10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2023

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, 2023, was $234.3 million.

The number of shares of Registrant’s Common Stock outstanding as of March 11, 2024 was 50,154,073.

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 71

Item 1B. Unresolved Staff Comments 124

Item 1C. Cybersecurity 124

Item 2. Properties 124

Item 3. Legal Proceedings 125

Item 4. Mine Safety Disclosures 125

PART II

Item 6. [Reserved] 127

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 135

Item 8. Financial Statements and Supplementary Data 135

Item 9A. Controls and Procedures 136

Item 9B. Other Information 136

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 136

PART III

Item 10. Directors, Executive Officers and Corporate Governance 137

Item 11. Executive Compensation 137

Item 14. Principal Accountant Fees and Services 137

PART IV

Item 15. Exhibits and Financial Statement Schedules 138

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 and NEK7-directed MGD, MRT-8102;

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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 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 platform, called QuEENTM, and to expand our proteomics and translational medicine capabilities;

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the potential advantages of our platform technology and product candidates;

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the extent to which our scientific approach and platform 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 platform technologies;

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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 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 one 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 platform 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 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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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. 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 have developed a proprietary and industry leading platform, 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 platform has identified numerous proteins for potential targeting by our MGDs, including those 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 400 unique low molecular weight scaffolds and about 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 platform.

We prioritize our product development on therapeutic target proteins backed by strong biological and genetic rationales. We are focused on developing solutions to clinically important indications, including oncology, inflammation, immunology, and others.

Our most advanced product candidate, MRT-2359, is an orally bioavailable MGD targeting the translation termination factor protein GSPT1. MRT-2359 is currently in clinical development for potential use in MYC-driven tumors, including metastatic non-small cell lung cancer, or NSCLC, small cell lung cancer, or SCLC, and high-grade neuroendocrine tumors. Our pre-clinical 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 creates a potential vulnerability in multiple MYC-driven tumors. The U.S. Food and Drug Administration or the “FDA” cleared the company’s investigational new drug application or “IND” for MRT-2359 in September 2022, and we initiated a phase 1/2 clinical trial for the treatment of MYC-driven solid and high-grade neuroendocrine tumors in October 2022. In October 2023, we presented interim data from the Phase 1 dose escalation part of our Phase 1/2 clinical trial of MRT-2359 demonstrating favorable pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and early, but we believe promising, signs of clinical activity, including tumor size reductions in patients with biomarker-positive cancers. In January 2023, MRT-2359 received Fast Track designation from the FDA for the treatment of patients with previously treated, metastatic NSCLC with L-MYC or N-MYC expression. In June 2023, MRT-2359 received Orphan Drug Designation from FDA for treatment of small cell lung cancer (SCLC). In December 2023, MRT-2359 received Fast Track Designation from the FDA for the treatment of patients with previously treated, metastatic SCLC with L-MYC or N-MYC expression.

Beyond GSPT1, we are advancing our pipeline of assets towards the clinic. Specifically, our VAV1 product candidate, MRT-6160, has concluded IND-enabling safety assessment and is advancing towards an anticipated U.S. FDA IND filing in Q2 of 2024, and clinical study initiation is expected in mid 2024. VAV1 plays a critical role in T- and B-cell receptor signaling and activity. As most autoimmune diseases are driven by an underlying dysregulation or hyperactivation of T- and/or B-cell receptor signaling, a VAV1-directed MGD such as MRT-6160 offers potential to ameliorate aberrant responses from both cell types to treat multiple T- or T-/B-cell mediated autoimmune diseases including inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and others.

In addition, we recently disclosed our first product candidate for our NEK7 program, MRT-8102, which is now in IND-enabling studies, with an IND filing with the FDA planned for Q1 of 2025.

Further our CDK2 program is in lead optimization and continues to advance towards product candidate selection. Our pipeline also includes multiple additional undisclosed discovery phase programs.

Our proprietary QuEENTM platform uniquely enables us to rationally design and develop our diverse library of MGDs and to deploy them against target proteins identified through our AI/ML approach. Uniquely, many of these target proteins are considered inadequately drugged or completely undruggable by other therapeutic modalities. 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 platform 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 platform are:

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AI/ML engines: Our proprietary AI/ML engines enable us to a) identify targets and associated E3 ligases leveraging the surface features on a protein that serve as MGD-dependent points of interaction between an E3 ligase and a therapeutically-relevant protein; b) rapidly guide the design and optimization of novel MGDs, using virtual screening, generative designs, absorption, distribution, metabolism, excretion, and toxicity, or ADMET, and synthesis models, and ternary complex models of an E3 ligase, an MGD, and a target protein or neosubstrate; and c) connect MGDs and their biological activity to disease-relevant biomarkers.

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High throughput screening, structural biology and proteomics capabilities: Our specialized and tailored suite of biochemical, structural biology, cellular, and proteomics assays and capabilities that enable and accelerate the discovery and optimization of MGD product candidates that efficiently recruit target proteins to E3 ligases.

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Proprietary MGD library: A wholly-owned, proprietary, diverse, and continuously growing chemical library of currently around 50,000 MGDs that we have rationally designed based on our growing expertise in molecular glue anatomy and design, large proteomics and screening databases, and AI/ML algorithms. Library compounds currently represent more than 400 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 the platform.

Our most advanced product candidate, MRT-2359, is a potent, highly selective orally bioavailable MGD of the translation termination factor protein GSPT1. MRT-2359 was identified using QuEENTM and is currently in development as a potential treatment for cancers dependent on or characterized by the expression of high levels of MYC family genes (c-MYC, L-MYC and N-MYC). The MYC transcription factors are some of the most frequently mutated, translocated and highly expressed oncogenes in human cancers and we propose targeting GSPT1 as a strategy for therapeutically addressing these cancers. MYC-driven cancer cells are highly addicted to protein translation, and we have shown in extensive pre-clinical studies that due to the key role of GSPT1 in protein synthesis, selective GSPT1 degradation by MRT-2359 in cells expressing high levels of L- or N-MYC leads to cell death. Further, we have demonstrated in these MYC-driven preclinical models that MRT-2359 potently and selectively induces GSPT1 degradation, leading to tumor regression after oral administration as a single agent. We have also shown that MRT-2359 combines with a variety of other agents, including androgen-receptor and estrogen-receptor antagonists, as well as mTOR inhibitors, and prevents development of resistance in a preclinical setting. Based on these preclinical results, we initiated clinical trials with MRT-2359 in October 2022. The Phase 1/2, open-label, multicenter study was designed to primarily assess the safety, tolerability, pharmacokinetic or “PK”, pharmacodynamic or “PD” and preliminary clinical activity of MRT-2359 in patients with previously treated selected solid tumors, including NSCLC, SCLC, high-grade neuroendocrine cancer of any primary site, diffuse large B-cell lymphoma or “DLBCL” and solid tumors with L-MYC or N-MYC amplification. In October 2023, we disclosed interim clinical data including PK, PD, safety and available initial efficacy from the Phase 1 arm of the ongoing Phase 1/2 clinical trial evaluating MRT-2359. Interim data demonstrated favorable pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and early, but we believe promising, signs of clinical activity, including tumor size reductions in patients with biomarker-positive cancers. We expect to announce the recommended Phase 2 dose for the MRT-2359 Phase 1/2 study in Q2 2024 and report updated Phase 1 clinical results thereafter. We also expect to initiate the Phase 2 portion of the study before year-end 2024.

Our development candidate for VAV1, MRT-6160 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader of VAV1, which in our in vitro studies has shown deep degradation of its

target with no detectable effects on other proteins. VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T- and B-cell receptors. VAV1 expression is restricted to blood and immune cells, including T and B cells. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor activity. This modulation is evident both in vitro and in vivo, demonstrated by a significant decrease in cytokine secretion, proteins vital for maintaining autoimmune diseases. Moreover, VAV1-directed MGDs have shown promising activity in preclinical models of neurologic and systemic autoimmune diseases and thus we believe have the potential to provide therapeutic benefits in multiple autoimmune indications, such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and dermatological disorders. Preclinical studies demonstrate MRT-6160 inhibits disease progression in in vivo autoimmunity models. We expect to submit an IND for MRT-6160 in Q2 2024 and to initiate a Phase 1 single ascending dose / multiple ascending dose, or SAD/MAD, study in healthy volunteers in mid-2024.

Our development candidate for NEK7, MRT-8102, is a potent, highly selective, and orally bioavailable investigational molecular glue degrader of NEK7 and an inhibitor of the IL-1β and NLRP3 inflammasome pathway. MRT-8102 is the first development candidate for our NEK7 program, targeting diseases driven by IL-1β and the NRLP3 inflammasome. The NLRP3 inflammasome is a multiprotein complex that serves as a central node to integrate cellular signals generated by pathogens, 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 gout, cardiovascular disease, neurological disorders including parkinson's disease and alzheimer's disease, ocular disease, diabetes, obesity, and liver disease. 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 an attractive therapeutic approach to preventing NLRP3 activation and release of IL-1β. In light of the strategic importance of our NEK7 program, we are advancing a second, differentiated chemical series through Lead Optimization.

