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Excellent Science - Combining Validated Targets with Breakthrough
Chemistry We Aim to Cure Experienced Management Team TM Novel FUSION System Biomea Fusion is a clinical-stage biopharmaceutical company focused on the discovery and development of oral covalent small-molecule drugs to treat BMF-219 -
Phase II Stage patients with genetically defined cancers and metabolic diseases. We believe that our approach may lead to significant improvement and extension of life for patients. Our team is engaged in all phases of drug BMF-500 - Phase I
Stage discovery and development, including target selection, small molecule design, and preclinical and clinical studies to develop innovative medicines. Development of Combination Assets Page 3
Aiming to Develop Some of the Most Impactful Medicines of Our Time A
Long History of Developing Successful Drugs - Together Franco Valle Thomas Butler Ramses Erdtmann Naomi Cretcher Heow Tan Steve Morris, M.D. Juan Fr as, M.D. Chief Financial President & COO Chairman & CEO Chief of People Chief Technical
& Chief Development Chief Medical Officer Quality Officer Officer Officer Co-Founder Co-Founder TM The FUSION SYSTEM * BMF-219 Co-Inventor Co-Inventor Page 4 *Note: BMF-219 is an investigational new drug
TM Biomea Leverages the FUSION System to Create a Suite of Novel
Covalent Agents to Potentially Improve and Extend the Lives of Patients Biomea's Development Principles Drugs pursuing Validated Disease Targets have a ~2x Validated Targets Breakthrough higher likelihood of approval than molecules pursuing
For Covalent Covalent Chemistry Validated a new mechanism of action Targets Sources: Nelson et al. (2015) Nat Genet.; Thomas et al. (2016) BIO; In a Landscape of 'Me Too' Drug Inhibition Validated Targets For Breakthrough Development, What Spurs
Radical Innovation? HBS Weekly Review (Jun 2018) Covalent Inhibition Covalent Chemistry Biology Chemistry Covalent Small Molecule Inhibitors provide deep target inactivation and a wider therapeutic window, allowing for longer duration on therapy
Covalent Sources: Singh et al. (2011) Nature Reviews Drug Discovery; Cheng et al. (2020) Journal of Hematology & Inhibitors Oncology; Strelow (2017) SLAS Discovery; Kalgutkar & Dalvie (2012) Expert Opin. Drug Discov.; Proprietary
Combinations Combination Therapy with non-overlapping Medicine resistance mechanisms results in more durable Proprietary Chemistry responses and better outcomes Combinations Sources: Palmer et al. (2019) eLife; Mokhtari et al. (2017) Oncotarget Page
Case Study PCI-32765 IMBRUVICA - Prolonged Target Occupancy Effect
without Prolonged Systemic Exposure Covalent Inhibitors Have Long Kinetic but Short Biological Half Life High Selectivity Long Kinetic Half Life % Active-Site Occupancy (left axis) indicates Two-step inhibition: 1) Initial reversible binding
followed by irreversible BTK Inhibition at cancer sites 2) covalent interaction, increasing target selectivity Short Biologic Half Life Deep Target Inactivation Plasma concentration (right axis) reflects systemic exposure to body Permanent
inactivation of bound protein drives target elimination through normal cellular degradation processes Greater Therapeutic Window Designed to maintain an effect without sustained systemic exposure, unlike conventional non-covalent inhibitors
*Pharmacyclics Corporate Deck 2012 Page 6 (ng/ml)
TM Our FUSION System We leverage our FUSION System to discovery and
