Biomea Fusion, Inc. · NASDAQ:BMEA
Biomea Fusion — WCIRDC Breakfast Symposium 2023
51 slides from Biomea Fusion's conference presentation, Dec 7, 2023
Slide 1: BMF-219: An Oral Menin Inhibitor in Clinical Development for Diabetes
BMF-219: An Oral Menin Inhibitor in Clinical Development as a Short-Term Treatment to Address the Root Cause of Diabetes, Beta-Cell Dysfunction December 7, 2023
Slide 2: Speakers and Presentation Topics
Thomas Butler MS, MBA Introduction to Biomea Fusion and the Chief Executive Officer and Discovery of the Covalent Menin Inhibitor, Chairman of the Board BMF-219 Biomea Fusion Priyanka Somanath PhD BMF-219 in Animal Models of Diabetes: Associate Director Durable Improvement in Beta-cell Function Biom
Slide 3: Agenda
Agenda • Company Background • Development Principles • Benefit of Covalency • BMF-219: Selectivity and Specificity of Covalent menin inhibition • Target Engagement (Kd) • Peptide Mapping • Treatment Analysis – ZDF & STZ Animal Models • Gene Expression – Human Islets • Proliferation Data – Human Isle
Slide 4: Biomea Fusion - A Biopharma Company Focused on Covalent Medicine since 2017
Excellent Science - Combining Validated Targets with Breakthrough Chemistry BIOMEA FUSION HISTORY Biomea Fusion - A Biopharma Company Focused on Covalent Medicine since 2017 2017 2019 2021 2023 Biomea and A2A Lead candidates • Initial Public • Biomea announces form Biomea selected for Offering initi
Slide 5: A Long History of Developing Successful Drugs - Together
Aiming to Develop Some of the Most Impactful Medicines of Our Time A Long History of Developing Successful Drugs - Together Thomas Butler Ramses Erdtmann Juan Frías, M.D. Naomi Cretcher Heow Tan Steve Morris, M.D. Franco Valle Chairman & CEO President & COO Chief Medical Chief of People Chief Techni
Slide 6: Biomea's Development Principles
Biomea Leverages the FUSIONTM System to Create a Suite of Novel Covalent Agents to Potentially Improve and Extend the Lives of Patients Biomea’s Development Principles Validated Targets Drugs pursuing Validated Disease Targets have a ~2x Breakthrough higher likelihood of approval than molecules purs
Slide 7: Team Fusion has a History of Covalent Successes
Developing Some of the Most Impactful Covalent Inhibitors Team Fusion has a History of Thomas Butler Chairman & CEO Covalent Successes Co-inventor of FUSION system Co-inventor of Remdesivir at Gilead Team Fusion developed the Biomea FusionTM System and built R&D facilities to allow for efficient dis
Slide 8: Covalent Inhibitors Have Long Kinetic but Short Biological Half Life
Case Study PCI-32765 IMBRUVICA - Prolonged Target Occupancy Effect without Prolonged Systemic Exposure Covalent Inhibitors Have Long Kinetic but Short Biological Half Life Long Kinetic Half Life High Selectivity % Active-Site Occupancy (left axis) indicates irreversible BTK Inhibition at cancer site
Slide 9: Our FUSION System
Our FUSION System TM We leverage our FUSION System to discovery and develop Novel irreversible inhibitors against targets essential for many diseases. • Novel Target Selection Process • Crystal Structure based Drug Design • Proprietary Scaffold Construction
Slide 10: Covalent Target/Ligand Identification
