Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Investor Presentation (January 2024)
53 slides from Monte Rosa Therapeutics's investor presentation, Jan 8, 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 | January 2024
Slide 2: Forward-Looking Statements
Forward-Looking Statements These materials include 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, and i
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: Molecular Glue Degraders (MGDs) - Drugging The Undruggable
Molecular Glue Degraders (MGDs) - Drugging The Undruggable Expanding target space, fostering a new generation of drugs Drugging the Druggable INHIBITOR Drugging the Undruggable MGDs Redrugging the Druggable PROTAC UNDRUGGABLE TARGETS E3 Ligase DRUGGABLE TARGETS E3 Ligase DRUGGABLE TARGETS Target Spa
Slide 5: Molecular Glue Degraders (MGDs) – A Highly Differentiated Modality
Access to undruggable space Exquisite selectivity High potency Oral bioavailability Cellular permeability Systemic distribution CNS penetration Long lasting pharmacodynamic effects Monte Rosa’s rationally designed MGDs address key limitations of first-generation protein degraders and expand potentia
Slide 6: Key Advantages of Our Rationally Designed MGDs
Key Advantageous of Our Rationally Designed MGDs Unique insights into anatomy of ternary complexes allows unprecedented MGD selectivity Unprecedented Selectivity Protein fold-change; (log2) Disease-agnostic platform with initial focus on highly credentialed oncology and I&I targets Unique Target Spa
Slide 7: Monte Rosa Therapeutics – 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 into IND enabling stud
Slide 8: Portfolio
Portfolio
Slide 9: Monte Rosa Pipeline and Upcoming Milestones
Monte Rosa Pipeline and Upcoming Milestones Oncology Inflammation Immunology Various MRT-2359 (GSPT1) NSCLC, SCLC and other MYC-driven Malignancies NEK7 Inflammatory Diseases MRT-6160 (VAV1) Autoimmune Disease Discovery Program/ Target Indication(s) RP2D in Q2 2024 Next Anticipated Milestone Ownersh
Slide 10: GSPT1 program
Mh. Monte Rosa Therapeutics GSPT1 program
Slide 11: Targeting MYC-driven Tumors and Their Addiction to Protein Translation
Targeting MYC-driven Tumors and Their Addiction to Protein Translation 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 GSPT1 GSPT1 is a therapeutic
Slide 12: 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 13: MRT-2359 Has 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 14: 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 15: 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 N-MYC High and/or L-MYC High Neuroendocrine tumors L-/N-MYC amplified tumors c-MYC High Heme Breast cancer ER positive metastatic SCLC (70-80% L/N-MYC high) NSCLC
Slide 16: Preclinical Validation of Activity of MRT-2359 in Lung Cancer PDX Models
Preclinical Validation of Activity of MRT-2359 in Lung Cancer PDX Models Collection of PDX models 16 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 17: MRT-2359 Active as Single Agent and in Combination with SOC in Xenografts
22RV1 - ARV7/MYC-positive Prostate Cancer MCF7 – ER/MYC-positive Breast Cancer MRT-2359 is Active as Single Agent and in Combination with SOC Against AR-V7/MYC- and ER/MYC-Positive Tumor Xenografts
Slide 18: MRT-2359-001 Phase 1/2 Clinical Study Design
DL1 5/9 Phase 2: Expansion Cohorts Phase 1: Dose Escalation DL3 5/9 DL2 5/9 * Prospective stratification per N-/L-MYC expression ** Retrospective stratification per N-/L-MYC expression MRT-2359-001 Phase 1/2 Clinical Study Design Lung cancer, DLBCL, high-grade neuroendocrine tumors and solid tumors
Slide 19: 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 20: 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 21: 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 22: 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 23: 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 24: 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 25: 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 26: 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 27: CDK2 Program
Mh. Monte Rosa Therapeutics CDK2 Program
Slide 28: CDK2 as a Target for Selected Solid Tumors
CDK2 as a Target for Selected Solid Tumors 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 inhibitors Cli
Slide 29: CDK2-directed MGDs are Selective and Inhibit Proliferation of CDK2-dependent Cancer Cells
CDK2-directed MGDs are Selective and Inhibit Proliferation of CDK2-dependent Cancer Cells CDK2 degradation arrests CDK2-dependent cells in G1 phase CDK2 degradation results in reduction of E2F pathway proteins Cell cycle analysis (DAPI and EdU) - MDA-MB-157 (24 hr) TMT Proteomics - MDA-MB-157 (1 uM/
Slide 30: CDK2-directed MGD Activity as Single Agent and in Combination with CDK4/6i
CDK2-directed MGD Demonstrates Activity as Single Agent and in Combination with CDK4/6i in ER+ Breast Cancer CDK2directed MGD induces strong tumor growth inhibition ER-positive MCF7 in vivo CDK2-directed MGD demonstrates significant PD modulation in vivo
