continued losses for the foreseeable future.

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We are very early in our development efforts. All but two of our programs are still in the preclinical stages of drug development. If we are unable to commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.

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Our approach to the discovery and development of product candidates, which may also be referred to herein as development candidates, based on our QuEENTM discovery engine is novel, which makes it difficult to predict the time, cost of development and likelihood of successfully developing any product candidates.

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We will need to raise substantial additional funding before we can expect to complete development of any of our product candidates or generate any revenues from product sales.

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We may not be successful in our efforts to identify or discover additional product candidates or we may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.

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If we are unable to successfully develop our current programs into a portfolio of product candidates, or experience significant delays in doing so, we may not realize the full commercial potential of our current and future product candidates.

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If we encounter difficulties enrolling patients in our clinical trials, these clinical development activities could be delayed or otherwise adversely affected.

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If we are unable to advance our product candidates through clinical development, obtain regulatory approval and ultimately commercialize our product candidates, or experience significant delays in doing so, our business will be materially harmed.

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Even if we receive marketing authorization for our product candidates, we will be subject to extensive ongoing regulatory obligations and continued regulatory review, which may result in significant additional expense and we may be subject to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our product candidates.

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If we are unable to obtain and maintain patent and other intellectual property protection for our technology and product candidates or if the scope of the intellectual property protection obtained is not sufficiently broad, our competitors could develop and commercialize technology and drugs similar or identical to ours, and our ability to successfully commercialize our technology and drugs may be impaired, and we may not be able to compete effectively in our market.

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Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.

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Business disruptions could seriously harm our future revenue and financial condition and increase our costs and expenses.

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Our executive officers, directors, principal stockholders and their affiliates exercise significant influence over our company, which will limit our stockholders' ability to influence corporate matters and could delay or prevent a change in corporate control.

PART I

Item 1. Business

Overview

We are a clinical-stage biotechnology company developing a portfolio of novel and proprietary molecular glue degraders, or “MGDs”. MGDs are small molecule drugs that employ the body’s natural protein destruction mechanisms to selectively degrade therapeutically relevant proteins, in effect editing the human proteome. MGDs function by inducing the engagement of an E3 ligase, such as cereblon, with defined structural features on surfaces of target proteins. These target proteins are also referred to as neosubstrates. The E3 ligase then tags the target protein for degradation by adding a molecular mark known as ubiquitin. We believe our MGDs provide significant advantages over existing therapeutic modalities, including other protein degradation approaches.

We have developed a proprietary and industry leading discovery engine, called QuEENTM (an abbreviation for “Quantitative and Engineered Elimination of Neosubstrates”) to enable our unique target-centric MGD discovery and development approach and our rational design of MGD product candidates.

We believe our MGDs provide significant advantages over existing therapeutic modalities, including other protein degradation approaches. To date, our QuEENTM discovery engine has identified numerous proteins for potential targeting by our MGDs, including those targeted by product candidates in our pipeline. We combine our artificial intelligence or “AI” / machine learning or “ML” engines with multiple proprietary experimental tools to identify therapeutically relevant target proteins amenable to degradation by our MGDs. We are continuously increasing our understanding of how MGDs function and we are using this understanding to develop design principles for the engineering of new MGDs. This growing expertise manifests in our expanding MGD library as well as our discovery and development pipeline. Using our insights, knowhow, and technology platform we have generated a library of MGDs that forms the basis for our MGD programs. At present, our library comprises a diverse set of rationally designed small molecules representing more than 1000 unique low molecular weight scaffolds and over 50,000 different MGD molecules. We also use our insights and learnings to continuously update and improve QuEENTM and our MGD library, consistently increasing the power of the discovery engine.

We prioritize our product development to address therapeutic targets backed by strong biological and genetic rationales. We are focused on developing solutions to clinically important indications, including indications in immunology, inflammation, oncology, and others. To date, our discovery engine has resulted in two programs in clinical development: MRT-2359, a GSPT1-directed MGD for MYC-driven solid tumors, and MRT-6160, a VAV1-directed MGD for immune-mediated diseases. We expect a third program, NEK7, to enter clinical development in the first half of 2025.

MRT-2359 is an orally bioavailable MGD targeting the translation termination factor protein GSPT1 and is currently in clinical development for potential use in MYC-driven tumors. GSPT1 (also known as eRF3a) is a translation termination factor that helps catalyze the termination of protein synthesis, facilitating the release of mRNA and newly synthesized protein from the ribosomal protein synthesis machinery. We have identified GSPT1 as a potential therapeutic vulnerability for MYC-driven cancers. MRT-2359, our GSPT1-directed MGD, is designed to preferentially affect growth and survival of cancer cells addicted to protein translation, such as those driven by high expression and activity of MYC family transcription factors. Our preclinical studies showed that through a functional association between GSPT1 and the MYC family of transcription factors, GSPT1 serves as a key regulator of MYC-induced protein translation, and that the degradation of GSPT1 using our MGDs, including MRT-2359, creates a potential vulnerability in multiple MYC-driven tumors. We initiated a Phase 1/2 clinical trial for the treatment of MYC-driven SCLC and NSCLC as well as high-grade neuroendocrine tumors and L- and N-MYC amplified tumors in October 2022. In the second half of 2024, we expanded this trial to include heavily pretreated castration-resistant prostate cancer (CRPC; in combination with enzalutamide) and heavily pretreated estrogen-receptor (ER+) positive breast cancer (in combination with fulvestrant), both tumor types characterized by high expression of c-MYC. Moving forward, we will deprioritize further development of MRT-2359 in SCLC, NSCLC, high-grade neuroendocrine tumors and L- and N-MYC amplified tumors, while prioritizing development in CRPC. This is based on a favorable safety profile and encouraging early signals of clinical activity in CRPC patients in combination with enzalutamide, including a confirmed RECIST response, and the lack of need for biomarker-based patient selection for this cohort of patients due to the widespread expression of c-MYC in this tumor type. This is in contrast to SCLC, NSCLC, high-grade neuroendocrine tumors and L-and N-MYC amplified tumors where further development would require continued investments into companion diagnostics, as well as more restrictive selection protocols for clinical trials. 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 our future clinical development of MRT-2359.

We are continuing to enroll and evaluate patients with CRPC and we have the option to expand our enrollment in this current study to include up to 20-30 patients, including if we continue to observe positive signs of activity. CRPC remains an area of high unmet need and constitutes a potentially significant commercial opportunity for a product approved in this indication. We are also still awaiting initial results from the breast cancer cohort. We expect to present additional results in H2 2025, including results on ongoing initial safety evaluation of our combination of MRT-2359 with fulvestrant in ER+ breast cancer.

MRT-6160 is a VAV1-directed MGD being developed for immune-mediated diseases. VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T- and B-cell receptors. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor activity. MRT-6160 has shown promising activity in preclinical models of neurologic and systemic autoimmune and inflammatory diseases and thus we believe has the potential to provide therapeutic benefits in multiple immune-mediated diseases, such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and dermatological disorders. In October 2024, we announced a global exclusive development and commercialization license agreement with Novartis for VAV1 MGDs, including MRT-6160, for which we received $150 million upfront payment. 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. We have announced initial clinical results from our Phase 1 study of MRT-6160, demonstrating deep VAV1 degradation of greater than 90%, significant T and B cell functional inhibition, profound inhibition of cytokine release from T and B cells ex-vivo, and a generally favorable safety and tolerability profile. We believe the data support a clear path to Phase 2 studies and broad potential applications in immune-mediated diseases.

Our first product candidate for our NEK7 program, MRT-8102, is now in IND-enabling studies, with an IND filing with the FDA planned for H1 2025. MRT-8102 is a NEK7-directed MGD targeting diseases driven by IL-1β and the NLRP3 inflammasome. The NLRP3 inflammasome is a multiprotein complex that serves as a central node to integrate cellular signals generated by pathogens, cell damage and stress, and subsequently triggers the generation of pro-inflammatory cytokines, such as IL-1β. Aberrant NLRP3 inflammasome activation has been implicated in several inflammatory disorders including pericarditis, gout, osteoarthritis, Parkinson’s disease, obesity, and atherosclerosis. NEK7 facilitates assembly and activation of the NLRP3 inflammasome in a kinase-independent manner, suggesting that degradation of NEK7 with an MGD molecule would be a potentially attractive therapeutic approach to preventing NLRP3 activation and release of IL-1β. In light of the strategic importance of our NEK7 program and the potential role of the NLRP3 inflammasome in inflammatory responses in the CNS in multiple systemic and neurologic disorders, we expect to advance a second NEK7 MGD product candidate optimized for CNS penetration through Lead Optimization and we anticipate being able to file an IND for this program in 2026.

We are also advancing programs directed at cyclin-dependent kinase 2 (CDK2) and cyclin E1 (CCNE1), key drivers of cell cycle progression in cancer.

Our CDK2-directed MGDs have demonstrated superior selectivity for CDK2 in preclinical models as compared to several clinical-stage small molecule CDK2 inhibitors, which we believe will be important to mitigate toxicity limitations reported for CDK2 inhibitors in development. In preclinical models of ER+ breast cancer our CDK2 MGDs reduced tumor burden when added to standard of care therapy. We believe our preclinical data supports further clinical evaluation of our CDK2 MGDs as a potential improvement over current standard of care therapies in ER+ breast cancer, including, potentially without the toxicity limitations reported for CDK2 inhibitors currently in development.

Cyclin E1 is a protein that plays a crucial role in the cell cycle and is a frequently amplified non-enzymatic driver oncogene relevant in multiple solid tumors, and that has not been druggable by conventional modalities. Our proprietary Cyclin E1 MGDs may represent a potential novel therapeutic approach for treatment of such solid tumors by directly and selectively targeting Cyclin E1. We believe our cyclin E1 MGDs could provide a highly differentiated alternative and additional approach to other cell-cycle focused therapeutics.

We are currently evaluating our CDK2 and Cyclin E1 MGD programs in multiple preclinical models to determine an optimal path to IND submission, the first of which is expected in 2026.

Our proprietary QuEENTM discovery engine uniquely enables us to rationally design and develop our diverse library of MGDs and to deploy them against target proteins identified through our QuEENTM discovery engine. Uniquely, many of these target proteins are considered inadequately drugged or completely undruggable by other

therapeutic modalities. We actually consider a target protein’s lack of druggability as one of our key criteria for our discovery and development selection and prioritization process. Our resulting MGDs are designed to reprogram the E3 ligase to bind to and induce the degradation of a therapeutically relevant target protein. Central to our QuEENTM discovery engine is a detailed understanding of the molecular interactions promoted by our MGDs between E3 ligases and structural features on the surface of therapeutically relevant proteins, which we refer to as degrons.

Key components of our QuEENTM discovery engine are:

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AI/ML engines: Our focus on protein surface characterization enables us to identify reprogrammable E3 ligases and E3 ligases-accessible targets. We have developed sophisticated and proprietary AI-powered algorithms to mine databases of protein sequences and structures, including structures determined from x-ray crystallography and cryoEM, and structures from predicted protein folding. Our AI/ML engine continuously learns from experimental results with our expanding MGD library, identifying new degrons and targetable proteins across the proteome.

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High throughput screening, structural biology and proteomics capabilities: We have developed a suite of high-throughput assays that rapidly assess our proprietary MGD library and MGDs generated during specific programs. Coupled with customized automation and robotic systems, our assays can measure ternary complex formation in both a biochemical and cellular format, as well as measure degradation of target proteins in cells, which we use to screen, identify and rapidly optimize our MGDs.

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Proprietary MGD library: Our wholly-owned, proprietary, diverse, and continuously growing chemical library of currently over 50,000 MGDs that we have rationally designed based on our growing expertise in molecular glue anatomy and design, our large proteomics and screening databases, and AI/ML algorithms. Library compounds currently represent more than 1000 unique low molecular weight scaffolds with favorable binding affinities for an E3 ubiquitin ligase.

By capturing our insights and experience with the identification of target proteins amenable to our approach as well as the discovery and development of MGDs through QuEENTM, we are constantly increasing the power of our discovery engine.

Our QuEENTM discovery engine continues to generate discovery stage programs targeting therapeutically relevant proteins otherwise considered undruggable or inadequately drugged. We are progressing our discovery stage programs for multiple other undisclosed target proteins. Our focus is on target proteins that have been considered undruggable or insufficiently drugged, that are highly credentialed preclinically or clinically, and that can potentially move into the clinic in indications with high unmet need and substantial commercial potential.

