Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Investor Presentation (October 2023)
60 slides from Monte Rosa Therapeutics's investor presentation, Oct 17, 2023
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 | October 2023
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 - Highlights
Monte Rosa Therapeutics - Highlights Taking molecular glue degraders (MGDs) to new heights Rationally designed MGDs with potential to solve many of the limitations of other modalities by selectively degrading therapeutically relevant proteins considered undruggable or inadequately drugged Highly pro
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 are a Clinically Validated Modality
Molecular Glue Degraders are a Clinically Validated Modality MGD Cereblon Cereblon & MGD Neosubstrate Ternary complex Favorable drug-like properties Differentiated target space Clinically validated Ubiquitination Proteasome-mediated degradation of neosubstrate Ubiquitin chain
Slide 6: Our Rationally Designed MGDs Selectively Target a Differentiated Target Space
Our Rationally Designed MGDs Selectively Target a Differentiated Target Space Across Protein Domains and Diseases Unique insights into anatomy of ternary complexes allows unprecedented MGD selectivity Selectivity Protein fold-change; (log2) p-value Rational Design AI-guided chemistry drives target-c
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: Leveraging a Leading Drug Discovery Platform
Targets Clinical Path Leveraging a Leading Drug Discovery Platform Purpose-built to discover and develop a wide landscape of therapeutically-relevant MGDs Undruggable and inadequately drugged proteins Proteins with non-catalytic and scaffolding functions High level of target validation, preclinicall
Slide 10: Monte Rosa Pipeline
Monte Rosa Pipeline Oncology Inflammation Immunology Genetic diseases MRT-2359 (GSPT1) NSCLC, SCLC and other MYC-driven Malignancies NEK7 Inflammatory Diseases MRT-6160 (VAV1) Autoimmune Disease Discovery Program/ Target Indication(s) Full Phase 1 data (update on timing in early 2024) Multiple SCD t
Slide 11: GSPT1 program
Mh. Monte Rosa Therapeutics GSPT1 program
Slide 12: 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 13: MRT-2359 is a Potent and Selective GSPT1 Degrader
MRT-2359 is a Potent and Selective GSPT1 Degrader 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 has a favorable ADME/DMPK profile MRT-2359 is a potent GSPT1 degrader ADM
Slide 14: MRT-2359 Has Optimized Degradation Kinetics, Selectivity and Bioavailability
MRT-2359 Has Optimized Degradation Kinetics, Selectivity and Bioavailability Kinetic measurements of degradation reveal novel parameter for optimization GSPT1 degradation kinetics are linked to its MoA MRT-2359 achieves a high preferential effect (2.4 U) in high-MYC NSCLC MRT-2359 has been rationall
Slide 15: Preferential Activity of MRT-2359 Observed in Lung Cancer Cell Lines
Preferential Activity of MRT-2359 Observed in Lung Cancer Cell Lines NSCLC/N-MYC Correlation to L- and N-MYC Expression SCLC/L-MYC NE Lung Prostate/c-MYC biomarker negative biomarker positive 250 nM
Slide 16: Activity of MRT-2359 in NSCLC, SCLC and Lung NE PDX Models
Activity of MRT-2359 in NSCLC, SCLC and Lung NE Patient-derived Xenograft 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 -
Slide 17: MRT-2359-001 Phase 1/2 Clinical Study Design
Dose level 1 MTD or RP2D Phase 2: Expansion Cohorts Phase 1: Dose Escalation NSCLC* – high N- or L-MYC expression – low N- and L-MYC expression Backfill slots for additional patients for each dose level Backfill Dose level 2 Dose level 3 Dose level X Backfill Backfill * Efficacy guided stratificatio
Slide 18: MRT-2359 Phase I Interim Data - October 2023
MRT-2359 Phase I Interim Data - October 2023
Slide 19: MRT-2359-001 Phase 1/2 – Phase 1 Interim Update
Dose level 1 Phase 1: Dose Escalation Backfill slots for additional patients for each dose level Backfill Dose level 2 Dose level 3 Dose level X Backfill Backfill Lung cancer (NSCLC & SCLC), DLBCL, high-grade neuroendocrine tumors, and N-/L-MYC amplified solid tumors MRT-2359-001 Phase 1/2 – Phase 1
Slide 20: Executive Summary
Executive Summary As of September 7th, 2023, 3 dose levels (0.5 mg, 1 mg, 2 mg) have been completed with 21 patients enrolled (including backfill patients) Observed dose dependent PK after oral dosing Clinical data support that 0.5 mg starting dose was fully active based on pharmacodynamic (PD) asse