Our QuEENTM platform continues to generate discovery stage programs targeting therapeutically relevant proteins otherwise considered undruggable or inadequately drugged. We have been able to identify highly selective MGDs for CDK2, an oncology target and key driver of cancers such as breast, ovarian, and uterine cancer. Our CDK2 program is currently in lead optimization and we have identified selective and orally bioavailable molecules that show activity in preclinical in vivo models of hormone receptor positive breast cancer as single agents or in combination with CDK4/6 inhibitors.

We also continue to progress 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 pre-clinical discovery and research activities until a defined point. Upon such point, Roche gains the right to exclusively pursue further pre-clinical 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 pre-clinical 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 pre-clinical, 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.

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 platform 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 oncology, inflammation, immunology and other diseases with high unmet needs. We currently retain exclusive worldwide rights to the programs shown in the Figure 1 below, except for the discovery targets included in the Roche collaboration.

Figure 1: Monte Rosa Pipeline

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 platform can provide distinct advantages over other modalities to address target proteins that have been considered undruggable or inadequately drugged.

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. 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 specificity, 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 a vast universe of target proteins not limited to those with 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 that may be beneficial in a broad range of indications, including oncology, immunology, inflammation, metabolic 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 VAV1-directed MGD MRT-6160 and our MGDs for NEK7, including MRT-8102.

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. These proteins may have a predominant scaffolding role , such as VAV1 and NEK7, an active site that is hard to target, such as VAV1, or may be considered to be undruggable by conventional small molecules. 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. MRT-2359 showed evidence of tumor size reductions, including partial responses, in heavily pretreated patients with biomarker-positive tumors. Optimal PD modulation of GSPT1 in peripheral blood mononuclear cells and tumor tissue biopsies was observed at all dose levels, consistent with its designed activity based on preclinical studies. We have generated data in preclinical models that demonstrate the potential of our GSPT1-directed MGDs to confer antitumor activity across multiple tumor types that are characterized by the expression of high levels of theMYC family of transcription factors. In January 2023, MRT-2359 received Fast Track designation from the FDA for the treatment of patients with previously treated, metastatic, NSCLC with L-MYC or N-MYC expression. In June 2023, MRT-2359 received Orphan Drug Designation from FDA for treatment of small cell lung cancer (SCLC). In December 2023, MRT-2359 received Fast Track Designation from the FDA for the treatment of patients with previously treated SCLC with L-MYC or N-MYC expression;

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Continue to advance our VAV1-directed MGD program through IND filing and into clinical trials. In May 2023, we announced development candidate MRT-6160, a VAV1-directed MGD, for the treatment of systemic and neurologic autoimmune diseases. We have presented preclinical data from multiple autoimmune disease models demonstrating that MRT-6160 attenuates autoimmune disease progression. We expect to submit an IND for MRT-6160 in the Q2 2024 and to initiate a Phase 1 single ascending dose / multiple ascending dose study in healthy volunteers in mid-2024;

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Continue to advance our NEK7-directed MGD program through IND filing and into clinical trials. In March 2024, we announced 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, including gout, cardiovascular disease, neurologic disorders including Parkinson’s disease and Alzheimer’s disease, ocular disease, diabetes, obesity, and liver disease. 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 using lipopolysaccharide from Escherichia coli, or LPS, and nigericin. IND-enabling studies are ongoing, and we expect to submit an IND for MRT-8102 in Q1 2025. In light of the strategic importance of our NEK7 program, we are advancing a second, differentiated chemical series through Lead Optimization;

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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 platform, we have identified a variety of additional degron-containing proteins that are amenable to our approach and are either undruggable of insufficiently drugged and we continue to build MGDs against these proteins. Our program for CDK2 is in the lead optimization stage, and we anticipate nominating a development candidate for this program in 2024. MRT-2359, MRT-6160, MRT-8102 and our CDK2 program are all examples of our successful application of our QuEENTM platform to the discovery of MGDs with the potential to be rapidly advanced through drug development. As we advance those programs in the clinic and to candidate selection, we continue to advance our other 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 oncology, immunology, inflammation, as well as others;

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Continue to enhance and expand the capabilities of our QuEENTM platform 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. Our QuEENTM platform enables us to vastly expand the degradable proteome beyond conventionally druggable target proteins. Our approach includes the computational identification of structural features on the surface of a protein that render a target protein amenable to complex formation with an E3 ligase bound by one of our MGDs. We combine our QuEENTM platform, including our AI/ML degron discovery engine, with our proprietary library of rationally designed MGDs to selectively connect degron-containing target proteins to E3 ligase proteins, including cereblon. QuEENTM has the potential to help us better understand the optimal pairing of degron-containing proteins with ligases to further expand our target space. We continue to invest in building our QuEENTM platform, including expanding our proprietary MGD library as well as our proteomics, in silico screening, pharmacogenomics and translational medicine capabilities;

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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 platform; 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 platform. 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. 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 glues

Proteins are large, complex molecules that are involved in essentially all biochemical reactions that take place in the body. Many human diseases are associated with abnormal intracellular protein behavior driven by modified functional activation or inactivation of the protein itself. Given their critical role, proteins are attractive therapeutic targets, including those that act inside the cell and on its surface. While significant progress has been made in the development of therapeutics that address malfunctioning proteins, about 75% of human proteins are still considered undruggable by traditional small molecule inhibitors.

Challenges with druggable vs. undruggable proteins

The most common methods of targeting proteins, including intracellular proteins, involve traditional small molecule inhibitors that bind to a pocket in the protein and, there, act to inhibit or modify the function of the protein. Having such a pocket is what has traditionally led to a protein being considered druggable, yet most proteins lack suitably sized and shaped binding pockets. In particular, proteins such as transcription factors, those that act as scaffolding for other proteins, and modulators of enzyme activity, all of which can play a critical role in disease, often don’t have binding pockets suited for efficient ligand binding. 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 other genetic therapies, are limited in their ability to address aberrant protein behavior. Some of the therapeutic modalities have meaningfully advanced the treatment of disease and improved the quality of life for millions of patients. However, these modalities face specific challenges related to their mode of delivery, scalability, and their therapeutic application. A summary of characteristics of various therapeutic modalities compared to MGDs is shown in Figure 2.

Figure 2: The Next Generation of Precision Medicine-Based Small Molecule Drugs; Selectively Editing the Human Proteome with Rationally Designed MGDs

Molecular glues: a new approach to protein degradation

A new and promising approach to modulating protein function using small molecules in cells has been elucidated: targeted 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 induced by small molecule-based degraders, including both PROteolysis Targeting Chimeras, or “PROTACs”, and MGDs. It was found that lenalidomide, an approved best-selling drug in multiple indications, functions as a small molecule-based degrader, or as an MGD, more specifically. In one of these indications, multiple myeloma, lenalidomide acts by causing two disease-driving transcription factors, IKZF1 and IKZF3, that lack druggable pockets, to bind to cereblon, an E3 ligase protein, resulting in their degradation. In this context, lenalidomide leads to the formation of a complex of IKZF1 and IKZF3 with cereblon by inducing surface complementarity between the components of the complex rather than by binding of the MGD into a succinct binding pocket on the protein target.

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.

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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 oral.

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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 another target protein molecule. Thus, the small molecule-based protein degrader acts catalytically, unlike protein inhibition, causing the removal of many target protein molecules, 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 mentioned above, there are multiple advantages of the protein degradation approach, but one of the most beneficial is the potential to achieve greater therapeutic efficacy resulting from the durable but reversible removal of a target protein from the cellular proteome.

Current approaches to protein degradation

While lenalidomide is an MGD, the majority of recent drug discovery efforts in the design of protein degraders has been focused on PROTACs. These heterobifunctional degraders are composed of two separate small molecules connected by a chemical linker. One molecule binds to a necessary binding pocket on the target protein and the other to a component of the E3 ubiquitin ligase complex. Binding of the PROTAC to both the protein of interest and the E3 ligase brings the target protein into proximity of the E3 ligase, resulting in tagging of the protein of interest for degradation. While this represents a novel way to eliminate therapeutically-relevant proteins from cells, we believe an MGD approach offers the following advantages over PROTACs:

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Ability to target undruggable proteins: MGDs utilize the richness of molecular surface features across the proteome allowing access to a broader and differentiated target space. In contrast, PROTACs require identification of a small molecule that binds to a defined binding pocket of a target of interest, which today largely constrains the approach to the universe of proteins that can already be addressed with small molecule inhibitors.

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Favorable pharmaceutical properties: The relative simplicity and size of an MGD generally allows for more rapid optimization for oral bioavailability. PROTACs often have a larger size and larger molecular weight due to their complex heterobifunctional structure, which may lead to challenges to develop the molecules into drugs suitable for oral dosing.