In October 2023, our wholly-owned subsidiary, Monte Rosa Therapeutics AG, or Monte Rosa AG, entered into a strategic collaboration and licensing agreement with F. Hoffmann-La Roche Ltd., or Roche Basel, and Hoffmann-La Roche Inc., or Roche US, and together with Roche Basel referred herein as Roche. Pursuant to the License Agreement, the parties will seek to identify and develop MGDs against cancer or neurological disease targets using our proprietary drug discovery platform for an initial set of targets in oncology and neuroscience selected by Roche, with Roche having an option to expand the collaboration with an additional set of targets under certain conditions, each target being subject to certain substitution rights owned by Roche. We will lead preclinical discovery and research activities until a defined point. Upon such point, Roche gains the right to exclusively pursue further preclinical and clinical development activities. Under the terms of the agreement, Monte Rosa 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, including up to $172 million for achieving preclinical milestones. Roche has an option to expand the collaboration with an additional set of targets under certain conditions. For the optional additional targets, Monte Rosa is entitled to receive from Roche an upfront payment of up to $28 million, and potential preclinical, clinical, commercial, and sales milestones exceeding $1 billion. We are also eligible to receive tiered percent royalties ranging from high-single-digit to low- teens on any products that are commercialized by Roche as a result of the collaboration.

territories. Monte Rosa and Novartis also agreed to a net profit and loss sharing arrangement, in which Monte Rosa will co-fund any global clinical development from Phase 3 onwards and will share 30% of any profits and losses associated with the manufacturing and commercialization of the licensed products in the United States. Monta Rosa is eligible to receive from Novartis potential sales milestones payments and tiered royalties in connection with sales outside of the United States. Monte Rosa will continue to be responsible for costs associated with the ongoing Phase 1 clinical study and Novartis will be responsible for costs associated with any subsequent clinical studies except for the Phase 3 cost covered by Monte Rosa under the profit and loss sharing agreement.

We are led by an experienced team of drug discovery and development experts with deep experience in targeted protein degradation, molecular glues, chemistry, structural biology, data science, disease biology, translational medicine, and clinical development.

Monte Rosa Therapeutics AG, a Swiss operating company, was incorporated under the laws of Switzerland in April 2018. Monte Rosa Therapeutics, Inc. was incorporated in the State of Delaware in November 2019. The Company is headquartered in Boston, Massachusetts with research operations in both Boston and Basel, Switzerland. Our principal executive office is located at 321 Harrison Avenue, Suite 900, Boston, MA 02118 and our telephone number is (617) 949-2643. Information about us is available on our corporate websites at www.monterosatx.com. Information available on our website is not a part of, and is not incorporated into, this Annual Report. We trade on the Nasdaq Global Select Market under the ticker symbol “GLUE”.

Our product pipeline

We have leveraged our QuEENTM discovery engine to generate our pipeline of product candidates with the potential to treat a diverse range of diseases through targeted protein degradation. Our current programs are focused on delivering therapies to target proteins that have been considered undruggable or inadequately drugged in well-characterized biological pathways across clinical indications in immunology, inflammation, oncology, and other diseases with high unmet needs. We currently retain exclusive worldwide rights to the programs shown in Figure 1 below, except for MGDs directed against VAV1 including MRT-6160, which we licensed to Novartis in October 2024, and the discovery targets included in the Roche collaboration.

Figure 1: Monte Rosa Pipeline

Over the next several years, we plan to expand our early-stage product portfolio into other therapeutic areas, leveraging the ability of our QuEENTM discovery engine to degrade therapeutically relevant proteins in areas including cardiovascular, metabolic, and genetic diseases, as shown in Figure 2.

Figure 2: Monte Rosa Pipeline Expansion Strategy

Our strategy

Our mission is to discover and develop a portfolio of novel small molecule MGDs that selectively eliminate therapeutically relevant proteins to benefit patients in a broad range of indications with significant unmet medical need. We believe the product candidates identified through our proprietary QuEENTM discovery engine can provide distinct advantages over other modalities, including to address target proteins that have been considered undruggable or inadequately drugged. We intend to fully develop certain programs internally, while also utilizing collaborations to advance programs in areas where we believe that external expertise and financial resources may enable us to more fully realize the therapeutic and commercial potential of a program.

Conventional small molecule inhibitor drugs generally work by interfering with the activity of a target protein through an interaction between the drug and a defined binding pocket on the target protein, typically an enzymatically active site of a protein, with a goal to inhibit that protein or its interaction with other proteins. This limits the application of such drugs to proteins with a succinct binding pocket. Within this field, as binding pockets tend to be highly conserved within protein classes and families, achieving selectivity can be challenging. Even where a protein’s active site can be targeted, potentially with selectivity, protein inhibition does not always provide the desired functional outcome.

MGDs on the other hand, provide for therapeutic opportunities not constrained by some of the key limitations of conventional small molecule inhibitor drugs. MGDs provide an opportunity to target the vast universe of target proteins without a defined binding pocket, in a highly selective way, due to the diversity of surfaces that can be targeted, resulting in reversible elimination of a target protein. More specifically, because MGDs work by inducing protein-protein interactions between target proteins and an E3 ligase, they do not require a defined binding pocket on the target protein of interest. Thus, MGDs offer a unique opportunity to unlock significant target space and enable us to address target proteins that have been considered undruggable or inadequately drugged. The interaction surfaces we utilize are often not conserved within protein classes and families, allowing us to potentially achieve significant selectivity for our MGD product candidates that we believe is superior to classical small molecule inhibitor drugs. Lastly, we focus on target proteins where experimental evidence suggests that removal of the target is superior to transiently inhibiting it, in particular proteins that have a scaffolding function.

Through our ability to produce potentially highly selective MGDs with fine-tuned speed and depth of degradation, we believe we can generate MGD product candidates with a wide therapeutic window and other therapeutic advantages that may be beneficial in a broad range of indications, including immunology, inflammation, oncology, metabolic diseases, cardiovascular diseases, genetic diseases, and diseases of the central nervous system or CNS. We believe our platform has the capability to produce MGDs suitable for distribution into any tissue, including MGDs designed to be CNS-penetrant, such as our MGDs for NEK7.

Our precision oncology programs are focused on the elimination of proteins that are highly validated driver oncogenes in cancer cells (“oncogene addiction”), that define a cancer lineage dependence (“lineage addiction”), or that create a vulnerability specific to tumor cells (“synthetic lethality”). By tuning the speed and depth of degradation and leveraging our proprietary pharmacogenomic tools, we optimize our oncology MGDs to selectively target biomarker-positive cells. Our platform enables us to potentially tune the activity (depth and speed of degradation) of our MGDs to the most relevant tumor lineages to achieve maximal phenotypic effects.

In immunology, we are uniquely able to target highly credentialed immune signaling proteins in pathologically relevant immune pathways. We prioritize target proteins that are validated through preclinical or clinical (including human genetic) evidence. We have shown that we are able to optimize our MGD product candidates to induce deep and selective degradation of immune-pathway relevant proteins.

Key elements of our strategy include:

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Continue to advance our GSPT1-directed MGD program through clinical development and towards seeking regulatory approval. We received FDA clearance of our IND for MRT-2359 in September 2022 and initiated patient dosing in our ongoing Phase 1/2 clinical trial in October 2022. In October 2023, we announced interim clinical data from the Phase 1 dose escalation part of our ongoing MRT-2359 Phase 1/2 study demonstrating favorable pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles in heavily pretreated patients, including lung cancers and high-grade neuroendocrine tumors. In the second half of 2024, we expanded this trial to include heavily pretreated castration-resistant prostate cancer (in combination with enzalutamide) and heavily pretreated estrogen-receptor (ER+) positive breast cancer (in combination with fulvestrant), both tumor types characterized by high expression of c-MYC. We recently announced additional results from our Phase 1/2 study of MRT-2359 demonstrating encouraging signals of clinical response in castration-resistant prostate cancer (CRPC) patients resistant to AR therapy, including a confirmed RECIST response. Moving forward, we will deprioritize further development of MRT-2359 in SCLC, NSCLC, high-grade neuroendocrine tumors and L- and N-MYC amplified tumors while prioritizing development in CRPC. This is based on a favorable safety profile and encouraging early signals of clinical activity in castration-resistant prostate cancer (CRPC) patients in combination with enzalutamide, including a confirmed RECIST response, and the lack of need for biomarker-based patient selection for this cohort of patients due to the widespread expression of c-MYC in this tumor type. This is in contrast to SCLC, NSCLC, high-grade neuroendocrine tumors and L-and N-MYC amplified tumors where further development would require continued investments into companion diagnostics, as well as more restrictive selection protocols for clinical trials. We believe 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 our future clinical development of MRT-2359. We are 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 emerge. CRPC remains an area of high unmet need and constitutes a potentially significant commercial opportunity if the initial data are confirmed in a larger sample of patients. We are also still awaiting initial results from the breast cancer cohort. We expect to present additional results in H2 2025, including results on ongoing initial safety evaluation of our combination of MRT-2359 with fulvestrant in ER+ breast cancer;

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Continue to advance our VAV1-directed MGD program through completion of activities to prepare for Phase 2 initiation, following which, pursuant to our Agreement with Novartis, Novartis will be responsible for all further clinical development and commercialization. We believe our global license agreement with Novartis will accelerate and broaden the scope of clinical development of MRT-6160 while retaining substantial value for us, including through milestone payments and our share of the US P&L for MRT-6160 provided under our Agreement;

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Continue to advance our NEK7-directed MGD program through IND filing and into clinical trials. In March 2024, we announced our development candidate MRT-8102, targeting diseases driven by IL-1β and the NRLP3 inflammasome. Aberrant NLRP3 inflammasome activation and the subsequent release of active IL-1β and interleukin-18 (IL-18) has been implicated in multiple inflammatory disorders such as pericarditis, gout, osteoarthritis, Parkinson’s disease, obesity, and atherosclerosis. MRT-8102 is an orally bioavailable MGD that has shown potent, selective, and durable degradation of NEK7 and near-complete reductions of IL-1β in a non-human primate model following ex vivo stimulation of whole blood. We expect to submit an IND for MRT-8102 in H1 2025. In light of the strategic importance of our NEK7 program and the crucial role of the NLRP3 inflammasome in inflammatory responses in the CNS in multiple systemic and neurologic disorders, we are advancing a second NEK7 program optimized for CNS penetration through Lead Optimization and we anticipate IND submission for this program in 2026.

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Advance our cell cycle program to IND submission. We believe our programs directed at CDK2 and CCNE1, key drivers of cancers with cyclin dependent kinase pathway alterations, have the potential to achieve greater selectivity for the CCNE/CDK2 complex versus conventional CDK inhibitors, as well as more sustained pathway inhibition compared to inhibitors. We are currently evaluating MGDs for both programs in multiple preclinical models to determine the optimal first MGD to advance to IND submission, which is expected in 2026.

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Continue to advance and develop our pipeline of rationally designed MGDs to transform the treatment of diseases in multiple therapeutic areas. Through our QuEENTM discovery engine, we have identified a variety of additional degron-containing proteins that are amenable to our approach and are either undruggable or insufficiently drugged and we continue to build MGDs against these proteins. We continue to advance programs into lead optimization, and to identify new degron-containing target proteins as well as MGDs. We will continue to prioritize therapeutically relevant target proteins backed by strong biological and genetic rationale with the goal of producing novel precision medicines. These opportunities include indications such as immunology, inflammation, oncology as well as others;

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Continue to enhance and expand the capabilities of our QuEENTM discovery engine to unlock the full therapeutic potential of our MGDs in our targeted therapeutic areas. We employ a core set of drug discovery and development principles to guide our target protein selection across various protein classes and therapeutic areas. We are specifically focused on delivering therapies to target proteins that have been considered undruggable or inadequately drugged in preclinically and clinically well-characterized biological pathways;

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Expand and protect our proprietary know-how and intellectual property.We continue to innovatively expand our intellectual property around our innovations in the field of targeted protein degradation and in particular MGDs. Our intellectual property, which includes proprietary know-how, patent applications and issued and expected patents, as well as trade secrets, applies not only to our product candidates, but also to all of our various innovations, including, for example, our drug discovery processes including our QuEENTM discovery engine; our AI-based E3 ligase characterization algorithms, AI-based degron discovery algorithms, AI-based novel MGD design algorithms, and in silico screening algorithms; our drug development tools; our growing library of MGDs; the innovative methods and approaches we have developed to rationally design MGDs to expand our library, and to certain biomarkers and therapeutic applications for our potential product candidates;

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Execute our discovery collaboration with Roche in the areas of cancer and neurology. Under the terms of the agreement, Monte Rosa will lead discovery and preclinical activities against multiple select cancer and neurological disease targets to a defined point. Upon such point, Roche gains the right to exclusively pursue further preclinical and clinical development of the compounds. We believe this collaboration will enable and accelerate expansion of our platform into neuroscience and additional areas of oncology; and

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Consider additional strategic collaborations in select therapeutic areas to fully realize the potential of our QuEENTM discovery engine. Our goal is to become a fully integrated biopharmaceutical company that delivers pioneering therapies for patients. We currently retain all rights to our programs and platform, except for the discovery targets included in the Roche collaboration and MRT-6160, for which we entered an exclusive global development and commercialization agreement with Novartis in October of 2024. To support our goal, we will selectively explore additional strategic partnerships where we can leverage complementary capabilities in discovery, development, and commercialization in disease areas within and outside our core areas of therapeutic focus to bring transformative therapies to patients with high unmet medical needs.

Background on targeted protein degradation and molecular glue degraders

Proteins drive nearly all biochemical reactions in the body and many diseases stem from abnormal intracellular protein activity. Proteins, including those inside the cell and on its surface, are attractive therapeutic targets; nevertheless, despite advances in therapeutic modalities, approximately 75% of human proteins remain undruggable by traditional small molecule inhibitors.

