Monte Rosa Therapeutics, Inc. · NASDAQ:GLUE
Monte Rosa Therapeutics — MRT-2359 KOL Webinar hosted by Cowen (October 2022)
25 slides from Monte Rosa Therapeutics's conference presentation, Oct 24, 2022
Slide 1: MRT-2359 KOL Webinar hosted by Cowen
MRT-2359 KOL Webinar hosted by Cowen October 24, 2022 Guest Speakers Jordi Rodon Ahnert, M.D., Ph.D., Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at MD Anderson Cancer Center Davide Ruggero, Ph.D., Professor, Department of Urology and Cellular & Molecular Pharmacol
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: MYC Transcription Factors are Undruggable Oncogenes
MYC Transcription Factors are Undruggable Oncogenes MYC family members are amongst the most Cells expressing high MYC are sensitive to MYC CRISPR KO dysregulated oncogenes in human cancer • MYC family: c-MYC, N-MYC, and L-MYC NSCLC – N-MYC SCLC – L-MYC • MYC dysregulation is frequently associated wi
Slide 4: Targeting Myc-driven Tumors and Their Addiction to Protein Translation
Targeting Myc-driven Tumors and Their Addiction to Protein Translation 1 Addiction To sustain growth, MYC-driven tumors are addicted to protein translation 1 2 Dependency This addiction creates a dependency on the translation termination factor GSPT1 3 3 Therapeutic vulnerability 2 GSPT1 is a therap
Slide 5: QuEEN Discovery Engine Facilitates the Discovery of MRT-2359
QuEEN™ Discovery Engine Facilitates the Discovery of MRT-2359 MRT-2359 is a potent Proprietary MGD library Rhapsody™ GSPT1 degrader Diverse library, rationally In silico ternary complex GSPT1 designed, using structural insights modelling using proprietary to engage a variety of degrons AI-powered al
Slide 6: MRT-2359 is a GSPT1-directed MGD with Favorable Drug-like Properties
MRT-2359 is a GSPT1-directed MGD with Favorable Drug-like Properties MRT-2359 is orally bioavailable and MRT-2359 is a selective GSPT1-directed MGD has favorable ADMET profile MRT-2359, µM - 0.3 3 30 30 30 Proximity – Turbo ID ADMET profile Bortezomib - - - - + - MLN-4924 - - - - - + CYP DDIs > 30 µ
Slide 7: 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 N-MYC overexpression sensitizes show preferential antiproliferative activity in N-MYC high cell lines NCI-H2023 resistant cells to MRT-2359 GSPT1 degradation Viability Doxycycline-i
Slide 8: MRT-2359 Shows Preferential Activity in MYC High or Neuroendocrine Positive Cancer Lines
MRT-2359 Shows Preferential Activity in MYC High or Neuroendocrine (NE) Positive Cancer Lines N-MYC - NSCLC lines L-MYC - SCLC lines NE positive lung lines 125 125 125 100 100 100 Viability (%) Viability (%) Viability (%) 75 75 75 50 50 50 25 25 25 0 0 0 0.00010.001 0.01 0.1 1 10 100 0.00010.001 0.0
Slide 9: MRT-2359 Shows Preferential Activity Compared to Rapid GSPT1 Degraders
MRT-2359 Shows Preferential Activity Compared to “Rapid” GSPT1 Degraders MRT-2359 ¨Rapid¨ GSPT1 degraders lack preferantial actvity in N-MYC high cell lines 100 100 100 75 Viability (%) 75 75 Viability (%) Viability (%) 50 50 50 25 25 25 0 0 0 0.00010.001 0.01 0.1 1 10 100 0.00010.001 0.01 0.1 1 10
Slide 10: Translation Initiation/Elongation Inhibitors Do Not Show Preferential Activity in MYC High Lines
Translation Initiation/Elongation Inhibitors Do Not Show Preferential Activity in MYC High NSCLC and SCLC Cell Lines MRT-2359 shows preferentially Translation initiation and elongation inhibitors lack differential activity activity in MYC high lung lines MRT-2359 Initiation inhibitor Elongation inhi
Slide 11: MRT-2359 Mechanism of Action
MRT-2359 Mechanism of Action
Slide 12: Mechanism of Action in MYC-driven Tumors
MRT-2359 Mechanism of Action in MYC-driven Tumors Synthetic lethality MRT-2359 impairs protein synthesis in MYC high lines Oncogene addiction MRT-2359 affects MYC and downstream in MYC high lines 12
