Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — Investor Presentation (January 2022)
41 slides from Monte Rosa Therapeutics's investor presentation, Jan 10, 2022
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 2022 Exhibit 99.1
Slide 2: 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 in some cases, can be identi
Slide 3: Monte Rosa Therapeutics Highlights
Monte Rosa Therapeutics Highlights Taking molecular glue degraders (MGDs) to new heights World-class leadership & SAB with deep drug discovery know-how and development expertise in precision medicine Next-generation molecular glue-based targeted protein degradation platform developing breakthrough s
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: Strong Cash Position and Investor Support
Strong Cash Position and Investor Support Over $455M raised since 2020 with top tier investors provides runway into late 2024 Aggregate IPO gross proceeds were approximately $255.6 million before deducting underwriting discounts and commissions and other offering expenses and include an additional $
Slide 6: Expanding Target Space through Molecular Glue Degraders (MGDs)
Expanding Target Space through Molecular Glue Degraders (MGDs) 3-10% of Proteome Uncharted Chemical and Target Space Drugging the Druggable Inhibitors Drugging the Undruggable MGDs Redrugging the Druggable PROTACs E3 Ligase UNDRUGGABLE TARGETS DRUGGABLE TARGETS E3 Ligase DRUGGABLE TARGETS
Slide 7: The Next Generation of Precision Medicine-based Small Molecule Drugs
The Next Generation of Precision Medicine-based Small Molecule Drugs Selectively editing the human proteome with rationally designed MGDs Traditional small molecule inhibitors Therapeutic Antibodies RNAi, RNA Editing CRISPR/Gene Therapy MGDs Ability to access undruggable space Cellular permeability
Slide 8: 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 Expanding the Degradable Proteome Neosubstrates - E.g. IKZF1 MGD E.g. Lenalidomide Cereblon
Slide 9: QuEEN™ Discovery Platform
QuEEN™ Discovery Platform Quantitative and Engineered Elimination of Neosubstrates
Slide 10: QuEEN™ Discovery Platform: A Target-Centric Approach to MGDs
Degron encyclopedia QuEEN™ Discovery Platform: A Target-Centric Approach to MGDs Cereblon binding (pIC50) 5 7 Molecular weight (Da) 190 300 Degron discovery using proprietary AI-powered algorithm Rationally designed, diverse and growing library engaging a variety of degrons Proprietary MGD library A
Slide 11: A Rich, Differentiated Target Space Across Protein Domains and Diseases
A Rich, Differentiated Target Space Across Protein Domains and Diseases Degron-containing domains Broad disease landscape Many highly credentialed targets >85% degrons have unique sequence >75% undruggable Diverse protein domains and classes Degron Encyclopedia >3000 proteins containing a predicted
Slide 12: Increasing MGD scaffold diversity: Library design and expansion
Increasing MGD scaffold diversity Library design and expansion Increasing Novelty and Structural Diversity to Match the Target Space Scaffold evolution Tanimoto similarity 0.6 1 Design focused on optimal drug-like properties High structural diversity and novelty Current library size 20K MGDs 0.8 MGD
Slide 13: Multiple points of contact for dialing in selectivity and potency
Multiple points of contact for dialing in selectivity and potency MGDs are rationally designed to exploit key contacts to selectively engage different neosubstrates MGDs Reprogram the Cereblon Surface Remodeled MGD-CRBN surface enables selective engagement of neosubstrates Effective ternary complex
Slide 14: Glueomics™ Toolbox Accelerates Identification of MGDs
in vitro screens Glueomics™ Toolbox Accelerates Identification of MGDs Multiple assays enable rapid identification and validation of MGDs for novel targets Chemoproteomics - proximity Protein fold-change; (log2) p-value Turbo-ID Cellular Biochemical Proteome-wide expression TMT Proteomics to evaluat
Slide 15: Rhapsody, QuEEN's in silico Engine
Rhapsody, QuEEN’s in silico Engine A suite of proprietary AI-powered algorithms to design, discover and develop MGDs Taking MGD discovery in silico to accelerate discovery Creation and E3 ligase docking of novel MGDs, expanding our library to engage more targets Ternary complex models enabling MRT s
Slide 16: 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 High level of target validation, preclinically and clinically Programs with bioma
Slide 17: Monte Rosa Pipeline
Monte Rosa Pipeline Rapidly advancing wholly owned MGD programs targeting undruggable proteins Oncology Autoinflammation Oncology / immunology Genetic diseases GSPT1 NSCLC, SCLC and other MYC-driven Malignancies CDK2 Ovarian Cancer, Breast Cancer NEK7 Inflammatory Diseases VAV1 T and B Cell Malignan
Slide 18: GSPT1 Program
yyy Monte Rosa Therapeutics GSPT1 Program
Slide 19: Targeting Myc-driven Tumors and Their Addiction to Protein Translation
Targeting Myc-driven Tumors and Their Addiction to Protein Translation GSPT1 is a key regulator and vulnerability of Myc-induced translational addiction To sustain growth, Myc-driven tumors are addicted to protein translation Myc regulates the expression of key genes related to protein translation,
Slide 20: MRT-2359 is a potent inducer of GSPT1-cereblon proximity