Challenges with druggable vs. undruggable proteins

Traditional small molecule inhibitors target proteins by binding to a pocket on the protein’s surface, but many proteins lack such pockets, making them undruggable. Key disease-driving proteins, including transcription factors, scaffolding proteins, and enzyme modulators, often lack druggable pockets. The absence of a binding

pocket presents a challenge to the development of traditional small molecule inhibitors. Other therapeutic modalities that can target such proteins, such as therapeutic antibodies, oligo-based nucleotides, and genetic therapies, are limited in their ability to address aberrant protein behavior. Although these therapies have improved patient outcomes, they face challenges in delivery, scalability, and therapeutic application. A summary of characteristics of various therapeutic modalities compared to MGDs is shown in Figure 3.

Figure 3: The Next Generation of Precision Medicine-Based Small Molecule Drugs; Selectively Editing the Human Proteome with Rationally Designed MGDs

Molecular glues: a rapidly emerging approach to protein degradation

Protein degradation is one of the body’s natural processes by which proteins are eliminated from human cells through the attachment of a molecular tag, called ubiquitin, to a protein by any of the approximately 600 human E3 ligases, marking the protein for degradation by the proteasome in the cell. Targeted protein degradation can be mediated by two small molecule classes: MGDs (molecular glue degraders) and PROTACs (proteolysis-targeting chimeras, also known as heterobifunctional degraders) (illustrated in Figure 4).

We believe the targeted protein degradation approach offers many features that make it an attractive therapeutic modality:

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Removal of a target protein: partial or complete removal of a target protein can lead to more complete inhibition of signaling and metabolic pathways, thus resulting in more profound and longer lasting pharmacodynamic effects than traditional reversible or irreversible inhibition can induce.

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Targeting intracellular proteins: small molecule-based protein degraders, in particular MGDs, readily cross cell membranes or can be optimized to do so.

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Ease of delivery: small molecule-based protein degraders, in particular MGDs, can be delivered through various routes of administration, including orally.

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Systemic and tissue distribution: since most small molecule-based degraders, in particular MGDs, are low molecular weight compared to other therapeutic modalities, tissue distribution, such as into the CNS or tumor tissues, poses less of an issue.

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Catalytic mode of action: after inducing degradation of a target protein molecule, the small molecule-based protein degrader-E3 ligase complex is able to induce the degradation of additional target protein molecules. Thus, the small molecule-based protein degrader acts catalytically, unlike protein inhibition, causing the removal of many target protein molecules with a single MGD molecule, thereby editing the cellular proteome.

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Event driven pharmacology: unlike with inhibitors where prolonged engagement of the drug with the protein is required for efficacy, small molecule-based protein degraders only require engagement with the E3 ligase and the target protein long enough to induce tagging for degradation.

As described above, there are multiple potential advantages of the protein degradation approach, but one of the most intriguing is the potential to achieve greater therapeutic benefits resulting from the durable but reversible removal of a target protein from the cellular proteome.

Figure 4: Molecular Glue Degraders; Expanding Target Space, Fostering a New Generation of Drugs

Our approach

MGDs are small molecule-based protein degraders designed to modify an E3 ligase’s binding specificity and thus can employ the body’s natural mechanisms of protein destruction to selectively eliminate therapeutically relevant proteins.

Our QuEENTM discovery engine was built for the rational, target-centric discovery of potent and selective MGDs with favorable drug-like properties, thus potentially systematically overcoming common challenges of MGD discovery, as illustrated in Figure 5.

Figure 5: QuEENTM is Redefining the Rules of MGD Discovery

We believe our discovery engine has the potential to continue to deliver MGD product candidates, including product candidates that could address target proteins that have been considered undruggable or inadequately drugged, while possessing attractive pharmaceutical properties. As shown in Figure 6, our initial programs are utilizing cereblon as the E3 ligase system to tag target proteins. Through our generation of data-at-scale, AI/ML platform and proprietary MGD library we have expanded and continue to expand chemical and target space, and have begun to leverage other E3 ligase systems.

Figure 6: Our Rational Approach to Unleash the Full Potential of MGDs

We have built our discovery engine on the insight that deep knowledge and understanding of features of protein surfaces drives MGD discovery. Surfaces and their unique features mediate protein-protein interactions and targeted protein degradation. As shown in Figure 7, interrogating surfaces using geometric deep learning enables us to identify reprogrammable ligases and the matching target protein space, creating broad potential opportunities to eliminate undruggable, disease-driving proteins through “only-in-class” MGDs.

Figure 7: Surface Interactions Drive "Only-in-Class" MGD Designs

QuEENTM Discovery Engine

We design and develop molecular glue degraders or MGDs in a rational and iterative approach using our industry-leading and dynamic QuEENTM discovery engine, encapsulating our team’s proprietary knowledge and discovery capabilities across biology, chemistry and computational sciences, from which we are generating our library and pipeline of MGD product candidates. Through our discovery engine, we have built intellectual property that allows us to induce a high degree of surface complementarity between the E3 ligase and a target protein, potentially leading to high potency and selectivity for the therapeutically relevant target proteins we select.

The QuEENTM discovery engine was built to support our target-centric approach to the discovery and development of MGD drugs that degrade a wide landscape of therapeutically-relevant target proteins by (i) systematically identifying degrons and other surface features on target proteins that may enable ternary complex formation and consequential degradation by E3 ligases, (ii) understanding how to reprogram the surface of endogenous E3 ligases using small molecule-based MGDs; and (iii) rationally designing MGDs that can be optimized towards high potency and selectivity, with favorable pharmaceutical properties. Our process of degron discovery and MGD design is highly iterative and interdisciplinary. Powerful AI modeling guides our high throughput screening and chemo-proteomics, which in turn feeds information back to the AI engine, and the accumulated knowledge is used to guide our MGD library expansion. For example, MGD discovery and development for a protein target can pass from degron identification, to MGD hit identification, to in silico improvement, to a round of chemo-proteomics validation, to chemical library alterations and back, until we reach the desired selectivity and degradation. Figure 8 provides a schematic overview of some of the unique and critical features of our QuEENTM discovery engine.

Figure 8: Monte Rosa’s QuEENTM Discovery Engine: An Industry Leading Target-Centric Approach to MGD Discovery and Development

Our Proprietary MGD library

We discover and develop lead MGDs for degron-containing target proteins by screening our MGD library of currently over 50,000 MGD molecules, and applying proximity screening tools, our chemo-proteomic capabilities and our knowledge of the cereblon-binding surface and variations in degron structures and other surface features. Our highly diverse library of MGDs is continuing to expand based on our growing expertise in MGD design and development captured in QuEENTM. We have developed unique and innovative synthetic chemistry approaches to access over 1,000 scaffolds, each designed to probe three-dimensional structural and chemical property space differently. These scaffolds are being utilized as building blocks to generate our proprietary library of highly diverse compounds. The modular construction of our library allows us to explore different areas of chemical space and follow-up rapidly on hits from our library. As shown in Figure 9, our highly diverse library of MGDs leverages different areas of the cereblon surface to engage diverse degrons and surface features on target proteins. Our library has given rise to multiple series of MGDs for each of the target proteins currently being studied across our disclosed and undisclosed portfolio.

Figure 9: Monte Rosa's Proprietary MGD Library: A Novel and Structurally Diverse Cereblon-Centric Library

Our AI/ML engine fAIceit identifies reprogrammable E3 ligases and E3 ligases-accessible target proteins

Our focus on protein surface characterization sets us apart, enabling us to identify reprogrammable E3 ligases as well as potential target proteins amenable to our approach. We have developed sophisticated and proprietary AI-powered algorithms to mine databases of protein sequences and structures, including structures determined from x-ray crystallography and cryoEM, and structures from predicted protein folding. fAIceit – our proprietary geometric deep learning engine for surface characterization - continuously learns from our expanding MGD library, identifying new degrons and surface features in targetable proteins across the proteome.

High throughput screening of our proprietary library identifies active MGDs

We have developed a suite of high-throughput assays that rapidly assess our proprietary MGD library and MGDs generated during specific programs. Coupled with customized automation and robotic systems, our assays can measure ternary complex formation in both a biochemical and cellular format, as well as measure degradation of target proteins in cells, which we use to screen, identify and rapidly optimize our MGDs.

Our quantitative proteomics profiling assays for neosubstrate identification and MGD optimization

Utilizing mass-spectrometry-based proteomics, we have developed a suite of high throughput quantitative profiling assays to assess cellular target degradation, selectivity of degradation, target ubiquitination, and ternary complex formation. Data are processed and available in BaseCamp, our proprietary data analysis platform. This large proprietary dataset is used to train our AI/ML algorithms, identify novel targets, and to assess our MGDs during lead optimization programs.

Ourstructural biology platformenables the rational design of our MGDs

Leveraging high-throughput crystallization and cryo-electron microscopy, we have established a robust pipeline for generating high resolution protein structures. We use structural insights derived from these to support the design of our MGD library, rationally optimize our MGDs during lead optimization programs, and validate novel binding modes. Our database includes ternary complex structures of novel binding modes that are highly diverse in structure and sequence.

Our QuEENTM discovery engine has enabled us to discover novel degrons and binding modes, some of which are shown in Figure 10, dramatically expanding our addressable target space. We have used our AI engine and a rational design approach to discover MGDs that are exquisitely selective, enabling us to potentially eliminate therapeutically relevant target proteins in pathways that are highly relevant for diseases with high unmet need in immunology, inflammation, and oncology as well as other diseases.

Figure 10: Novel Binding Modes that are Highly Diverse in Structure, Sequence

QuEENTM expansion

Our QuEENTM discovery engine was originally focused on identifying and developing MGDs that induce the binding of degron-containing neosubstrates to cereblon as a means of targeting them for degradation. Using our established tools, we are expanding the scope of QuEENTM to further grow the cereblon target space, to leverage additional E3 ligases for targeted protein degradation, and to extend the utility of our MGDs as next-generation antibody conjugates.

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Expand chemical space: As we rationally designed our MGD compound library to increase diversity, our preclinical studies identified novel degrons and surface features on potential target proteins that engage cereblon in new binding modes. Our AI-driven algorithms predict proteins containing these novel degrons and surface features, and our rational design approach expands the chemical diversity of our MGD library to engage this diverse and growing set of cereblon-accessible proteins. We have now grown our library to 1,000 unique scaffolds and more than 50,000 MGD molecules;

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Activate new E3 ligases: We believe that we will be able to reprogram other E3 ligases through the discovery of ligase specific MGDs as well as specific ligase-accessible degrons, thus enabling us to generate ternary complexes with a further subset of the approximately 600 E3 ligases;

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Grow target space: We believe expanding degron identification, E3 ligase activation, and MGD chemical space will unlock previously undruggable proteins for therapeutic intervention;

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ACDCs: We have shown in vitro the potential to degrade several currently undruggable, pan-lethal targets with MGDs. MGDs to these proteins are compatible with common linker technologies and may be ideal next-generation antibody cargos.

Figure 11: QuEENTM Discovery Engine Expansion

Our Precision Medicine Approach for MYC-driven Cancers

MRT-2359, a highly selective and orally bioavailable GSPT1-directed molecular glue degrader (MGD) in development for the treatment of MYC-driven cancers

Overview

GSPT1 (also known as eRF3a) is a translation termination factor that helps catalyze the termination of protein synthesis, facilitating the release of mRNA and newly synthesized protein from the ribosomal protein synthesis machinery. We have identified GSPT1 as a potential therapeutic vulnerability for cancers will high levels of protein translation, including MYC-driven cancers.

MRT-2359 is an orally bioavailable MGD that we have shown using extensive in vitro and in vivo studies to induce the degradation of GSPT1. MRT-2359 is designed to preferentially affect growth and survival of cancer cells addicted to protein translation, such as those driven by high expression and activity of MYC family transcription factors. In vivo, once daily oral dosing of MRT-2359 led to a potent anti-tumor activity in MYC-driven, cell-line-derived xenograft models as well as patient-derived xenograft models of NSCLC and SCLC. MRT-2359 is currently in a Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT05546268). Based on our clinical work to date, we plan to continue development of MRT-2359 in CRPC, while deprioritizing further development in SCLC, NSCLC, high-grade neuroendocrine tumors and L- and N-MYC amplified tumors.

Development of GSPT1-directed MGDs to Target Downstream Vulnerabilities of MYC Activation

In humans, the MYC family transcription factors comprise three proteins, c-MYC, L-MYC, and N-MYC. Upon activation in tumor cells, MYC family transcription factors can function as oncogenes. They have long been recognized as drivers of multiple human cancers and are among the most frequently mutated, translocated and highly expressed oncogenes. However, despite several decades of drug discovery efforts, MYC has remained largely recalcitrant to new drug development and no approved therapies directly or indirectly targeting MYC family transcription factors have been developed to date.

It is well established that abnormal activation of MYC through translocation or high levels of expression results in uncontrolled cell growth that is associated with high rates of protein synthesis and ramp up of the protein translation machinery. MYC-driven tumors are therefore widely believed to be addicted to protein translation, and this addiction to protein translation creates an inherent dependency on critical components of the translation machinery, such as GSPT1, illustrated in Figure 12.

As part of our research program, we identified GSPT1 as a potential novel vulnerability of MYC-driven cancers and, based on this observation, we believe that targeting GSPT1 with MGDs represents a viable approach for the

treatment and management of patients with MYC-driven cancers. We believe that the administration of our GSPT1-directed MGD product candidate, MRT-2359, has the potential to address a critical downstream vulnerability of oncogenic MYC activation and provide a unique opportunity for therapeutic intervention.