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Broader tissue distribution: The physicochemical properties of PROTACs may also limit the drug distribution within the body, thereby reducing the potential in certain therapeutics areas such as central nervous systems disorders. MGDs are more traditional small molecules and hence do not have these issues.

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No observable hook effect: MGDs show a more typical concentration response where increasing concentrations elicit increasing efficacy caused by the catalytic interaction. In contrast, PROTACs require a precise concentration range to elicit efficacy due to the loss of degradation potential at higher concentrations caused by their heterobifunctional structure (also known as “hook effect”).

Current well-established approaches to protein degradation are illustrated in Figure 3. As shown in Figure 3, MGDs are non-heterobifunctional and do not require an active site or binding pocket on target proteins. We believe these properties potentially expand the universe of amenable target proteins while also maintaining the favorable drug-like properties of small molecule therapeutics.

Figure 3: Molecule Glue Degraders; Expanding Target Space, Fostering a New Generation of Drugs

Our approach

We design and develop molecular glue degraders or MGDs in a rational and iterative approach using our industry-leading and dynamic QuEENTM platform, summarized in Figure 4.

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. Lenalidomide and pomalidomide are two approved drugs that were found to function as MGDs by causing the degradation of therapeutically-relevant proteins through the induced interaction with the E3 ligase cereblon, and provide clinical validation to the MGD approach.

Following the discovery that the clinically and commercially successful lenalidomide and pomalidomide were in fact MGDs, it was believed that the discovery of MGDs would mostly be through serendipitous findings, that MGDs could not be rationally designed and optimized to high levels of selectivity and achieve drug-like properties through conventional medicinal chemistry efforts, and that the target protein space for this approach is limited. Our QuEENTM platform was designed and built to address these issues. With QuEENTM we can discover and develop MGD product candidates that are potentially potent, selective and have favorable drug like properties in a target-centric, prospective and rational way against a wide variety of target proteins.

Figure 4: QuEENTM is Redefining the Rules of MGD Discovery

We believe our platform has the potential to continue to deliver MGD product candidates that could address target proteins that have been considered undruggable or inadequately drugged, while possessing attractive pharmaceutical properties. As shown in Figure 5, 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. Further, we have started using the platform to leverage other E3 ligase systems as well.

Figure 5: Our Rational Approach to Unleash the Full Potential of MGDs

Our proprietary and industry-leading 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) understanding how to reprogram the surface of endogenous E3 ligases using small molecules (ii) systematically identifying degrons and other surface features on target proteins that may enable degradation by E3 ligases through our approach; and (iii) rationally designing MGDs that can be optimized towards high potency and selectivity, with favorable pharmaceutical properties. Our proprietary library of rationally designed MGDs currently includes about 50,000 unique small molecules built around 400 cereblon binding scaffolds. Through our platform, we have built expertise 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. Figure 6 provides a schematic overview of some of the most unique and critical features our QuEENTM platform.

Figure 6: Monte Rosa’s QuEENTM Discovery Engine; An Industry Leading Target-Centric Approach to MGD Discovery and Development

Our proprietary and industry leading Quantitative and Engineered Elimination of Neosubstrates discovery engine, or QuEENTM discovery engine, encapsulates our team’s deep and growing expert knowledge and discovery capabilities across biology, chemistry and computational sciences, from which we are generating our library and pipeline of MGD product candidates. Our experienced team of data scientists, structural biologists, biochemists, biologists and chemists have innovated proprietary tools designed to broadly match our MGDs against degron-containing target proteins. Our MGD design capabilities are driven by both in silico and laboratory-based assays that predict and assess the ability of our MGDs to induce the binding of target proteins to E3 ligase components, such as cereblon, and directly measure target degradation.

Central to our QuEENTM discovery engine is a detailed understanding of the molecular interactions promoted by our MGDs between E3 ligases and therapeutically-relevant target proteins, which have been considered undruggable or inadequately drugged. We believe this depth of knowledge allows us to leverage our platform to rationally design MGDs with favorable pharmaceutical properties that have the potential to translate into clinical success across multiple therapeutic areas. Our capabilities have been developed through key features of our QuEENTM discovery engine, which include our AI/ML engines, proprietary MGD library, and our toolbox of assays and capabilities used to generate data-at-scale.

Our process of degron discovery and MGD design is highly iterative and interdisciplinary and is guided by our experience and powerful AI modeling. Computational predictions and analyses guide our high throughput screening and chemo-proteomics, which in turn provide more information to feed back into the AI engine, and all 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 7: Monte Rosa's Proprietary QuEENTM Discovery Engine Iteratively Integrates Predictions, Designs, and Data Generation for Target Identification and MGD Design

Target identification and MGD discovery is guided by AI/ML algorithms and large, proprietary datasets

We have developed sophisticated and proprietary AI-powered algorithms that are trained on both internal and external datasets. We have established a large, moated database of proteomics, structural biology, high throughput screens, and virtual screens. We have used these data to learn the rules of MGD discovery, connecting protein surfaces to MGD feature activity, and created a suite of AI/ML modules for E3 ligase reprogrammability assessment, target identification and MGD design.

Figure 8: Monte Rosa’s Proprietary AI/ML Engine allows for Discovery of Glueable Target Proteins and Highly Selective MGDs

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

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. We believe one of our key advantages is our focus on protein surface characterization, integrating topological, structural and sequence features associated with published, or canonical, as well as newly discovered, or non-canonical, degrons and encode these features into fAIceitTM, our AI/ML-powered algorithm. fAIceit comprises our suite of AI-powered algorithms that include modules leveraging highly customized multi-dimensional geometric deep learning, deep neural networks, and quantum and molecular dynamics to characterize E3 ligase surfaces, such as patches with propensity to form protein-protein interactions (PPIs) and the presence of small molecule ligand-binding pockets. We developed these tools using publicly available three-dimensional protein structures to successfully identify proteins with surface features associated with known cereblon canonical degrons. Using our growing repository of ternary complex structures induced by our proprietary chemistry that show novel binding modes and associated neosurfaces, we have successfully deployed fAIceit to computationally predict more disease-associated protein targets that have these novel surface features and are thus potentially addressable using our library of cereblon-binding MGDs. Indeed, we have confirmed many proteins with the potential to be neosubstrates, including many in disease relevant pathways.

A key feature of the fAIceit process is the ability to integrate new discoveries from our proximity screening platform: as we characterize the activity of our expanding MGD library, fAIceit learns more degron features and, projecting these features into the entire proteome, identifies more potential neosubstrates targetable by our MGDs. We are also applying fAIceit to identify candidate complementary target proteins to E3 ligases beyond cereblon.

Figure 9: Monte Rosa’s Protein Surface Exploration AI Engines

Our AI/ML engines enable in silico discovery of novel and highly selective MGDs

We have developed sophisticated and proprietary AI-powered algorithms for all stages of drug development, from library design and hit identification through to lead optimization. The engine includes modules for in silico docking, molecular fingerprinting, SAR cliff discovery, generative designs and enumeration, ADMET models, synthesis path filtering, structure- and ligand-based virtual screening for on- and off-target activity, and ternary complex models. Evaluation of the model allows us to rapidly predict which parts of the MGD anatomy are involved in target recruitment and which parts may be modified. This enables us to maintain or enhance the target-specific potency of the MGD, while optimizing its selectivity, and its other chemical and biological properties.

In practice, we match a protein target to an E3 ligase using fAIceit. For novel E3 ligases, we have performed virtual screening using our algorithm HeadlongTM and successfully identified novel ligand binders that we then expanded into full virtual libraries using our generative chemistry algorithm FlashTM and ML-based ADMET models GlueAIDTM. We then use our HitManTM algorithm to design physical small molecule libraries that take into account the E3 ligase induced-surface.

For hit expansion and MGD optimization, our ternary complex algorithm, which we have named RhapsodyTM, is used to generate an in silico model of the MGD-specific, MGD-induced ternary complex. We use the ternary complex models for the design of novel MGDs, for virtual screening, for structure activity relationship or SAR optimization, and for in-depth medicinal chemistry optimization. Our platform leverages ensembles, molecular dynamics and quantum mechanics to identify and prioritize MGDs for synthesis and testing. Combined with Flash generative designs and GlueAID ADMET models, Rhapsody virtual screens create and identify novel MGDs that are predicted to induce neosubstrate-specific ternary complex formation, have excellent ADMET properties, are available for rapid synthesis, and can be prioritized for follow-up experiments.

While many of our tools were initially developed around cereblon as an E3 ligase we are now extending their use to additional E3 ligases.

