Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Investor Presentation (January 2025)
82 slides from Monte Rosa Therapeutics's investor presentation, Jan 10, 2025
Slide 1: Proteome Editing Through Molecular Glue Degraders
Proteome Editing Through Molecular Glue Degraders Innovating Beyond New Heights | January 2025
Slide 2: Forward-Looking Statements
Forward-Looking Statements This communication includes express and implied “forward-looking statements,” including forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements that are not historical facts an
Slide 3: Monte Rosa Therapeutics – Company Overview
Monte Rosa Therapeutics – Company Overview Proteome editing with molecular glue degraders Arsenal of rationally designed MGDs to edit the proteome by degrading proteins with unprecedented precision Industry-leading discovery engine combining use of AI with experimental platform to enable rational de
Slide 4: Our Molecular Glue Degraders Edit the Proteome
Monte Rosa’s rationally designed MGDs have potential applications in Oncology, Immunology, Neuroscience and other therapeutic areas Our Molecular Glue Degraders (MGDs) Edit the Proteome Ternary complex Ubiquitination Proteasome-mediated degradation of neosubstrate Ubiquitin chain Neosubstrate Ligase
Slide 5: Key Insights into Surface Interactions Drive Only-in-Class MGD Designs
Interrogating surfaces using geometric deep learning informs reprogrammable ligase and matching target space… Key Insights into Surface Interactions Drive Only-in-Class MGD Designs E3 ligase Neosubstrate footprint MGD footprint E3 ligase neosurface
Slide 6: Broad opportunity to eliminate undruggable proteins through only-in-class MGDs
...and creates broad opportunity to eliminate undruggable, disease-driving proteins through “only-in-class” MGDs Key Insights into Surface Interactions Drive Only-in-Class MGD Designs Grow Target Space (e.g., I&I, neurology) Activate New E3 Ligases Expand Chemical Space (MGD Library) CRBN MGDs Ligas
Slide 7: Three Ways to Eliminate a Disease-Causing Protein
Three Ways to Eliminate a Disease-Causing Protein MGDs can directly and precisely target proteins that cause disease DNA mRNA protein CRISPR gene editing RNAi/ASO MGD MGD
Slide 8: Three Ways to Eliminate a Disease-Causing Protein: MGD Advantages
Three Ways to Eliminate a Disease-Causing Protein MGDs provide advantages of large molecule modalities with orally dosed small molecules DNA mRNA protein CRISPR RNAi/ASO MGD Address undruggable space Properties Highly selective Orally bioavailable Scalable manufacturing nucleus MGD Rev
Slide 9: Key Advantages of Our Rationally Designed MGDs
Key Advantages of Our Rationally Designed MGDs Unique insights into anatomy of protein-protein-MGD interaction allows unprecedented MGD selectivity Unprecedented Selectivity Long lasting, catalytic protein degradation effect creates differentiated target product profiles Catalytic Mechanism of Actio
Slide 10: Portfolio and Partnerships
My. Monte Rosa Therapeutics Portfolio and Partnerships
Slide 11: Monte Rosa Pipeline and Upcoming Milestones
Monte Rosa Pipeline and Upcoming Milestones Oncology Inflammation Immunology Various GSPT1 NSCLC, SCLC and other MYC-driven Malignancies IL-1β/NLRP3 driven Inflammatory Diseases VAV1 Autoimmune Disease – Systemic and CNS Discovery Target Indication(s) Additional Phase 1 data in Q1 2025 Next Anticipa
