Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Investor Presentation (March 2023)
64 slides from Monte Rosa Therapeutics's investor presentation, Mar 16, 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 | March 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 Developing breakthrough drugs that selectively degrade therapeutically-relevant proteins previously considered undruggable AI-based degron prediction & rational design of highly selective MGDs enable a next-ge
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 Differentiated target space Favorable drug-like properties Broad tissue distribution No “hook effect” (seen with PROTACS) Clinically validated Proteasome-mediated degradation of neosubstrate Ubiquitination Proteasome Ubiquitin Neosubstrate
Slide 6: QuEEN is Redefining the Rules of MGD Discovery
QuEENTM is Redefining the Rules of MGD Discovery ‘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 target centric and systematic discovery of MGDs ‘Med Chem rules d
Slide 7: Portfolio
Portfolio
Slide 8: 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 degron-containing proteins Target non-catalytic and scaffolding functions High level of target validation, p
Slide 9: Monte Rosa Pipeline
Monte Rosa Pipeline Rapidly advancing wholly owned MGD programs targeting undruggable proteins Oncology Inflammation Immunology Genetic diseases GSPT1 (G-loop) NSCLC, SCLC and other MYC-driven Malignancies CDK2 (new) Ovarian Cancer, Breast Cancer NEK7 (G-loop) Inflammatory Diseases VAV1 (new) Autoim
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 1 2 3 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 therap
Slide 12: Discovery of MRT-2359
Discovery of MRT-2359
Slide 13: MRT-2359 – GSPT1-directed MGD in Clinical Development for MYC-Driven Tumors
MRT-2359 – our GSPT1-directed MGD in Clinical Development for MYC-Driven Tumors MRT-2359 is a highly selective GSPT1-directed MGD designed through our QuEENTM platform Has favorable drug like properties and is orally bioavailable Has optimal degradation kinetics to achieve preferential activity in M
Slide 14: QuEEN Discovery Engine Facilitates the Discovery of MRT-2359
QuEEN™ Discovery Engine Facilitates the Discovery of MRT-2359 in vitro data CRBN binding, Ki 113 nM Ternary complex, EC50 < 7 nM Degradation, DC50 /Dmax (in disease relevant cell lines) 1 - 20 nM / 100% MRT-2359 induces selective GSPT1 degradation and has a favorable ADME/DMPK profile MRT-2359 is a
Slide 15: 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 16: MRT-2359 Shows Preferential Activity in MYC-Driven NSCLC Lines
MRT-2359 Shows Preferential Activity in MYC-Driven NSCLC Lines MRT-2359 induces GSPT1 degradation and shows preferential activity in N-MYC high cell lines Viability GSPT1 western blot at 6 hr (N-MYC high) and 24 hr (low). 72 hr viability assay (CTG) GSPT1 degradation N-MYC overexpression sensitizes
Slide 17: MRT-2359 Shows Preferential Activity in MYC High or NE Cancer Cell Lines
MRT-2359 Shows Preferential Activity in MYC High or Neuroendocrine (NE) Cancer Cell Lines Low L-MYC NCI-H2286 NCI-H196 High L-MYC NCI-H1836 NCI-H1876 72 hr viability assay (CTG) SCLC cell lines (L-MYC) Lung cancer cell lines (NE) Low NE High NE NCI-H2405 NCI-H1693 NCI-H810 NCI-H1770 Prostate cell li
Slide 18: Mechanism of Action of MRT-2359
Mechanism of Action of MRT-2359
Slide 19: Three Mechanisms Driving Preferential Activity in MYC High Cancer Lines