Fusion System – Discovery and Development of Novel Covalent Inhibitors Covalent Target/Ligand Identification A) Target not known PDB – Crystal Structure B) Target known CYS Survey Protein Warhead and linker • Identify ligand Data Bank for placement/reactivity covalent targets • Biomea BIOMEA CYS Pat
Slide 11: Human Genome Wide Covalent Pocket Analysis
Fusion System – Discovery and Development of Novel Covalent Inhibitors Human Genome Wide Covalent Pocket Analysis CYS site spheres hydrophobic • 23,391 human genes as predicted • Analyze Apo structures without • Top ranking pocket with sufficient structures; 14,159 novel vs PDB ligands hydrophobic c
Slide 12: Restoring Balance in Menin Dependent Diseases is Context Specific
BMF-219 a covalent inhibitor of menin with unique properties Restoring Balance in Menin Dependents Diseases is Context Specific Pathological State Effector Genes CDK inhibition results in beta-cell quiescence Treating Diabetes Treating Cancer Menin dependent effector genes Menin dependent effector g
Slide 13: Target Engagement (Kd)
Target Engagement (Kd) Biomea Compounds Tested against Menin
Slide 14: BMF-219 Target Engagement (Kd) with Menin
Biomea Compounds Tested against Menin BMF-219 Target Engagement (Kd) with Menin Compound Kd (nM) BMF-203 250 BMF-219 <0.001 (Compound D) BMF-222 1,250 BMF-224 1,804 BMF-5 3,191 *Compound D displays a Kdis rate that supports covalent engagement Page 14
Slide 15: Covalent Adduct Formation
Covalent Adduct Formation Peptide Mapping with BMF-219
Slide 16: BMF-219 Binding to Single Specific Cysteine in Menin
BMF-219 - Menin Protein Mapping BMF-219 Binding to Single Specific Cysteine in Menin Overview: (CRO) Identify attachment site(s) of BMF-219 to Human rMenin Experimental Summary: • Incubated rMenin and BMF-219 • After incubation, treat with solution to digest Tryp/Lys-C to split rMenin into singular
Slide 17: BMF-219 Binding to Specific Cysteine in Menin
BMF-219 Binding to Specific Cysteine in Menin Targetable Binding Cysteine Selectivity Peptide Mapping Results Summary Menin CYS1 100.0% • Analyzed all reactions through Freestyle CYS2 0.0% CYS3 0.0% • Only observed BMF-219 attached to Cys1 (Biomea numbering) CYS4 0.0% CYS5 0.0% • Did not observe BMF
Slide 18: Gene Expression – Human Islets
Gene Expression – Human Islets BMF-219 Impact on Menin Gene Signatures
Slide 19: BMF-219 Impact on Beta Cell Proliferation Gene Expression (CCNA2)
BMF-219 – Impact on Beta Cell Proliferation Gene Expression Ex-Vivo Experiments – Human Islets (CCNA2 encodes Cyclin A2) CCNA2 Ccna2 2.5 Human pancreatic islet Fold Change 2–ΔΔCt ± SD 2.0 40 (relative to RPL30) Ccna2 1.5 35 Rpl30 30 Pbk CT Value 1 25 Treatment for 5 days 20 0.5 15 0.0 10 1 2 3 4 5 6
Slide 20: BMF-219 Impact on Beta Cell Proliferation Gene Expression (Pbk)
BMF-219 – Impact on Beta Cell Proliferation Gene Expression Ex-Vivo Experiments – Human Islets Pbk Pbk Pbk BMF-219 BMF-219 3.5 BMF-219 3.5 6 BF-50 @ 100nM BF-50 @ 30nM (30nM) (100nM) Fold Change 2–ΔΔCt ± SD Fold Change 2–ΔΔCt ± SD Fold Change 2–ΔΔCt ± SD BF-50 @ 10nM 3.0 (10nM) 3.0 5 (relative to RP
Slide 21: The Goal for BMF-219 is to Improve Glycemic Control without Continuous Medication
BMF-219 – Mechanism of Action The Goal for BMF-219 is to Improve Glycemic Control without Continuous Medication BMF-219 is aimed to increase beta cell mass and function, thereby Proposed effect of BMF-219 increase insulin production in order to achieve glycemic control Proposed effect of BMF-219 - w
