Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Investor Presentation (March 2025)
85 slides from Monte Rosa Therapeutics's investor presentation, Mar 20, 2025
Slide 1: Proteome Editing Through Molecular Glue Degraders
Proteome Editing Through Molecular Glue Degraders Innovating Beyond New Heights | March 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 Unique and differentiated “only in class” portfolio Arsenal of rationally designed MGDs to edit the proteome by degrading proteins with unprecedented precision Industry-leading discovery engine combining use of
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: MGDs provide advantages of large molecule modalities
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 GSPT1 Castration-resistant Prostate Cancer IL-1β/NLRP3-driven Inflammatory Diseases VAV1 Immune-mediated Diseases Discovery Target Indication(s) Additional CRPC data in H2 2025 Next Anticipated Milestone Ownership Multiple Targets I&I, Genetic Diseases, On
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 – 2025 2026+ 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: VAV1 Program (MRT-6160)
My. Monte Rosa Therapeutics VAV1 Program (MRT-6160)
Slide 15: VAV1 is an Upstream Targeting Node
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 16: 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 17: MRT-6160 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 18: 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 19: MRT-6160 Attenuates Disease in a T Cell-Mediated Model of IBD
MRT-6160 Attenuates Disease in a T Cell-Mediated Model of IBD MRT-6160 attenuates T cell-mediated pathogenic processes and pro-inflammatory cytokines associated with IBD pathophysiology Similar efficacy seen in several other T- and T/B-cell driven models
Slide 20: 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 21: Safety, PK and PD Data from SAD and MAD Phase 1 Trial of MRT-6160
Safety, PK and PD Data from SAD and MAD Healthy Volunteers Phase 1 Trial of VAV1 MGD MRT-6160
Slide 22: MRT-6160 Healthy Volunteers Study: Design and Objectives
MRT-6160 Phase 1 Healthy Volunteers Study: Design and Objectives All cohorts randomized & placebo controlled SAD cohorts MAD cohorts One oral dose 7 daily oral doses SAD DL5 SAD DL4 SAD DL3 SAD DL2 SAD DL1 MAD DL3 MAD DL2 MAD DL1 Study Endpoints Primary Safety and tolerability Secondary & explorator
Slide 23: MRT-6160 Dose-Dependent Human Pharmacokinetic Profile
MRT-6160 Displayed a Dose-Dependent Human Pharmacokinetic Profile Dose Level T1/2 (hr) Cmax (ng/mL) AUC0-24 (hr*ng/mL) 1 24.1± 2.6 18.3 ± 1.0 300.3 ± 16.4 2 26.8 ± 1.9 32.6 ± 2.2 527.0 ± 30.3 3 33.3 ± 2.9 100.9 ± 4.6 1736.3 ± 67.1 4 28.3 ± 1.6 216.2 ± 7.0 3615.2 ± 190.8 5 27.2± 1.7 399.0 ± 31.1 6593
Slide 24: In Vitro Assay Validation of PD and Immune Cell Functional Testing
In Vitro Assay Validation of PD and Immune Cell Functional Testing Degradation assessment Ex vivo stimulation of whole blood to monitor T- & B-cell functions CD69 upregulation on T & B cells by flow cytometry VAV1 protein expression by flow cytometry CD69 IL-2 T cell B cell T cell IL-17A CD69 TCR =
Slide 25: MRT-6160 Achieved Dose-Dependent VAV1 Degradation >90%
MRT-6160 Achieved Dose-Dependent VAV1 Degradation >90% in Peripheral Blood T Cells After Single and Multiple Dose Administration Dose-dependent, marked degradation of VAV1 in peripheral blood T cells (> 90%; except DL1) Similar results observed in peripheral blood B cells VAV1 protein reduction is s
Slide 26: VAV1 Degradation Resulted in Functional Inhibition of T and B Cells
VAV1 Degradation by MRT-6160 Resulted in Significant Functional Inhibition of T and B Cells following a Single Dose Administration MRT-6160 treatment: Significantly attenuated CD69 upregulation on T and B cells following TCR stimulation, reflecting functional inhibition Significantly (up to 99%) inh
Slide 27: Sustained Suppression of TCR-mediated CD69 Activation