Slide 12: Portfolio Strategy
Portfolio Strategy Build discovery capability with focused disease interest Expand portfolio with broader therapeutic area lenses via our powerful discovery engine Cardiovascular Metabolic Current programs + emerging novel projects Genetic 2020 – 2024 2025+ Strategic Goal Therapeutic Areas of Focus
Slide 13: Creating Value through Strategic Agreements
Creating Value through Strategic Agreements Scope Global license agreement to advance VAV1-directed molecular glue degraders including MRT-6160 (announced Oct. 2024) Strategic collaboration to discover novel MGDs targeting cancer and neurological diseases (announced Oct. 2023) Financials $150M upfro
Slide 14: GSPT1 program (MRT-2359)
My. Monte Rosa Therapeutics GSPT1 program (MRT-2359)
Slide 15: MYC is a Key Regulator of Cancer Growth and Immune Evasion
Frequently activated across many cancers including some of the most common (e.g. lung, prostate, breast) Drives cancer progression through effects on both cancer cells and tumor microenvironment MYC signaling can enable tumor cells to evade immune response Very challenging to drug with conventional
Slide 16: Targeting MYC-driven Tumors Through GSPT1 Degradation
Targeting MYC-driven Tumors and Their Addiction to Protein Translation Through GSPT1 Degradation Addiction To sustain growth, MYC-driven tumors are addicted to protein translation Dependency Therapeutic vulnerability 1 2 3 This addiction creates a dependency on the translation termination factor GSP
Slide 17: MRT-2359 is a Potent and Highly Selective GSPT1-directed MGD
MRT-2359 is a Potent and Highly Selective GSPT1-directed MGD in vitro data CRBN binding, Ki 113 nM Ternary complex, EC50 < 7 nM Degradation, DC50 (in disease relevant cell lines) 1 - 20 nM MRT-2359 induces selective GSPT1 degradation and shows favorable ADME/DMPK profile MRT-2359 is a potent GSPT1-d
Slide 18: MRT-2359 Has Optimized Depth of Degradation
MRT-2359 Has Optimized Depth of Degradation To Achieve Preferential Activity in MYC High Cancer Cells %GSPT1 degraded (Dmax) determined by Western blot Differential Effect (MYC vs non-MYC-driven) less degradation Preferential activity in MYC high cells MRT-2359 MRT-2136 MRT-2359 displays preferentia
Slide 19: Three Mechanisms Driving Preferential Activity in MYC High Tumor Cells
Three Mechanisms Driving Preferential Activity in MYC High Tumor Cells MRT-2359 CRBN GSPT1 Preferential GSPT1 degradation MRT-2359 leads to deeper degradation of GSPT1 in cancer cells with high MYC expression Inhibition of translation MRT-2359-induced reduction of GSPT1 preferentially impairs protei
Slide 20: Large Potential Opportunities in MYC-Driven Tumors
Large Potential Opportunities in MYC-Driven Tumors High unmet need with no currently approved therapies specifically for MYC high tumors Neuroendocrine tumors L-/N-MYC amplified tumors Heme Breast cancer ER positive metastatic SCLC (70-80% L/N-MYC high) NSCLC N-MYC high (5-10%) SCLC/NE transformatio
Slide 21: Preclinical Validation of MRT-2359 in Lung Cancer PDX Models
Preclinical Validation of Activity of MRT-2359 in Lung Cancer PDX Models Collection of PDX models 21 SCLC Adeno NSCLC NE-LC biomarker negative biomarker positive Targeted mass spectrometry in 7 representative models PD modulation 100 50 0 -50 -100 N-Myc (qPCR) Best % TV change 100 50 0 -50 -100 N-My