develop Novel covalent inhibitors against targets essential for many diseases. Novel Target Selection Process Crystal Structure based Drug Design Proprietary Scaffold Construction
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 Top ranking pocket with sufficient Analyze Apo structures without structures; 14,159 novel vs PDB hydrophobic
character ligands Remove spurious N- and C-termini (blue) Virtual screening for ligands Pocket identification using Analyze individual domains if needed - Biomea Linker/Warhead established methods SiteMap
potential artificial inter-domain pockets Determination Protocol "bindability" ranking Manual curation for high interest targets Lead Molecule(s) CONFIDENTIAL Page 8
Biomea's Pipeline Expands into 5 Clinical Trials with 2 Novel
Agents Multiple Upcoming Milestones in the Near Term Study Indications Milestones Expected Timeline COVALENT-111 Type 2 Diabetes Phase II - Dose Escalation Completion, ATTD 1Q 2024 2024 Phase II - Initial Proof of Concept COVALENT-112 Type 1
Diabetes BMF-219 Menin Liquid Tumors COVALENT-101 Phase I - Dose Escalation Completion, RP2D 2024 Program COVALENT-102 Solid Tumors Phase I - Dose Escalation Completion, RP2D 2024 BMF-500 AML/ALL FLT3 COVALENT-103 Phase I - Dose Escalation
Completion, RP2D 2024 (acute leukemia) Program Additional Progress Update 2024 Target # 3 TBA Program Page 9
Aiming to Develop Some of the Most Impactful Medicines of Our Time Juan
Pablo Fr as, M.D. is Appointed as Biomea's Chief Medical Officer August 31, 2023 Dr. Fr as is a board-certified endocrinologist who has served as principal investigator on over 250 clinical diabetes studies, with over half of those
being Phase III studies, and has participated in the clinical development of more than 20 approved diabetic agents Previous Pharmaceutical Leadership Positions: in Clinical and Medical Affairs at Eli Lilly, Amylin Pharmaceuticals, Pfizer,
and Johnson & Johnson, where he served as CMO and Global Vice President of Clinical and Medical Affairs, Diabetes Care. Academic Positions: University of Colorado Health Sciences Center, Barbara Davis Center for Diabetes
Clinical Faculty at University of California San Diego School of Medicine Published over 125 articles in peer reviewed journals Page 10
Diabetes - the Biggest Epidemic of the 21st Century 2 in 5
Americans Will Develop Diabetes during Their Lifetime th 37.3 million US adults have Diabetes is the 7 leading cause of death in the US. 80% of diabetes today; A total of $413 people with diabetes will die from this disease. Premature
Billion was spent in 2022 mortality caused by diabetes results in an estimated 12-14 years of life lost. Source: National library of Medicine 1(2); 2007 Jul PMC3068646 Diabetes creates one of the largest economic burdens on the US health
care system. $1 out of every $4 in US health care costs is being spent on caring for people with diabetes. In 2022 the US spent $412.9 Billion to treat diabetes. On average, people with diagnosed diabetes have medical expenditures 2.6 times higher
than would be expected without diabetes. According to the CDC, worldwide 537 million adults have diabetes. In the United States alone, 37.3 million adults have diabetes, 11.3% of the population. 96 million adults (more than 1 in 3) in the US
have prediabetes. CDC.gov - By the Numbers: Diabetes in America In a study conducted by Prime Therapeutics, 68% of patients using GLP-1 drugs to address weight loss, stopped using them within the first year, according to 16M insured members.