Slide 31: Inflammation and Immunology (I&I) Programs
Inflammation and Immunology (I&I) Programs
Slide 32: QuEEN™: Accessing Undruggable Targets in Immune Pathways
Biology Multiple highly validated, undruggable targets amenable to our platform identified QuEEN™ platform enables exquisite selectivity required for non-oncology diseases CRBN shown to allow tunable elimination of immune target proteins VAV1 and NEK7 are our most advanced Immunology & Inflammation
Slide 33: VAV1 Program
Mh. Monte Rosa Therapeutics VAV1 Program
Slide 34: VAV1-directed MGDs: Unique MOA Targeting Both T and B Cells
VAV1-directed MGDs: Unique MOA Targeting Both T and B Cells 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 KO mice VAV1 degradation is predicted to impact both T- & B-
Slide 35: VAV1 is a Highly Validated Target for Attenuating T- and B-cell Activity
VAV1-/- mice are viable, fertile, and display loss-of-function T- and B-cell phenotypes Multiple CRISPR screens identified VAV1 as key player in human T-cell function VAV1 is a Highly Validated Target for Attenuating T- and B-cell Activity Schmidt et al., Science 2022 Primary human T cells Betzler e
Slide 36: MRT-6160 is a Potent, Selective VAV1 MGD with Favorable Drug-like Profile
MRT-6160 is a Potent, Selective VAV1 MGD with a Favorable Drug-like Profile VAV1 ternary complex (Cryo-EM) 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 selectivi
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 Relative protein expression levels Azathioprine VAV1 MGD Tyk2i BT coculture assay: T-cell-mediated B-cell activity PBMC + B cells + BCR stim + sub-mitogenic TCR stim * Experiment performed by Eurofins T-cell independent Tyk2i, Deucravaci
Slide 39: MRT-6160 Inhibits Disease Progression in Collagen-Induced Arthritis Model
MRT-6160 Inhibits Disease Progression, Joint Inflammation & Auto-Antibody Production in the Collagen-Induced 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
Slide 40: MRT-6160 Inhibits Disease Progression in Inflammatory Bowel Disease Model
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 41: 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 model EAE = MOG35-55 peptide-induced experimental autoimmune encephalitis Dosing: QD (oral) for 14 days starting at disease onset; PD analys
Slide 42: 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 43: 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 Potential Early Proof-of-Concept Indications Provide early insights into safety, PK/PD, and effects on key immunomodulatory signaling pathways – Ulcerative
Slide 44: NEK7 Program
Mh. Monte Rosa Therapeutics NEK7 Program
Slide 45: NEK7 as a Target for Inflammatory Disease
NEK7 (NIMA-Related Kinase 7) as a Target for Inflammatory Disease NEK7 is an essential regulator of the inflammasome Therapeutic hypothesis: Activation of the NLRP3 inflammasome critically depends on NEK7 NEK7 licenses NLRP3 assembly in a kinase-independent manner NEK7-deficient macrophages are seve
Slide 46: NEK7 MGDs Inhibit NLRP3 Activation by Monosodium Urate
NEK7 MGDs Inhibit NLRP3 Activation by Monosodium Urate Human monocyte-derived macrophages LPS + MSU stimulation Pretreatment with molecular glue degrader (MGD) or NLRP3 inhibitor (NLRP3i) Signal 1 Signal 2 TLR MSU crystals Potassium efflux Pyroptotic pore IL-1b pro-IL-1b IL-1b K+ K+ K+ Gasdermin-D N
Slide 47: MRT-8102 is a NEK7-Directed MGD With Favorable Drug-like Properties
MRT-8102 is a NEK7-Directed MGD With Favorable Drug-like Properties 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 LogD 1.47 MW <450 T
Slide 48: MRT-8102 Potently Suppresses Inflammasome Activation in Primary Human Macrophages
MRT-8102 potently suppresses inflammasome activation in primary human macrophages MRT-8102 induces highly selective NEK7 degradation p-value (-log10) Protein fold-change (log2) MRT-8102 at 10 µM in hPBMC, 24h Additional cell lines screened: U937, Kelly and MM1S Human monocyte-derived macrophage (hMD
Slide 49: MRT-8102 Inhibits Caspase-1 Activity in hMDMs After Stimulation
MRT-8102 inhibits caspase-1 activity in hMDMs after stimulation Human monocyte-derived macrophage (hMDM) assay Pre-incubation with MGD/NLRP3i; stimulated with LPS + MSU Supernatants analyzed post-stimulation MRT-8102 Potently Inhibits NLRP3 Inflammasome-mediated Activation in Human Monocyte-derived
Slide 50: MRT-8102 Leads to NEK7 Degradation In Vivo
MRT-8102 leads to NEK7 degradation in vivo 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 in Non-human Primates No clinical observations reported IL-1β in plasma after ex viv
Slide 51: Team
Team
Slide 52: World-Class Leadership
World-Class Leadership Deep expertise in molecular glue discovery, drug development and precision medicine Jullian Jones, Ph.D., J.D., MBA Chief Business Officer Filip Janku, M.D., Ph.D. Chief Medical Officer Markus Warmuth, M.D. Chief Executive Officer John Castle, Ph.D. Chief Data Scientist & Info
Slide 53: Monte Rosa Therapeutics
Mh. Monte Rosa Therapeutics
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