Slide 22: MRT-2359 Disrupts MYC and AR Signaling in Prostate Cancer
MYC overexpression drives AR dependence and therapy resistance in CRPC MRT-2359 inhibits expression of AR-regulated genes and has significant activity in human prostate cancer models MRT-2359 disrupts MYC and AR Signaling in Prostate Cancer E-box ARE AR driven genes Sustained tumor growth Therapy re
Slide 23: MRT-2359 Leads to Tumor Regressions in ER-positive Breast Cancer Model
MRT-2359 Leads to Tumor Regressions in Preclinical Model of ER-positive Breast Cancer MRT-2359 displays activity in MCF7 model of ER-positive breast cancer MRT-2359 reduces MYC and CCND1 in vivo MCF7 Breast CDX (ER+, HER2-)
Slide 24: MRT-2359-001 Phase 1/2 Clinical Study Design
0.5mg 5/9 Phase 2: Possible Expansion Cohorts Phase 1: Dose Escalation 1.5mg 5/9 1mg 5/9 MRT-2359-001 Phase 1/2 Clinical Study Design Lung cancer, high-grade neuroendocrine tumors and solid tumors with N-/L-MYC amplification 2mg 5/9 5/9 = 5 days on drug, 9 days off drug; 21/7 = 21 days on drug, 7 da
Slide 25: MRT-2359 Phase I Interim Data – October 2023
MRT-2359 Phase I Interim Data – October 2023 Objectives of Phase I interim analysis Demonstrate dose dependent PK Demonstrate significant GSPT1 degradation at safe dose levels in PBMCs and tissue biopsies (60% based on preclinical data) Share potential preliminary efficacy signals in biomarker posit
Slide 26: MRT-2359 Induces Optimal GSPT1 Degradation in PBMCs
MRT-2359 displayed dose dependent plasma exposure MRT-2359 Induces Optimal GSPT1 Degradation in PBMCs* MRT-2359 displayed deep GSPT1 degradation in PBMCs at all dose levels GSPT1 expression assessed using targeted mass spectrometry PD modulation in PBMCs observed across all dose levels; level of deg
Slide 27: MRT-2359 Induces Optimal GSPT1 Degradation in Tissue Biopsies
MRT-2359 Induces Optimal GSPT1 Degradation in Tissue Biopsies* MRT-2359 reduced GSPT1 protein expression in human tissue biopsies GSPT1 degradation assessed from pre-treatment screening biopsies and biopsies taken at day 19 Matched biopsies obtained from 11 patients across the 3 cohorts analyzed GSP
Slide 28: Summary of Treatment-Related Adverse Events
Summary of Treatment-Related Adverse Events (AEs) in > 2 patients# No observed clinically significant hypocalcemia or hypotension/cytokine release syndrome AE Preferred Term 0.5 mg (N=9)## 1 mg (N=7)## 2 mg (N=5) ## Overall (N=21) Any Grade Grade > 3 Any Grade Grade > 3 Any Grade Grade > 3 Any Grade
Slide 29: Confirmed Partial Response in High Grade Neuroendocrine Bladder Cancer
Confirmed Partial Response in High Grade Neuroendocrine Bladder Cancer* Baseline 8 weeks 4 weeks High Grade (HG) neuroendocrine bladder cancer Baseline tumor biopsy demonstrated high N-MYC expression 4 prior lines of therapy including chemotherapy and pembrolizumab Patient initiated on 2 mg for firs
Slide 30: Unconfirmed Partial Response in NSCLC with SCLC/NE Transformation
Unconfirmed Partial Response in NSCLC with SCLC/NE Transformation* Baseline 3 weeks NSCLC (adenocarcinoma) Baseline tumor biopsy demonstrated SCLC/NE transformation, low N- and L-MYC expression Multiple lines of prior therapy including chemotherapy, pembrolizumab and atezolizumab Patient initiated o
Slide 31: MRT-2359-001 – Preliminary Efficacy Data
