#1EPIGENOMIC PROGRAMMING FOR PRECISION GENOMIC CONTROL ROADSHOW PRESENTATION July 2021 ©2021 Omega Therapeutics Inc. OMEGA THERAPEUTICS#2Disclaimer and Forward-Looking Statements The material in this presentation and the accompanying oral presentation (this "Presentation") regarding Omega Therapeutics, Inc. ("we" or the "Company") is for informational purposes only. This Presentation shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. All statements other than statements of historical facts contained in this Presentation, including statements regarding our operations and financial position, business strategy, product candidate development, research and development activities and costs, timing and likelihood of success of our business plans, plans and objectives of management, future results and timing of clinical trials, plans for regulatory submissions, treatment potential of our product candidates, and the market potential of our product candidates, are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. The words "anticipate," "believe," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements include, but are not limited to, statements about the our ability to develop product candidates based on our novel technology, the potential benefits, activity, effectiveness and safety of our product candidates, the success and timing of our preclinical studies, plans for clinical trials, including the timing of regulatory submissions, the size and growth of the potential markets for our product candidates, the sufficiency of our cash resources, and need for additional financing, regulatory developments in the United States and other countries, the rate and degree of market acceptance of any product candidates we may develop, the implementation of our business model and strategic plans for our business and product candidates, our ability to obtain and maintain intellectual property protection for our product candidates, the hiring and retention of key scientific or management personnel and the anticipated trends and challenges in our business and the market in which we operate. These forward-looking statements are only predictions and we may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, so you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions, and expectations disclosed in the forward-looking statements we make. We have based these forward-looking statements largely on our current expectations and projections about future events and trends we believe may affect our business, financial condition, and operating results. The Company has filed a registration statement (including a prospectus) with the Securities and Exchange Commission (the "SEC") for the offering to which this presentation relates. The registration statement has not been declared effective. Before you invest, you should read the registration statement (including the prospectus), and in particular the "Risk Factors" contained therein, for more complete information about the Company and the proposed offering. You may obtain these documents for free by visiting EDGAR on the SEC website at www.sec.gov. Alternatively, you may request a copy of the prospectus by contacting Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, New York 10282, telephone: 1-866-471-2526, facsimile: 212-902-9316 or by emailing [email protected]; Jefferies LLC, Attn: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, New York 10022, by telephone at (877) 821-7388 or by email at [email protected]; or Piper Sandler & Co., 800 Nicollet Mall, J12S03, Minneapolis, Minnesota 55402, Attention: Prospectus Department, by telephone at (800) 747-3924 or by email at [email protected]. ©2021 Omega Therapeutics, Inc.