Preferential inhibition of translation MYC down modulation MRT-2359 preferentially impairs protein synthesis in tumor cells with high MYC expression Three Mechanisms Driving Preferential Activity in MYC High Cancer Lines Preferential GSPT1 degradation MRT-2359 leads to rapid and deeper degradation o
Slide 20: MRT-2359 Degrades GSPT1 More Rapidly in MYC-Driven Tumor Cells
MRT-2359 Degrades GSPT1 More Rapidly in MYC-Driven Tumor Cells GSPT1 2 h 6 h 24 h GAPDH MRT-2359, μM 0 0.03 0.3 3 0 0.03 0.3 3 0 0.03 0.3 3 2 h 6 h 24 h 0 0.03 0.3 3 0 0.03 0.3 3 0 0.03 0.3 3 Low N-MYC NCI-H2023 High N-MYC NCI-H1155 Similar effects shown in additional cancer cell lines
Slide 21: MRT-2359 Preferentially Impairs Protein Synthesis in Tumor Cells with High MYC Expression
MRT-2359 Preferentially Impairs Protein Synthesis in Tumor Cells with High MYC Expression MRT-2359 induces ribosome stalling at stop codon only in N-MYC high cell line Metagene plots Peak density Peak density MRT-2359 completely abrogates protein synthesis only in N-MYC high cell line Puromycin inco
Slide 22: MRT-2359 Affects the MYC Pathway in N-MYC High NSCLC Cell Lines
MRT-2359 induce GSPT1 degradation leading to N-MYC protein downregulation in NCI-H1155 Degradation of GSPT1 leads to downregulation of N-MYC transcriptional output in NCI-H1155 MRT-2359 Affects the MYC Pathway in N-MYC High NSCLC Cell Lines GSPT1 N-MYC 0.03 0.3 3 - 0.03 0.3 3 0.03 0.3 3 Tubulin 0 6
Slide 23: Benchmarking of MRT-2359
Benchmarking of MRT-2359
Slide 24: MRT-2359 Shows Superior Characteristics Compared to CC-90009
MRT-2359 Shows Superior Characteristics Compared to CC-90009 Assay MRT-2359 CC-90009 in vitro Selectivity (TMT Px, WB) GSPT1, GSPT2 GSPT1, GSPT2, SALL4, FIZ1, RNF166, ODC1 CYP DDI (2B6, 1A2, 2D6,3A4, 2C8,2C9, 2C19) > 30 uM CYP2C19 @ 1.5 uM hERG (patch clamp) > 30 uM 5.3 uM CEREP a1A > 50% @ 10 uM M1
Slide 25: Superior Activity of MRT-2359 in MYC-driven Lung Cancer Cell Lines Compared to CC-90009
Superior Activity of MRT-2359 in MYC-driven Lung Cancer Cell Lines Compared to CC-90009 * Comparison based on internal profiling Low MYC High MYC Low MYC High MYC SCLC NSCLC CC-90009 EC50 (nM) MRT-2359 EC50 (nM) Low MYC High MYC Low MYC High MYC SCLC NSCLC MRT-2359 CC-90009 72 hr viability assay (CT
Slide 26: MRT-2359 - Unique Preferential Activity in MYC High Lung Cancer Lines
72 hr viability assay (CTG). Other therapeutic agents targeting protein translation process or machinery lack preferential activity in the MYC high lung lines MRT-2359 - Unique Preferential Activity in MYC High Lung Cancer Lines MRT-2359 Similarly for agent targeting Myc transcriptional reprogrammin
Slide 27: in vivo activity of MRT-2359
in vivo activity of MRT-2359
Slide 28: MRT-2359 Induces Tumor Regressions in N-MYC-driven Xenograft Models
Oral dosing of MRT-2359 shows anti-tumor activity and regressions in NCI-H1155 Dose- and time-dependent degradation of GSPT1 is associated with N-MYC downregulation MRT-2359 Induces Tumor Regressions in N-MYC-driven Xenograft Models Similar observations in other high N-MYC expression models (ABC-1,
Slide 29: MRT-2359 Mouse-trial in NSCLC, SCLC and Lung NE Patient-derived Xenografts
MRT-2359 Mouse-trial in NSCLC, SCLC and Lung NE Patient-derived Xenografts Models selected across a range of N-MYC and L-MYC mRNA expression levels or NE status were treated with Vehicle MRT-2359 10 mg/kg PO QD 3 mice for each treatment group Collection of PDX models All models have been characteriz
Slide 30: MRT-2359 Demonstrates Preferential Anti-tumor Activity in PDX Models