https://www.primetherapeutics.com/news/real-world-analysis-of-glp-1a-drugs-for-weight-loss-finds-low-adherence-and-increased-cost-in-first-year/ In a study published by the Obesity Journal, only 59% of adults were still taking GLPs after
three months and only 32% after one year (semaglutide was used 40% after 1 year). Early- and later-stage persistence with antiobesitymedications: A retrospective cohort study Page 11
Diabetes - the Biggest Epidemic of the 21st Century Number of
Patients with Diabetes Relying on Insulin Continues to Rise despite Novel Diabetic Agents Approved, without Improving the A1c Outcome 7th GLP-1 RA 6th GLP-1 RA 4th SGLT2 First SGLT2 First GLP-1 RAs approved by approved by approved by approved by
approved by FDA FDA FDA FDA FDA Year 2004 2006 2008 2010 2012 2014 2016 2018 2020 2022 30 Number of Patients Diagnosed with Diabetes 25 20 15 10 7.7 Number of Patients with Diabetes Relying on Insulin 8 6 6.8 4 4.5 2 2004 2006 2008 2010 2012 2014
2016 2018 2020 2022 Percentage of Diabetes Patients with A1c<7 60 52.7 52.9 0 2004 2006 2008 2010 2012 2014 2016 2018 2020 2022 United States Diabetes Surveillance System. Diabetic medication use. Centers for Disease Control and Prevention. Page
12 Available from https://gis.cdc.gov/grasp/diabetes/diabetesatlas-surveillance.html#. Accessed 6 Jan 2024 Patient Number Percentage of Patient Number (million) Patients (%) (million)
Diabetes - the Biggest Epidemic of the 21st Century
Investigational BMF-219 - A Unique Value Proposition: Beta Cell Health st BMF-219: 1 in Class Potential for Differentiated Profile Complementary Agent Well-Tolerated Profile Non-Chronic Oral Small Molecule to Available Diabetes After First Read Out
Dosing Therapies Continued Glycemic Control Even After Disease Modifying Potential Cessation of Dosing Addressing the Root Cause of Diabetes Addressable Market May Include All Diabetic Patients Page 13
Role of Beta Cells in Diabetes Beta Cells Proliferate - Just not enough
to overcome pre-existing metabolic disorder "We conclude that during pregnancy, placental hormones act through the prolactin receptor to increase beta cell mass by up regulating beta cell "In nondiabetic obesity, an expansion in
proliferation by engaging Jak2, Akt, menin/p18, beta cell mass occurs to provide sufficient and p21." insulin and to prevent hyperglycemia. This Hughs et al. Endocrinology, March 2011, 152(3):847-855 expansion is at least in part due to
beta cell proliferation. Linnmann et al. American Society for Nutrition. Adv. Nutr. 5: 278-288, 2014 "This quantitative morphological study shows a marked enlargement of the islets of Langerhans in pregnant women." F. A. Van Assche
et al. British Jornal of Obstetrics and Gynaecology, 1978 November Page 14
Role of Menin in Diabetes Menin Controls Beta-Cell Proliferation and
Mass Menin is a transcriptional scaffold protein that controls the expression of proteins that regulate beta-cell proliferation. - Menin has been found to control islet growth in pregnant mice. Pregnancy Menin is thought to act as a
brake on beta stimulated proliferation of maternal cell turnover / beta cell growth, supporting pancreatic islet b-cells was accompanied by the notion that inhibition of menin could reduced islet levels of menin and its targets. - Prolactin, a
hormonal regulator of lead to the reactivation, protection, and pregnancy, repressed islet menin levels and regeneration of beta cells, which could be a stimulated b-cell proliferation. disease-modifying approach to treat type 2 Dr. Kim, S.K. et
al., Science. 2007 Nov 2. doi: 10.1126/science.1146812. diabetes. BMF-219 is a small molecule designed by the Biomea Fusion Team to covalently inhibit menin. Preclinical studies have shown that the inhibition of menin leads to the overall
rehabilitation of beta cell health and function, and thereby to increased insulin production and glycemic control. Clinical trials with BMF-219 are under way to investigate oral dosing for a limited time only until the pool of healthy beta cells are