#3IPO Offering Summary Issuer (Exchange / Ticker) Omega Therapeutics, Inc. (NASDAQ Global Market / OMGA) Base Offering Size $125 million (100% primary) Shares Offered 7,400,000 shares (100% primary) Option to Purchase Additional 1,110,000 shares (100% primary) Shares Price Range Lock-Up Period Use of Proceeds Bookrunners Stabilization Agent Expected Pricing Date Ⓒ2021 Omega Therapeutics, Inc. $16.00-$18.00 per share 180 day lock up of the Company, Directors, Officers, and Substantially All Shareholders Omega Therapeutics intends to use the net proceeds from the offering as follows: to support Omega's continued research and development of its OECS to support IND-enabling studies and the potential initiation of clinical studies to continue advancing the OMEGA Epigenomic Programming Platform and discovery-stage research for other potential programs to build out a manufacturing facility for working capital and other general corporate purposes Goldman Sachs & Co. LLC, Jefferies LLC, Piper Sandler & Co., Wedbush Securities Inc. Goldman Sachs & Co. LLC Thursday, July 29, 2021#4Omega was founded to harness the power of epigenetics, nature's fundamental mechanism for gene control and cell differentiation Epigenetics is the mechanism that systematically controls every aspect of an organism's life from cell growth and differentiation to cell death. What if.….. www Epigenetics worked through a universal operating system? We could interrogate that system and therapeutically intervene to control gene expression? © 2021 Omega Therapeutics, Inc. Invented and Founded in 2017 by Flagship Pioneering#5Tumor inhibition by targeting and controlling cMYC MYC • Is an essential master regulator of cell growth • Regulates 15-20% of entire human genome Signal transduction Cell cycle Metabolism Wat signaling pathway Translation Cyclins CDK CDKis GLUTI LOH,GLS elf-2a Transcription E2F Myc MILHI BINI DNA repair MYC dysregulation Protein biosynthesis mRNA tRNA Ribosomal biogenesis Let 7 family 0301 integrin cdc42 Other target Others MicroRNAs Cell adhension and cytoskeleton Is present in >50% of human cancers Is associated w/ poor prognosis and mortality Chen, et al., Signal Transduction and Targeted Therapy (2018) 3:5 ©2021 Omega Therapeutics, Inc. Tumor Volume (mm³) 1000₁ 800 600- 400 200 Statistically significant inhibition of HCC tumor growth by direct targeting of MYC at the pre- transcriptional level Negative Control OEC Candidate Day *HH 10 *Statistically significant vs negative control, t-test p<0.05 starting on day 6 Arrows denote dosing days#6Our pioneering OMEGA Epigenomic Programming platform is designed to coopt nature's universal operating system for Precision Genomic Control It turns out that... Nature has organized genes and their regulatory elements in evolutionarily conserved structures called Insulated Genomic Domains (IGDS). This is nature's operating system for genomic control. IGDS are the fundamental structural and functional units for gene control. We have created the OMEGA Epigenomic Programming platform to develop product candidates and use IGDs as drug targets without altering DNA sequences 2021 Omega Therapeutics, Inc. . . IGD - The "Control Room" of Biology E.g., Lung tissue IGD Chromosome Chromatin Lung cell -15,000 IGDs across 23 chromosomes in every cell Contain gene(s), enhancers/repressors, promoters Insulated from outside transcription by CTCF Unique sequences for all regulatory elements#7The OMEGA Epigenomic Programming Platform Novel Epigenomic Targets, Programmable Medicines, Customized Delivery EpiZips Proprietary database of thousands of novel DNA-sequence-based targets (epigenomic "zip codes") Sa HEK293.17.pX.Y Z.817 ©2021 Omega Therapeutics, Inc. Omega Epigenomic Controllers (OECS) Engineered, programmable medicines encoded as mRNA Engineered, customized drug delivery LNPs and other Industry-leading expertise Codified learnings and insights for continued platform optimization THE AUD#8IGENE EXPRESSION DAD#9EpiZips and OECs The OMEGA platform enables targeting of EpiZips within and across IGDs for Precision Genomic Control OECs: mRNA-encoded epigenetic medicines Omega's proprietary DNA-binding domain Linker 2021 Omega Therapeutics, Inc. Epigenomic effector protein Key Advantages mRNA-encoded proteins delivered in LNP High specificity, tunability and durability Multiplexed single or multiple gene control No changes in nucleic acid sequences OEC 1 Promoter- Brampe p HEP 20Xv2623 Enhancer/ Repressor Example 2 HSP 204x Y.2824) OEC 2 OEC 3 IGD and EpiZips CTCF xemple Epizo HP 20qX.V.2.625) DNA Gene IGD#10Insulated Genomic Domains IGDS present differentially in pristine and diseased states and the OMEGA platform leverages