Slide 21: MRT-2359 displayed dose dependent plasma exposure
MRT-2359 displayed dose dependent plasma exposure Summary of Pharmacokinetics and Pharmacodynamics 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 degrada
Slide 22: GSPT1 Degradation by Targeted Mass Spectrometry in Tissue Biopsies
GSPT1 Degradation by Targeted Mass Spectrometry in Tissue Biopsies MRT-2359 reduced GSPT1 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 GSPT1 e
Slide 23: MRT-2359: Treatment-Related AEs
MRT-2359: Treatment-Related AEs Occurring 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 Grade >
Slide 24: Confirmed PR in High Grade Neuroendocrine Bladder Cancer
Confirmed PR 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 first 5/9 regimen,
Slide 25: Unconfirmed PR in NSCLC with SCLC/NE Transformation
Unconfirmed PR 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 on 0.5 mg CT on
Slide 26: Summary and Next Steps
Summary and Next Steps Clinical data support that 0.5 mg starting dose was active based on PD assessment (PBMC and tissue), with optimal PD modulation across dose levels tested Encouraging initial clinical activity at all dose levels: 2 PRs (1 confirmed, 1 unconfirmed) and 1 SD in 6 evaluable, heavi
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: Tumors with CDK2 pathway activation by high CyclinE1/E2 expression Clinical Opportunity: CDK2 driven cancers: ER positive breast cancer pre and post treatment with CDK4/6 inhibitors (474K patients), ovarian cancer (64K patients), and
Slide 29: CDK2 Degradation Affects E2F Downstream Proteins and Inhibits Proliferation
CDK2 Degradation Affects E2F Downstream Proteins and Inhibits Proliferation of CDK2-dependent Cancer Cells p-value (-log10) Protein fold-change (log2) p-value (-log10) Protein fold-change (log2) E2F hallmark genes CDK2 CDC6 MGD-induced selective degradation of CDK2 results in reduction of E2F downst
Slide 30: CDK2-directed MGDs Have a Differentiated MoA Compared to CDK2 Inhibitors
CDK2-directed MGDs Have a Differentiated MoA Compared to CDK2 Inhibitors CDK2 Inhibitor, PF-07104091, upregulates CCNE1 and causes pRb rebound MDA-MB-157 cells, pRb (S780) / total Rb multiplex AlphaLISA, 24h 0.032 1 3.2 10 DMSO 0.1 0.32 0.01 0.0032 0.001 0.00032 CCNE1 GAPDH PF-07104091 (mM) No CCNE1
Slide 31: Inflammation and Immunology (I&I) Programs
Inflammation and Immunology (I&I) Programs
Slide 32: QuEEN™ Enables Access to 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 programs lead the way with multiple additional t
Slide 33: VAV1 Program
Mh. Monte Rosa Therapeutics VAV1 Program
Slide 34: VAV1 as a Target for Autoimmune Disease
VAV1 as a Target for Autoimmune Disease Therapeutic hypothesis: VAV1 relays signals from both the T and B cell receptor VAV1 knockout/mutant mice have dysfunctional T cells and are resistant to immunopathologies such as autoimmune disease or graft-versus-host disease Clinical Opportunity: Autoimmune
Slide 35: VAV1 is a Highly Validated Target for Attenuating T- and B-cell Activity
VAV1-/- mice are viable 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 et al., Fro
Slide 36: 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 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 selective VAV1 degradation and has a favorable ADME/DMPK profile MRT-6160 is a potent VAV1-directed MGD ADMET profile
Slide 38: MRT-6160 Demonstrates Differentiated BioMAP Profile
MRT-6160 Demonstrates Differentiated 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, Deucravacitinib, 400
Slide 39: MRT-6160 Elicits Dose-Dependent Efficacy 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 MRT-6160 Elicits Dose-Dependent Efficacy in T-cell-mediated Multiple Sclerosis Autoimmune Disease Model T-cell mediated model EAE = MOG35-55 peptide-induced
Slide 40: MRT-6160 Inhibits Disease Progression in Rheumatoid Arthritis Model
MRT-6160 inhibits disease progression in a rheumatoid arthritis model MRT-6160 inhibits joint inflammation and damage MRT-6160 Inhibits Disease Progression and Joint Inflammation/Damage in a T/B-cell-mediated Rheumatoid Arthritis Disease Model T/B-cell (auto-antibody) driven model CIA = collagen-ind
Slide 41: MRT-6160 Inhibits Disease Progression in a Colitis Model
