Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Corporate Update (March 2024)
62 slides from Monte Rosa Therapeutics's corporate update, Mar 14, 2024
Slide 1: From Serendipity to Rational Design: Taking Molecular Glue Degraders to New Heights
From Serendipity to Rational Design Taking Molecular Glue Degraders to New Heights | March 2024
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 Taking molecular glue degraders (MGDs) to new heights Arsenal of rationally designed MGDs with potential to solve many of the limitations of other modalities by degrading therapeutically relevant proteins with unprecedented precision Highly productive, indu
Slide 4: 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 5: 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 6: Molecular Glue Degraders – A Highly Differentiated Modality
Molecular Glue Degraders (MGDs) – A Highly Differentiated Modality Advantages of large molecule modalities with orally dosed small molecules DNA mRNA protein CRISPR RNAi/ASO MGD Address undruggable space Properties Orally bioavailable Systemic distribution Scalable manufacturing Reversible
Slide 7: 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 Protein degradation (fold-change; log2) Disease-agnostic platform with initial focus on highly credentialed, undruggable oncol
Slide 8: Key Firsts and Accomplishments
Monte Rosa Therapeutics – Key Firsts and Accomplishments From serendipity to rational design of MGDs Established a target-centric drug discovery approach combining experimentation with AI enabling rational design of highly potent and selective MGDs Progressed VAV1 MGD MRT-6160 and NEK7 MGD MRT-8102
Slide 9: Portfolio
Portfolio
Slide 10: 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) RP2D in Q2 2024 Next Anticipated Milestone Owner
Slide 11: GSPT1 program (MRT-2359)
Mh. Monte Rosa Therapeutics GSPT1 program (MRT-2359)
Slide 12: 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 13: 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 14: 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 15: MRT-2359 Optimized Depth of Degradation for Preferential Activity in MYC High 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 16: 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 17: 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 18: 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 18 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 19: MRT-2359 Tumor Regressions in Prostate Cancer Models
MRT-2359 Leads to Tumor Regressions in Preclinical Models of Castration Resistant Prostate Cancer and ARV7-driven Prostate Cancer MRT-2359 displays activity in castrate resistant VCAP model MRT-2359 displays activity in ARV7 driven 22RV1 model
Slide 20: MRT-2359 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 21: MRT-2359-001 Phase 1/2 Clinical Study Design
0.5mg 5/9 Phase 2: 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 Backfill: Up to 6 additional pts for each dose level DL 3 21/7 2mg X 5/9 5/9 = 5 day
Slide 22: 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 23: 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 24: 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 25: 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 26: 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 27: 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 28: 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 29: Favorable Safety at Clinically Active Doses
Favorable Safety 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 GI-relat
Slide 30: CDK2 Program
Mh. Monte Rosa Therapeutics CDK2 Program
Slide 31: CDK2 as a Key Driver of Cell Cycle Progression in Cancer
CDK2 as a Key Driver of Cell Cycle Progression in Cancer Therapeutic hypothesis: CDK2 is a key driver of cancers with cyclin dependent kinase pathway alterations MGDs will achieve greater selectivity against other CDKs and kinases in general, as well as more sustained pathway inhibition compared to
Slide 32: MRT-9643 is Selective and Shows Biological Activity in a CDK2 Dependent Cell Line
Orally Bioavailable MGD MRT-9643 is Selective and Shows Biological Activity in a CDK2 Dependent Cell Line CDK2-directed MGD inhibits proliferation of CDK2 dependent cells CDK2 degradation arrest CDK2-dependent cells in G1 phase Selective CDK2 degradation reduces E2F pathway genes TMT Proteomics (24
Slide 33: MRT-9643 Activity as Single Agent and in Combination with CDK4/6i
Orally Bioavailable MGD MRT-9643 Demonstrates Activity as Single Agent and in Combination with CDK4/6i in ER+ Breast Cancer CDK2 MGD is orally bioavailable and degrades CDK2 in vivo Plasma PK exposure MCF7 ER+ BC CDX Oral PK/PD study HCC1159 BC CDX Orally dosed CDK2 MGD induces strong TGI in combina
Slide 34: VAV1 Program (MRT-6160)
Mh. Monte Rosa Therapeutics VAV1 Program (MRT-6160)
Slide 35: VAV1 is a Key Regulator of T- and B-cell Receptor Activity
VAV1 is a Key Regulator of T- and B-cell Receptor Activity Therapeutic hypothesis: VAV1 is a pivotal scaffolding protein and signaling molecule downstream of both the T-cell and B-cell receptors – confirmed by multiple CRISPR screens VAV1 knockout (KO) mice VAV1 degradation is predicted to impact bo
Slide 36: VAV1: Unique Mechanism with Broad Potential Applications
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. Drug class sales from Evaluate Pharma. 2028E sales may include sales from anticipated future approvals. Pso
Slide 37: MRT-6160 is a Potent and Selective VAV1-directed MGD
MRT-6160 is a Potent and 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 ADMET
Slide 38: MRT-6160 Demonstrates Differentiated Activity (BioMAP) Profile
MRT-6160 Demonstrates Differentiated Activity (BioMAP) Profile JAKi TYK2i BTKi VAV1 MGD Relative protein expression levels BT coculture assay: T-cell-mediated B-cell activity PBMC + B cells + BCR stim + sub-mitogenic TCR stim T-cell independent Upadacitinib, 1000nM Deucravacitinib, 400nM Ibrutinib,