MRT-2359-001 – Preliminary Efficacy Data* As of September 7th, 2023, of 15 evaluable patients treated across 3 cohorts, tumors from 6 patients were identified as biomarker positive Of these 6 biomarker positive patients, 2 have experienced a PR (1 confirmed, 1 unconfirmed) and 1 patient has SD PR (-
Slide 32: Favorable Safety Profile at Clinically Active Doses
Favorable Safety Profile at Clinically Active Doses* Safety profile supports further development Preferential and more rapid degradation of GSPT1 in MYC high tumor cells enables favorable adverse event (AE) profile at clinically active doses of 0.5 and 1 mg – no Grade ≥3 AEs Grade 1-2 AEs primarily
Slide 33: VAV1 Program (MRT-6160)
My. Monte Rosa Therapeutics VAV1 Program (MRT-6160)
Slide 34: VAV1 is a Key Regulator of T- and B-cell Receptor Activity
VAV1 is a Key Regulator of T- and B-cell Receptor Activity Pivotal scaffolding protein and signaling molecule downstream of both the T-cell and B-cell VAV1 degradation impacts both T- & B-cell function, with the potential to treat a broad set of immune-mediated diseases Cytokine receptor TYK2 JAK TC
Slide 35: VAV1 is an Upstream Targeting Node Associated with Clinically Validated Pathways
Clinically validated pathway in autoimmune/inflammatory disease VAV1 is an Upstream Targeting Node Associated with Clinically Validated Pathways T cell activation B cell activation/Plasma cell differentiation (Antibody production) Pro-inflammatory cytokine production Th17 response VAV1 signaling is
Slide 36: MRT-6160 is a Potent and Highly Selective VAV1-directed MGD
MRT-6160 is a Potent and Highly Selective VAV1-directed MGD in vitro data CRBN binding, IC50 670 nM Ternary complex, EC50 11 nM Degradation, DC50 /Dmax (Jurkat) 7 nM / 97 % MRT-6160 induces highly selective VAV1 degradation and has a favorable ADME/DMPK profile MRT-6160 is a potent VAV1-directed MGD
Slide 37: MRT-6160 is a Potent, Highly Selective VAV1 MGD with Favorable Drug-like Profile
MRT-6160 is a Potent, Highly Selective VAV1 MGD with a Favorable Drug-like Profile MGD Activity Profile CRBN Binding (HTRF, IC50) 0.67 µM VAV1 Ternary Complex (HTRF, EC50) 11 nM VAV1 Degradation (Jurkat, DC50 /Dmax) 7 nM / 97% Selectivity (TMT proteomics) Large VAV1 selectivity window Physicochemica
Slide 38: 28-day GLP Toxicology Summary
28-day GLP Toxicology Summary Robust VAV1 degradation and recovery observed in both low and high dose groups in cyno GLP tox study 28-day GLP Toxicology Studies Establish Highly Favorable Safety Margins 0.5 mg/kg/day 30 mg/kg/day *data shown from female cyno PBMCs, similar data obtained in males Pre
Slide 39: MRT-6160 Blocks T-cell-Mediated B-cell Activity in BioMAP Profile
MRT-6160 Blocks T-cell-Mediated B-cell Activity in BioMAP® Profile Upadacitinib, 1000 nM Deucravacitinib, 400 nM Ibrutinib, 1100 nM MRT-6160, 1000 nM Azathioprine, 100 μM BT coculture assay: T-cell-mediated B-cell activity T-cell independent JAKi TYK2i BTKi VAV1 MGD Azathioprine Relative protein exp
Slide 40: MRT-6160 Ameliorates T Cell Transfer-Induced Colitis
Treatment initiated at time of model induction on Day 0 MRT-6160 Ameliorates T Cell Transfer-Induced Colitis Better than Standard of Care Non-pathogenic CD45RBlow or pathogenic CD45RBhigh cells were transferred into SCID mice to induce colitis. Mice were treated with vehicle, MRT-6160 (PO QD), or an
Slide 41: MRT-6160 Reduces Colon Damage and Cytokine Production in Colitis Model