this knowledge for potential therapeutic interventions Example of IGD Control Pristine IGD Enhancer/Repressor sequence mRNA CTCF- CTCF binding site -Promoter mRNA -Gene IGD with structural alteration ©2021 Omega Therapeutics, Inc. OEC Overexpressed mRNA Over- expressed gene DNA Overexpress protein Ribosome Additional enhancer Aberrant CTCF binding OEC corrects aberrant binding OEC correcting aberrant CTCF binding Correct CTCF binding site IGD restored to pristine state Restored CTCF binding Normal prote expression Normal mRNA expression Extraneous, functional IGD alterations (e.g., due to pathogenic insults, oxidative stress, etc.) could also be corrected OEC natura degradation 10#11Investment Highlights Investment Highlights Programmable mRNA medicines delivered via LNPS Ⓒ2021 Omega Therapeutics, Inc. Novel DNA- sequence-based epigenomic targets enabling precision gene tuning Leading program in CMYC as only the first; 8 high-value development programs A What We Have Achieved To Date Programmable mRNA-encoded OECs with high specificity, tunability and durability Proprietary database of thousands of novel EpiZip targets, across the ~15,000 IGDs Initiated 8 programs using our Epigenomic Controllers; over 100 more discovery targets Raised over $200M; 15 leading investor partners Assembled a world class team Omega aims to be a leader in genomic medicines by selectively controlling the human genome to treat and cure serious diseases#12A world-class management team to deliver on our vision Mahesh Karande President & CEO NOVARTIS McKinsey & Company Roger Sawhney CFO NOVARTIS BAIN COMPANY MACROLIDE ARMACEUTICALE Ⓒ2021 Omega Therapeutics, Inc. Leadership BCG KKR Thomas McCauley CSO Shire Translate BIO RONA Archemix Joe Newman VP, Biology Zıkanı AstraZeneca Founded by Flagship Pioneering Noubar Afeyan Chairman & Founder Q: David Berry Founder XX Noubar Afeyan Co-Founder Chairman Flagship, Founder & CEO John Mendlein Executive Partner, Flagship Founding Scientific Advisors MIT & Whitehead Institute Rudolf Jaenisch Richard A. Young Board of Directors David Berry Co-Founder Flagship, General Partner Mary Szela TrisalusLife Sciences, CEO Rick Young MIT, Professor of Biology: Whitehead Institute, Member Elliott Levy Amgen, BMS Luke Beshar NPS Pharma 12#13OMEGA platform - Pioneering Epigenomic Programming company Companies: Focus 2017 Epigenomic Controllers OMEGA THERAPEUTICS Epigenome DOOG Epigenomic programming Ⓒ2021 Omega Therapeutics, Inc. Gene-based Therapies Beam 2013 T MLA CRISPR Spark THERAPEUTICS DNA Gene editing Gene therapy 2010 RNA Medicines moderna Alnylam mRNA mRNA therapeutics ncRNA therapeutics 1976 1849 mABs, Small Molecules Genentech Pfizer Protein Inhibitors, Agonists, Metabolites 13#14Omega's platform has the potential to be an unprecedented and pioneering approach to high-value transformative therapies in pursuit of high-value targets Focus "table-stakes" of most gene- based therapies Select Monogenic Diseases Precisely correct genetic or epigenetic dysregulation in monogenic rare and non-rare diseases (e.g., alopecia, Hypercholesterolemia, Fragile X, FA) ©2021 Omega Therapeutics, Inc. Omega's transformative value creation Regenerative Medicine Recapitulate developmental and mature-state gene expression to drive cellular regeneration and restore normal function (e.g., Liver, Pancreas, Heart, Cornea regen., T cell prog.) Multigenic Diseases Including Immunology Precisely up- or down-regulate single or multiple genes within an IGD or across IGDs (e.g., ARDS (Covid19), RA, IBD, Obesity, CHF, IPF) Oncology Precisely regulate target oncogenes including historically challenging or un-druggable targets in various cancers (e.g., HCC, NSCLC, Pancreatic cancer. GBM) Source: Evaluate pharma, market research reports, internal analysis Market potential $25B+ $ 150B+ $100B+ 14#15Our Portfolio 8 Development Programs Regenerative Medicine Multigenic Diseases incl. Immunology Oncology Select Monogenic Diseases Anticipated Milestones Target Gene(s)/ EpiZip(s) ©2021 Omega Therapeutics, Inc. HNF4A HEP.20.qx.Y.Z.552 Undisclosed CXCL 1-8 A549.04.qX.Y.Z.533 Undisclosed MYC H3B.08.qX.Y.Z.930 MYC H2009.08.qX.Y.Z.930 Undisclosed SFRP1 HFDP.08.pX.Y.Z.644 Disease(s) Liver