Our Proprietary MGD library

We discover and develop lead MGDs for degron-containing target proteins by screening our MGD library of currently around 50,000 MGD molecules, and applying proximity screening tools, our chemo-proteomic capabilities and our knowledge of the cereblon-binding site and variations in degron structures. 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 400 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 10, our highly diverse library of MGDs leverages different areas of the cereblon surface to engage diverse degrons and 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 10: Monte Rosa Proprietary MGD Library: A Novel and Structurally Diverse Cereblon-Centric Library

Our high-throughput proximity screening platform for the rapid assessment of our MGD library

We have developed a suite of high-throughput assays that measure specific steps of the MGD-induced cascade and allow for rapid assessment of our proprietary MGD library and any MGDs generated during specific programs. Coupled with customized automation systems for screening in 384 and 1586-well formats, our set of assays can measure ternary complex formation in both a biochemical and cellular format, as well as measure degradation of target proteins in cells. We are using our tailored suite of biochemical and cellular assays to screen, identify and rapidly optimize our MGDs.

Figure 11: Customized Automation and High-Throughput Assays Enable Rapid Assessment of MRT Library

Our quantitative proteomics profiling assays for neosubstrate identification and MGD optimization

Utilizing our expertise in mass-spectrometry-based proteomics, we have developed a suite of high throughput quantitative profiling assays to assess multiple parameters, including cellular target degradation, selectivity of degradation, target ubiquitination, and ternary complex formation in cells. We utilize this information in multiple ways, including:

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To assess target degradation and determine the selectivity of our MGDs: Proteome wide changes in expression levels of proteins after treatment with a MGD are measured. Downregulation of protein levels is suggestive of degradation.

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To assess ternary complex formation and ubiquitination induced by our MGDs in cells: Proteins that are induced by the MGD to be proximal to the E3 ligase are tagged and enriched using a Turbo-ID proximity assay. This induced spatial proximity is suggestive of cellular ternary complex formation. Proteins that are ubiquitinated as a result of ternary complex formation are identified using diGLY proteomics methods.

We use these assays to validate screen hits, to support MGD optimization during lead optimization programs, but also to identify novel neosubstrates that our AI/ML platform is not yet predicting. Screening of our MGD library with the proximity and degradation-based assays provides additional unbiased data to identify novel degrons and train our computational degron prediction algorithms to further expand the target space.

Using our custom software tools we have created BaseCamp, a proprietary database for storage, analysis, and visualization of proteomics data which includes hundreds of novel target discoveries.

Figure 12: Proteomics platform accelerates degron and MGD discovery and optimization

Our structural biology platformsupports the rational design of our MGDs

Leveraging our expertise and capabilities in 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 our MGD library, rationally optimize our MGDs for a prioritized protein target, and validate novel binding modes and degrons. Using our custom software tools, we have created a database of our proprietary structures, which we have included into BaseCamp. Our database houses ternary complex structures of more than 10 different protein targets, and as shown in Figure 14, includes multiple novel binding modes that are highly diverse in structure and sequence.

Figure 13: Proprietary Database of Experimental Structures Supports the Rational Design of our MGDs

Figure 14: Novel Binding Modes that are Highly Diverse in Structure, Sequence

As shown in Figure 15, our QuEENTM platform has enabled us to discover a broad landscape of degrons and degron-containing proteins. We have used our AI engine and a rational design approach to discover MGDs that are exquisitely selective. All combined, this allows us to potentially eliminate therapeutically-relevant target proteins in pathways that are highly relevant for diseases with high unmet need in oncology, immunology, inflammation as well as other diseases.

Figure 15: Discovering Diverse Degrons and Developing Highly Selective MGDs Against Them

QuEENTM expansion

Our QuEENTM platform 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. 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 the cereblon neosubstrate universe: As we rationally designed our MGD compound library to increase diversity, we found in preclinical studies that there are novel degrons with a diversity of amino acid sequences and 3-dimensional structures that can be targeted, and we have shown we can induce efficient protein degradation through these previously undiscovered degrons. We have used our proprietary AI-driven algorithms to predict the existence of degrons from the primary sequences and the topology of proteins and

are using our rational design approach to continuously expand the chemical diversity of our MGD library against this diverse set of cereblon-accessible degrons.

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Utilize additional 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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Next-generation antibody drug conjugates (ADCs):We have showen 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. We call these potential MGD-antibody conjugates GluLAs for Glue Loaded Antibodies.

Expanding the universe of neosubstrates or target proteins and recruitment of such to additional E3 ligases through the continued identification of degrons has the potential to bring more therapeutically-relevant target proteins into the universe of degradable targets, which we anticipate will allow us to address additional therapeutic target proteins that are undruggable or insufficiently drugged.

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

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. 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. 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 for the treatment of MYC-driven and high-grade neuroendocrine tumors (ClinicalTrials.gov Identifier: NCT05546268).

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 16. 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 16: 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 platform. Key features and parameters of MRT-2359 are provided in Figure 17.

Figure 17: MRT-2359 is a Selective and Orally Bioavailable GSPT1-directed MGD Rationally Designed Using our QuEENTM Discovery Engine

As shown in Figure 18, 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.

Figure 18: MRT-2359 Has Optimized Depth of Degradation to Achieve Preferential Activity in MYC High Cancer Cells

As shown in Figure 19, the sole ectopic overexpression of L-MYC or N-MYC was sufficient to sensitize initially insensitive NSCLC cells (NCI-H2023) to MRT-2359, corroborating a pivotal role of GSPT1 for the survival of MYC-driven cancer cells and demonstrating the potential of MRT-2359 to selectively inhibit growth and survival of L- and N-MYC expressing tumor cells. We believe these studies establish a causal link between L-MYC and N-MYC expression and the sensitivity to MRT-2359 not seen for other agents.

Figure 19: Overexpression of L-MYC or N-MYC is Sufficient to Sensitize Initially Resistant NSCLC Cells to MRT-2359

Preferential activity of MRT-2359 on growth and survival of MYC-driven cells was further validated in a panel of representative lung cancer cell lines. As shown in Figure 20, MRT-2359 profoundly and preferentially affected growth and survival of MYC-driven cell lines, such as high L- and N-MYC expressing NSCLC and SCLC lines,

compared to their MYC low expressing counterparts. Similar observations were made in neuroendocrine or NE positive versus negative lung cancer cell lines.

Figure 20: Preferential Activity of MRT-2359 in MYC High NSCLC, SCLC or Neuroendocrine (NE) Positive Cancer Lines

As shown in Figure 21, MRT-2359 induced significant ribosomal stalling at the stop codon of mRNA transcripts only in the MYC high cell lines such as the NSCLC cell lines NCI-H1155. Only minimal effects on ribosomes were seen in the MYC low cell line NCI-H2023. In addition, MRT-2359 rapidly and completely abrogated protein synthesis in NCI-H1155 cells while exhibiting only marginal effects on translation and protein synthesis in NCI-H2023 cells.

Figure 21: MRT-2359 Strongly and Preferentially Impaired Protein Translation in the N-MYC High Compared to the MYC Low NSCLC Cancer Cell Line

As shown in Figure 22, down modulation of the N-MYC oncogene and of its downstream target genes was observed in the NCI-H1155 cell line following MRT-2359 induced degradation of GSPT1. Further, N-MYC could

not be detected in the NCI-H2023 cell line, and no significant effects were detectable on N-MYC downstream target genes after degradation of GSPT1.

Figure 22: MRT-2359 Downmodulated N-MYC and Its Downstream Target Genes in the N-MYC High Compared to the MYC Low NSCLC Cancer Cell Lines

Collectively, we believe that the 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 23.

Figure 23: Three Mechanisms Driving Preferential Activity in MYC High Cancer Lines

As shown in Figure 24, MRT-2359 demonstrated significant dose-dependent anti-tumor activity in vivo, including regressions, in an NCI-H1155 cell line-based xenograft model of NSCLC with high N-MYC expression, and in an NCI-H1836 cell line-based xenograft model of SCLC with high L-MYC expression. In these studies, MRT-2359 was dosed orally (PO) once daily (QD) at 1, 3 and 10 mg/kg.

Figure 24: Anti-tumor Activity of MRT-2359 in the N-MYC High NCI-H1155 NSCLC and L-MYC High NCI-H1836 Xenograft Models

The anti-tumor activity of MRT-2359 was further assessed in 78 fully annotated lung cancer patient-derived xenograft, or PDX, models.

As shown in Figure 25, oral dosing of MRT-2359 demonstrated preferential activity in models expressing high levels of N-MYC in NSCLC PDXs, and in models expressing high levels of N-MYC, L-MYC and/or neuroendocrine features in SCLC and neuroendocrine lung cancer PDXs, including numerous instances of tumor regressions. Pharmacodynamic modulation of GSPT1 measured through targeted mass spectrometry in seven representative models was approximately -60%, in line with the optimal PD modulation seen in vitro, as depicted in Figure 18.