MRT-2359 Demonstrates Preferential Anti-tumor Activity in MYC High or Neuroendocrine (NE) Lung Cancer Patient-derived Xenografts NSCLC SCLC NE Lung Cancer L-MYC and N-MYC low L-MYC or N-MYC high MRT-2359 10 mg/kg, PO, QD Large cell NE carcinoma or NE lung cancer N-MYC and L-MYC low
Slide 31: MRT-2359 Clinical Development
MRT-2359 Clinical Development
Slide 32: 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 33: Targeting L-/N-MYC Positive and Neuroendocrine Tumors with MRT-2359
Targeting L-/N-MYC Positive and Neuroendocrine Tumors with MRT-2359 Patient diagnosed incidence #s, major markets (US, EU and JP): Decision Resources Group (DRG) % population based on preliminary internal cut offs for high vs low expression applied to real world data provided by Tempus 33 Small cell
Slide 34: CDK2 Program
Mh. Monte Rosa Therapeutics CDK2 Program
Slide 35: 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 Loss of RB Clinical Opportunity: CDK2 driven cancers: ER positive breast cancer pre and post treatment with CDK4/6 inhibitors (474K patients), ovarian cancer (64K pa
Slide 36: CDK2-directed MGD Shows Selective Degradation Over the Other CDKs
CDK2-directed MGD Shows Selective Degradation Over the Other CDKs NanoBiT assay (24hr) - HEK293 CDK2-directed MGD induces CDK2 degradation CDK2-directed MGDs are selective over other CDKs TMT Proteomics (24hr) – HEK293 p-value (-log10) Protein fold-change (log2) CDKs CDK2
Slide 37: CDK2-directed MGD Shows Biological Activity in a CDK2-dependent Cell Line
CDK2-directed MGD Shows Biological Activity in a CDK2-dependent Cell Line CDK2 degradation results in reduction of E2F pathway proteins CDK2-directed MGD inhibits proliferation of CDK2 dependent cells TMT Proteomics (24 hr) – MDA-MB-157 p-value (-log10) Protein fold-change (log2) E2F target genes CD
Slide 38: 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 PF-07104091 (mM) CCNE1 GAPDH pRb/Rb N
Slide 39: Inflammation and Immunology (I&I) Programs
Inflammation and Immunology (I&I) Programs
Slide 40: 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 41: VAV1 Program
Mh. Monte Rosa Therapeutics VAV1 Program
Slide 42: 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 43: VAV1 is a Highly Validated Target for Attenuating T-cell Activity
VAV1 is a Highly Validated Target for Attenuating T-cell Activity Multiple CRISPR screens identified VAV1 as key player in T-cell function TCR = T-cell receptor VAV1 controls several aspects of T-cell activity Schmidt et al., Science 2022 Primary human T cells
Slide 44: Discovery of Highly Selective VAV1-directed MGDs
Human primary pan-T cells TCR stimulation = α-CD3/CD28 MGD-induced degradation of VAV1 results in inhibition of TCR-mediated CD69 activation, IL-2 secretion, and proliferation IL-2 secretion Proliferation CD69 activation Discovery of Highly Selective VAV1-directed MGDs Protein fold-change (log2) p-v
Slide 45: VAV1-directed MGD Inhibits Disease Progression in an EAE Mouse Model
VAV1-directed MGD Inhibits Disease Progression in an EAE Mouse Model MGD inhibits disease progression in experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis MGD induces VAV1 degradation in PBMCs after a single oral dose in mice Additional autoimmune and immunology disea
Slide 46: NEK7 Program
Mh. Monte Rosa Therapeutics NEK7 Program
Slide 47: 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 48: NEK7-directed MGDs Modulate NLRP3 Pathway in Human Macrophages
NEK7-directed MGDs Modulate NLRP3 Pathway in Human Macrophages p-value (-log10) Protein fold-change (log2) TMT Proteomics (24hr) – U937 IL-1b and IL-18 release (24hr) - human macrophages LPS/MSU stimulated NEK7-directed MGD shows high selectivity NEK7-directed MGD compared to NLRP3 inhibitor IL-1b s