restored. The goal is to address diabetes with BMF-219 at the root cause. Page 15
Diabetes - the Biggest Epidemic of the 21st Century Beta Cell
Compensation in Physiological and Pathophysiological States in Mammals Pregnancy -Cell Mass -Cell Replication Pregnancy Pregnancy -Cell Size Adapted from Science 2005 Page 16
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 increase insulin Proposed effect of BMF-219 production in order to achieve glycemic control Proposed effect of BMF-219 - without the
need of continuous medication. Page 17 *Int. J. Mol. Sci. 2016, 17, 744; doi:10.3390/ijms17050744
BMF-219 - Impact on Beta Cell Proliferation and Insulin Secretion
in Ex Vivo Models BMF-219 Induced a Glucose-Dependent Enhancement in -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 -cell
Fraction Day 14 Day 14 Day 21 Day 21 0.3 * 0.2 0.1 0.0 BMF-219 BMF-219 BMF-219 BMF-219 Data represent mean SEM of 1 donor with n = 9-12 technical replicates. One-way ANOVA with Dunnett's post hoc test rel. to DMSO control. *p < 0.05,
**p < 0.01, ***p < 0.001 Donor 2 Age BMI HbA1c Proliferation observed only under elevated glucose conditions, which mimic diabetic levels. Caucasian 32 25.0 5.2 Page 18 + + + EdU NKX6.1 / NKX6.1 % DMSO 0.075 M 0.15 M 0.3 M
Harmine 10 M DMSO 0.075 M 0.15 M 0.3 M Harmine 10 M DMSO 0.075 M 0.15 M 0.3 M Harmine 10 M DMSO 0.075 M 0.15 M 0.3 M Harmine 10 M
BMF-219 - Mechanism of Action BMF-219 Preserved, Reactivated and
Regenerated Beta Cells in Preclinical Studies Reactivation Preservation Regeneration +96% Normal (Adequate) State +351% Quantitative Analysis of pancreatic islet tissue BMF-219 demonstrated a significant level of beta BMF-219 increased HOMA-B by 96%
in a type 2 cross sections shows BMF-219 treated ZDF animals cell function compared to vehicle at day 31 in an animal model (STZ = 50% Beta Cell destruction). show novel effects in Beta Cell Mass growth and insulin resistant type 2 diabetes animal
model Homa B, a measurement of Beta Cell function, was maintenance. BMF-219 was able to maintain Beta (ZDF). Homa B, a measurement of Beta Cell analyzed using 4 h fasting glucose and insulin levels. Cell function and prevent Beta Cell Mass loss in a
function, was analyzed using 4 h fasting glucose BMF-219 in ex-vivo Human Donor Islets (Ex-Vivo) model of insulin resistance. Importantly, Beta Cell and insulin levels. It increased up to ~351% versus statistically significant increased beta cells
with BMF-219. Mass is maintained, despite cessation of dosing. vehicle, despite cessation of therapy. Page 19 Butler et al. Oral long-acting menin inhibitor normalizes type 2 diabetes in two rat models; Ex-vivo Human Islets data EASD 2022
BMF-219 Mechanism of Action BMF-219 is a Potential First-in-Class
Diabetic Agent - Addressing the Root Cause of Disease BMF-219: Menin Inhibition a Potential New Class of Diabetes Agents Beta cell reactivation, preservation and proliferation Beta Cell Mass Beta Cell Health Nat Rev Endocrinol
12, 337-346 (2016). https://doi.org/10.1038/nrendo.2016.51 Control of Glycemia even after Cessation of Dosing BMF-219 represents a potential new class of diabetes Currently approved therapies are primarily targeting the agents addressing the:
Root Cause of Diabetes Symptoms of Type 2 Diabetes: Hyperglycemia - Loss of Beta Cell Mass and Function - Page 20
COVALENT-111 Study Design (Type 2 Diabetes Patients Failing Standard of
Care) Additional Dose Levels and Various Dosing Durations Are Being Explored in the Escalation and Expansion Portion of COVALENT-111 Part 1 Dose Escalation, Part 2 Dose Expansion, n=216 - 288 incl. 4 weeks dosing+ 12 weeks follow up 12 weeks
dosing + 40 weeks follow-up Healthy Volunteers n=16 100 mg Arm A* 50 mg QD, n=10 x 8 wks x 4 wks 100 mg Arm B x 12 wks 100 mg QD, n=20 x 4 wks 100 mg 200 mg Arm C x 8 wks x 4 wks 200 mg QD / 100 mg BID, n=22 Anticipated to be added based on data