Slide 22: BMF-219: 1st in Class Agent with a Differentiated Profile
Diabetes – the Biggest Epidemic of the 21st Century Investigational BMF-219 - Focusing on Beta Cell Health BMF-219: 1st in Class Agent with a Differentiated Profile Complementary Agent Well-Tolerated Profile Short-Treatment Oral Small Molecule to Available Diabetes To-Date Duration Therapies Disease
Slide 23: BMF-219 in Animal Models of Diabetes
BMF-219 in Animal Models of Diabetes Durable Improvement in Beta-cell Function and Glycemic Control Priyanka Somanath, PhD Associate Director, Translational Drug Discovery & Development Biomea Fusion CONFIDENTIAL
Slide 24: Study Design: Zucker Diabetic Fatty (ZDF) Rat Model of T2D
BMF-219 – ZDF Diabetes Rat Model Study Design: Zucker Diabetic Fatty (ZDF) Rat Model of T2D Study Objective Measure the ability of BMF-219 to restoring glycemic control in Zucker Diabetic Fatty (ZDF) Rat over a 4-week dosing study. Treatment Scheme of ZDF Rat Model Image Source: Charles River Labora
Slide 25: BMF-219 Substantially Controlled Blood Glucose Levels in a 4-Week Dosing Study
BMF-219 – ZDF Diabetes Rat Model BMF-219 Substantially Controlled Blood Glucose Levels in a 4-Week Dosing Study 4-hr Fasting Blood Glucose 2-hr post-OGTT glucose ✱ * p<0.05 ** p<0.001 **** p<0.0001 ✱ 800 ✱ ✱✱✱ Blood glucosse (mg/dL) 600 Mean ± SEM 400 200 0 Day 1 Day 21 Day 29 4-hr Fasting Insulin 4
Slide 26: BMF-219 Restores Beta-Cell Function over 4 Weeks of Treatment
BMF-219 – ZDF Diabetes Rat Model BMF-219 Restores Beta-Cell Function over 4 Weeks of Treatment BMF-219 restores and maintains HOMA-B index to normal state (>201) over 4 weeks of treatment 4 hr Fasting HOMA-B (Day 21) 4 hr Fasting HOMA-B (Day 29) HOMA-B (4 hr Fasting) Last day of treatment 400 400 25
Slide 27: BMF-219 Significantly Reduces HbA1c vs. Vehicle
BMF-219 – ZDF Diabetes Rat Model BMF-219 Significantly Reduces HbA1c (-3.5%) vs. Vehicle during Treatment and Maintains Lowering Effect during 2 Weeks of Drug Washout * p<0.05 Hemoglobin A1c (%) ** p<0.01 * ****p<0.0001 ✱✱✱✱ ✱✱✱✱ 15 Vehicle vs BMF-219: HbA1c delta = 3.5% ✱✱✱✱ ✱✱✱✱ HbA1c (%), Mean ±
Slide 28: Summary of Key Animal Data
BMF-219 – Preclinical Animal Data Summary of Key Animal Data BMF-219 was well-tolerated in all animals. BMF-219 displayed significant glycemic control in ZDF rats, outperforming liraglutide in reduction of fasting blood glucose by Day 29 and by OGTT on day 25. BMF-219 significantly reduced HbA
Slide 29: Menin Inhibition: What May Explain the Effects of BMF-219
Menin Inhibition: What May Explain the Effects of BMF-219 on β-Cell Function and Glycemic Control? Rohit N. Kulkarni MD PhD
Slide 30: β-Cell Compensation in Physiological and Pathophysiological States in Mammals
β-Cell Compensation in Physiological and Pathophysiological States in Mammals Pregnancy β-Cell Mass β-Cell Replication Pregnancy Pregnancy β-Cell Size Adapted from Science. 2005
Slide 31: Evidence for Enhanced β-Cell Mass in Humans
Evidence for Enhanced β-Cell Mass in Humans Non-Diabetic Humans T2D Rahier et al. Diabetes, Obesity and Metabolism. 2008 Saisho et al. Diabetes Care. 2012