Figure 25: MRT-2359 Demonstrated Preferential Anti-tumor Activity in MYC High or Neuroendocrine (NE) Lung Cancer PDXs

Non-small cell lung cancer

Lung cancer is the third most frequent cancer in the United States and the most frequent cause of cancer-related death. In 2020, there were an estimated 228,820 new cases and 135,720 patients were estimated to have died. NSCLC accounts for 85% of all lung cancer cases. Despite significant advances over the last 2 decades, treatment outcomes in NSCLC remain unsatisfactory. Overall, 25% of all patients are alive 5 years or more after diagnosis (Ettinger, et al. 2021). Patients in early stages can achieve long-term remission or even cure with surgery, with or without chemotherapy; however, patients with locally advanced or metastatic disease remain incurable, with palliative treatment options to prolong survival at best. The 5-year survival rate for metastatic disease is approximately 6% when patients receive cytotoxic chemotherapy (Ettinger, et al. 2021). Development of novel targeted therapies and immunotherapies has improved 5-year survival rates to approximately 15% to 50% in some patients. In advanced/metastatic NSCLC, first-line therapy typically includes chemotherapy with or without programmed cell death protein 1/programmed death-ligand 1 antibodies, monotherapy with programmed cell death protein 1/programmed death-ligand 1 antibodies, or targeted therapies in patients with druggable EGFR, ALK, ROS1, BRAF, MET, NTRK, or RET alterations. First-line therapy has an expected progression-free survival between 4 to 6 months in case of chemotherapy, 8 to 10 months for immunotherapy/chemoimmunotherapy, and up to 18 or more months for targeted therapies. Recently, a KRAS G12C inhibitor has been added to the therapeutic armamentarium to be used in previously treated KRAS G12C-mutated NSCLC (Skoulidis, et al. 2021).

Our analysis of real-world data (from real world molecular and genomic data analysis in collaboration with Tempus Labs, Inc.) revealed that N-MYC is highly expressed in about 10% NSCLC-adenocarcinomas.

Small cell lung cancer

SCLC accounts for approximately 15% of all lung cancers, or about 30,000 new cases a year in the United States. SCLC is a rapidly progressive disease with short overall survival after initial therapeutic responses. SCLC is derived from neuroendocrine cells and is distinguished clinically from NSCLC by its rapid doubling time and the early development of metastases. Most patients have metastatic disease at the time of their initial diagnoses. Unlike in NSCLC, which has seen a steady stream of new drug approvals over the last 2 decades, the progress and consequent improvement in treatment outcomes in SCLC have been more modest. The 5-year survival rate for patients with extensive stage SCLC, which accounts for 80% of all patients diagnosed, remains at 3% with a median survival between 10 to 13 months. Patients with limited stage SCLC can be treated with combined chemoradiation; however, the 5-year survival rates fluctuate between 30% to 40%. Most patients with SCLC are responsive to chemotherapy, but eventually relapse. Cisplatin or carboplatin in combination with etoposide remains the backbone for the first-line therapy. In extensive stage SCLC, immune checkpoint inhibitors

atezolizumab and durvalumab have been approved for use in conjunction with chemotherapy. Overall response rates for chemotherapy, with or without immunotherapy, are around 60%; however, the median progression-free survival ranges from 4 to 5 months and the overall survival ranges from 10 to 13 months. Upon relapse, patients are offered alternative therapies based on their quality and duration of response to initial treatment, but most are chemotherapy-based such as retreatment with platinum and etoposide in patients with platinum-sensitive disease or second-line regimens such as lurbinectedin or topotecan. Expected outcomes in previously treated patients remain unsatisfactory with response rates between 25% to 35%. There are no targeted therapeutics available for SCLC patients.

Our analysis of real-world data (from real world molecular and genomic data analysis in collaboration with Tempus Labs, Inc.) revealed that L-MYC or N-MYC mRNA are highly expressed in about 72% of SCLC tumor samples.

Potential Indications

We believe that there are multiple other tumor types, beyond NSCLC and SCLC, in which the MYC pathway is highly activated. As shown in Figure 26, in addition to the current indications included in the MRT-2359-001 Phase 1/2 clinical study, future indications may include c-MYC driven cancer types such as prostate cancer including tumors with the ARV7 splice variant and hormone receptor-positive breast cancer.

Figure 26: Potential Opportunities in MYC-Driven Tumors

We believe that our preclinical studies support the potential activity of MRT-2359 against c-MYC driven cancers. As shown in Figure 27, MRT-2359 is active in preclinical studies as a single agent and in combination with standard of care against prostate cancer including cancers with ARV7 splice variant.

Figure 27: Anti-tumor Activity of MRT-2359 in Preclinical Models of Castration Resistant Prostate Cancer

Figure 28 illustrates that MRT-2359 is active in preclinical studies as a single agent and in combination with standard of care against ER/MYC-positive breast cancer tumor xenografts.

Figure 28: Anti-tumor Activity of MRT-2359 in Preclinical Model of ER/MYC-positive Breast Cancer

MRT-2359-001 Phase 1/2 Study

Our ongoing Phase 1/2, open-label, multicenter study, illustrated in Figure 29, is designed to assess the safety, tolerability, PK, PD, and preliminary clinical activity of MRT-2359 in patients with previously treated selected solid tumors. In the Phase 1 dose escalation portion of the clinical trial, we are enrolling patients with tumors that have a significant likelihood of being MYC-driven, including patients with NSCLC, SCLC, high-grade neuroendocrine cancer of any primary site, DLBCL and patients with solid tumors that harbor L-MYC or N-MYC amplifications. In this phase of the trial, tumors will be tested retrospectively for biomarkers of MYC activation. Patients will receive escalating doses of MRT-2359 to determine the maximum tolerated dose or MTD and recommended Phase 2 dose or RP2D.

Once the MTD and/or RP2D are determined, the anti-tumor activity of MRT-2359 will be assessed in the Phase 2 portion of the study, which will enroll NSCLC and SCLC patients stratified per L-MYC or N-MYC expression, and patients with solid tumors with L-MYC or N-MYC amplification, amongst others.

Dosing is currently ongoing in backfill cohorts at clinically active doses determined using the 5 days on, 9 days off-drug dosing schedule, and in dose escalation cohorts using a 21 days on, 7 days off-drug schedule, starting at 0.5 mg per day. Once the RP2D is identified, the study is expected to advance to Phase 2 expansion cohorts, which include monotherapy with MRT-2359 in NSCLC, SCLC and solid tumors with L-MYC or N-MYC amplification. NSCLC and SCLC expansion cohorts will utilize a two-stage design and patients will be stratified per L-MYC and/or N-MYC expression levels in the tumor. Potential inclusion in the Phase 2 study of additional cohorts such as a combination of MRT-2359 with the estrogen-receptor antagonist fulvestrant in hormone receptor-positive, HER2-negative breast cancer and a combination of MRT-2359 and the androgen-receptor antagonist enzalutamide in non-neuroendocrine prostate cancer is under consideration.

Figure 29: MRT-2359 Phase 1/2 Clinical Study Design

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

In October 2023, we reported interim data from the Phase 1 dose escalation part of the ongoing Phase 1/2 open-label, multicenter study of MRT-2359 in patients with MYC-driven solid tumors, including lung cancers and high-grade neuroendocrine cancer. We believe our interim clinical data from the MRT-2359 study demonstrated favorable tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in heavily pre-treated patients with lung cancers and high-grade neuroendocrine cancer. We observed that MRT-2359 significantly reduced GSPT1 protein levels in patient tumors and we were very encouraged to report early evidence of tumor size reductions, including partial responses, in two heavily pretreated patients with biomarker-positive tumors, including one confirmed and one unconfirmed partial response.

At the analysis cutoff date of September 7, 2023, 21 patients had been dosed, with 15 of the 21 patients evaluable for clinical activity.

As shown in Figure 30, MRT-2359 displayed dose dependent plasma exposure, in line with preclinical PK models. No food effect was observed. MRT-2359 displayed deep GSPT1 degradation in peripheral blood mononuclear cells (PBMCs) at all dose levels. PD modulation in PBMCs was observed across all dose levels; the level of degradation of ~ 60% was in line with optimal degradation observed in preclinical studies, each observed using targeted mass spectrometry as the method of analysis, and with the levels we observed in preclinical studies.

Figure 30: MRT-2359 Pharmacokinetics and Pharmacodynamics

As shown in Figure 31, MRT-2359 reduced GSPT1 protein expression in human tissue biopsies. GSPT1 degradation was assessed from pre-treatment screening biopsies and biopsies taken at day 19. Matched biopsies were obtained from 11 patients across the 3 cohorts analyzed. GSPT1 expression was assessed using targeted mass spectrometry. Optimal PD modulation was seen in tissue biopsies with an average of ~ 60% degradation of GSPT1 measured across all cohorts. PD modulation was in line with the degree of GSPT1 degradation seen preclinically at dose levels that showed anti-tumor activity using same assay (targeted mass spectrometry). The level of degradation was equivalent across all dose levels, suggesting saturated PD responses from 0.5 mg to 2 mg and supporting that pharmacodynamically, 0.5 mg is a fully active dose.