MRT-6160 Reduces Inflammation-Mediated Damage of the Colon and Cytokine Production in a T-Cell Transfer Model of Ulcerative Colitis Flow cytometric (upper row) and cytokine bead array (lower row) analysis of mesenteric lymph node CD4+ T cells and colon tissue respectively CD45RBlow non-pathogenic co
Slide 42: MRT-6160 Reduces Expression of Pro-Inflammatory Disease Genes
MRT-6160 Reduces Expression of Human Disease-Relevant Pro-Inflammatory and Disease-Associated Genes MRT-6160 attenuates expression of a pro-inflammatory disease gene signature Vehicle vs. Control differential expression in the IBD mouse model was mapped to human ulcerative colitis vs healthy differe
Slide 43: MRT-6160 Inhibits Disease Progression in Rheumatoid Arthritis Model
MRT-6160 Inhibits Disease Progression, Joint Inflammation & Auto-Antibody Production in a Rheumatoid Arthritis Disease Model MRT-6160 inhibits anti-collagen II auto-antibodies MRT-6160 inhibits disease progression Collagen-induced arthritis T/B-cell (auto-antibody) driven model Mice were immunized w
Slide 44: MRT-6160 Reduces Pro-Inflammatory Cytokine Production in Arthritis Model
MRT-6160 Reduces Pro-Inflammatory Cytokine Production in a Rheumatoid Arthritis Disease Model Collagen-induced arthritis T/B-cell (auto-antibody) driven model Dosing: Vehicle, MRT-6160; PO QD. Anti-TNF; IP BIW. Mice were treated for 21 days from disease onset (Day 0) Serum cytokine analysis on Day 2
Slide 45: MRT-6160 Elicits Dose-Dependent Activity in Multiple Sclerosis Model
PD Analysis MRT-6160 inhibits disease progression in a mouse model of multiple sclerosis MRT-6160-mediated activity correlates with VAV1 levels T-cell mediated experimental autoimmune encephalitis (EAE) model C57BL/6 mice were immunized with MOG35-55 peptide on Day -12 then administered pertussis to
Slide 46: Phase 1 Biomarker Strategy to Demonstrate MRT-6160 Pharmacodynamic Effects
Phase 1 Biomarker Strategy to Demonstrate MRT-6160 Pharmacodynamic Effects VAV1 protein degradation Flow cytometry on T and B cells: whole blood (WB) Potential: Mature B cell typing in MAD Key downstream PD Flow cytometry for CD69 protein on T & B cells: WB Immunoassay for IL-2, IL-6, IL-17 hs C-rea
Slide 47: VAV1: Unique Mechanism with Broad Potential Applications
Humira, Enbrel Taltz, Cosentyx Actemra, Kevzara Vyvgart Ocrevus, Rituxan Rinvoq, Xeljanz, Olumiant Sotyktu VAV1: Unique Mechanism with Broad Potential Applications Potential to address multiple autoimmune diseases with safe, oral therapy Note: Chart adapted from Hosack et al., Nat Rev Immunol 2023.
Slide 48: NEK7 Program (MRT-8102)
My. Monte Rosa Therapeutics NEK7 Program (MRT-8102)
Slide 49: NEK7 is a Key Regulator of NLRP3 Inflammasomes, IL-1 and IL-18
Inflammation-driven diseases (selected examples) NEK7 is a Key Regulator of NLRP3 Inflammasomes, IL-1 and IL-18 Joints Gout Brain Parkinson Heart Pericarditis Obesity Atherosclerosis Cytokine secretion Pyroptosis pro-IL-1b pro-IL-18 IL-1b IL-18 Metabolic Inactive NLRP3 NEK7 Active NLRP3 Wheel-like o
Slide 50: IL-1/NLRP3 Signaling is a Clinically Validated Pathway
IL-1/NLRP3 Signaling is a Clinically Validated Pathway Recurrent pericarditis Rilonacept (IL-1α/β) – approved for recurrent pericarditis Atherosclerotic cardiovascular disease Canakinumab (IL-1β) – reduction in cardiac events Cardio-immunology Rheumatology Neurology Metabolic Weight loss Multiple NL