Slide 32: Evidence for Replicating and Functional β-cells in Long-Standing Type 1 Diabetes
Evidence for Replicating and Functional β-cells in Patients with Long-Standing (>50 yrs) Type 1 Diabetes Medalists: 50+ yrs with insulin-dependent diabetes, mean duration= 65 yrs Singlets Few within a few islets Several in islets in outside islet few lobes 48/48 36/48 7/48 Keenan, Bonner-Weir, King
Slide 33: Molecular Mechanisms Regulating Human β-Cell Proliferation
Molecular Mechanisms Regulating Human β-Cell Proliferation ? Role for Menin Basile et al. Current Diabetes Reports. 2019
Slide 34: Menin Controls Growth of Pancreatic B-Cells in Pregnant Mice
Science AYAAAS 2007 Menin Controls Growth of Pancreatic B-Cells in Pregnant Mice and Promotes Gestational Diabetes Mellitus Satyajit K. Karnik,’ Hainan Chen,’* Graeme W. McLean,’ Jeremy J. Heit,’* Xueying Gu,” Andrew Y. Zhang, Magali Fontaine,” Michael H. Yen,*? Seung K. Kim??+ During pregnancy, mat
Slide 35: Ex-Vivo Human Islet Microtissues: Assay Set-Up and Read Outs
Ex-Vivo Human Islet Microtissues: Assay Set-Up and Read Outs • Compound treatment 1-3 weeks (+/- compound washout) • Assayed under standard (5.5 mM) and high (8.0 mM) glucose Cadaver-derived Islet human islets aggregation (non-diabetic donors) 1 week 2 weeks Proliferation of beta cells 3 weeks I
Slide 36: BMF-219 Induced a Glucose-Dependent Enhancement in β-Cell Proliferation (Donor 1)
BMF-219 Induced a Glucose-Dependent Enhancement in β-Cell Proliferation Proliferating beta cells as a fraction of total beta cells Donor 1 Standard glucose High glucose Donor 1; Day 14, High glucose Proliferating β-cell Fraction Day 14 Day 21 Day 14 Day 14 Day 21 Day 14 2.5 + washout + washout EdU+
Slide 37: BMF-219 Induced a Glucose-Dependent Enhancement in β-Cell Proliferation (Donor 2)
BMF-219 Induced a Glucose-Dependent Enhancement in β-Cell Proliferation Proliferating beta cells as a fraction of total beta cells Donor 2 Standard glucose High glucose Donor 2; Day 14, High glucose Proliferating β-cell Fraction Day 14 Day 21 Day 14 Day 21 0.3 * EdU+ NKX6.1+ / NKX6.1+ % 0.2 0.1 0.0
Slide 38: BMF-219 Induced a Glucose-Dependent Enhancement in β-Cell Insulin Content
Donor 2 Donor 1 Total Insulin Content (ng/MT) Total Insulin Content (ng/MT) 10 20 30 0 10 20 30 0 DMSO DMSO 0.075 μM Biomea 0.3 μM Day 14 0.15 μM Harmine Day 14 *** 10 μM BMF-219 0.3 μM DMSO Harmine 10 μM *** Biomea DMSO 0.3 μM Day 21 Harmine *** 0.075 μM 10 μM Standard glucose 0.15 μM DMSO Day 21 B
Slide 39: Summary and Ongoing Studies on BMF219
Summary and Ongoing Studies on BMF219 • BMF-219 promotes controlled proliferation and enhances insulin content in β-cells in human islets ex vivo in a glucose- and dose-dependent manner • Data suggests induction of β-cell proliferation as a mechanism for the improved glycemic control in BMF-219-trea
Slide 40: BMF-219 in People with T2D
BMF-219 in People with T2D Select Results of a Multiple Ascending Dose Study Juan Pablo Frias, MD Chief Medical Officer, Head of Diabetes Biomea Fusion CONFIDENTIAL
Slide 41: Study Objectives of T2D Multiple Ascending Dose (MAD) Cohorts
COVALENT-111 Study Study Objectives of T2D Multiple Ascending Dose (MAD) Cohorts Primary Objective: To assess the safety and tolerability of multiple ascending oral doses of BMF-219 Key Secondary Objectives: • To determine the pharmacokinetics following multiple ascending doses of BMF-219 • To deter