MRT-6160 Resulted in Sustained Suppression of TCR-mediated CD69 Activation following Single or Multiple Dose Administration MAD Marked suppression of CD69 upregulation (>90%) in peripheral blood T and B cells following TCR stimulation (data for selected SAD and MAD dose shown as example) Similar res
Slide 28: Sustained Suppression of TCR-mediated Cytokine Production
MRT-6160 Resulted in Sustained Suppression of TCR-mediated Cytokine Production following Single or Multiple Dose Administration SAD MAD Significant and sustained suppression of IL-2, IL-17A and IFN-γ secretion from whole blood following ex vivo stimulation of TCR (data for selected SAD and MAD dose
Slide 29: MRT-6160 was well tolerated with no serious adverse events
MRT-6160 was well tolerated with no serious adverse events (SAE) Observed treatment-emergent adverse events (TEAE) were mild (82%) or moderate (18%) and self-limiting Overall TEAE frequency was similar between MRT-6160 and placebo TEAE observed in 2 or more subjects treated with MRT-6160: SAD: pain
Slide 30: Conclusions
Pharmacodynamic and functional ex vivo studies suggest significant effects on cytokine production can be achieved following marked and sustained degradation of VAV1 Demonstrated levels of VAV1 degradation consistent with levels of degradation required to induce efficacy in preclinical models Functio
Slide 31: NEK7 Programs (MRT-8102 and CNS optimized)
NEK7 Programs (MRT-8102 and CNS optimized)
Slide 32: 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 33: MRT-8102 is a Potent, Selective NEK7 MGD Development Candidate
MRT-8102 is a Potent, Selective Development Candidate NEK7 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
Slide 34: MRT-8102 potently degrades NEK7
MRT-8102 potently degrades NEK7 MRT-8102 induces highly selective NEK7 degradation MRT-8102, a Potent and Highly Selective NEK7-directed MGD, Induced Durable Pharmacodynamic Modulation In Vivo MRT-8102 exposure results in prolonged PD effect Cyno @ 10 mg/kg single dose MRT-8102 exposure prolonged PD
Slide 35: Preclinical GLP Tox Study Suggests Considerable Safety Margin
Preclinical GLP Tox Study Suggests Considerable Safety Margin In vivo NEK7 degradation leads to inhibition of Caspase-1 activity and IL-1β release in ex vivo stimulation assay Toxicology summary in rats and cynos (28d GLP tox) No MRT-8102 related clinical signs, no changes in immunophenotyping, no g
Slide 36: MRT-8102 Reduced MSU Crystal-driven Effects in Rabbit Gout Model
MRT-8102 Reduced MSU Crystal-driven Effects in Rabbit Gout Model Daily dosing from day -1 Intra-articular injection of MSU on day 0 MSKUS = musculoskeletal ultrasound *** denotes p < 0.0005 compared to MSU + Vehicle condition Joint swelling MSKUS pathologic findings Histopathology score
Slide 37: IL-1/NLRP3 Signaling is a Clinically Validated Pathway
IL-1/NLRP3 Signaling is a Clinically Validated Pathway for Inflammatory Diseases Recurrent pericarditis Rilonacept (IL-1α/β) – approved for recurrent pericarditis Atherosclerotic cardiovascular disease Canakinumab (IL-1β) – reduction in cardiac events Cardio-immunology Rheumatology Neurology Metabol
Slide 38: NLRP3/NEK7 activation in chronic inflammation
NLRP3/NEK7 activation in chronic inflammation Canakinumab (anti-IL-1β) leads to reductions in CRP Lowering of CRP Levels Anticipated as a Result of NEK7 Degradation C-reactive protein (CRP) is an acute-phase protein downstream of NLRP3/NEK7 inflammasome IL-1α and IL-1β are highly inflammatory cytoki
Slide 39: MRT-8102: Efficient Development Path in Peripheral Inflammatory Diseases
MRT-8102: Efficient Development Path in Peripheral Inflammatory Diseases Phase 1 HV Planned Phase 1 (PoC) in High CRP, Cardio-immunology Indications Further Development in Gout/Pseudogout, Osteoarthritis Goal/Objective Safety, tolerability, and pharmacokinetics in healthy volunteers NEK7 degradation
Slide 40: CNS-Optimized NEK7 Program
CNS-Optimized NEK7 Program
Slide 41: Brain-Penetrant NEK7 MGDs Could Impact Neurodegeneration, Obesity
Neurodegeneration Obesity Disease Stimulus CNS Inflammation CNS Saturated fatty acids Ab Monomer Oligomer Fibrils Periphery Fat-associated macrophages Activated microglia Activated microglia Activated microglia/ Fat-associated macrophage pro-IL-1b pro-IL-18 IL-1b IL-18 Activated NLRP3 complex NEK7 4