Slide 51: MRT-8102 is a Potent, Selective NEK7-Directed MGD
MRT-8102 is a Potent, Selective NEK7-Directed MGD With a Favorable Drug-like Profile MGD Activity Profile CRBN Binding (HTRF, IC50) 0.2 µM NEK7 Degradation (CAL51, DC50 /Dmax) 10 nM / 89% Selectivity (TMT proteomics) Excellent selectivity profile in different cell lines Physicochemical Properties Lo
Slide 52: MRT-8102 Potently Degrades NEK7
MRT-8102 potently degrades NEK7 MRT-8102 induces highly selective NEK7 degradation MRT-8102 is a Potent, Durable, and Highly Selective NEK7-directed MGD No degradation of other known CRBN neosubstrates MRT-8102 exposure results in prolonged PD effect Cyno 10 mg/kg single-dose MRT-8102 exposure prolo
Slide 53: MRT-8102 Leads to Potent Inhibition of NLRP3 Inflammasome In Vitro
Reduced caspase-1 and IL-1β in human monocyte-derived macrophages Reduced inflammasome activation (ASC speck formation) in human whole blood MRT-8102 Leads to Potent Inhibition of NLRP3 Inflammasome In Vitro LPS + Nigericin Unstim LPS+Nig LPS+Nig MRT-8102 (0.1μM) Gating strategy: Single cells_CD45+_
Slide 54: MRT-8102 Induces Degradation of NEK7 In Vivo
MRT-8102 induces degradation of NEK7 in vivo over several days In vivo NEK7 degradation leads to inhibition of NLRP3 inflammasome in ex vivo stimulation assay Suppression of Ex Vivo Inflammasome Activation Following Degradation of NEK7 After Single and Multi-dose Study in Non-human Primates No clini
Slide 55: MRT-8102 Displays Significant Blood Brain Barrier Penetration
MRT-8102 Displays Significant Blood Brain Barrier Penetration Daily dose of 30 mg/kg MRT-8102 for 7 days Analysis on day 8 (24 hr post-final dose) by JESS Simple Western Significant NEK7 degradation in various brain regions 24h post treatment PBMCs Brain MRT-8102 displays CNS-penetrance single-dose
Slide 56: CDK2 Program
My. Monte Rosa Therapeutics CDK2 Program
Slide 57: CDK2 is a Key Driver of Cell Cycle Progression in Cancer
CDK2 is a Key Driver of Cell Cycle Progression in Cancer CDK2: a key cell cycle regulator Patient diagnosed incidence #s, major markets (US, EU and JP): Decision Resources Group (DRG) Therapeutic hypothesis: CDK2 is a key driver of cancers with cyclin dependent kinase pathway alterations MGDs will a
Slide 58: MRT-9643 is a Potent, Highly Selective CDK2 MGD
MRT-9643 is a Potent, Highly Selective CDK2 MGD with a Favorable Drug-like Profile MGD Activity Profile CRBN Binding (HTRF, IC50) 0.3 µM CDK2 Ternary Complex (HTRF, EC50) 6 nM CDK2 Degradation (HEK, DC50 /Dmax) 56 nM / 64% Selectivity (TMT proteomics in MCF7) Large CDK2 selectivity window Physicoche
Slide 59: MRT-9643 is a Potent and Highly Selective CDK2-directed MGD
MRT-9643 is a Potent and Highly Selective CDK2-directed MGD in vitro data CRBN binding, IC50 289 nM Ternary complex, EC50 6 nM Degradation, DC50 / Dmax (HEK 293) 56 nM / 64 % MRT-9643 induces highly selective CDK2 degradation and has a favorable ADME/DMPK profile MRT-9643 is a potent CDK2-directed M
Slide 60: MRT-9643 Inhibits Proliferation of CDK2-dependent Cancer Cells
MRT-9643 Inhibits Proliferation of CDK2-dependent Cancer Cells CDK2 degradation arrests CDK2-dependent cells in G1 phase Cell cycle analysis (DAPI and EdU) MDA-MB-157 (24 hr) CDK2 degradation inhibits proliferation WB degradation (24 hr) MDA-MB-157 CyQuant proliferation assay (7 d) MDA-MB-157 CDK2 d