Figure 31: MRT-2359 Pharmacodynamics in Human Tissue Biopsies

At the September 7th, 2023 data cutoff, of the 15 evaluable patients that have been administered MRT-2359 across three dose cohorts (0.5 mg, 1 mg, and 2 mg in a 5 days on-drug, 9 days off-drug dosing schedule), we identified six as biomarker-positive in indicated tumor types, specifically N-MYC high non-small cell lung cancer (NSCLC) adenocarcinoma, L-/N-MYC high small cell lung cancer (SCLC), L-/N-MYC high-grade neuroendocrine tumors (prostate, bladder, and others) and neuroendocrine tumors of the lung.

We reported that we observed clinical activity across all dose levels. Of the six biomarker positive patients, we reported that two experienced a partial response (PR), of which one was confirmed and one unconfirmed, and one SCLC patient exhibited stable disease and had remained on therapy for over 4 months as of the data cutoff.

Figure 32 illustrates the best observed tumor response per RECIST 1.1 criteria. In addition, one patient with NSCLC and unclear biomarker status remained on therapy for more than 7 months as of the data cutoff with stable disease.

No clinical activity was reported in biomarker negative patients.

Figure 32: Best Observed Tumor Response in Biomarker Positive Patients

Included in our interim data release, Figure 33 shows computed tomography (CT) scans from a patient with high grade neuroendocrine bladder cancer with a confirmed partial response. The baseline tumor biopsy demonstrated high N-MYC expression. The patient had four prior lines of therapy including chemotherapy and pembrolizumab. The patient initiated on 2 mg of MRT-2359 for the first 5 days on, 9 days off drug regimen. The dose was then lowered stepwise to 0.5 mg and the patient remained on therapy for over 3 months as of the data cutoff date. The CT scan after 4 weeks demonstrated a partial response (-34% per RECIST 1.1) that continued to improve at week 8 (-59% per RECIST 1.1).

Figure 33: CT Scans from High Grade Neuroendocrine Bladder Cancer Patient

Included in our interim data release, Figure 34 shows computed tomography (CT) scans from a patient with non-small cell lung adenocarcinoma with small cell lung cancer/neuroendocrine (SCLC/NE) transformation. The baseline tumor biopsy demonstrated SCLC/NE transformation, low L- and M-MYC expression. The patient had multiple lines of prior therapy including chemotherapy, pembrolizumab and atezolizumab. The patient initiated on 0.5 mg of MRT-2359. The CT scan after approximately three weeks demonstrated resolution of liver metastases (-41% per RECIST 1.1). The patient experienced frequent dose interruptions due to bowel obstruction deemed unrelated to MRT-2359 and showed progression in a follow up scan attributed to the lack of sufficient dose intensity.

Figure 34: CT Scans from non-small cell lung adenocarcinoma patient with small cell lung cancer/neuroendocrine transformation

As reported in our interim data release, we believe the MRT-2359 safety data summarized in Figure 35 support further clinical development. There were no observations of previously reported limitations of other GSPT1-targeted agents, including no observed clinically significant hypocalcemia or hypotension associated with cytokine release syndrome at any dose level. The 0.5 mg and 1 mg dose levels of MRT-2359 resulted in Grade 1 or 2 treatment-related adverse events (AEs) only, which were primarily GI-related and manageable. At the 2 mg dose level, Grade 4 thrombocytopenia (dose-limiting toxicity (DLT), n=2) and Grade 4 neutropenia (non-DLT, n=1) were observed, findings consistent with preclinical toxicology studies. No patients discontinued treatment due to AEs at

any dose level, and the Grade 4 AEs observed at the 2 mg dose were transient and resolved with dose reductions.

Based on the favorable tolerability profile of MRT-2359 reported in our interim data release, we expanded our protocol to allow our investigation of a denser dosing schedule of 21 days on, 7 days off dosing schedule, starting at 0.5 mg.

Figure 35: Summary of Treatment-Related Adverse Events (AEs) in > 2 patients

We are encouraged by the progress MRT-2359 continues to make in the clinic, including the continuing evidence of a favorable tolerability profile and encouraging early signs of clinical activity. We are also encouraged that our observations of early clinical activity are in biomarker positive patients, reinforcing our belief in our hypothesis that GSPT1 is a therapeutic vulnerability in MYC-driven tumors. We look forward to continuing to advance our clinical evaluation of MRT-2359.

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 36. 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 estrogen receptor-positive (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 36: 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 platform 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 orally bioavailable with favorable in vitro ADMET properties and pre-clinical safety profiles.

In vitro data

Our lead CDK2-directed MGD MRT-9643 selectively degrades CDK2 and reduces E2F pathway proteins, with no significant effect on other CDKs or other kinases, as shown in Figure 37. Our data also support that our CDK2 MGD MRT-9643 blocks DNA replication during S phase in CDK2 dependent cells and inhibits cellular proliferation in a concentration-dependent manner.

Figure 37: CDK2-directed MGD MRT-9643 is Selective and Shows Biological Activity in a CDK2 Dependent Cell Line

In vivo data

Oral dosing of our CDK2-directed MGD MRT-9643 at 10 mg/kg and 100 mg/kg achieved dose-proportional exposures in tumor bearing mice, as shown on Figure 38. In line with this, 5-day oral BID dosing resulted in dose-dependent degradation of CDK2 protein in a breast cancer cell line derived xenograft model. Furthermore, in a cell line based xenograft model of estrogen-receptor positive breast cancer using MCF7 cells oral administration at 30 mg/kg and 100 mg/kg BID for 25 days was shown to synergize with the CDK4/6i ribociclib in an leading to ~94% tumor growth inhibition (TGI) at bose dose levels used for MRT-9643, when compared to 58% TGI induced by ribociclib treatment alone.

Figure 38: Oral Dosing of CDK2-directed MGD MRT-9643 Induces Tumor Growth Inhibition (TGI) in vivo

Our Approach for Immunologic and Inflammatory Diseases

Our QuEEN platform has generated multiple programs with potential applications in immunological and inflammatory diseases, including our VAV1 program, for systemic and central nervous system autoimmune diseases, and our NEK7 program, for IL-1β/NLRP3 driven Inflammatory Diseases.

MRT-6160, a highly selective and orally bioavailable VAV1-directed molecular glue degrader (MGD) in development for the treatment of T- and T-/B-cell mediated autoimmune 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 autoimmune diseases are thought to be driven by an underlying dysregulation or hyperactivation of T- and/or B-cell receptor signaling, a VAV1-directed MGD, which we believe will ameliorate aberrant responses from both cell types, has broad potential application for autoimmune diseases.

There are multiple published reports providing preclinical data that supports VAV1’s potential as an attractive target for attenuating T- and B-cell activity. Examples of such reports include that VAV1 knockout mice are viable, fertile, display various loss-of-function T- and B-cell phenotypes and are protected from experimentally induced autoimmune disease; and 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 (summarized in Figure 39).

Figure 39: VAV1 is a Highly Validated Target for Attenuating T-cell and B-cell Activity

Furthermore, 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. We believe the public literature, summarized above, coupled with our data package, summarized below, provides strong support for a VAV1 MGD in multiple important systemic and central nervous system autoimmune diseases. Based on this support, we are advancing our VAV1 development candidate, MRT-6160 towards clinical studies. As of March 2024, MRT-6160 has concluded IND-enabling safety assessment and IND filing is expected in Q2 2024 and initiation of a Phase 1 clinical trial anticipated in mid-2024.

Development of VAV-directed MGDs

A summary of the VAV1 signaling pathway is illustrated in Figure 40. 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 40: VAV1 is a Key Regulator of T- and B-cell Receptor Activity

MRT-6160 is a first-in-class molecular glue degrader of VAV1 and is our first development candidate for our VAV1 program. 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 platform 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 VAV family proteins. 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 41.

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). We recently completed preclinical GLP toxicology studies in rats and non-human primates, demonstrating a highly favorable profile with no significant changes in peripheral immunophenotyping assessments compared to controls.

Figure 41: MRT-6160 is a Potent, Selective VAV1 MGD Development Candidate with a Favorable Drug-Like Profile

The potency and selectivity profile of MRT-6160 was characterized in primary human peripheral mononuclear blood cells (hPBMCs). As shown in Figure 42, left panel, MRT-6160 elicited dose-dependent degradation of VAV1 in primary human T and B cell subsets. As shown in Figure 42, 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.

Figure 42: MRT-6160 Selectively degrades 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 43, 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 43: VAV1 degradation by MRT-6160 results 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 44, 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 maintained for 24 hours (right panel), suggesting significant degradation of VAV1 protein induced by MRT-6160.

Figure 44: Oral dosing of MRT-6160 leads to rapid degradation of VAV1 in vivo

Given these favorable PK/PD properties in mice, MRT-6160 was evaluated in a 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 45, left panel) daily oral dosing of MRT-6160 following disease onset inhibited disease progression in a dose-dependent manner comparable to that of supraphysiological 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 45, MRT-6160 induced dose-dependent degradation of mVAV1 commensurate with inhibition of disease progression.