MRT-2359 is a potent inducer of GSPT1-cereblon proximity MRT-2359 is a selective GSPT1-directed MGD MRT-2359 is a Potent and Selective GSPT1-directed MGD GAPDH IKZF1 IKZF3 ZFP91 CK1a GSPT1 - 0.3 3 30 30 30 6hr post treatment in MM1S and Kelly (SALL4) - - - - + - - - - - - + SALL4 1hr post treatment
Slide 21: Myc-Driven NSCLC lines are Highly Sensitive to MRT-2359
Myc-Driven NSCLC lines are Highly Sensitive to MRT-2359 Myc-driven NSCLC cell lines are sensitive to MRT-2359 Each dot represents a cell line MRT-2359 induces GSPT1 degradation in all cell models, but selective killing in high N-Myc lines only Viability GSPT1 western blot at 6 hr (N-Myc high) and 24
Slide 22: MRT-2359 Affects N-Myc Pathway only in Myc-driven Cells
MRT-2359 Affects N-Myc Pathway only in Myc-driven Cells GSPT1 N-Myc 0.03 0.3 3 - 0.03 0.3 3 0.03 0.3 3 Tubulin 0 6 hr 24 hr 48hr MRT-2359 (μM) Myc-driven (NCI-H1155) - - 0.03 0.3 3 - GSPT1-directed MGD degradation affects translation, a critical vulnerability of Myc-driven cells Non-Myc-driven (NCI-
Slide 23: Oral dosing of MRT-2359 shows anti-tumor activity and regressions
Oral dosing of MRT-2359 shows anti-tumor activity and regressions in NCI-1155 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, N
Slide 24: MRT-2359 Anti-tumor Activity in L- and N-Myc-positive NSCLC PDXs
MRT-2359 Anti-tumor Activity in L- and N-Myc-positive NSCLC PDXs Tumor progression to ≥800 mm3
Slide 25: Targeting Myc-positive Tumors with MRT-2359
Targeting Myc-positive Tumors with MRT-2359 Potential indications and patient stratification hypotheses Patient diagnosed incidence #s, major markets (US, EU and JP): Decision Resources Group (DRG) Patient stratification %s: Schaub - Cell Systems 2018; Massó-Vallés – Exp. Op. therapeutic targets 202
Slide 26: Early Phase Clinical Development
Early Phase Clinical Development Dose Level 1 MTD or RDE Expansion cohorts Dose escalation BOIN design Lung cancer (NSCLC, SCLC), solid tumors with L-/N-Myc amplification and diffuse large B-cell lymphomas SCLC – Enriched for high L-/N-Myc expression NSCLC – Enriched for high L-/N-Myc expression Dos
Slide 27: Targeting Myc-addicted Tumors with MRT-2359
Targeting Myc-addicted Tumors with MRT-2359 IND-enabling activities have been initiated Rationally designed potent and selective GSPT1-directed MGD Favorable drug-like properties and ADMET profile Orally bioavailable development candidate Robust antitumor activity in vivo in multiple tumor models IN
Slide 28: NEK7 Program
yyy Monte Rosa Therapeutics NEK7 Program
Slide 29: 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 30: Rationally Designed NEK7-Directed MGDs are Selective
Rationally Designed NEK7-Directed MGDs are Selective Rhapsody model enables rapid chemistry optimization NEK7-directed MGD promotes selective degradation of NEK7 Rationally designed MGDs promote selective CRBN proximity TMT-Proteomics – 24hr post treatment Turbo-ID – 6hr post treatment Protein fold-
Slide 31: NEK7-directed MGDs Modulate NLRP3 Pathway in Human Macrophages
NEK7-directed MGDs Modulate NLRP3 Pathway in Human Macrophages MRT-3483 promotes NEK7 degradation and pathway engagement in hMDMs NEK7-directed MGD compared to NLRP3 inhibitor MRT-3483 (nM) + LPS + Nigericin Treatment (6hr) of primed hMDMs Treatment (20 hr) of primed hMDMs Western blot – 24 hr IL-18
Slide 32: Overactivation of the NLRP3 Inflammasome in Diseases
Overactivation of the NLRP3 Inflammasome in Diseases *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 33: CDK2 Program
yyy Monte Rosa Therapeutics CDK2 Program
Slide 34: CDK2 as a Target for Selected Solid Tumors
CDK2 as a Target for Selected Solid Tumors Therapeutic hypothesis: Tumors with CDK2 pathway activation by: CyclinE1/E2 amplification or loss of AMBRA1 Loss of RB Clinical Opportunity: CDK2 driven cancers: ER positive breast cancer (444K patients), ovarian cancer (63K patients), and endometrial cance
Slide 35: Rationally Designed CDK2-Directed MGDs are Selective
Rationally Designed CDK2-Directed MGDs are Selective Rhapsody model enables rapid chemistry optimization CDK2-directed MGD promotes selective degradation Rationally designed MGD promotes selective CRBN proximity TMT-Proteomics – 24hr post treatment Turbo-ID – 6hr post treatment Protein fold-change;
Slide 36: VAV1 and BCL11A Programs
yyy Monte Rosa Therapeutics VAV1 and BCLila Programs
Slide 37: VAV1 as a Target for Autoimmune Disease
VAV1 as a Target for Autoimmune Disease Therapeutic hypothesis: Diseases with VAV1 activating mutations or autoimmune disorders VAV1 activation mutations identified in leukemia, lymphoma and lung cancer VAV1 KO mice improved multiple autoimmune models Clinical Opportunity: First-in-class VAV1 degrad
Slide 38: BCL11A as a Target for Hemoglobinopathies (SCD and β-Thalassemia)
BCL11A as a Target for Hemoglobinopathies (SCD and β-Thalassemia) Therapeutic hypothesis: Reactivate expression of fetal hemoglobin (HbF) to compensate for mutated adult globin Clinical Opportunity: First-in-class BCL11A degraders for Sickle cell disease (SCD) 155,000 patients (US and EU) >6M patien
Slide 39: Summary
yyy Monte Rosa Therapeutics Summary
Slide 40: 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 41: Monte Rosa Therapeutics
one & Mh. Monte Rosa Therapeutics
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