Slide 61: MRT-9643 Displays Superior Selectivity Compared to CDK2 Inhibitors
MRT-9643 Displays Superior Selectivity Compared to Clinical CDK2 Inhibitors Clinical-stage CDK2 inhibitors demonstrate off target activity in biochemical kinome profiling CDK2 inhibitors but not CDK2 MGDs display activity in CDK2-independent RB1 KO line 7-day CyQuant Assay; MDA-MB-157 cell line Carn
Slide 62: CDK2 MGD and CDK4/6 Inhibitor Combination
CDK2 MGD and CDK4/6 inhibitor combination MRT-9643/ribociclib combination delays resistance onset in ER+ model in vitro CDK2 MGD/Ribociclib Combination Delays Resistance Onset in ER+ Model in vitro Incucyte confluence monitoring, MCF7
Slide 63: MRT-9643 Induces Tumor Regression with CDK4/6 Inhibition and Fulvestrant
MRT-9643 induces robust tumor regression in combination with CDK4/6 inhibition and fulvestrant CDK2 MGD Demonstrates Activity in Combination with CDK4/6 Inhibitor (and Fulvestrant) in ER+ Breast Cancer (MCF7) 28-day efficacy evaluation in MCF7 CDX Model (MRT-9643 dosed at 30 mpk BID) 63 MRT-9643 ind
Slide 64: CCNE1 Program
My. Monte Rosa Therapeutics CCNE1 Program
Slide 65: CCNE1 (Cyclin E1) is a Target for Solid Tumors
CCNE1 (Cyclin E1) is a Target for Solid Tumors with Deregulated Cyclin E1 Therapeutic hypothesis: CCNE1 (Cyclin E1) is a well-recognized human oncogene that drives multiple hallmarks of cancer, and has been considered undruggable Selective degradation of cyclin E1 can target tumors with deregulated
Slide 66: CCNE1 Degradation Leads to Downstream Pathway Suppression
CCNE1 degradation leads to downstream pathway suppression MRT-50969 induces robust G1/S cell cycle arrest MRT-50969 is a Potent and Highly Selective CCNE1-directed MGD Western blot, OVISE, 24h TMT Proteomics, MDA-MB-157 Rb K/O 1μM, 24h P-value (-log10) Protein fold-change (log2) CCNE1 MRT-50969 is h
Slide 67: CCNE1 MGD Sensitivity Correlates with CCNE1 Dependency
CCNE1 MGD Sensitivity is Highly Correlated with CCNE1 Gene Dependency, Copy Number and Expression 5 Day CyQuant assay, 50 cancer cell line panel; Gene dependency and genomics data from DepMap/Broad Institute Gene Dependency Copy Number mRNA Expression
Slide 68: MRT-50969 Shows Superior Differential Activity vs CDK2 Inhibitors
GI50 = growth inhibition 50%, the concentration of drug required to inhibit the growth of cancer cells in vitro by 50% MRT-50969 Shows Superior Differential Activity in CCNE1 Dependent Cell Lines Compared to Clinical-Stage CDK2 Inhibitors OVCAR3 vs A2780 MDA-157 vs T47D 5 Day CyQuant assay, bars ind
Slide 69: MRT-50969 Inhibits Tumor Growth in CCNE1 Amplified Breast Cancer Model
MRT-50969 inhibits tumor growth in CCNE1 amplified breast cancer model MRT-50969 Inhibits Tumor Growth in a CCNE1 Amplified Breast Cancer Model in vivo MRT-50969 degrades CCNE1 in vivo HCC1569 CDX, 28-day efficacy study Day 28/8h and 24h PD, Western blot, HCC1569 CDX
Slide 70: MRT-50969 Inhibits Tumor Growth in CCNE1 Amplified Gastric Cancer Model
21-day efficacy study in MKN1 CDX model MRT-50969 Inhibits Tumor Growth in a CCNE1 Amplified Gastric Cancer Model in vivo Day 21/8h and 24h PD, Western blot, MKN1 CDX MRT-50969 inhibits tumor growth in CCNE1 amplified gastric cancer model MRT-50969 degrades CCNE1 in vivo
Slide 71: QuEEN Discovery Engine