Slide 42: CNS-Optimized NEK7 MGD Reduced Inflammatory Cytokines in Neuroinflammation Model
CNS-Optimized NEK7 MGD Substantially Reduced Inflammatory Cytokines in an LPS-induced Murine Model of Neuroinflammation CereblonI391V mice; n=5 per group MRT-51126: 30 mg/kg, BIDx5, p.o. Selnoflast: 50 mg/kg, QDx5, p.o. LPS: 1 mg/kg, QDx3, i.p. Sampling of left hemisphere of brain 4 hr post-final LP
Slide 43: CNS-Optimized NEK7 MGD Showed NEK7 Degradation in Cynomolgus Monkey
CNS-Optimized NEK7 MGD Demonstrated Profound NEK7 Degradation and Pathway Inhibition In Vivo Over Several Days in Cynomolgus Monkey NEK7 in cyno PBMC NEK7 in cyno CSF IL-1β post-ex vivo stimulation Excellent exposure in cyno blood and CSF, correlating with deep NEK7 degradation and functional inhibi
Slide 44: Building Future Opportunities in I&I
Building Future Opportunities in I&I
Slide 45: MGD Strengths Align with I&I Requirements
High degradation in immune and blood cells MGD Strengths Align with I&I Requirements Catalytic MOA drives sustained PD effect Degrading upstream nodes modulates multiple cytokines MRT-8102 exposure prolonged PD effect Macrophage T cell B cell Auto-antibodies IL-17 IL-6 TNF IL-1 Cyno, 10 mg/kg single
Slide 46: CAR-T in a Pill: Degrading Undruggable Targets in I&I
“CAR-T in a Pill” Degrading Undruggable Targets in Critical I&I Disease Pathways B-cell modulation Inflammatory & auto-inflammatory mDC Neutrophil NK cell pDC Complement T cell B cell Immune complex Autoantibodies Apoptotic cell Monocyte Type I IFN INNATE ADAPTIVE Neutrophil Asthma & allergies Near
Slide 47: GSPT1 program (MRT-2359)
My. Monte Rosa Therapeutics GSPT1 program (MRT-2359)
Slide 48: 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 49: 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 50: MRT-2359 Optimized Depth of Degradation for MYC High Cancer Cells
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 51: MYC-Driven Pathologies Explored in MRT-2359 Phase 1/2 Trial
MYC-Driven Pathologies Explored in MRT-2359 Phase 1/2 trial Neuroendocrine tumors L-/N-MYC amplified tumors Heme Breast cancer ER positive metastatic SCLC L/N-MYC high NSCLC N-MYC high SCLC/NE transformation Neuroendocrine lung cancer Prostate cancer AR positive including AR-V7 N-MYC High and/or L-M
Slide 52: MRT-2359 Clinical Study Results
MRT-2359 Clinical Study Results
Slide 53: 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 54: Patient Demographics and Clinical Characteristics in Dose Escalation
Patient Characteristic Total (N=59)* Age, median (range), years 63 (30-80) Female, N (%) 30 (51) Race, N (%) White 48 (81) Black 4 (7) Asian 3 (5) Other 4 (7) ECOG performance status, N (%) 0 or 1 58 (98) 2 1 (2) Cancer type, N (%) Non-small cell lung cancer 23 (39) Small cell lung cancer 13 (22) Hi
Slide 55: MRT-2359 Treatment-Related AEs in >10% of Patients
MRT-2359 Treatment-Related AEs in > 10% patients (N=59) Dose Level 0.5 mg 5/9 (N=9) 1 mg 5/9 (N=13) 1.5 mg 5/9 (N=5) 2 mg 5/9 (N=5) 0.5 mg 21/7 (N=18) 0.75 mg 21/7 (N=9) CTC AE V5 Grade G1-2 (%) G3 (%) G4 (%) G1-2 (%) G3 (%) G4 (%) G1-2 (%) G3 (%) G4 (%) G1-2 (%) G3 (%) G4 (%) G1-2 (%) G3 (%) G4 (%)
Slide 56: Biomarker Status and PD Modulation in MYC Amplified Tumors
Biomarker Status and PD modulation in L-/N-MYC Amplified Tumors, NSCLC, SCLC and High-Grade NE Tumors L-MYC and N-MYC expression in tumor tissue obtained at baseline was assessed in 46 patients Overall, as compared to preclinical data, lower than expected frequency of tumors with high L-MYC or N-MYC
Slide 57: Summary of Activity in SCLC, NSCLC, High-Grade NE Tumors
Summary of Activity in SCLC, NSCLC, high-grade Neuroendocrine Tumors and L- and N-MYC Amplified tumors L-MYC and N-MYC expression in tumor tissue obtained at baseline or known L-MYC or N-MYC amplification in the absence of tissue was available in 48 patients and 37 were evaluable for response assess
Slide 58: MRT-2359 and Enzalutamide in Castrate-Resistant Prostate Cancer