Slide 42: Key Eligibility Criteria and Study Design
COVALENT-111 Study Key Eligibility Criteria and Study Design COVALENT-111 T2D MAD Cohorts Eligibility Criteria • T2D, age 18-65 years 50 mg QD, without food x 4 weeks • Duration of diabetes ≤15 years • HbA1c 7.0-10.0%, inclusive 100 mg QD, without food • Treated with diet/exercise ± up to 3 x 4 week
Slide 43: Baseline Characteristics and Demographics
COVALENT-111 Study Baseline Characteristics and Demographics BMF-219 100mg QD BMF-219 100mg QD without food with food Placebo (n=10) (n=10) (n=4) Age (year, min-max) 52 (38-63) 51 (35-60) 47 (35-61) Sex (n, M/F) 6/4 7/3 4/0 Duration of diabetes (year, min-max) 4.2 (0.5-9.0) 8.7 (4.0-14.0) 4.3 (0.75-
Slide 44: Pharmacokinetics: Exposure With and Without Food
COVALENT-111 Study Pharmacokinetics: 100 mg QD without food resulted in approximately 2.7-fold greater BMF-219 exposure than 100 mg QD with food 100 mg QD without food 100 mg QD with food BMF-219 mean AUClast BMF-219 mean Cmax 300 100 AUClast (ng*hr/mL) 75 Cmax (ng/mL) 200 50 100 25 0 0 100 mg QD 10
Slide 45: Summary of Glycemic Results at Week 12
COVALENT-111 Study Summary of Glycemic Results at Week 12 (8 Weeks after Final BMF-219 Dose) BMF-219 100mg QD BMF-219 100mg QD without food with food Placebo (n=10) (n=10) (n=6) Mean change in HbA1c (%) -1.0 -0.1 1.0 Mean placebo-corrected change in HbA1c (%) -1.1 -0.2 - Percent of participants with
Slide 46: Change in HbA1c from Baseline for All Participants and Top 50%
COVALENT-111 Study Change in HbA1c from Baseline at Week 12 for All Participants and for the 50% of Participants Who Had the Greatest HbA1c Response at Week 4 All participants Top 50%* 0 0 Mean change in HbA1c (%) Mean change in HbA1c (%) -0.5 -0.5 -1.0 -1.0 ∆ HbA1c at Wk 12 ∆ HbA1c at Wk 12 100mg w
Slide 47: Case Study: 51-Year-Old Man with 4-Year History of T2D
COVALENT-111 Study Case Study: 51-Year-Old Man with 4-Year History of T2D • 51-year-old man with 4-year history of T2D • BMF-219 100 mg QD without food for 4 weeks • Metformin 500mg BID • Metformin continued • HbA1c 8.9%; FPG 184 mg/dL; BMI 32 kg/m2 • No tolerability issues or adverse events reporte
Slide 48: Safety and Tolerability
COVALENT-111 Study Safety and Tolerability • BMF-219 was generally well tolerated and safe • There were no severe or serious adverse events reported • No dose discontinuations or modifications • No symptomatic or clinically significant hypoglycemia Page 48
Slide 49: Summary and Conclusions
COVALENT-111 Study Summary and Conclusions • In patients with T2D, 4 weeks of BMF-219 100 mg once-daily resulted in clinically meaningful improvements in glycemic control at Week 12 (8 weeks after the final dose) • Higher BMF-219 exposure, as measured by BMF-219 AUC at Week 4, resulted in greater im
Slide 50: Question & Answer Session
Question & Answer Session CONFIDENTIAL
Slide 51: Poster, Oral and Tabletop Presentation Schedule
Poster Oral Tabletop Presentation Presentation Exhibit • Thursday, Dec. 7th 6:35-7:30pm • Friday, December 8th 7:30-9:00pm • Thursday, December 7th • Exhibit Hall/Sierra Ballroom A • Sierra Ballroom B – Lobby Level • Friday , December 8th • Abstract #0088 • Exhibit Hall/Sierra Ballroom A