My. Monte Rosa Therapeutics QuEEN™ Discovery Engine
Slide 72: Overcoming Past Limitations of Molecular Glue Degraders
Overcoming Past Limitations of Molecular Glue Degraders Traditional thinking Monte Rosa Therapeutics approach ‘Target space is limited’ QuEENTM has vastly expanded the degradable target space across a broad range of undruggable protein classes ‘MGDs are identified by serendipity’ QuEENTM enables tar
Slide 73: Rationally-designed MGDs Create Diverse E3 Ligase Neosurfaces
Rationally-designed MGDs create diverse E3 ligase neosurfaces, enabling recruitment of new targets Our geometric deep learning algorithms use surfaces to predict targets. Our surface-based algorithms design MGDs to recruit targets. Our platforms generate actionable data-at-scale to test & train (“da
Slide 74: GlueShot: de novo MGD Design for Novel Targets
AF, Rosetta, PDB GlueShot: de novo MGD Design for Novel Targets E3 ligase structures Protein structures AF, Rosetta, PDB Surface fingerprint fAIceit™ Virtual library FLASH™ & GlueAID™ Surface of MGD + ligase COSMOS™ Fingerprint matching Headlong™ & fAIceit™ Nobel prize MGDs that induce PPIs with dru
Slide 75: QuEEN Unique Capabilities
QuEEN™ Unique Capabilities AI/ML In silico discovery using proprietary AI-powered algorithms Proximity Screening Specialized suite of biochemical, cellular and proteomics assays to assess proximity and degradation in high throughput Structure-based Design Proprietary database of protein structures t
Slide 76: Proprietary AI/ML Engines Enable Discovery of Selective MGDs
Target ID Guided by surface mimicry In silico screening Screen for activity in ternary complexes Proprietary AI/ML Engines Enable the Discovery of Reprogrammable Ligases, Neosubstrates, and Selective MGDs Proprietary AI/ML engines Ligase matching PPI propensity & surface complementarity MGD discover
Slide 77: QuEEN: How it Works
QuEENTM: How it Works Target and ligase ID Surface-centric discovery process Actionable data-at-scale Proteomics Virtual screens Structural biology High throughput screens Predict Design Test & Train AI-powered chemistry Surface-aware MGD generation & optimization
Slide 78: QuEEN Toolbox to Rapid Discovery of Oral MGDs
QuEEN™ Toolbox to Rapid Discovery of Oral MGDs Predict Target & ligase ID fAIceit™ Ultra-fast fingerprint search for surface-based matchmaking E3 ligase reprogrammability fAIceit mimicry target ID Structural biology X-ray & cryo-EM Headlong™ virtual screens Proteomics mass-spec farm HT library scree
Slide 79: Algorithms Use MGD-focused, Moated Data to Identify Targets
in silico experimentation Algorithms Use MGD-focused, Moated Data to Identify Targets and Design MGDs FLASH™ virtual library Proteomics mass-spec farm HT library screening MILLION protein measurements fAIceit mimicry target ID Structural biology X-ray & cryo-EM Headlong™ virtual screens 37 6.5 >125
Slide 80: Team
Team
Slide 81: World-Class Leadership
World-Class Leadership Deep expertise in molecular glue discovery, drug development and precision medicine Filip Janku, M.D., Ph.D. Chief Medical Officer Markus Warmuth, M.D. Chief Executive Officer John Castle, Ph.D. Chief Data and Information Officer Sharon Townson, Ph.D. Chief Scientific Officer
Slide 82: Thank You
4 ic, Oe : Thank You — -_ _ My. Monte Rosa Therapeutics
Monte Rosa Therapeutics — Investor Presentation (January 2025) on 6ix