Regeneration Corneal Regeneration ARDS / COVID-19 Idiopathic Pulmonary Fibrosis Hepatocellular Carcinoma Non-Small Cell Lung Cancer Small Cell Lung Cancer Alopecia By Mid-2022 Declaration of 2-3 New Development Candidates OEC OTX-2002 2021 Discovery IND-Enabling Studies Preclinical 1H 2022 IND Filing in MYC HCC Phase 1 Clinical Phase 2 Phase 3 2H 2022 | Early 2023 Additional IND Filing Route of Administration (top to bottom): IV (Liver Regeneration). Topical (Corneal Regeneration), IV/Pulmonary (ARDS/COVID-19), IV/Pulmonary (IPF), IV (HCC), IV (NSCLC), IV (SCLC), Topical (Alopecia) 15#16Our Data © 2021 Omega Therapeutics, Inc.#17Specificity Highly specific targeting of EpiZips within IGDs and disease-specific cellular modulation with OECS Significance (log scale) 2 Ⓒ2021 Omega Therapeutics, Inc. 5 6 Highly specific targeting of EpiZip using OEC Chromosomes 10 11 12 13 14 15 16 17 HEK293.17.pX.Y.Z.817 -23,000 CTCF sites at natural level of flux remained untouched by Controller 19 20 21 22 -Targeted single CTCF binding of an IGD on chromosome 17 18 17#18Tunability and Durability Effect on master regulators and durable modulation of target gene expression Tunability Bi-directional effects on a master regulatory gene in human cells % Relative expression to Control EpiZip: HEP.20.qX.Y.Z.552 400- 300- 200- 100- -100- Ⓒ2021 Omega Therapeutics, Inc. Controller A Controller B 6 mRNA fold change normalized to - ve control d Durability Durable modulation of gene expression over days, weeks and months EpiZip: H3B.08.qX.Y.Z.930 Days Negative control Lead controller mRNA fold change normalized to - ve control 0.8- 0.6 0.4 0.0- EpiZip: K562.15.X.Y.Z.547 Weeks Negative control Lead contrailer 18#19In vitro Specificity Data in Oncology Program - HCC Targeting specific EpiZip within diseased IGD enables selective cellular modulation in cancer cells; lack of modulation in normal primary cells % Untreated 120 100- 80 60- 40 20- 0 OECS targets Epizip to downregulate MYC expression Negative control Ⓒ2021 Omega Therapeutics, Inc. Cancer cells MYC expression is dysregulated Cell Viability 0.5ug/mL 1ug/mL ➡2ug/mL OEC % Untreated 120- 100- 80- 60 40 20- 0 Lowered MYC protein primes cells to undergo apoptosis Negative control Normal cells MYC expression is properly regulated OEC 0.5ug/mL 1ug/mL 2ug/mL 19#20In vivo PoC Data in Oncology Program - HCC Statistically significant reduction of tumor growth after 2 or 3 IV treatments every five days with OEC candidate in HCC xenograft tumor model (Hep3B) Tumor Volume (mm³) 1000- 800- 600- 400- 200- Negative Control OEC Candidate Small molecule comparator Ⓒ2021 Omega Therapeutics, Inc. 5 Day HHHH H*HH 10 % Body Weight Change from Baseline 20- 10- 10- -10- -20+ 10 I Negative Control OEC Candidate Small molecule comparator *Statistically significant vs negative control, t-test p<0.05 starting on day 6 Arrows denote dosing days 5 Day 10 20#21In vivo PoC Data in Oncology Program - HCC Inhibition of tumor growth after IV treatment every five days with OEC candidate in HCC orthotopic liver tumor model (Hep3B) % Change in luminescence 30000 20000 10000- 0 Negative control OEC Candidate Sorafinib Ⓒ2021 Omega Therapeutics, Inc. 10 Day 15 W 20 ** Not statistically different % Body Weight Change from Baseline ន 10- Negative control OEC Candidate Sorafenib** Statistically significant vs negative control, t-test p<0.05 Sorafenib administered 50 mg/kg po, once daily Arrows denote dosing days L 10 Day 15 H 20 21#22Mouse 1 In vivo MoA in Oncology Program - HCC Program HCC tumors from xenograft model treated with OEC candidate effected regulation of MYC(↓), Ki67(↓) and Caspase-3 (1) Mouse 2 MYC OEC candidate treated Caspase 3 ©2021 Omega Therapeutics, Inc. Ki67 Mouse 3 Mouse 4 Protein present MYC Negative control Caspase 3 Ki67 22#23In vivo poC Data in Oncology Program - NSCLC Statistically significant reduction of tumor growth after IV treatment every five days with OEC candidate in NSCLC xenograft tumor model (H2009) Tumor volume (mm³) 1200- 1000- 800- 600- 400- 200- Negative control OEC candidate Cisplatin Ⓒ2021 Omega Therapeutics, Inc. 10 Day HAHA 20 *HHHH HHH 20 10- P -10- % Body Weight Change from Baseline -20- *OEC candidate, t-test