Figure 45: MRT-6160 elicits 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 46, left panel, 1 mg/kg MRT-6160 inhibited disease progression comparably to 10 mg/kg anti-TNF⍺. The right panel of Figure 46 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 46: MRT-6160 inhibits 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. Mice were orally administered vehicle or MRT-6160 daily following T-cell transfer. Anti-TNF⍺ was administered intraperitoneally every third day as a standard of care control. As shown in Figure 47, left panel, oral dosing with 1 mg/kg MRT-6160 demonstrated superior disease inhibition compared to 10 mg/kg anti-TNF⍺. The right panel of Figure 47 shows mesenteric lymph node CD4+ T cell assessment by flow cytometry where MRT-6160 reduced the frequency of IL-17A+ and TNF⍺+ CD4+ T cells, known drivers of inflammatory bowel disease in humans. Collectively, preclinical data 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.

Figure 47: MRT-6160 Inhibits Disease Progression and Cytokine Production in a Model of Inflammatory Bowel Disease

MRT-6160 has been progressed to non-human primate in vivo studies for further characterization. In a five day, multiple-dose study, MRT-6160 exhibited dose dependent plasma concentrations as the doses increased. Moreover, as shown in Figure 48, MRT-6160 elicited dose dependent degradation on day 1. By day 5, all dose levels showed >90% reduction in VAV1 protein levels and upon ceasing MRT-6160 administration, VAV1 protein recovered to pre-dose levels by day 10.

Figure 48: MRT-6160 Induces VAV1 degradation in Non-Human Primates that is Reversible Following Dosing Cessation

Indication Overview

We believe that VAV1’s mechanism of action provides for broad therapeutic potential for systemic and central nervous system autoimmune diseases, and we look forward to advancing MRT-6160 towards proof of concept. Within the autoimmune disease space, both peripheral and CNS based, we are currently evaluating clinical development studies to establish initial proof of concept in ulcerative colitis, rheumatoid arthritis, multiple

sclerosis, and myasthenia gravis. We do not consider this list to be exhaustive, and we will continue to evaluate additional indications as our clinical programs advance.

Ulcerative Colitis

Ulcerative colitis (UC) is one of the two primary forms of idiopathic inflammatory bowel disease (IBD). UC is a chronic, relapsing inflammatory disease of the large intestine and rectum characterized by inflammation and ulceration of mainly the mucosal and occasionally submucosal intestinal layers. Estimated prevalence of UC is approximately 236 cases per 100,000 persons in Europe and 242 cases per 100,000 persons in United States (Ng, et al. 2017, da Silva B, et al. 2014).

Hallmark clinical symptoms of UC include diarrhea, bloody stool and abdominal pain. The clinical course is marked by exacerbation and remission (Dignass, et al. 2012) Patients with UC are at an increased risk for colon cancer, and the risk increases with the duration of disease as well as extent of colon affected by the disease (Rutter, et al. 2004). Approximately 15% of UC patients experience a severe clinical course, and 30% of these patients require removal of the colon/rectum, to eliminate the source of the inflammatory process, although accompanied by significant morbidity (Aratari, et al. 2008). Colectomy rates have been trending lower with increased use of biologics (Wong et al, 2019).

The aim of medical treatment in UC is to control inflammation and reduce symptoms. Available pharmaceutical therapies are limited, do not always completely abate the inflammatory process, and may have significant adverse effects. Therapies for mild to moderate active UC include 5-aminosalicylic acid derivatives and immunosuppressants. Corticosteroids are used in patients with more severe symptoms but are not useful for longer term therapy due to associated toxicities. Patients with moderate to severe symptoms may derive some benefits from immunomodulatory agents such as azathioprine, 6-mercaptopurine, or methotrexate; however, the use of these agents is limited as induction treatment due to a slow onset of action (3 to 6 months) and as maintenance therapy due to toxicities including bone marrow suppression, infections, hepatotoxicity, pancreatitis, and malignancies (Kornbluth, et al. 2010; Beaugerie, et al. 2009).

Biological agents targeting specific immunological pathways have been evaluated for their therapeutic effect in treating patients with UC. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for IBD. Infliximab, adalimumab, and golimumab are approved for the treatment of UC. Vedolizumab, an anti-adhesion therapy, as well as IL-12/-23 targeting biologics, have been approved for the treatment of IBD. Potential risks with anti-TNF therapies include infusion or injection site reactions, serious infections, lymphoma, heart failure, lupus-like syndromes, and demyelinating conditions (Turner, et al. 2010). Despite the beneficial results achieved with the available biologic agents, only 17% to 45% of patients who receive them are able to achieve clinical remission (Rutgeerts, et al. 2005; Sandborn, et al. 2012; Feagan, et al. 2005; Sandborn, et al. 2014).

More recently, oral Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1PR) modulators have been approved, in the post-anti-TNF setting and in non-pretreated patients, respectively. These options offer alternatives to biologics, but also have limitations. JAK inhibitors have safety concerns reflected in U.S. FDA “black box” warnings, and S1PRs require ECG prior to treatment initiation due to potential transient decrease in heart rate. Some improvement in maintenance clinical remission rate have been reported, ranging from 32% to 57% (Sandborn, et al. 2021; Sandborn, et al. 2023; Danese, et al. 2022). There remains a clear medical need for additional therapeutic options in UC for patients with inadequate response to or intolerance to conventional therapies and biologic therapies.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology. The hallmark feature of RA is an inflammatory process manifested by persistent symmetric polyarthritis of synovial joints which can ultimately lead to bone erosions, deformity, and disability. Left untreated, or inadequately treated, progressive functional impairment with increasing disability occurs leading to a reduction in quality of life. The prevalence of RA in the general population is approximately 1%, and increases with age in both genders, with women being more prone to developing RA than men. Early therapy with disease-modifying anti-rheumatic drugs (DMARDs) is the standard of care, including conventional synthetic DMARDs (csDMARDs) such as methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide, and biologic DMARDs (bDMARDs) such as anti-tumor necrosis factor (TNF) and non-anti-TNF biologics.

Despite major progress in the treatment of RA, there still remains a large unmet medical need, as only a small percentage of RA patients reach or maintain a status of low disease activity (LDA) or clinical remission (CR) over time, and many patients discontinue standard of care treatments due to safety or tolerability issues. Novel

therapies are therefore needed to complement the available interventions to address the unmet need (Burmester, et al. 2014; Emery, 2014; Meier, et al. 2014).

Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal/neuronal destruction, ultimately leading to severe disability. MS affects approximately 2.5 million individuals worldwide.

Relapsing-remitting MS (RRMS) is the most frequent clinical presentation of the disease. Approximately 85% of patients present with RRMS, characterized by recurrent acute exacerbations (relapses) of neurological dysfunction followed by recovery. After 15 to 20 years, ~50% of patients with RRMS have progressed to secondary progressive MS (SPMS), which is a stage of the disease characterized by continuous worsening of disability that occurs independently of relapses. The term of relapsing MS applies to those affected patients either with a RRMS or SPMS with superimposed relapses. Patients with relapsing MS constitute a common target for current treatment options. There are no clear criteria that mark the transition from RRMS to SPMS (EMA/CHMP/771815/2011, Rev. 2. 2015).

For patients with relapsing MS, interferon-β and glatiramer acetate have long been used as first-line drugs. However, these drugs require frequent self-injections and increase the burden on patients. In recent years, oral drugs such as fingolimod, dimethyl fumarate and teriflunomide have become available and enhanced the convenience of treatment for patients. In addition, treatment with more potent biologic drugs including natalizumab, alemtuzumab and ocrelizumab have been put into practice. Despite the increased options available, many patients experience disease activity that cannot be fully controlled, in part due to the heterogeneity of MS, and some patients cannot tolerate the currently available drugs. The need therefore remains to develop drugs with alternative mechanisms of action, convenient dosing, and a favorable safety profile.

Clinical Development Plan

As illustrated in Figure 49, our Phase 1 healthy volunteer single ascending dose / multiple ascending dose SAD/MAD program expected to be initiated in mid-2024, subject to IND clearance by FDA, is designed to enable assessment of safety and pharmacokinetics and lead to candidate doses for the subsequent stages. The healthy volunteer study is expected to be followed by a series of early proof of concept (PoC) studies in indications supported by preclinical data. These PoC studies are planned to cover various T and T- and B-cell-mediated indications,including potentially ulcerative colitis, rheumatoid arthritis, axial spondyloarthritis, multiple sclerosis, myasthenia gravis, psoriasis, and cutaneous lupus erythematosus.

Figure 49: Preliminary MRT-6160 Development Plan Through Early POC (Subject to Regulatory Clearance)

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 50, aberrant NLRP3 inflammasome activation and the subsequent release of active interleukin-1β (IL-1β) and interleukin-18 (IL-18) has been implicated in several inflammatory disorders including gout, cardiovascular disease, inflammatory bowel disease, neurodegenerative diseases including Parkinson's disease and Alzheimer's disease, ocular disease, diabetes, obesity, liver disease and Type 2 inflammatory diseases such as asthma and urticaria. 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 50: NEK7 is an Essential Regulator of the NLRP3 Inflammasome and Release of IL-1β and IL-18

In the setting of gout, monosodium urate (MSU) crystals deposit in joints, acting as endogenous danger signals to activate the NLRP3 inflammasome, causing an acutely painful inflammatory reaction mediated by IL-1β, shown in Figure 51.