Slide 39: MRT-6160 Attenuates T- and B-Cell Activity and Cytokine Production
Direct impact on T-cell and B-cell effector functions Reduction of T-cell dependent antibodies against self-antigens (auto-Ab production) MRT-6160 Attenuates T- and B-Cell Activity and Cytokine Production Experimental demonstration of activity overlapping with clinically validated mechanisms IL-2 (%
Slide 40: MRT-6160 is a Potent, Selective VAV1 MGD with a Favorable Drug-like Profile
MRT-6160 is a Potent, 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 Physicochemical Prope
Slide 41: MRT-6160 in the Collagen-Induced Arthritis Disease Model
MRT-6160 Inhibits Disease Progression, Joint Inflammation & Auto-Antibody Production in the Collagen-Induced Arthritis Disease Model Collagen-induced arthritis T/B-cell (auto-antibody) driven model MRT-6160 inhibits anti-collagen II auto-antibodies MRT-6160 inhibits disease progression
Slide 42: MRT-6160 in a Model of Inflammatory Bowel Disease
MRT-6160 Inhibits Disease Progression and Cytokine Production in a Model of Inflammatory Bowel Disease MRT-6160 reduces pro-inflammatory cytokine production by CD4+ T cells MRT-6160 inhibits disease progression in a model of colitis CD4+ T cell transfer-induced colitis model
Slide 43: MRT-6160 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 MRT-6160 MRT-6160 Elicits Dose-Dependent Activity in T-cell-mediated Multiple Sclerosis Aut
Slide 44: MRT-6160 Induces Significant VAV1 Degradation in Non-human Primates
MRT-6160 Induces Significant VAV1 Degradation in Non-human Primates Increased degradation with repeat dosing Maximal VAV1 degradation at very low doses VAV1 levels return to baseline within 5 days of last dose
Slide 45: Preliminary MRT-6160 Development Plan through Early POC
Preliminary MRT-6160 Development Plan through Early POC Potential in multiple I&I indications with T cell and T/B cell-mediated pathophysiology SAD/MAD study expected to initiate mid-2024 Potential Early Proof-of-Concept Indications Provide early insights into safety, PK/PD, and effects on key immun
Slide 46: NEK7 Program (MRT-8102)
Mh. Monte Rosa Therapeutics NEK7 Program (MRT-8102)
Slide 47: NEK7 is a Key Regulator of NLRP3 Inflammasomes and IL-1β and IL-18 Production
NEK7 is a Key Regulator of NLRP3 Inflammasomes and IL-1β and IL-18 Production Pro-IL-1β Pro-IL-18 IL-18 IL-1β Liver Liver fibrosis Liver damage Heart pericarditis myocarditis myocardial infarction Metabolism Obesity Type II Diabetes Atherosclerosis Brain Parkinson’s disease Alzheimer’s disease Multi
Slide 48: MRT-8102 Suppresses Inflammasome Activation in Primary Human Macrophages
MRT-8102 potently suppresses inflammasome activation in primary human macrophages MRT-8102 induces highly selective NEK7 degradation MRT-8102 is a Potent and Selective NEK7-directed MGD in vitro data CRBN binding, IC50 200 nM Degradation, DC50 /Dmax (CAL51) 10 nM / 89 % ADMET profile hERG No inhibit
Slide 49: MRT-8102 is a Potent, Selective NEK7-Directed MGD With a Favorable Drug-like Profile
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 50: MRT-8102 Inhibits NLRP3 Inflammasome-mediated Activation in Human Macrophages
MRT-8102 Potently Inhibits NLRP3 Inflammasome-mediated Activation in Human Monocyte-derived Macrophages MRT-8102 inhibits caspase-1 activity in hMDMs after stimulation MRT-8102 inhibits IL-1β secretion by hMDMs after stimulation MRT-8102 inhibits IL-18 secretion by hMDMs after stimulation
Slide 51: 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 52: QuEEN Discovery Engine
Mh. Monte Rosa Therapeutics QuEEN™ Discovery Engine
Slide 53: 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 identifed by serendipity’ QuEENTM enables targ
Slide 54: 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 55: QuEEN Discovery Engine: Unique Capabilities
QuEEN™ Discovery Engine: Unique Capabilities Enable Our Rational and Target-Centric Approach to MGDs Specialized suite of biochemical, cellular and proteomics assays to assess proximity and degradation in high throughput Proprietary database of protein structures to enable rapid optimization of MGD
Slide 56: Proprietary AI/ML Engines Enable Discovery of Ligases, Neosubstrates, and MGDs
Proprietary AI/ML Engines Enable the Discovery of Reprogrammable Ligases, Neosubstrates, and Selective MGDs MGD discovery Target identification Ligase reprogrammability Proprietary AI/ML engines In silico screening Match interaction sites on neosubstrates Discover protein interaction hotspots Genera
Slide 57: QuEEN: How it Works
QuEENTM: How it Works Predict Surface-centric discovery process Target and ligase ID Design AI-powered chemistry Surface-aware MGD generation & optimization Test & Train Actionable data-at-scale Proteomics Virtual screens Structural biology High throughput screens
Slide 58: QuEEN Toolbox to Rapid Discovery Oral MGDs
QuEEN™ Toolbox to Rapid Discovery Oral MGDs Predict Surface-centric discovery process Target and ligase ID Design AI-powered chemistry Surface-aware MGD generation & optimization fAIceit™ Ultra-fast fingerprint search for surface-based matchmaking Rhapsody™ ternary complexes FLASH™ virtual library G
Slide 59: Algorithms Use MGD-focused, Moated Data to Identify Targets and Design MGDs
Lab experimentation 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 34 million protein measurements 6 million MGD activity measurements fAIceit mimicry target ID Structural bio
Slide 60: Team
Team
Slide 61: 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 Scientist & Information Officer Sharon Townson, Ph.D. Chief Technology
Slide 62: Monte Rosa Therapeutics
Mh. Monte Rosa Therapeutics
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