Slide 49: Overactivation of the NLRP3 Inflammasome in Disease
Overactivation of the NLRP3 Inflammasome in Disease *Muckle-Wells Syndrome **familial cold autoinflammatory syndrome, #Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease Over-activated NLRP3 inflammasome Pro-IL-1β Pro-IL-18 IL-18 IL-1β Liver Liver
Slide 50: Sickle Cell Disease Program
Mh. Monte Rosa Therapeutics Sickle Cell Disease Program
Slide 51: 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 52: QuEEN Discovery Engine
QuEEN™ Discovery Engine Quantitative and Engineered Elimination of Neosubstrates
Slide 53: QuEEN Discovery Engine: Unique Capabilities Enable Our Rational and Target-Centric Approach
QuEEN™ Discovery Engine: Unique Capabilities Enable Our Rational and Target-Centric Approach to MGDs Proprietary MGD library Protein fold-change; (log2) p-value AI engine Chemo-proteomics Proximity screening Specialized suite of in vitro assays to assess proximity and degradation in high throughput
Slide 54: A Rich, Differentiated Target Space Across Protein Domains and Diseases
A Rich, Differentiated Target Space Across Protein Domains and Diseases Degrons have unique sequences enabling design of MGDs with unprecedented level of selectivity QuEEN has enabled the discovery of diverse degrons across various protein domains and classes Degrons Selectivity Protein fold-change;
Slide 55: Proprietary AI/ML Engines
Proprietary AI/ML Engines
Slide 56: Proprietary AI/ML Engines Enable Discovery of Ligases, Neosubstrates, and MGDs
Surface evaluation for E3 ligase PPI propensity & reprogrammability fAIceit™ surface complementarity connects E3 ligases to degron-containing neosubstrates Candidate neosubstrates Reprogrammable E3 ligase prioritization Proteome-wide neosubstrate identification in-silico MGD discovery Rhapsody™ mode
Slide 57: Creating a Highly Diverse CRBN-directed Library
Creating a Highly Diverse CRBN-directed Library
Slide 58: 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 59: Increasing MGD Scaffold Diversity
Increasing MGD scaffold diversity MGD library is derived from > 400 unique low molecular weight scaffolds with favorable CRBN binding affinities Warhead CRBN binding domain Core CRBN binding, degron domain MGD scaffold anatomy Increasing Novelty and Structural Diversity to Match the Degron Space Sca
Slide 60: Expanded MGD Diversity Engages More Degron Classes
Expanded MGD diversity engages more degron classes MGD diversification Expanding MGD Exit Vectorology Engages Novel Degron Classes 400+ Scaffolds Side- chains PPI domain Chemical fingerprints of MGD hits Target A Target B Target C Target D Current library size ~35K MGDs, continuing to expand High st
Slide 61: Summary
Summary
Slide 62: 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 Silvia Buonamici, Ph.D. SVP, Drug Discovery Biology Filip Janku, M.D., Ph.D. Chief Medical Officer Markus Warmuth, M.D. Chief Executive Of
Slide 63: Monte Rosa Therapeutics: From Serendipity to Rational Design of MGDs
Monte Rosa Therapeutics From serendipity to rational design of MGDs Proprietary, target-centric drug discovery platform enabling rational design, and anticipated rapid development, of molecular glue-based degraders targeting the undruggable proteome in oncology and non-oncology diseases Extensive an
Slide 64: Monte Rosa Therapeutics
Mh. Monte Rosa Therapeutics
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