Figure 12: The Role of GSPT1 in MYC-driven, Translationally Addicted Cancer Cells

Targeting GSPT1 with MRT-2359 (preclinical data and studies)

MRT-2359 is a potent and selective GSPT1-directed MGD discovered and rationally designed using our QuEENTM discovery engine. Key features and parameters of MRT-2359 are provided in Figure 13.

Figure 13: MRT-2359 is a Selective and Orally Bioavailable GSPT1-directed MGD Rationally Designed Using our QuEENTM Discovery Engine

As shown in Figure 14, MRT-2359 has optimized depth of degradation to achieve preferential activity in MYC high cancer cells. Compared with a non-optimal GSPT1 degrader, MRT-2359 displays preferential activity in MYC

driven NSCLC cells, as shown in the top right panel. The optimal level of GSPT1 degradation to achieve preferential activity in MYC high cells is approximately 60-70% as determined by Western blot, as shown in the left panel. Higher levels of degradation lead to a more pan-toxic phenotype without differential activity in MYC high cells.

Figure 14: MRT-2359 Has Optimized Depth of Degradation to Achieve Preferential Activity in MYC High Cancer Cells

Collectively, we believe that our data supports that the preferential inhibition of growth and survival of MYC-driven versus MYC-independent tumor cells results from a combination of (i) preferential degradation of GSPT1 in cancer cells with high MYC expression, (ii) inhibition of translation, whereby MRT-2359-induced reduction of GSPT1 preferentially impairs protein synthesis in tumor cells with high MYC expression and (iii) downregulation of MYC expression and transcription activity in MYC-addicted but not MYC-independent tumor cells, as depicted in Figure 15.

Figure 15: Three Mechanisms Driving Preferential Activity in MYC High Cancer Lines

Indications Investigated in Our Study

We believe that there are multiple tumor types in which the MYC pathway is highly activated, and several (indicated in figure 16) were explored in our Phase 1/2 clinical trial. As shown in Figure 16, in our Phase 1/2 clinical trial, in addition to L-MYC and N-MYC driven smaller indications that we believe may require a precision medicine approach for patient identification, we are testing the potential of MRT-2359 in c-MYC-driven tumors that present large potential opportunities, including c-MYC driven cancer types such as prostate cancer (including tumors with the AR-V7 splice variant) and breast cancer. We believe such indications will not require patient selection due to the widespread overexpression and activation of c-Myc in those tumor types, which will simplify patient recruitment for our ongoing study.

Figure 16: MYC-Driven Pathologies Explored in MRT-2359 Phase 1/2 Trial

MRT-2359-001 Phase 1/2 Study

Our ongoing Phase 1/2, open-label, multicenter study, illustrated in Figure 17, is designed to assess the safety, tolerability, PK, PD, and preliminary clinical activity of MRT-2359 in patients with select previously treated solid tumors.

Patients have been dosed with MRT-2359 in 6 dose levels across two dosing schedules: a 5-days on and 9-days off drug (5/9) dosing schedule; and a 21-days on and 7-days off drug (21/7) dosing schedule. The study has enrolled patients with a diverse set of tumor types, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), high-grade neuroendocrine (NE) tumors of the prostate, bladder and other organs of origin, heavily pretreated androgen receptor-positive prostate cancer, and heavily pretreated estrogen receptor-positive breast cancer.

In December 2024, we provided a development progress update, including the selection of 0.5 mg using the 21/7 dose schedule as the recommended phase 2 dose (RP2D) for any expansion cohorts of the Phase 1/2 study. Furthermore, using the 5/9 dosing schedule, daily doses of 0.5 mg and 1 mg were identified as having a generally favorable safety profile, 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 0.5 and 0.75 mg were identified as having a generally favorable safety profile.

Figure 17: MRT-2359 Phase 1/2 Clinical Study Design

Results from MRT-2359-001 Phase 1/2 Study

A total of 59 patients were dosed with MRT-2359 as a monotherapy in 6 dose levels across the two dosing schedules. 32 patients were treated on the 5/9 schedule and 27 on the 21/7 schedule. Patient demographics and clinical characteristics in the dose escalation cohorts are shown in Figure 18. The median age was 63, and approximately half the patients were female. Patients were predominantly ECOG performance status 0 or 1. There were 23 NSCLC patients, 13 SCLC patients, 16 high grade NE patients, and 7 N-MYC or L-MYC amplified cancer patients. The median number of prior lines of therapy was 3.

Figure 18: Patient Demographics and Clinical Characteristics in Dose Escalation

Doses of 0.5 mg and 1 mg at the 5/9 drug schedule and 0.5 mg and 0.75 mg on the 21/7 drug schedule were well tolerated with mostly low-grade adverse events (AEs). Doses of 1.5 mg or higher were above the maximum tolerated dose (MTD). Dose limiting toxicities were thrombocytopenia (N=6), with or without neutropenia/leukopenia, and 1 patient Grade 3 ALT/AST elevation. Figure 19 details treatment related AEs occurring in 10% of more of patients.

Importantly, dose-limiting toxicities reported with non-selective competitor GSPT1 degraders such as hypocalcemia, hypotension and cytokine release syndrome were not reported in the MRT-2359 study.

Figure 19: MRT-2359 Treatment-Related AEs in > 10% patients (N=59)

L-MYC and N-MYC expression in tumor tissue obtained at baseline was assessed in 46 patients and 35 were evaluable for response assessment per RECIST 1.1. Overall, as compared to preclinical data, we observed lower than expected frequency of tumors with high L-MYC or N-MYC expression in NCSLC (0% biomarker positive),

SCLC, including cases were NSCLC had transformed to SCLC (31% biomarker positive), and high grade NE tumors (17% biomarker positive). Figure 20 graphs the biomarker status for patients where this could be assessed.

Figure 20: Biomarker Status in L-/N-MYC Amplified Tumors, NSCLC, SCLC and High-Grade NE Tumors

To assess pharmacodynamic (PD) modulation of GSPT1 in tumors following treatment, targeted mass spectrometry was performed on 17 paired tumor biopsies that met internal quality control criteria. Optimal degradation of approximately 60-70% (in line with preclinical data) was seen in tumor samples of patients with biomarker positive cancers, defined by L-/N-MYC high expression or amplification/fusion. Consistent with our hypothesis and preclinical findings, degradation of GSPT1 was lower in biomarker negative tumors.

Figure 21: PD modulation in L-/N-MYC Amplified Tumors, NSCLC, SCLC and High-Grade NE Tumors

L-MYC and N-MYC expression levels 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 which 37 were evaluable for response per RECIST 1.1

Activity was assessed per RECIST 1.1 criteria in biomarker positive and negative patients. There were 13 patients determined to be biomarker positive with high L-MYC or N-MYC expression, including patients with L-MYC or N-MYC amplification without tumor tissue for expression analysis. Of these 13 patients, one patient had a confirmed partial response (PR), and 4 patients had stable disease (SD), for a disease control rate (DCR; PR/SD) of 38%.

24 patients were determined to be biomarker negative, based on low L-MYC and N-MYC expression. Of these patients, one patient had an unconfirmed PR and 3 patients had SD. The DCR rate was 17%.

In aggregate, we believe that the low biomarker positivity in the cancer types tested in the dose escalation cohorts and the need for companion diagnostic development moving forward does not support our prioritizing additional studies in lung cancer, high-grade neuroendocrine tumors and L- and N-MYC amplified tumors. In light of early clinical results from our CRPC cohort, where expression of c-MYC is widespread and biomarker-based patient selection will not be required, we plan to prioritize development in CRPC, and we do not plan to open expansion cohorts in in SCLC, NSCLC, high-grade neuroendocrine tumors and L- and N-MYC amplified tumors. This is in contrast to SCLC, NSCLC, high-grade neuroendocrine tumors and L-and N-MYC amplified tumors where further development would require continued investments into companion diagnostics, as well as more restrictive selection protocols for clinical trials. We believe 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 our future clinical development of MRT-2359.

Further evidence of activity of MRT-2359 is shown in Figure 22, which presents a confirmed PR in a heavily treated high grade NE bladder cancer patient. The patient had four lines of prior therapy, including multiple lines of chemotherapy and pembrolizumab. The baseline tumor biopsy demonstrated high N-MYC expression. The patient experienced Grade 4 neutropenia (which was not a dose limiting toxicity) after the first 5 days of administration of 2 mg resulting in a dose reduction to 1 mg and then developed Grade 4 thrombocytopenia (which was considered a dose limiting toxicity), resulting in treatment interruption and further dose reduction to 0.5 mg. CT scan demonstrated a confirmed PR with continuing shrinkage of target lesions from -31% on the first assessment to -89% after 11 months on therapy.

Figure 22: Confirmed PR in Heavily Pretreated HG NE Bladder Cancer Patient

Preliminary Data from MRT-2359/Enzalutamide Study in Castration-Resistant Prostate Cancer

As of the March 10, 2025, data cutoff, tumor response per RECIST 1.1 criteria was available for 3 patients treated with MRT-2359 and enzalutamide combination therapy. One patient showed a confirmed partial response (PR), with tumor reduction of -57% after 4 treatment cycles. This patient harbors an AR H875Y mutation (revealed by standard of care molecular testing by the clinical trial site), typically associated with resistance to AR antagonists, including enzalutamide. Additionally, two patients that were positive for the AR-V7 variant presented stable disease. Both of these patients had undergone multiple prior treatments including abiraterone and/or enzalutamide. PSA response was available for 2 patients showing 1 PSA response (-90%) in the patient with a confirmed PR.

The safety profile observed as of the data cutoff date has been favorable.

The safety and efficacy assessment continues following a Simon 2-stage design. As noted above, we have the option to expand enrollment of this study to include up to 20 - 30 CRPC patients.

We are also enrolling hormone receptor positive breast cancer patients to study the combination of MRT-2359 and fulvestrant. Further data from both combination cohorts is expected in H2 2025.

Figure 23 presents additional data on the refractory CRPC patient with a confirmed partial response. The patient had undergone prior therapies including androgen deprivation therapy, abiraterone, olaparib, docetaxel, Pluvicto, and a different investigational therapy. The patient had an AR H875Y mutation, typically associated with resistance to AR antagonists including enzalutamide. The patient had a prostate specific antigen (PSA) partial response of -85% after cycle 1 and -90% after cycle 4. The patient showed a reduction in tumor burden, with a confirmed partial response per RECIST 1.1 criteria of -46% after cycle 2 and -57% after cycle 4. The patient continues on study for 5+ months.

Figure 23: Confirmed PR in Refractory CRPC with AR H875Y Mutation

CDK2-directed MGD molecules for the treatment of cancer

Cyclin dependent kinases, or CDKs, are a family of closely related kinases that regulate progression through the cell cycle. CDK activity is modulated by specific cyclins. For example, cyclin E1 activates cyclin-dependent kinase 2, or CDK2, as shown in Figure 24. CDK2 can be activated in tumors by the amplification or overexpression of Cyclin E1 or E2. Cyclin E1 dysregulation has been found in several cancers, including ovarian and triple negative breast cancer. In addition, cyclin E1 dysregulation and CDK2 activation has also been found to be one of the mechanisms of resistance in ER+ breast cancer patients treated with CDK4/CDK6 inhibitors such as ribociclib. Therefore, we believe selective elimination of CDK2 using CDK2-directed MGDs may provide benefit to these patients. Previously reported small molecule inhibitors and PROTACs of CDK2 have been limited in their selectivity due to the high degree of similarity among the active sites of kinases, in particular within the CDK family itself. We have identified multiple MGD molecules that selectively promote the association of CDK2 and cereblon in vitro, while avoiding other CDKs. Through ongoing lead optimization chemistry, the most advanced compounds are orally bioavailable and can robustly and selectively induce CDK2 protein degradation in multiple cancer cell lines in vitro and in disease relevant models in vivo, leading to strong tumor growth inhibition.

Figure 24: CDK2 is One of the Key Regulators of the Cell Cycle

Lead optimization towards orally bioavailable CDK2-directed MGDs

Our CDK2-directed MGDs form a strong ternary complex with CDK2 and cereblon through a newly characterized non-canonical degron which was unveiled through application of our QuEENTM discovery engine technologies. The unique character of the CDK2 degron interaction with cereblon, and the optimized features of our MGDs provide a high degree of selectivity over closely related proteins such as CDK1, CDK4, and CDK9. Our MGDs are designed to be orally bioavailable with favorable invitro ADMET properties and preclinical safety profiles.

In vitro data

Our lead CDK2-directed MGD MRT-51443 has shown the ability to selectively degrade CDK2 and reduce E2F pathway proteins in vitro, with no significant effect on other CDKs or other kinases, as shown in Figure 25. Our data also support that our CDK2 MGD MRT-51443 can block DNA replication during S phase in CDK2 dependent cells and inhibits cellular proliferation in a concentration-dependent manner.

Figure 25: CDK2-directed MGD MRT-51443 is Selective and Showed Biological Activity in a CDK2 Dependent Cell Line

MRT-51443 displayed superior selectivity compared to clinical CDK2 inhibitors, as shown in Figure 26. Clinical-stage CDK2 inhibitors show off-target activity in biochemical kinome profiling. CDK2 inhibitors, but not a CDK2 MGD, display CDK2-independent activity, as demonstrated by their suppression of cell proliferation in the absence of their primary target, CDK2.

