Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Investor Presentation (January 2023)
42 slides from Monte Rosa Therapeutics's investor presentation, Jan 9, 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 | January 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-gene
Slide 4: 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 Markus Warmuth, M.D. Chief Executive Officer Ajim Tamboli, CFA Chief Financial Officer John Castle, Ph.D. Chief Data Scientist Silvia Buon
Slide 5: 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 6: QuEEN Discovery Engine
QuEEN™ Discovery Engine Quantitative and Engineered Elimination of Neosubstrates
Slide 7: Our Rational Approach to Unleash the Full Potential of MGDs
Our Rational Approach to Unleash the Full Potential of MGDs Beyond cereblon Beyond the canonical degrome Unraveling the canonical degrome Neosubstrates - Eg. IKZF1 MGD Eg. Lenalidomide Cereblon Expanding the Degradable Proteome Chemical Space Target Space Degron
Slide 8: QuEEN Discovery Engine: Unique Capabilities
QuEEN™ Discovery Engine: Unique Capabilities Enable Our Rational and Target-Centric Approach to MGDs Diverse and growing library rationally designed using structural insights to engage a variety of degrons Proprietary MGD library Glueomics™ Engine Specialized suite of in vitro assays to globally ass
Slide 9: A CRBN-Centric Library Characterized by Novelty and Structural Diversity
A CRBN-Centric Library Characterized by Novelty and Structural Diversity Chemical fingerprints of MGD hits Current library size 27K MGDs, continuing to expand High structural diversity and novelty Design focused on optimal drug-like properties Library characteristics Leveraging different areas of th
Slide 10: Omics Platforms Accelerate Degron and MGD Discovery and Validation
Omics Platforms Accelerate Degron and MGD Discovery and Validation Chemo-transcriptomics Chemo-proteomics p-value p-value Protein fold-change; (log2) Protein fold-change; (log2) Target A Target A Proximity (Turbo-ID) Degradation Proteome-wide profiling of up to 10K proteins to characterize MGD proxi
Slide 11: Proprietary AI/ML Engines Allow for Discovery of Glueable Targets
Proprietary AI/ML Engines Allow for Discovery of Glueable Targets and Highly Selective MGDs PPI propensity & pocket identification for reprogrammability Surface complementarity connecting E3 ligases to neosubstrates E3 ligase Candidate neosubstrates E3 ligase surface evaluation Proteome-wide glueabi
Slide 12: 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 13: Portfolio
Portfolio
Slide 14: 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 15: Monte Rosa Pipeline
Monte Rosa Pipeline Rapidly advancing wholly owned MGD programs targeting undruggable proteins Oncology Autoinflammation Oncology / immunology Genetic diseases GSPT1 (G-loop) NSCLC, SCLC and other MYC-driven Malignancies CDK2 (new) Ovarian Cancer, Breast Cancer NEK7 (G-loop) Inflammatory Diseases VA
Slide 16: GSPT1 Program
Mh. Monte Rosa Therapeutics GSPT1 Program
Slide 17: MYC Family Transcription Factors are Key Cancer Dependence Genes
MYC Family Transcription Factors are Key Cancer Dependence Genes MYC up-regulation dysregulates key cellular processes (e.g. ribosome biogenesis and protein synthesis) MYC dysregulation is frequently associated with poor prognosis and unfavorable patient survival MYC family: c-MYC, N-MYC, and L-MYC
Slide 18: Targeting MYC-driven Tumors Through Degradation of GSPT1
Oncogene addiction MRT-2359 impairs protein synthesis in MYC high lines Synthetic lethality MRT-2359 affects MYC and targets in MYC high lines Targeting MYC-driven Tumors and Their Addiction to Protein Translation Through Degradation of GSPT1 To sustain growth, MYC-driven tumors are addicted to prot
Slide 19: QuEEN Discovery Engine Facilitates the Design of MRT-2359
QuEEN™ Discovery Engine Facilitates the Design of MRT-2359 Diverse library, rationally designed, using structural insights to engage a variety of degrons In silico ternary complex modelling using proprietary AI-powered algorithms in vitro data CRBN binding, Ki 113 nM Ternary complex, EC50 < 7 nM Deg
Slide 20: MRT-2359 is a GSPT1-directed MGD with Favorable Drug-like Properties
MRT-2359 is a GSPT1-directed MGD with Favorable Drug-like Properties GAPDH IKZF1 IKZF3 ZFP91 CK1a GSPT1 - 0.3 3 30 30 30 6hr post treatment in MM1S and Kelly (SALL4) - - - - + - - - - - - + SALL4 1hr post treatment Protein fold-change; (log2) p-value MRT-2359, mM Bortezomib MLN-4924 Proximity – Turb
Slide 21: Preferential Activity of MRT-2359 in MYC-Driven NSCLC Lines
Preferential Activity of MRT-2359 in MYC-Driven NSCLC Lines MRT-2359 induces GSPT1 degradation in all cell models, but show preferential antiproliferative 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 degradatio
Slide 22: MRT-2359 Shows Preferential Activity in MYC High or Neuroendocrine Positive Cancer Lines
N-MYC high NSCLC lines MRT-2359 Shows Preferential Activity in MYC High or Neuroendocrine (NE) Positive Cancer Lines Low L-MYC NCI-H2286 NCI-H196 High L-MYC NCI-H1836 NCI-H1876 72 hr viability assay (CTG) L-MYC high SCLC lines NE positive lung lines Low NE High NE Low N-MYC NCI-H2023 NCI-H441 High N
Slide 23: 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 characteri
Slide 24: MRT-2359 Demonstrates Preferential Anti-tumor Activity in Lung Cancer PDXs
MRT-2359 Demonstrates Preferential Anti-tumor Activity in MYC High or Neuroendocrine (NE) Lung Cancer PDXs 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 25: MRT-2359-001 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 26: 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 26 Small cell
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 Loss of RB Clinical Opportunity: CDK2 driven cancers: ER positive breast cancer pre and post treatment with CDK4/6 inhibitors (444K patients), ovarian cancer (63K pa
Slide 29: 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 30: 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 31: VAV1 Program
Mh. Monte Rosa Therapeutics VAV1 Program
Slide 32: 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 VAV1 is a Highly Validated Target for Attenuating T-cell Activity Schmidt et al., Science 2022 Primary human T cells
Slide 33: 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 34: 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 35: NEK7 Program
Mh. Monte Rosa Therapeutics NEK7 Program
Slide 36: 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 37: 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 38: Sickle Cell Disease Program
Mh. Monte Rosa Therapeutics Sickle Cell Disease Program
Slide 39: 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) 155,000 patients (US and
Slide 40: Summary
Summary
Slide 41: 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 disease Extensive and
Slide 42: Monte Rosa Therapeutics
Mh. Monte Rosa Therapeutics
Monte Rosa Therapeutics — Investor Presentation (January 2023) on 6ix