Current Data for MRT-2359 and Enzalutamide in Castrate-Resistant Prostate Cancer As of 10 March 2025, RECIST 1.1 is available for 3 patients showing: 1 PR (confirmed, -57%; heavily pretreated CRPC with AR LBD mutation H875Y) 2 SDs (both CRPC with AR-V7 transcripts, multiple prior treatments includin
Slide 59: Confirmed PR in Refractory CRPC with AR H875Y Mutation
Confirmed PR in Refractory CRPC with AR H875Y Mutation Baseline After 2 cycles After 4 cycles -46% -57% Patient continues on study (C5)
Slide 60: Encouraging early data in CRPC
Encouraging early data in CRPC: 1 PR and 2 SD in first 3 evaluable, heavily pretreated patients with either AR mutations or AR-V7 expression Opportunity to enroll 20 - 30 patients if positive efficacy signal continues to be observed Large, high unmet need indication not requiring biomarker-based pat
Slide 61: CDK2 Program
My. Monte Rosa Therapeutics CDK2 Program
Slide 62: 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 63: MRT-51443 is Selective and Inhibits Proliferation of CDK2-dependent Cells
MRT-51443 is Selective and Inhibits Proliferation of CDK2-dependent Cancer Cells Cell cycle analysis (DAPI and EdU) MDA-MB-157 (24 hr) CDK2 degradation inhibits proliferation CyQuant proliferation assay (5 d) MDA-MB-157 CDK2 degradation results in reduction of E2F pathway proteins TMT Proteomics (24
Slide 64: MRT-51443 Displays Superior Selectivity Versus CDK2 Inhibitors
MRT-51443 Displays Superior Selectivity Versus Clinical CDK2 Inhibitors Clinical CDK2 inhibitors demonstrate off target activity in biochemical kinome profiling 7-day CyQuant Assay CDK2 inhibitors but not MGDs inhibit proliferation in part through CDK2-independent mechanisms Carna Mobility Shift Ass
Slide 65: CDK2 MGD and CDK4/6 inhibitor combination
CDK2 MGD and CDK4/6 inhibitor combination MRT-51443/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 66: MRT-51443 induces tumor regression in combination with CDK4/6 inhibition
MRT-51443 induces robust tumor regression in combination with CDK4/6 inhibition and fulvestrant MRT-51443 triple combination substantially reduces tumor growth vs. ribo + fulv MCF7 T47D Median: -10% Median: -61% Median: -3% Median: -77% Ribociclib + Fulvestrant MRT-51443 + Ribo + Fulv Ribociclib + F
Slide 67: CCNE1 Program
My. Monte Rosa Therapeutics CCNE1 Program
Slide 68: 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 69: CCNE1 degradation leads to downstream pathway suppression
69 CCNE1 degradation leads to downstream pathway suppression MRT-50969 induces robust G1/S cell cycle arrest 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 highly selective for CCNE1 FACS, EdU incorporation, 48h In v
Slide 70: MRT-50969 Shows Superior Differential Activity in CCNE1 Dependent Cell Lines
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 71: 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 72: 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 73: QuEEN Discovery Engine
My. Monte Rosa Therapeutics QuEEN™ Discovery Engine
Slide 74: 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 75: 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 76: 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 77: 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 78: Our Proprietary and Unique MGD Library
Our Proprietary and Unique MGD Library Creates Future High Value Programs Rational library design Enabled by proprietary chemistry Deep understanding of CRBN surfaces Optimised drug-like properties Continued diversification Each sublibrary captures a unique design concept Cover novel MGD chemical-sp
Slide 79: Proprietary AI/ML Engines Enable Discovery of Reprogrammable Ligases
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 80: 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 81: 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 82: 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 83: Team
Team
Slide 84: 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 85: Thank You
4 ic, Oe : Thank You — -_ _ My. Monte Rosa Therapeutics
Monte Rosa Therapeutics — Investor Presentation (March 2025) on 6ix