Figure 26: CDK2-directed MGD Displayed Superior Selectivity Compared to CDK2 Inhibitors

The combination of MRT-51443 and ribociclib delayed resistance onset in an ER+ breast cancer model in vitro, as shown in Figure 27.

Figure 27: CDK2 MGD/Ribociclib Combination Delayed Resistance Onset

In vivo data

As shown in Figure 28, when dosed orally in preclinical models of HR-positive/HER2-negative breast cancer, MRT-51443 drove deep tumor regression in triple combination with a CDK4/6 inhibitor (ribociclib) and endocrine therapy (fulvestrant) and substantially reduced tumor burden versus ribociclib + fulvestrant combination therapy alone.

Figure 28: CDK2 MGD Demonstrated Activity in Combination with CDK4/6 Inhibitor and Fulvestrant in ER+ Breast Cancer Model

Cyclin E1-directed MGD molecules for the treatment of cancer

Cyclin-dependent kinase protein complexes (cyclin-CDK) regulate progression through the cell cycle, whereby different combinations of the two subunits control different stages of the cell cycle. They are formed by an association of a regulatory, subunit, a cyclin, with an inactive catalytic (kinase) subunit, cyclin-dependent kinase (CDK). Once the complex is formed, it transitions into an active state, whereby the kinase (CDK) subunits can phosphorylate downstream effector substrates.

Cyclin E proteins, encoded by the CCNE1 and CCNE2 genes, complex with CDK2 to form an active Cyclin E-CDK2 complex, regulating G1-to-S transition of the cell cycle and initiation of DNA replication, as shown in Figure 29. Under normal conditions, cyclin E expression is tightly regulated and restricted to the G1-S phase of the cell cycle. However, many cancer types, including ovarian, endometrial, gastric, and breast cancers, bear frequent amplification or overexpression of the CCNE1 gene, resulting in increased Cyclin E1 protein expression and aberrant regulation of cell growth. As such, Cyclin E1 represents a genuine oncogenic driver and Cyclin E1 amplified cancers are greatly dependent on sustained high levels of Cyclin E1 for their continued growth and survival. Hence, pharmacologic suppression of high Cyclin E1 protein levels is expected to inhibit tumor growth, in line with the classical “oncogene addiction” paradigm.

Figure 29: CCNE1 (Cyclin E1) Drives Multiple Hallmark Cancer Mechanisms and is a Target for Solid Tumors with Deregulated Cyclin E1

As a regulatory subunit with no catalytic activity, Cyclin E1 has been considered “undruggable” to date. We have identified multiple MGD molecules that selectively promote the association of Cyclin E1 and cereblon in vitro, while sparing the Cyclin E2 paralog. These compounds have shown the ability to robustly and selectively induce Cyclin E1 degradation in multiple cancer cell lines in vitro and in disease relevant models in vivo. In addition, they suppress cancer cell line proliferation preferentially when CCNE1 is amplified and/or overexpressed, suggesting robust biomarker-driven activity.

In vitro data

As shown in Figure 30, the Cyclin E1-directed MGD MRT-50969 selectively degrades Cyclin E1, leads to downstream pathway suppression and induces robust G1/S cell cycle arrest. Cyclin E1 degradation blocks cell cycle progression and proliferation in CCNE1-amplified and -dependent cancer cell lines by inducing G1-S cell cycle arrest in a concentration-dependent manner.

Figure 30: Cyclin E1-directed MGDs are selective and showed biological activity in CCNE1-amplified cell lines

MRT-50969 showed superior differential suppression of tumor growth in CCNE1 dependent cell lines compared to clinical-stage CDK2 inhibitors, as shown in Figure 31. Unlike MRT-50969, several tested clinical stage CDK2 or WEE1 inhibitors did not fully recapitulate genetic dependency, potentially indicating off-target activity.

Figure 31: MRT-50969 Showed Superior Differential Activity in CCNE1 Dependent Cell Lines

In vivo data

When dosed orally as a single agent in preclinical cell line-based xenograft models of CCNE1-amplified breast cancer and gastric cancer, the cyclin E1-directed MGD MRT-50969 induced robust tumor growth suppression and regression in both models, as shown in Figures 32 and 33.

Figure 32: MRT-50969 Inhibited Tumor Growth in a CCNE1Amplified Breast Cancer Model in vivo

Figure 33: MRT-50969 Inhibited Tumor Growth in a CCNE1Amplified Gastric Cancer Model in vivo

The CCNE1 MGD program is currently in lead optimization. We are benchmarking MGD molecules for both the CDK2 and CCNE1 programs against each other in multiple preclinical models to determine the optimal MGD to advance to IND submission, which is expected in 2026.

Our Approach for Immunologic and Inflammatory Diseases

MRT-6160, a highly selective and orally bioavailable VAV1-directed molecular glue degrader (MGD) in development for the treatment of immune-mediated diseases

Overview

VAV1 is a Rho-family guanine nucleotide exchange factor that plays a critical role in T- and B-cell receptor signaling and activity. As many immune-mediated diseases are thought to be driven by an underlying dysregulation or hyperactivation of T- and/or B-cells, a VAV1-directed MGD, which we believe will ameliorate aberrant responses from both cell types, has broad potential application for immune-mediated diseases.

There are multiple published studies providing preclinical data supporting VAV1’s potential as an attractive target for attenuating T- and B-cell activity (summarized by illustration in Figure 34). For example, studies report that VAV1 knockout mice are viable and fertile, but display various loss-of-function T- and B-cell phenotypes, and are protected from experimentally induced autoimmune disease. Other studies describe whole-genome CRISPR screens in primary human T cells that indicate a role for VAV1 as a key player in T-cell function and showing that genetic loss of VAV1 confers loss of IL-2 secretion.

Figure 34: VAV1 is a Highly Validated Target for Attenuating T-cell and B-cell Activity

Furthermore, we have demonstrated, in vivo, once daily oral dosing of MRT-6160 inhibited disease progression in well-established models of multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, as shown in the Figures and discussion below. We believe the public literature, summarized above, coupled with our data package, summarized below, provides strong support for use of a VAV1-directed MGD in multiple systemic and central nervous system autoimmune diseases. Based on this support, we advanced our VAV1 development candidate, MRT-6160 into clinical studies. In August 2024, we announced initiation of our MRT-6160 Phase 1 single ascending dose/multiple ascending dose (SAD/MAD) study. We provide initial results from the Phase 1 study below.

In October 2024, we and Novartis entered into a License Agreement under which Monte Rosa granted to Novartis an exclusive license to develop, manufacture, and commercialize VAV1-directed MGDs including MRT-6160. Monte Rosa is responsible for completing the ongoing Phase 1 clinical study and Novartis is responsible for all subsequent development and commercial activities starting at Phase 2. Monte Rosa received from Novartis an upfront payment of $150 million and is eligible to receive up to $2.1 billion in development, regulatory, and sales milestones, beginning upon initiation of Phase 2 studies and including potential development and regulatory milestone payments, exceeding $1.5 billion if multiple indications achieve regulatory approval in multiple territories. Monte Rosa and Novartis also agreed to a net profit and loss sharing arrangement, in which Monte Rosa will co-fund any global clinical development from Phase 3 onwards and will share 30% of any profits and losses associated with the manufacturing and commercialization of the licensed products in the United States.

Monta Rosa is eligible to receive from Novartis potential sales milestone payments in connection with sales outside of the United States, and tiered royalties on sales outside of the United States. Monte Rosa will continue to be responsible for costs associated with the ongoing Phase 1 clinical study and Novartis will be responsible for costs associated with any subsequent clinical studies except for the Phase 3 cost covered by Monte Rosa under the profit and loss sharing agreement.

Development of VAV1-directed MGDs

A summary of the VAV1 intracellular signaling pathway is illustrated in Figure 35. We believe our VAV1-directed MGDs have the potential to modulate both T- and B-cell function as well as the cross talk between these cell types when activated in autoimmune disease. Despite being a preclinically validated target for attenuating T- and B-cell activity, VAV1 has remained undruggable to date using small molecule inhibitor approaches. Therefore, targeting VAV1 with a VAV1-directed MGD and eliminating its activity could provide therapeutic benefits in multiple T- and/or B-cell mediated autoimmune diseases.

Figure 35: VAV1 is a Key Regulator of T- and B-cell Receptor Activity

VAV1 is an upstream signaling node associated with multiple clinically validated pathways, as shown in Figure 36. These include T cell activation, B cell activation and plasma cell differentiation, Th17 response, and pro-inflammatory cytokine production. Therapies targeting these pathways individually have been approved for multiple autoimmune and inflammatory diseases.

Figure 36: VAV1 is an Upstream Targeting Node Associated with Clinically Validated Pathways

MRT-6160 is a first-in-class molecular glue degrader of VAV1. MRT-6160 forms a strong ternary complex with VAV1 and cereblon through a newly characterized non-canonical degron which was unveiled through application of our QuEENTM discovery engine technologies. The unique character of the VAV1 degron and its interaction with cereblon induced by MRT-6160 result in a high degree of selectivity over commonly degraded neosubstrates and other closely related VAV family proteins. Our studies show that MRT-6160 degrades human VAV1 with a DC50 of 7 nM and Dmax of 97%, is orally bioavailable across species, and displays favorable in vitro ADMET properties. The favorable drug-like profile of MRT-6160 is summarized in Figure 37.

Figure 37: MRT-6160 is a Potent, Selective VAV1 MGD Development Candidate with a Favorable Drug-Like Profile

Degradation of VAV1 in the periphery is observed following MRT-6160 oral administration. Additionally, MRT-6160 has brain penetrance with anticipated dose dependent degradation of VAV1 in the CNS. Non-clinical safety profiling showed a clean profile with respect to mutagenicity (mini-Ames), hERG activity, CYP inhibition and induction, and broad off-target screening (CEREP panel).

Preclinical 28-day GLP toxicology studies in rats and non-human primates (cynomolgus macaque or cyno) demonstrated a highly favorable profile. The no observed adverse effect level (NOAEL) was set at the highest

doses in both species. The exposure at NOAEL for rats was approximately 1000-fold over the projected human efficacious exposure, and the exposure at NOAEL for cynos was approximately 600-fold over the projected human efficacious exposure. In healthy cynos, no adverse immunotoxicity or impact on peripheral immune compartments was observed. There was no observed impact on bone marrow and peripheral hematopoietic cell counts. No gastrointestinal toxicity was observed. Furthermore, there were no off-target effects identified in in-vitro safety profiling, no genotoxicity, no phototoxicity, and no hERG activity.

The potency and selectivity profile of MRT-6160 was evaluated in primary human peripheral mononuclear blood cells (hPBMCs). As shown in Figure 38, left panel, MRT-6160 elicited dose-dependent degradation of VAV1 in primary human T and B cell subsets. As shown in Figure 38, right panel, tandem mass tag (TMT)-global proteomics assessment revealed selective degradation of VAV1 over its closely related family members VAV2 and VAV3 in addition to other proteins expressed in hPBMCs and detectable in the assay.

Figure 38: MRT-6160 Selectively Degraded VAV1 in Primary Human Immune Cells

MRT-6160 was further characterized for anticipated on-target pharmacodynamic and functional activity in primary human T and B cells. As shown in Figure 39, in primary human T cells (top panel), VAV1 degradation by MRT-6160 resulted in inhibition of TCR-mediated pharmacodynamic (CD69) and functional activity (IL-2 secretion and proliferation). In primary human B cells (bottom panel), VAV1 degradation by MRT-6160 resulted in inhibition of BCR-mediated pharmacodynamic (CD69) and functional activity (IL-6 and soluble IgG secretion) demonstrating expected on-target activity in disease-relevant cell types.

Figure 39: VAV1 degradation by MRT-6160 resulted in inhibition of T- and B-cell receptor activity

In vivo validation of VAV1 MGD MRT-6160

To determine the oral bioavailability and subsequent pharmacokinetics (PK) and pharmacodynamics (PD) of MRT-6160 in vivo, mice were orally administered a single dose of 10 mg/kg MRT-6160. PBMC, and spleen samples were collected at 2, 6, and 24 hours post-dosing. As shown in Figure 40, concentrations of MRT-6160 were comparable in both serum and spleen with a proportional decrease over 24 hours (left panel). Furthermore, VAV1 protein levels were reduced in both PBMCs and spleen tissue within 6 hours of administration of MRT-6160 (left panel) and degradation was maintained for 24 hours (left and right panel).

Figure 40: Oral dosing of MRT-6160 led to rapid degradation of VAV1 in vivo

MRT-6160 was evaluated in various well-established T- as well as T- and B-cell mediated in vivo models of autoimmune disease. In a T-cell-mediated experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (Figure 41, left panel), daily oral dosing of MRT-6160 following disease onset inhibited disease

progression in a dose-dependent manner comparable to that of supratherapeutic doses of dexamethasone, a corticosteroid used broadly in autoimmune disease. After 6 days of dosing, samples from mice were assessed by western blot for murine (m) VAV1 levels in diseased tissue. Shown in the right panel of Figure 41, MRT-6160 induced dose-dependent degradation of mVAV1 commensurate with inhibition of disease progression.