MRT-6160 inhibits disease progression in a colitis model MRT-6160 reduces colitis-associated body weight loss MRT-6160 Inhibits Disease Progression and Incidence in a CD4 T-cell Transfer-induced Colitis Model CD4+ T cell transfer-induced colitis model Naïve CD4+ (CD45Rb high) T cells were transferre
Slide 42: MRT-6160 Induces Significant VAV1 Degradation in Non-human Primates
Degradation of VAV1 in non-human primates Plasma exposure MRT-6160 Induces Significant VAV1 Degradation in Non-human Primates Plasma Concentrations (ng/mL) @ 6hr mg/kg 0.02 0.08 0.2 D1 8 27 62 D5 15 41 104
Slide 43: MRT-6160 – Our VAV1-directed MGD for Autoimmune Disease
MRT-6160 – Our VAV1-directed MGD for Autoimmune Disease MRT-6160 is a highly selective VAV1-directed MGD designed through our QuEENTM platform and the first MGD being developed specifically for a non-oncology indication Attenuates multiple aspects of T- and B-cell receptor signaling in relevant prec
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 Pyroptosis Gasdermin D Active NLRP3 inflammasome Cytokines secretion Pro-IL-1β Pro-IL-18 IL-18 IL-1β NEK7 NLRP3 Pro-Caspase-1 ASC N-terminal C-terminal N-terminal Caspase-1 N-terminal
Slide 46: NEK7 as a Target to Attenuate NLRP3 Inflammasome Disease Activity
NEK7 as a Target to Attenuate NLRP3 Inflammasome Disease Activity Misfolded α-synuclein activates the inflammasome in vitro Inflammasome inhibition with MCC950 reduces misfolded α-synuclein, neuronal loss and protects against motor deficits in the Parkinson PFF disease model pS129 α-synuclein in the
Slide 47: NEK7 MGDs Inhibit NLRP3 Activation by Monosodium Urate
NEK7 MGDs Inhibit NLRP3 Activation by Monosodium Urate US prevalence ~9.2 M and increasing Monocyte/macrophage caspase-1 activation IL-1β, IL-18 release Monosodium Urate (MSU) crystals Strong link to NLRP3 biology Unwanted side effects and contra-indications with SOC agents (e.g. NSAIDs, colchicine)
Slide 48: 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 49: MRT-8102 Potently Suppresses Inflammasome Activation in Primary Human Macrophages
MRT-8102 potently suppresses inflammasome activation in primary human macrophages MRT-8102 induces 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 6 hr treatment in Kelly (SALL4) or MM.1S 2 µM
Slide 50: 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 51: MRT-8102 Induces NEK7 Degradation In Vivo
MRT-8102 induces NEK7 degradation in vivo Lack of ex vivo activation of NLRP3 inflammasome following degradation of NEK7 Suppression of Ex Vivo Inflammasome Activation Following Degradation of NEK7 in Non-human Primates No clinical observations reported IL-1β in plasma after ex vivo stimulation with
Slide 52: Sickle Cell Disease Program
Mh. Monte Rosa Therapeutics Sickle Cell Disease Program
Slide 53: Transcriptional Repressors as Targets for Hemoglobinopathies
Transcriptional Repressors as Targets for Hemoglobinopathies (SCD and β-Thalassemia) Therapeutic hypothesis: To reactivate expression of fetal hemoglobin (HbF) to compensate for mutated adult globin Clinical Opportunity: First-in-class degraders for Sickle cell disease (SCD) 180,000 patients (US and
Slide 54: Our MGD Library
Our MGD Library A rationally designed library as a starting point to tackle unprecedented neosubstrates
Slide 55: MGDs Reprogram the Ligase Surface
Multiple points of contact mediate formation of ternary complex Known MGDs mediate vastly different binding modes despite representing limited chemical space MGDs Reprogram the Ligase Surface Remodeled MGD-CRBN surface enables selective engagement of neosubstrates Effective ternary complex formation
Slide 56: Library Expansion Unlocks Novel Degron and Target Space
Ligase binding Structurally diverse scaffolds retain potent CRBN binding Library Expansion Unlocks Novel Degron and Target Space Scaffold Evolution Thalidomide Scaffold Selected for diversification Cereblon binding (pIC50) Properties Well within drug-like property space
Slide 57: Creating Diverse and Proprietary Chemical Space
Creating diverse and proprietary chemical space … … unlocks a large and unique targetable space Clearly differentiated sub-libraries that are clearly distinct from other’s libraries External space = SciFinder search based on published compounds (40K) containing glutarimide and MW < 500. The external
Slide 58: Team
Team
Slide 59: 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 60: Mh. Monte Rosa
Mh. Monte Rosa Therapeutics
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