Figure 51: Monosodium Urate Crystals Activate the NLRP3 Inflammasome and are a Causative Agent in Gout

Identification of NEK7 degron and NEK7-directed MGDs

NEK7 contains a well-defined degron, as identified using our proprietary QuEENTM platform and confirmed by crystal structure (shown in Figure 52, left panel). Given the kinase-independent role of NEK7 in activating the NLRP3 inflammasome, suggesting that inhibition of the catalytic activity of NEK7 would be ineffective in blocking NLRP3 inflammasome activation, we believe that degradation of NEK7 with our MGDs will be preferable over conventional catalytic inhibition strategies. We have generated MGDs from multiple chemical series that promote the association of NEK7 with cereblon. Our first NEK7 product candidate, MRT-8102, derived from one of these series, is a NEK7-directed MGD with favorable drug-like properties that has been selected to move forward into IND-enabling studies (shown in Figure 52, right panel). MRT-8102 is a first-in-class NEK7 MGD. 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 52: 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 53, 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 selective 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, Kelly, MM1S and induced pluripotent stem cells reveal similarly selective proteomic profiles when treated with MRT-8102.

Figure 53: MRT-8102 Induces Highly Selective NEK7 Degradation

Development Candidate NEK7 MGD, MRT-8102, achieves 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, we treated human monocyte-derived macrophages (hMDM), with increasing concentrations of MRT-8102 or MCC950, an NRLP3 inhibitor. We measured caspase-1 activation and IL-1β release from hMDM following pre-treatment with our MGD and subsequent exposure to inflammasome stimulators LPS and MSU crystals.The MSU stimulus is relevant to the setting of gout, where high uric acid levels lead to accumulation of MSU crystals in joints and the subsequent pathogenic activation of NLRP3 inflammasome. As shown in Figure 54, 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 MCC950, a direct inhibitor of the ATPase activity of NLRP3 itself. We also performed a similar assay in cynomolgus monkey whole blood using LPS and nigericin as NLRP3 inflammasome stimuli. In this setting, MRT-8102 was also shown to be superior to a different NLRP3 inhibitor, selnoflast, in inhibiting caspase-1 activity (top right) and IL-1β release (bottom right).

Figure 54: MRT-8102 Achieves Potent Inhibition of NLRP3 Inflammasome in Human and Monkey Cells In Vitro

In vivo validation 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. In a five day, multiple-dose study of MRT-8102, no unusual clinical observations were reported. MRT-8102 was administered once-daily for 5 days at 5 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 Days 10 and 15. As shown in Figure 55, left panel, data represent the average cyno PBMC NEK7 protein levels on the y-axis. PBMC NEK7 degradation showed reduction to 44% of pre-dose levels on day 1, that was further reduced to 15% by day 5. Upon ceasing MRT-8102 administration, NEK7 protein recovered to pre-dose levels by day 15.

Commensurate with NEK7 levels, production of IL-1β was inhibited in an ex vivo whole blood stimulation assay, shown in Figure 55, right panel. Similar results were obtained when measuring caspase-1 activity. The deep and

sustained inhibition of IL-1β release 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 55: In Vivo Dosing of MRT-8102 in Cynomolgus Monkeys Leads to NEK7 Degradation and Inhibition of IL-1β Release

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 neuroinflammation-associated neurological diseases. The identification of multiple chemical series within the NEK7 program offers a significant opportunity for the development of multiple drug-like MGDs with differentiated profiles. Our NEK7-directed MGDs, including MRT-8102, are selective, orally bioavailable and can penetrate the blood-brain-barrier, hence are potentially applicable to target inflammatory diseases of the CNS.

In light of the strategic importance of our NEK7 program, we are advancing a second, differentiated chemical series through Lead Optimization. As shown in Figure 56 (left panel), a representative NEK7-directed MGD has been progressed to in vivo studies in mice to assess the evidence of blood-brain barrier penetration. In a single dose study at 10 mg/kg, the compound demonstrated favorable bioavailability and brain penetration with a Kpuu of 0.8 (ratio of free plasma to free brain concentration), supporting the potential of this class. The compound exhibits high potency with regards to modulation of the NLRP3 pathway in a human monocyte-derived macrophage assay. Figure 56 (right panel) shows a dose-dependent decrease in caspase-1 activity and IL-1β release which was more potent than the NLRP3 inhibitor selnoflast.

Multiple compounds with favorable drug-like features and CNS exposure from the differentiated chemical series are currently under characterization and we are planning to advance an additional Development Candidate in the future.

Figure 56: Evidence of Brain Penetration for NEK7 MGD with Potent Activity in an In Vitro Functional Assay

Other programs

We are specifically focused on developing product candidates for target proteins that have been deemed undruggable or inadequately drugged. Our QuEENTM platform 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 molecules that can be optimized towards high potency and selectivity, with properties that we believe to be favorable. Our early pipeline includes programs in genetically defined oncology indications, as well as inflammatory, immunologic and other disease indications. We are further engaged in the discovery of additional target proteins in other indications, including, but not limited to, neurodegenerative and other neurological diseases. Figure 57 illustrates some of our key accomplishments.

Figure 57: Monte Rosa Therapeutics; From Serendipity to Rational Design of MGDs

Our services, collaboration and licenses agreements

Roche agreement

On October 16, 2023, Monte Rosa Therapeutics AG, a wholly-owned subsidiary of Monte Rosa Therapeutics, Inc., entered into a Collaboration and License Agreement with F. Hoffmann-La Roche Ltd (“Roche Basel”) and Hoffmann-La Roche Inc. (“Roche US” and together with Roche Basel, “Roche”) (the “Agreement”). Pursuant to the Agreement, the parties will seek to identify and develop molecular glue degraders (“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 pre-clinical discovery and research activities until a defined point. Upon such point, Roche gains the right to exclusively pursue further pre-clinical and clinical development activities.

Under the 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 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 pre-clinical 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 pre-clinical, 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 Agreement will remain in effect for each product licensed under the 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 Agreement in its entirety, on a country-by-country or a target-by-target basis.

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.

Competitors in our efforts to develop MGD therapeutics for patients, include, but are not limited to, BioTheryX Therapeutics, Inc., C4 Therapeutics, Inc., Nurix Therapeutics, Inc., Kymera Therapeutics, Inc., Seed Therapeutics, Inc., Plexium Inc, Bristol-Myers Squibb, Novartis, Proxygen GmbH, VantAI, Inc., Orionis Biosciences, Inc., Dunad Therapeutics, Ltd, and Captor Therapeutics, SA, all of whom have reported having MGD product candidates in preclinical or clinical development. In addition, lenalidomide and pomalidomide, which are both marketed by Bristol-Myers Squibb, have been shown to function as MGDs. Further, several large pharmaceutical companies have disclosed investments in this 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 platform 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 intend to 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 platform, we generally intend to pursue patent protection covering our approaches, methods, and research and development tools relevant to our degron database, our Rhapsody, tools, and our library of MGDs. 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 continue 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, or 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, 2023, we solely owned a patent portfolio that included thirty-one (31) pending patent families, including fifteen pending patent application filed under the Patent Cooperation Treaty and multiple pending United States provisional patent applications. Our portfolio is being built to cover our MGDs product candidates and various uses thereof, MGDs drawn to currently undisclosed target proteins and uses thereof, and our industry-leading QuEENTM platform, as further described below. Patent prosecution related to our portfolio is currently in the early stages and, as such, no patent examiner has yet fully scrutinized the merits of any of our pending patent applications.

Wholly Owned Product Candidates

With respect to our GSPT1 program, as of December 31, 2023, our portfolio included one United States provisional patent application, four pending PCT patent applications, five pending non-provisional patent application 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 owned one pending non-provisional U.S. application and

one pending European application, that cover 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, 2023, our portfolio included three pending PCT applications that cover various CDK2-directed MGDs and uses thereof. The earliest scheduled expiration of any U.S. or foreign patents issuing from these PCT applications or U.S. provisional 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, 2023, our portfolio included one U.S. provisional patent application that covers 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 VAV1 program, as of December 31, 2023, our portfolio included one U.S. provisional patent application that covers various VAV1-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.

QuEENTM platform

With respect to our QuEENTM platform, as of December 31, 2023, our portfolio included one U.S. provisional patent application, two pending U.S. non-provisional patent applications, one pending European patent application and four pending PCT patent applications drawn to our QuEENTM platform 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, 2023, we owned various registered and unregistered trademarks in the United States, including Monte Rosa Therapeutics, our housemark logo, the name of our QuEENTM platform, and the name of our Glueomics resource.

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.

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GLUE · 10-K · period ended 2023-12-31

Item 1. Business

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GLUE · 10-K · period ended 2023-12-31

Item 1. Business

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