Slide 13: MRT-2359 Impairs Protein Synthesis in N-MYC High NSCLC Cell Lines
MRT-2359 Impairs Protein Synthesis in N-MYC High NSCLC Cell Lines MRT-2359 induces ribosome stalling MRT-2359 rapidly and completely abrogates only in N-MYC high cell line protein synthesis only in N-MYC high cell line Peak density GSPT1 protein levels Puromycin incorporation 120 180 DMSO 160 MRT-23
Slide 14: MRT-2359 Affects MYC and MYC Pathway in N-MYC High NSCLC Cell Lines
MRT-2359 Affects MYC and MYC Pathway in N-MYC High NSCLC Cell Lines MRT-2359 induce GSPT1 degradation leading Degradation of GSPT1 leads to downregulation to N-MYC protein downregulation in NCI-H1155 of N-MYC transcriptional output in NCI-H1155 Time course RNAseq 0 6 hr 24 hr 48hr MYC targets gene s
Slide 15: MRT-2359 and Other Clinical Stage GSPT1 Degrader
MRT-2359 and Other Clinical Stage GSPT1 Degrader
Slide 16: MRT-2359 Shows Superior Characteristics Compared to Clinical GSPT1 Degrader
MRT-2359 Shows Superior Characteristics Compared to Clinical GSPT1 Degrader Assay MRT-2359 Clinical GSPT1 Degrader Selectivity (TMT Px, WB) GSPT1, GSPT2 GSPT1, GSPT2, SALL4, FIZ1, RNF166, ODC1 CYP DDI > 30 uM CYP2C19 @ 1.5 uM in vitro (2B6, 1A2, 2D6,3A4, 2C8,2C9, 2C19) hERG (patch clamp) > 30 uM 5.3
Slide 17: Superior Activity of MRT-2359 in MYC-driven Cancer Cell Lines
Superior Activity of MRT-2359 in MYC-driven Cancer Cell Lines Clinical GSPT1 Degrader EC50 (nM) MRT-2359 EC50 (nM) Low MYC High MYC Low MYC High MYC Low MYC High MYC Low MYC High MYC NSCLC SCLC Lymphoma NSCLC SCLC Lymphoma 17 * Comparison based on internal profiling
Slide 18: Preclinical Anti-tumor Activity of MRT-2359 in MYC-driven Animal Models
Preclinical Anti-tumor Activity of MRT-2359 in MYC-driven Animal Models
Slide 19: Mouse Trial in NSCLC, SCLC and Lung NE Patient-derived Xenograft
MRT-2359 Mouse-trial in NSCLC, SCLC and Lung NE Patient-derived Xenograft N-MYC mRNA expression Log2 (TPM+1) Selected NSCLC 48 models Collection of PDX models Models selected across range L-MYC mRNA expression Log2 (TPM+1) of N-MYC and L-MYC mRNA expression levels or NE status were treated with: N-M
Slide 20: MRT-2359 Demonstrates Preferential Anti-tumor Activity in MYC High or NE Lung Cancer PDXs
MRT-2359 Demonstrates Preferential Anti-tumor Activity in MYC High or Neuroendocrine (NE) Lung Cancer PDXs NSCLC SCLC NE Lung Cancer Large cell NE carcinoma or NE lung cancer L-MYC and N-MYC low L-MYC or N-MYC high N-MYC and L-MYC low 20 MRT-2359 10 mg/kg, PO, QD
Slide 21: High Frequency of L-MYC and N-MYC Expression in NSCLC and SCLC from Real-world Data
High Frequency of L-MYC and N-MYC Expression in NSCLC and SCLC from Real-world Data NSCLC SCLC 3053 samples 188 samples Demographic and Diseases N-MYC mRNA expression Characteristic • There is no notable difference in the proportion of MYC high expressors Log2 (TPM+1) across disease staging, gender
Slide 22: Phase 1/2 Clinical Study
Mp. Monte Rosa Therapeutics Phase 1/2 Clinical Study
Slide 23: MRT-2359-001 Clinical Study Design
MRT-2359-001 Clinical Study Design Phase 1: Dose Escalation Phase 2: Expansion Cohorts Lung cancer (NSCLC & SCLC), DLBCL, high-grade neuroendocrine tumors, and N-/L-MYC amplified solid tumors MTD or RP2D NSCLC* – high N- or L-MYC expression Dose level X – low N- and L-MYC expression Dose level 4 Bac
Slide 24: Clinical Sites
Clinical Sites Clinical Site PI Expertise MDACC Dr. Rodon Phase I/Lung SCRI Dr. Spigel Lung MSKCC Dr. Choudhury Phase I/Lung DFCI Dr. Janne Lung Mary Crowley CR Dr. Barve Phase I START TX Dr. Papadopoulos Phase I Honor Health Dr. Tsai Phase I Indiana University Dr. Opyrchal Phase I ClinicalTrials.go
Slide 25: Thank You
~ Mp. Monte Rosa Therapeutics
Monte Rosa Therapeutics — MRT-2359 KOL Webinar hosted by Cowen (October 2022) on 6ix