Figure 41: MRT-6160 elicited dose-dependent activity in a T-cell mediated Multiple Sclerosis Autoimmune Disease Model

MRT-6160 was also evaluated in a T- and B-cell mediated collagen-induced arthritis (CIA) model of rheumatoid arthritis. Mice were orally administered MRT-6160 daily following disease onset and scored for clinical signs of disease. As shown in Figure 42, left panel, 1 mg/kg MRT-6160 inhibited disease progression comparably to 10 mg/kg anti-TNF-Alpha. The right panel of Figure 42 shows that treatment with MRT-6160 reduced the serum levels of anti-collagen II IgG1 and total anti-collagen II IgG antibodies, demonstrating inhibition of auto-antibody production.

Figure 42: MRT-6160 inhibited disease progression and auto-antibody production in the collagen-induced arthritis disease model

MRT-6160 was also evaluated in a T-cell transfer-induced model of colitis, as shown in Figure 43. In a prophylactic model shown in the left panel, mice were orally administered vehicle or MRT-6160 daily following T-cell transfer. Anti-TNF-Alpha was administered intraperitoneally every third day as a standard of care control. Oral dosing with 1 mg/kg MRT-6160 demonstrated superior disease inhibition compared to 10 mg/kg anti-TNF-Alpha. In a therapeutic model shown in the right panel, mice were orally administered MRT-6160 starting on Day 17 following disease induction. MRT-6160 was compared to two commonly used oral therapies for rheumatoid arthritis, a JAK inhibitor and a S1PR antagonist, as well as vehicle control. MRT-6160 was superior in controlling clinical signs of disease as compared to both active comparators.

Figure 43: MRT-6160 Ameliorated T Cell Transfer-Induced Colitis Equal to or Better than Standard of Care

Figure 44, left panel, shows reduction of inflammation-mediated damage and swelling of the colon with MRT-6160 treatment in the prophylactic T-cell transfer-induced model of colitis. The right panel of Figure 44 shows mesenteric lymph node and colon CD4+ T cell assessment by flow cytometry where MRT-6160 reduced the frequency of IL-17A+, TNF-Alpha+, and IL-6+ CD4+ T cells, known drivers of inflammatory bowel disease in humans.

Figure 44: MRT-6160 Inhibited Inflammation-Mediated Damage and Cytokine Production in a Model of Inflammatory Bowel Disease

Collectively, we believe the preclinical data we have generated for MRT-6160 demonstrate significant on-target attenuation of TCR and BCR-mediated activity both in vitro and in multiple preclinical in vivo models of T- and T/B-cell mediated disease.

MRT-6160 Phase 1 Study

In a Phase 1 study of healthy volunteers, MRT-6160 was dosed in five single ascending dose (SAD) cohorts and three multiple ascending dose (MAD) cohorts, as shown in Figure 45. All cohorts were randomized and placebo controlled, and over 70 subjects were enrolled in total. The primary endpoint of the study was safety and tolerability of MRT-6160. The secondary endpoints were pharmacokinetic and pharmacodynamic assessments using various readouts in multiple different analytes.

Figure 45: MRT-6160 Phase 1 Healthy Volunteers Study Design and Objectives

VAV1 degradation was assessed by flow cytometry of CD3+ T cells and CD19+ B cells, as shown in Figure 46. In addition, ex vivo activation of whole blood was performed to assess T and B cell functions, including CD69 upregulation on T and B cells measured by flow cytometry, and cytokine secretion measured by immunoassay.

Figure 46: In-Vitro Assay Validation of PD and Immune Cell Functional Testing

Analysis of plasma concentrations of MRT-6160 over time demonstrated a dose dependent human pharmacokinetic profile, as shown in Figure 47. MAD dosing resulted in an approximately two-fold increase in exposure at steady. No food effect was observed.

Figure 47: MRT-6160 Displayed a Dose-Dependent Human Pharmacokinetic Profile

As shown in Figure 48, MRT-6160 achieved degradation exceeding 90% at all but DL1 of the single ascending dose cohorts and at all multiple ascending dose cohorts, based on analysis of peripheral blood T cells. Reduction of VAV1 protein levels was sustained, with dose-dependent recovery following cessation of treatment. Similar results were observed in peripheral blood B cells.

Figure 48: MRT-6160 Achieved Dose-Dependent Degradation >90% in Peripheral Blood T cells After Single and Multiple Dose Administration

VAV1 degradation by MRT-6160 resulted in significant functional inhibition of T and B cells following ex vivo activation of T and B cells derived from whole blood, as shown in Figure 49 for all single ascending dose cohorts. MRT-6160 treatment significantly attenuated CD69 upregulation (a marker of immune cell activation) on T and B cells following TCR stimulation, reflecting functional inhibition of both cell types. In addition, MRT-6160 treatment significantly inhibited IL-2, IFN-γ and IL-17A secretion from whole blood derived T cells following ex-vivo activation of TCR, demonstrating reductions up to 99% from pre-dose levels. MRT-6160 also attenuated IL-6 production by 60-90% across dose levels, and over 80% at all but the lowest dose level, following B cell activation. Alignment with the pharmacodynamic studies above suggests robust functional effects on cytokine production can be achieved with 80% and higher degradation of VAV1.

Figure 49: VAV1 Degradation by MRT-6160 Resulted in Significant Functional Inhibition of T and B Cells

Suppression of CD69 upregulation following single or multiple doses of MRT-6160 and ex vivo TCR stimulation of whole blood was significant as well as sustained during post treatment observation periods, as shown in Figure 50 (data for selected SAD and MAD dose shown as example). Marked and sustained suppression of CD69 upregulation (> 90%) was seen in both peripheral blood T and B cells following TCR stimulation. Similar results were observed in peripheral blood B cells following BCR-stimulation.

Figure 50: MRT-6160 Resulted in Sustained Suppression of TCR-mediated CD69 Activation following Single or Multiple Doses of MRT-6160

MRT-6160 demonstrated a sustained effect on TCR-mediated cytokine production following single and multiple dose administration and ex vivo stimulation of whole blood, as shown in Figure 51. MRT-6160 treatment resulted

in significant and sustained suppression of IL-2, IL-17A and IFN-γ secretion from whole blood derived T cells following ex-vivo activation of TCR (data for selected SAD and MAD dose shown as example).

Figure 51: MRT-6160 Resulted in Sustained Suppression of TCR-mediated Cytokine Production following Single or Multiple Doses of MRT-6160

MRT-6160 was well tolerated with no serious adverse events (SAE) observed. Observed treatment-emergent adverse events (TEAEs) were mild (82%) or moderate (18%) and self-limiting. Overall TEAE frequency was similar between MRT-6160 and placebo. TEAE observed in 2 or more subjects treated with MRT-6160 were: in the SAD cohorts, pain from vessel puncture (2); in the MAD cohorts, cough (2), diarrhea (3), feeling hot (4), headache (5), nasal congestion (2), oropharyngeal pain (3) and pyrexia (2).

In summary, the pharmacodynamic and functional ex-vivo studies suggest significant effects on cytokine production can be achieved following treatment with MRT-6160. Furthermore, we believe the levels of VAV1 degradation observed clinically are consistent with levels of degradation we observed to induce efficacy in preclinical models. The functional impact on cytokine production is also consistent with levels predicted to be required to achieve efficacy in humans, based on benchmark clinical data from other compounds.

In summary, we believe the Phase 1 data described here as well as chronic toxicology package support a clear path into Phase 2 studies and broad potential applications of MRT-6160 in multiple immune-mediated diseases.

NEK7-directed MGDs for the treatment of inflammatory disease

Overview

Activation of the NLRP3 inflammasome critically depends on NIMA related kinase 7, or NEK7, a serine/threonine-protein kinase that facilitates assembly of the active NLRP3 inflammasome complex in a kinase-independent manner. The NLRP3 inflammasome is a multi-protein complex that serves as a central node to integrate signals generated by pathogens, damage and stress, and triggers the generation of pro-inflammatory cytokines. As depicted in Figure 52, aberrant NLRP3 inflammasome activation and the subsequent release of active interleukin-1β (IL-1β) and interleukin-18 (IL-18) has been implicated in several inflammation-driven diseases including pericarditis, gout, osteoarthritis, Parkinson’s disease, obesity, and atherosclerosis. The assembly of NEK7 and NLRP3 with ASC and pro-caspase 1 induces cleavage of pro-caspase 1, which then activates the cytokines IL-1β and IL-18 and leads to their release via a cell death event known as pyroptosis. NEK7 has been shown to be required for NLRP3 inflammasome activation and IL-1β release both in vitro and in vivo. Furthermore, our own in vitro and in vivo work, described below, shows that NEK7 is critical for the production of IL-1β downstream of NLRP3 inflammasome activation. Consequently, we believe NEK7 degradation with a highly selective MGD, such as our product candidate MRT-8102, has the potential to inhibit and/or prevent NLRP3 inflammasome activation and the associated downstream production of IL-1β, and thereby to be an important treatment modality for a variety of inflammatory diseases.

Figure 52: NEK7 is a Key Regulator of NLRP3 Inflammasomes, IL-1 and IL-18

Extensive clinical data exists to support the relevance of IL-1 and NLRP3 signaling to multiple diseases in therapeutic areas spanning cardio-immunology, rheumatology, and neurology, as illustrated in Figure 53. For example, rilonacept (IL-1α/β blocker) has demonstrated efficacy and safety for recurrent pericarditis, and canakinumab (IL-1β blocker) treatment in the CANTOS trial resulted in 15% reduction in a combined major adverse cardiac events (MACE) endpoint. Canakinumab treatment also benefited osteoarthritis patients in the CANTOS trial, with a 0.73 hazard ratio (HR) for osteoarthritis-related adverse events (AEs).

Figure 53: IL-1/NLRP3 Signaling is a Clinically Validated Pathway for Inflammatory Diseases

IL-1 is upstream of the acute-phase response, which leads to production of interleukin-6 (IL-6) and C-reactive protein (CRP), as shown in Figure 54. Elevated CRP concentration is a feature of many inflammatory conditions, including acute pericarditis flares and coronary artery disease and CRP is a long-term predictor of atherosclerotic-cardiovascular risk. Several NLRP3 inhibitors have shown promising reductions in CRP in early clinical trials. Our

therapeutic hypothesis is that MRT-8102 may be able to mitigate systemic inflammation by degrading the NEK7 protein, leading to decreased production of IL-1β and lowered serum levels of CRP.

Figure 54: C-reactive Protein (CRP) is an Acute-phase Protein downstream of the NEK7/NLRP3 inflammasome

Plans for clinical development of MRT-8102 are summarized in Figure 55. Safety is expected to be assessed initially in healthy volunteers, after which proof-of-concept studies in asymptomatic subjects with elevated cardiovascular risk as indicated by high levels of CRP, and in cardio-immunological conditions are planned. We believe this study design provides potential for efficient demonstration of broad proof of concept for our therapeutic hypothesis using established endpoints and for maximal optionality for informed future clinical development of MRT-8102. Based on our preclinical data, we are also evaluating development opportunities in gout, pseudogout (calcium pyrophosphate deposition disease), osteoarthritis and other inflammatory conditions.

Figure 55: MRT-8102: Development Path in Peripheral Inflammatory Diseases

Identification of NEK7 degron and NEK7-directed MGDs

NEK7 contains a well-defined degron, as identified using our proprietary QuEENTM discovery engine and confirmed by crystal structure (shown in Figure 56, left panel). The kinase-independent role of NEK7 in activating the NLRP3 inflammasome suggests that inhibition of the catalytic activity of NEK7 would be ineffective in blocking NLRP3 inflammasome activation. Removal of NEK7 by MGD-mediated degradation is expected to inactivate

formation of the NLRP3 inflammasome and is therefore preferable over conventional catalytic inhibition strategies. We have generated MGDs from multiple chemical series that promote the association of NEK7 with cereblon and lead to its degradation. MRT-8102 is a first-in-class NEK7 MGD developed from one of our chemical series that we have advanced into IND-enabling studies. As shown in Figure 56, right panel, MRT-8102 forms a strong ternary complex with NEK7 and cereblon through a canonical G-loop degron that results in profound NEK7 degradation (DC50 10 nM and Dmax 89%). MRT-8102 is highly selective over commonly degraded cereblon neosubstrates and other NEK family members, it is orally bioavailable across species and displays favorable in vitro ADMET properties. Non-clinical safety profiling showed a clean profile with respect to mutagenicity (mini-ames), hERG activity, and broad off-target screening (CEREP panel).

Figure 56: MRT-8102 is a Potent, Selective Development Candidate NEK7 MGD with a Favorable Drug-Like Profile

The amino acid sequence of the NEK7 degron is unique among the NEK family members, indicating the potential to identify MGDs that are highly selective for NEK7. As shown in Figure 57, human peripheral blood mononuclear cells (PBMC) were treated with MRT-8102 for 24 hours, followed by TMT-global proteomic profiling. Highly selective and profound degradation of NEK7 is evidenced by a selective several fold-change decrease in NEK7 protein, without significant changes in other detected proteins. Other NEK family members are highlighted on the volcano plot and were not degraded. Several other cell types, including U937, MM1S and induced pluripotent stem cells (iPSC) revealed similarly selective proteomic profiles when treated with MRT-8102.

In a PK/PD study in cynomolgus monkeys, a single oral dose of 10 mg/kg of MRT-8102 was sufficient to achieve deep and sustained NEK7 degradation beyond the PK exposure window of the compound (Figure 57, right panel).