p<0.005; compared to negative control Arrows denote dosing days 10 ↑ Day 20 Negative control OEC candidate Cisplatin 23#24In vivo POC Data in Regenerative Medicine Program - HNF4A Improvement in liver histology after IV treatment with 1 or 2 weekly doses of OEC candidate in murine model of fibrosis (CCl4-induced) 1 dose (with continued CC14) 2 doses (with continued CCIA) Ⓒ2021 Omega Therapeutics, Inc. Treated Normal CCIA Controls 24#25In vivo Control of Master Regulator Translation across species demonstrated for OEC candidate in healthy liver tissues through increase in HNF4a expression Species Liver Cells Relative expression (%) 500- 400- 300- 200 100- Ⓒ2021 Omega Therapeutics, Inc. Mouse Mouse (48h) Negative control 4 OEC Candidate Relative expression (%) 250- 200- 150- 100- 50- Nonhuman primate Nonhuman primate (24h) Negative control *Significant, paired 1-test p<0.05 OEC Candidate Relative expression (%) 150- 100- 50- FRG Mouse Human (24h) Negative control OEC Candidate 25#26In vivo PoC in Complex Multi-genic Disease Program - ARDS Systemic administration of OEC candidate in lung-targeting LNP significantly decreased neutrophil infiltration in inflamed lung OEC candidate reduced infiltration of inflammatory mediators in lung (72h) 8x105. Neutrophils cells/mL BALF 6x105- 4x105- 2x105- 0 Normal Disease control OEC Dexamethasone Ⓒ2021 Omega Therapeutics, Inc. OEC candidate significantly different compared to disease control, Mann Whitney ● OEC candidate administration prior (-2h) to challenge and at peak of inflammation (8h) Significantly decreased neutrophil infiltration in bronchioalveolar lavage (BALF) at 72 hrs 26#27Ex vivo PoC in Monogenic Disease Program - Alopecia Downregulation of SFRP1 at 7 days post-treatment in primary human hair follicle dermal papilla (HFDP) cells %Change in expression 150 100 50 Untreated Negative control Controller 1 Controller 2 *Hawkshaw et. al. 2018 PLOS Biology 16(5): e2003705. © 2021 Omega Therapeutics, Inc. Therapeutic threshold* Controller 3 SFRP1 regulates intrafollicular canonical Wnt/ß-catenin activity in the human hair bulb Inhibiting SFRP1 activity has the potential to enhance hair shaft production, hair shaft keratin expression 27#28OMEGA THERAPEUTICS Promoter Enhancer Repressor ©2021 Omega Therapeutica DEC DNA Gene CTCF IGD TM Omega has developed pioneering science that has the potential fidents and proprietary#29Corporate Summary © 2021 Omega Therapeutics, Inc.#30Corporate Overview -$200M+ Gross proceeds raised since company formation in 2017 -$130M Cash and cash equivalents (as at 3/31/21) At least 12 months Expected cash runway based on current clinical plans, including base deal IPO proceeds ~100+ Patent applications filed to date across the OMEGA platform © 2021 Omega Therapeutics, Inc. Premier Life Science Syndicate Partners Capital from Flagship Pioneering, Joined by Invus, Fidelity Management & Research Company, Funds and Accounts Managed by BlackRock, Cowen, and Others Flagship Pioneering COWEN LIFESCI VENTURE PARTNERS LOGOS CAPITAL NIM Monashee MIRAE ASSET INVESTMENT MANAGEMENT SPHERA octagon TERRA MAGNUM INVUS II IRVING INVESTORS Point 72 Omega has completed three successful private financing rounds with leadership and participation by well-known life sciences investors and strategic partners 30#31Investment Summary a ©2021 Omega Therapeutics, Inc Programmable mRNA therapeutics delivered by LNPs to specific cells and tissues It G ng DO Pioneering biology to precisely modulate gene expression by targeting IGDS without nucleic acid sequence changes Historically undruggable target cMYC as only the first of many Robust pre-clinical in-vivo data across multiple high-value uniquely addressable targets Over $200M raised with a diversified, world-class investor syndicate World class team focused on building an iconic company 31#32Thank you. Ⓒ2021 Omega Therapeutics, Inc.#33Engineered, Customized Drug Delivery Omega's LNP technology and formulations expertise enables selective functional delivery of OECs to liver, lung, brain, joints and tumors ©2021 Omega Therapeutics, Inc. Systemic Systemic Local (joint) Local (intrathecal) Lung Liver Joint Brain Lung- Tumor SubQ Tumor Systemic Systemic 33