Figure 57: MRT-8102, a Potent and Highly Selective NEK7-directed MGD, Induces Durable Pharmacodynamic Modulation In Vivo

Development Candidate NEK7 MGD, MRT-8102, showed high potency modulation of the NLRP3 pathway in human monocyte-derived macrophage and cynomolgus whole blood stimulation assays

To assess the functional impact of NEK7 degradation on NLRP3 inflammasome activation, human monocyte-derived macrophages (hMDM) were treated with increasing concentrations of MRT-8102 or selnoflast, an NRLP3 inhibitor. Caspase-1 activation and IL-1β release from hMDM were measured following pre-treatment with MRT-8102 and subsequent exposure to the inflammasome stimulators lipopolysaccharide (LPS) and nigericin.As shown in Figure 58, MRT-8102 led to a dose-dependent decrease in caspase-1 activity (top left) and IL-1β release (bottom left), which was more potent than the effect of selnoflast, a direct inhibitor of the ATPase activity of NLRP3 itself. As shown on the right panel, a flow cytometry-based ASC speck formation assay in human whole blood was performed to measure inflammasome activation. Within the monocyte population, ASC specks were formed upon stimulation with LPS plus nigericin, but this formation was prevented in the presence of 0.1 μM MRT-8102.

Figure 58: MRT-8102 Led to Potent Inhibition of NLRP3 Inflammasome In Vitro

In vivo evaluation of NEK7 MGD MRT-8102 as a potent inhibitor of IL-1β

MRT-8102 is orally bioavailable and has been progressed to in vivo studies in cynomolgus (cyno) monkeys. MRT-8102 was administered once-daily for 5 days at 0.2 mg/kg to a single male and female cyno monkey. PBMC samples were collected at 0 (pre-dose) and 24 hours post-dose on Days 1 and 5, and on Day 10. As shown in Figure 59, left panel, data represent the average cyno PBMC NEK7 protein levels on the y-axis. PBMC NEK7 levels showed a reduction to 40% of pre-dose levels on day 1, with a further reduction to 27% by day 5. Upon ceasing MRT-8102 administration, NEK7 protein recovered to 88% of pre-dose levels by day 10.

Commensurate with NEK7 levels, production of IL-1β was inhibited in an ex vivo whole blood stimulation assay, shown in Figure 59, middle panel. Similar results were obtained when measuring caspase-1 activity following ex-vivo stimulation, in Figure 59 right panel. The deep and sustained inhibition of IL-1β release and caspase-1

activity in the ex vivo assay after oral administration over five consecutive days suggests that MRT-8102 is capable of controlling inflammation driven by IL-1β.

Figure 59: In Vivo Dosing of MRT-8102 in Cynomolgus Monkeys Led to NEK7 Degradation and Inhibition of Both IL-1β Release and Caspase-1 Activity

MRT-8102 showed activity in an in vivo model of gout

Daily oral dosing of MRT-8102 at 50 mg/kg reduced pathogenic effects associated with gout driven by intra-articular injection of monosodium urate (MSU) crystals in rabbits, including reduction in joint swelling, musculoskeletal ultrasound (MSKUS) pathologic findings, and cumulative histopathology scores as assessed by a blinded pathologist.

Figure 60: MRT-8102 reduced MSU crystal-driven effects in a rabbit gout model

MRT-8102 GLP toxicology study suggests considerable safety margin

In 28-day repeat-dose GLP toxicology studies in male and female rats and cynomolgus monkeys, no MRT-8102 related clinical signs, no changes in immunophenotyping, and no gross or clinical pathology findings were observed at any dose level. In these studies, a no-observed-adverse-effect level (NOAEL) was established at 150 mg/kg/day and 100 mg/kg/day (the highest doses tested), respectively, leading for both species to a greater than

200-fold exposure margin over the projected human efficacious dose. Additional IND-enabling GLP safety studies did not indicate significant safety concerns related to in vitro off-targets, mutagenicity, phototoxicity, hERG or in vivo respiratory or CNS safety pharmacology (assessed in rats) or cardiovascular safety pharmacology (assessed in cyno).

MRT-8102 is currently completing IND-enabling studies with IND submission expected in the first half of 2025.

NEK7 MGDs for diseases of the CNS

The NLRP3 inflammasome plays a crucial role in inflammatory responses in the CNS and represents a promising therapeutic target for the treatment of neurological diseases associated with neuroinflammation. The identification of multiple chemical series within the NEK7 program offers a significant opportunity for the development of multiple drug-like MGDs with differentiated distribution profiles. Our NEK7-directed MGDs are selective, orally bioavailable and can be tuned to penetrate the blood-brain-barrier, and hence are potentially applicable to target inflammatory diseases of the CNS, including those with CNS and peripheral organ involvement, as illustrated in Figure 61.

Figure 61: Brain-Penetrant NEK7 MGDs Have Potential to Impact Neurodegeneration, Obesity and Other Diseases

We have identified NEK7 MGDs from a structurally distinct chemical series with high potency and selectivity for NEK7 degradation, favorable in vitro ADMET properties and excellent blood-brain-barrier penetration.

To assess the functional impact of one such brain-penetrant MGD on NLRP3 inflammasome activation, hMDM were treated with increasing concentrations of the CNS-optimized NEK7-directed MGD MRT-51126 or the NLRP3 inhibitor selnoflast, as shown in Figure 62. Caspase-1 activation and release of IL-1β, IL-1α and IL-18 from hMDM was measured following pre-treatment with our MGD and subsequent exposure to inflammasome stimulators LPS and nigericin.As shown in Figure 62, MRT-51126 led to a dose-dependent decrease in caspase-1 activity and IL-1β, IL-1α and IL-18 release, which was more potent than the effect of selnoflast.

Figure 62: MRT-51126 Demonstrated Potent Inhibition of NLRP3 Inflammasome In Vitro

MRT-51126 demonstrated substantial reduction in inflammatory cytokines in the brain after induction of neuroinflammation using multiple doses of LPS in mice, as shown in Figure 63. Specifically, CereblonI391Vmice, a mouse strain expressing a humanized version of cereblon, dosed with LPS three times daily at 1 mg/kg intraperitoneally and MRT-51126 at 30 mg/kg orally twice daily, showed significantly reduced levels of NEK7 protein in the brain (left panel), along with lower levels of IL-1β (middle panel) and IL-6 (right panel) in brain tissue, relative to animals dosed with LPS and vehicle control.

Figure 63: MRT-51126 Inhibited Brain Cytokines in an LPS-induced Neuroinflammation Model in Mice

In a study in cynomolgus (cyno) monkeys, multiple dosing of MRT-51126 at 0.5 mg/kg demonstrated profound NEK7 degradation in cyno peripheral blood mononuclear cells (PBMC) and in cyno cerebrospinal fluid (CSF), as shown in Figure 64.

As shown in the left panel, PBMC NEK7 levels showed a reduction to 39% of pre-dose levels on day 1, that was further reduced to 3% of pre-dose level by day 5. Additionally, NEK7 protein levels were measured in the cerebrospinal fluid (CSF; middle panel) and deep degradation was observed after the first and final doses. Commensurate with NEK7 levels, production of IL-1β was inhibited in an ex vivo whole blood stimulation assay, shown in Figure 64, right panel. The deep and sustained inhibition of IL-1β release in the ex vivo assay after oral administration over five consecutive days suggests that MRT-51126 is capable of controlling inflammation driven by IL-1β.

Figure 64: MRT-51126 Demonstrated Profound NEK7 Degradation and Pathway Inhibition In Vivo Over Several Days in Cynomolgus Monkey

Other programs

We are specifically focused on developing product candidates for target proteins that have been deemed undruggable or inadequately drugged. Our QuEENTM discovery engine was purpose-built to support the discovery and development of drugs that degrade a wide landscape of therapeutically relevant proteins by (i) systematically identifying therapeutically relevant target proteins that may be amenable to molecular glue-based degradation; and (ii) rationally designing MGD molecules that can be optimized towards high potency and selectivity, with properties that we believe to be favorable, so to become MGD product candidates. Our pipeline includes programs in immunology and inflammation (I&I) indications as well as in oncology. We also have early-stage efforts in areas including cardiovascular, metabolic and genetic diseases.

The primary focus of our discovery efforts for 2025 is building a portfolio of additional oral MGDs for immunology and inflammation indications. We believe that the strengths of MGDs align very well with requirements for I&I drugs, as shown in Figure 65. Namely, we have shown that MGDs can achieve deep degradation of target proteins in immune and blood cells as cereblon is expressed highly in those cells and in immune relevant sites and organs; the catalytic mechanism of action of MGDs drives a sustained pharmacodynamic effect, potentially allowing for dose regimens that are convenient for patients; the exquisite selectivity of MGDs enables a high therapeutic index; and MGDs have the potential to deplete both membrane receptors and intracellular signaling nodes critical for immune cell regulation.

Figure 65: MGD Strengths Align with I&I Requirements

We are advancing novel discovery programs for I&I targets that we believe have the potential to be highly differentiated, by designing oral MGD product candidates that are 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-targeting antibodies and biologics, as illustrated in Figure 66.

Figure 66: Degrading Undruggable Targets in Critical I&I Disease Pathways

Our services, collaboration and licenses agreements

Roche agreement

On October 16, 2023, Monte Rosa AG entered into a Collaboration and License Agreement with Roche Basel and Roche US, and together with Roche Basel, Roche, or the “Roche Agreement”. Pursuant to the Roche Agreement, the parties will seek to identify and MGDs against cancer or neurological disease targets using our proprietary drug discovery platform for an initial set of targets in oncology and neuroscience selected by Roche, with Roche having an option to expand the collaboration with an additional set of targets under certain conditions, each target being subject to certain substitution rights owned by Roche. We will lead preclinical discovery and research activities until a defined point. Upon such point, Roche gains the right to exclusively pursue further preclinical and clinical development activities.

Under the Roche Agreement, Roche will have a worldwide, exclusive license under patents and know-how controlled by us to develop and commercialize products directed to applicable targets. The research collaboration activities governed by the Roche Agreement will be overseen by a joint research committee.

Under the terms of the agreement, we received an upfront payment of $50 million, and are eligible to receive future preclinical, clinical, commercial and sales milestone payments that could exceed $2 billion, including up to $172 million for achieving preclinical milestones. Roche has an option to expand the collaboration with an additional set of targets under certain conditions. For the optional additional targets, we are entitled to receive from Roche an upfront payment of up to $28 million, and potential preclinical, clinical, commercial, and sales milestones exceeding $1 billion. We are also eligible to receive tiered royalties ranging from high-single-digit percent to low-teens percent on any products that are commercialized by Roche as a result of the collaboration.

Unless earlier terminated, the Roche Agreement will remain in effect for each product licensed under the Roche Agreement until expiration of the royalty term for the applicable product. The parties have included customary termination provisions in the agreement, allowing termination of the Roche Agreement in its entirety, on a country-by-country or a target-by-target basis.

Novartis agreement

On October 25, 2024, Monte Rosa AG and Novartis entered into a global exclusive development and commercialization license agreement, or the Novartis Agreement. Pursuant to the Novartis Agreement, we granted to Novartis an exclusive, royalty-bearing, sublicensable and transferable license to develop, manufacture, and commercialize VAV1 MGDs, including MRT-6160, which is currently in Phase 1 clinical development for immune-mediated conditions. We are responsible for completing the ongoing Phase 1 clinical study and Novartis is responsible for all subsequent development and commercial activities starting at Phase 2. Development and commercial activities governed by the Novartis Agreement will be overseen by a Development Committee and a Commercialization Committee.

Pursuant to the Novartis Agreement, we received from Novartis an upfront payment of $150 million, and are eligible to receive from Novartis (1) up to $2.1 billion in development, regulatory, and sales milestones, beginning upon initiation of Phase 2 studies including (a) potential development and regulatory milestone payments, exceeding $1.5 billion if multiple indications achieve regulatory approval in multiple territories, (b) potential sales milestones payments in connection with sales outside of the United States, and (2) tiered royalties on sales outside of the United States. We will continue to be responsible for costs associated with the ongoing Phase 1 clinical study and Novartis will be responsible for costs associated with any subsequent clinical studies. We and Novartis also agreed to a net profit and loss sharing arrangement, pursuant to which we will co-fund any global clinical development from Phase 3 onwards and will share 30% of any profits and losses associated with the manufacturing and commercialization of the licensed products in the United States. We have defined opportunities to opt out of the net profit and loss sharing arrangement, in such case, sales in the United States would be entitled to the potential sales milestones payments and tiered royalties on sales available outside of the United States. Any costs for any co-funded development and commercialization activities are subject to budgets reviewed by the Development Committee and Commercialization Committee, respectively. The Novartis Agreement includes customary termination provisions, including Novartis’ ability to terminate the Novartis Agreement in its entirety. On December 11, 2024, we announced the closing of the Novartis Agreement.

Competition

The biotechnology industry is extremely competitive in the race to develop new products and the industry is characterized by a high level of innovation and strong emphasis on proprietary products and intellectual property

rights. While we believe we have significant competitive advantages due to our management team’s years of expertise in protein degradation, molecular glues and clinical and preclinical development of precision medicines in general, coupled with our unique scientific expertise and our growing portfolio of intellectual property rights, we currently face and will continue to face competition for our development programs from other companies that develop heterobifunctional degraders, similar molecular glue degraders or have protein degradation development platforms and their own associated intellectual property. Our competition will also include companies focused on existing and novel therapeutic modalities such as small molecule inhibitors antibodies and gene therapies. The competition is likely to come from multiple sources, including large and specialty pharmaceutical companies, biotechnology companies and academic institutions that are in the business of research, development, manufacturing and commercialization. Moreover, the existence of large numbers of patents and frequent allegations of patent infringement is typical in our industry.

The main competitors in our efforts to develop targeted protein degraders or MGD therapeutics for patients, include, but are not limited to, C4 Therapeutics, Inc., Nurix Therapeutics, Inc., Kymera Therapeutics, Inc., Bristol-Myers Squibb, Novartis, all of whom have reported having TPD or MGD product candidates in preclinical or clinical development. Several large pharmaceutical companies have disclosed investments in the TPD field.

In addition to the competitors we face in developing small molecule-based protein degraders, we will also face competition in the indications we expect to pursue with our MGD programs. Many of these indications already have approved standards of care which may include existing therapeutic modalities. In order to compete effectively with these existing therapies, we will need to demonstrate that our MGDs perform favorably when compared to existing therapeutics.

Manufacturing

We do not own or operate manufacturing facilities for the production of our product candidates and we currently have no plans to build our own clinical or commercial scale manufacturing capabilities. We currently contract with third-party contract manufacturing organizations, or CMOs, for the manufacture of our product candidates and we intend to continue to do so in the future. We rely on and expect to continue to engage on third-party manufacturers for the production of both drug substance and finished drug product. We currently obtain our supplies from these manufacturers on a purchase order basis and do not have long-term supply arrangements in place. Should any of these manufacturers become unavailable to us or their services to us become delayed for any reason, we believe that there are a number of potential replacements, although we may incur some delay in identifying and qualifying such replacements.

Intellectual property

We are an innovation-driven company and we seek to aggressively protect the innovations, intellectual property, and proprietary technology that we generate that we consider important to our business, including by pursuing patent applications that cover our product candidates and methods of using the same, innovations around our industry leading QuEENTM discovery engine and our proprietary library of MGDs, as well as any other relevant innovations, inventions, and improvements that are considered potentially commercially relevant to the development of our business and to maintain our perceived competitive advantages. We also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our proprietary and intellectual property position. For our product candidates, we generally pursue patent protection covering compositions of matter, pharmaceutical compositions, methods of use, including combination therapies, methods of administration including dosing methods, methods for monitoring potential clinical events, compositions and methods for personalizing, monitoring, and potentially refining clinical use, including biomarkers, processes of manufacture and process intermediates, where relevant. For our QuEENTM discovery engine, we generally intend to pursue patent protection covering our approaches, methods, and research and development tools. We continually assess and iteratively refine our intellectual property strategies as we develop new innovations and product candidates. We currently plan to continue to invest in filing additional patent applications based on our intellectual property strategies to build value in our business and/or to improve our business and potential partnering opportunities, where appropriate.

Our commercial success depends, in part, on our ability to obtain, maintain, enforce and protect our intellectual property and other proprietary rights for the technology, inventions and improvements we consider important to our business, and to defend any patents we may own or in-license in the future, prevent others from infringing any patents we may own or in-license in the future, preserve the confidentiality of our trade secrets, and operate

without infringing, misappropriating or otherwise violating the valid and enforceable patents and proprietary rights of third parties.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our product candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted. However, our pending provisional and Patent Cooperation Treaty (PCT) patent applications, and any patent applications that we may in the future file or license from third parties, may not result in the issuance of patents and the validity and/or enforceability of any of our issued patents may be challenged by third parties. Further, as with other companies, the patents we may obtain do not guarantee us the right to practice our technology in relation to the commercialization of our products. Regarding obtaining issued patents, here in the United States as well as in other jurisdictions of interest to our business, the patent positions for biopharmaceutical companies like us are generally uncertain and can involve complex legal, scientific, and factual issues. Further, the laws governing the protection of intellectual property may change over time due to the issuance of new judicial decisions or the passage of new laws, rules or regulations. In addition, the coverage claimed in a patent application can be significantly reduced before a patent is issued and its scope can be reinterpreted and challenged even after issuance. As a result, we cannot guarantee that any of our product candidates will be protected or remain protectable by valid, enforceable patents. We also cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented, or invalidated by third parties.

The exclusivity terms of our patents depend upon the laws of the countries in which they are obtained. In the countries in which we currently intend to file, the patent term is 20 years from the earliest date of filing of a non-provisional patent application. The term of a U.S. patent may be extended to compensate for the time required to obtain regulatory approval to sell a drug (referred to as a patent term extension) or by delays encountered during patent prosecution that are caused by the United States Patent and Trademark Office (referred to as patent term adjustment). For example, the Hatch-Waxman Act permits a patent term extension for FDA-approved new chemical entity drugs of up to five years beyond the ordinary expiration date of one patent that covers the approved drug or its use. The length of the patent term extension is related to the length of time the drug is under regulatory review and diligence during the review process. Patent term extensions in the United States cannot extend the term of a patent beyond a total of 14 years from the date of product approval and only one patent covering an approved drug or its method of use may be extended. A similar kind of patent extension, referred to as a Supplementary Protection Certificate, is available in Europe. Legal frameworks may also be available in certain other jurisdictions to extend the term of a patent. We currently intend to seek patent term extensions for our products on any of our issued patents in any jurisdiction where we have a qualifying patent and the extension is available; however, there is no guarantee that the applicable regulatory authorities, including the FDA in the United States, will agree with our assessment of whether extensions of this nature should be granted and, even if granted, the length of these extensions. Further, even if any of our patents are extended or adjusted, those patents, including the extended or adjusted portion of those patents, may be held invalid or unenforceable by a court of final jurisdiction in the United States or a foreign country.

Patents and Patent Applications

As of December 31, 2024, we solely owned a patent portfolio that included thirty-nine (39) pending patent families, including pending patent applications filed under the Patent Cooperation Treaty, national and regional phase patent applications, and multiple pending United States provisional patent applications. Our portfolio is built to cover our MGDs product candidates and various uses thereof, and our industry-leading QuEENTM discovery engine, as further described below. Patent prosecution related to our portfolio is currently in the early stages and, as such, only two patent applications have proceeded to allowance in the United States.

Wholly Owned Product Candidates

With respect to our GSPT1 program, as of December 31, 2024, our portfolio included one granted US patent, one pending PCT patent application, ten pending non-provisional patent applications in the United States, and patent applications in Australia, Canada, Chile, China, Europe, Israel, Japan, Mexico, Nigeria, New Zealand, Singapore and South Africa that cover various GSPT1-directed MGDs and uses thereof. These patent applications are drawn to composition of matter, pharmaceutical compositions, and methods of using our GSPT1-directed MGDs. We also own one pending European patent application that covers biomarkers related to use of our GSPT1-directed MGDs. The earliest scheduled expiration of any U.S. or foreign patent drawn to our GSPT1-directed MGDs, if such patent is issued, would be 2040, excluding any additional term for available patent term adjustment or patent term extension, and assuming timely payment of all applicable maintenance or annuity fees.

With respect to our CDK2 program, as of December 31, 2024, our portfolio included two pending PCT applications, two pending non-provisional patent applications in the United States, two pending United States provisional patent applications, and a pending European patent application, that cover various CDK2-directed MGDs and uses thereof. The earliest scheduled expiration of any U.S. or foreign patents issuing from these patent applications, if such patents are issued, would be 2042, excluding any additional term for available patent term adjustment or patent term extension.

With respect to our NEK7 program, as of December 31, 2024, our portfolio included one pending PCT patent application and two U.S. provisional patent applications that cover various NEK7-directed MGDs and uses thereof. The earliest scheduled expiration of any U.S. or foreign patents issuing from these U.S. provisional patent applications, if such patents are issued, would be 2044, excluding any additional term for available patent term adjustment or patent term extension.

With respect to our CCNE1 program, as of December 31, 2024, our portfolio included one pending U.S. provisional patent application that covers CCNE1-directed MGDs.

With respect to our VAV1 program, on October 25, 2024, the patent rights protecting our VAV1 MGDs were exclusively licensed to Novartis Pharma AG.

QuEENTM discovery engine

With respect to our QuEENTM discovery engine, as of December 31, 2024, our portfolio included three pending PCT patent applications, four pending U.S. non-provisional patent applications, one U.S. provisional patent application, and a pending European patent application, that protect our QuEENTM discovery engine and uses thereof for the design, discovery, and development of MGD product candidates. The earliest scheduled expiration of any U.S. or foreign patent issuing from these U.S. provisional patent applications, if such patents are issued, would be 2042, excluding any available additional term for patent term adjustment or patent term extension.

Trademarks

As of December 31, 2024, we owned various registered and unregistered trademarks in the United States and Switzerland, including Monte Rosa, Monte Rosa Therapeutics and our housemark ‘M’ logo.

Trade Secrets and Know How

As an innovation driven biotechnology company, we rely on trade secrets, technical know-how and continuing innovation to develop and maintain the competitive advantage relevant to our business. Under the agreements we enter into with our employees and consultants, full rights in any intellectual property are assigned to us. We also rely on confidentiality or other agreements with our employees, consultants, other advisors and business partners to protect our proprietary information. Our policy is to require third parties that receive material confidential information to enter into confidentiality or other agreements with us that contain appropriate protections for our confidential and trade secret information.

Government regulation

The FDA and other regulatory authorities at federal, state and local level, as well as in foreign countries and local jurisdictions, extensively regulate among other things, the research, development, testing, manufacture, quality control, sampling, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record-keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs. We, along with our vendors, contract research organizations, or CROs, and contract manufacturers, will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our product candidates. The process of obtaining regulatory approvals of drugs and ensuring subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

In the U.S., the FDA regulates drug products under the Federal Food, Drug, and Cosmetic Act, or FD&C Act, as amended, its implementing regulations and other laws. If we fail to comply with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other legal requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale, we may become subject to administrative or judicial sanctions or other legal consequences. These sanctions or consequences could include, among other things, the FDA’s refusal to approve pending applications, issuance of clinical holds for ongoing studies, withdrawal of approvals, warning or untitled letters, product withdrawals or recalls, product seizures,

relabeling or repackaging, total or partial suspensions of manufacturing or distribution, injunctions, fines, civil penalties or criminal prosecution.

The process required by the FDA before a drug may be marketed in the U.S. generally involves the following:

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completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice, or GLP, requirements;

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submission to the FDA of an IND application, which must become effective before clinical trials may begin;

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approval by an IRB or independent ethics committee at each clinical trial site before each trial may be initiated;

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performance of adequate and well-controlled clinical trials in accordance with applicable IND regulations, GCP requirements and other clinical trial-related regulations, to establish the safety and efficacy of the investigational product for each proposed indication;

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submission to the FDA of a NDA;

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a determination by the FDA within 60 days of its receipt of a New Drug Application, or an NDA, to accept the filing for review;

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satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

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potential FDA audit of the clinical trial sites that generated the data in support of the NDA;

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payment of user fees for FDA review of the NDA; and

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FDA review and approval of the NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the U.S.

Preclinical studies and clinical trials for drugs

Before testing any drug in humans, the product candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluations of drug chemistry, formulation and stability, as well as in vitro and animal studies to assess safety and in some cases to establish the rationale for therapeutic use. The conduct of preclinical studies is subject to federal and state regulations and requirements, including GLP requirements for safety/toxicology studies. The results of the preclinical studies, together with manufacturing information and analytical data must be submitted to the FDA as part of an IND. An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before clinical trials may begin. Some long-term preclinical testing may continue after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises concerns or questions about the conduct of the clinical trial, including concerns that human research patients will be exposed to unreasonable health risks, and imposes a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. Submission of an IND may result in the FDA not allowing clinical trials to commence or not allowing clinical trials to commence on the terms originally specified in the IND.

The clinical stage of development involves the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirements that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters and criteria to be used in monitoring safety and evaluating effectiveness. Each protocol, and any subsequent amendments to the protocol must be submitted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable related to the anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative, and must monitor the clinical trial until completed. The FDA, the IRB or the sponsor may suspend or discontinue a clinical trial at any time on various grounds, including a finding that the patients are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which

provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trials to public registries. Information about applicable clinical trials, including clinical trial results, must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.

A sponsor who wishes to conduct a clinical trial outside of the U.S. may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor must submit data from the clinical trial to the FDA in support of an NDA. The FDA will accept a well-designed and well-conducted foreign clinical trial not conducted under an IND if the trial was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Clinical trials to evaluate therapeutic indications to support NDAs for marketing approval are typically conducted in three sequential phases, which may overlap or be combined.

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Phase 1—Phase 1 clinical trials involve initial introduction of the investigational product into healthy human volunteers or patients with the target disease or condition. These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, excretion the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness. In the case of some products for severe or life-threatening diseases, such as cancer, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

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Phase 2—Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

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Phase 3—Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval and physician labeling. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA. Written IND safety reports must be submitted to the FDA and the investigators fifteen days after the trial sponsor determines the information qualifies for reporting for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human volunteers and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must also notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than seven calendar days after the sponsor’s initial receipt of the information.

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GLUE · 10-K · period ended 2024-12-31

Item 1. Business

GLUE US Equity☆

GLUE · 10-K · period ended 2024-12-31

Item 1. Business

GLUE US Equity