All 8 patients treated with OTX-2002 in initial two cohorts achieved highly specific on-target genomic engagement, intended epigenetic state change and robust downregulation in expression of c-MYC, a historically ‘undruggable’ target

First-known clinical observation of pre-transcriptional gene modulation using a programmable epigenomic mRNA candidate

Clinical proof-of-platform established; potential applicability across a broad range of diseases

CAMBRIDGE, MA, USA I September 26, 2023 I Omega Therapeutics, Inc. (Nasdaq: OMGA) (“Omega”), a clinical-stage biotechnology company pioneering the development of a new class of programmable epigenomic mRNA medicines, today announced encouraging preliminary safety, tolerability, pharmacokinetic and translational data from the initial two dose level cohorts (n=8) from Part 1 of its ongoing Phase 1/2 MYCHELANGELO™ I study evaluating OTX-2002 in patients with hepatocellular carcinoma (HCC) and other solid tumors associated with the c-MYC (MYC) gene. OTX-2002, the Company’s lead development candidate, is designed to pre-transcriptionally downregulate MYC, a master oncogene implicated in more than 50% of all cancers and approximately 70% of HCC cases.

“We believe these promising data represent a landmark moment for Omega that supports the potential of our approach and marks a new era of therapeutic development utilizing programmable mRNA candidates for controlled epigenomic modulation,” said Mahesh Karande, President and Chief Executive Officer of Omega Therapeutics. “For the first time ever in the clinical setting, we have site-specifically targeted and controllably modulated the expression of the MYC oncogene, one of the most promising targets in oncology that has proven difficult to successfully drug by other modalities. We are excited to continue advancing OTX-2002 as we aim to deliver a new class of medicines for patients in need.”

“We are thrilled to see that all eight patients evaluated at these initial low doses demonstrated clear evidence of on-target epigenetic changes and correlated rapid, robust and durable decreases in MYC mRNA expression levels,” added Thomas McCauley, Ph.D., Chief Scientific Officer of Omega Therapeutics. “These early clinical data are consistent with our preclinical experiments, giving us confidence that our approach has the potential to translate to anti-tumor activity and clinical benefit. Coupled with encouraging safety and predictable pharmacokinetics, we believe that OTX-2002 holds transformative potential for patients living with HCC.”

MYCHELANGELO I (NCT05497453) is an ongoing Phase 1/2 open label trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of OTX-2002 as a monotherapy (Part 1) and in combination with standard of care therapies (Part 2) in patients with relapsed or refractory HCC and other solid tumor types known for association with the MYC oncogene. These preliminary data cover the first two dose cohorts from the monotherapy dose escalation portion of the trial, which is currently being conducted at clinical sites across the United States and Asia. Patients were treated intravenously with either 0.02 mg/kg (n=4) or 0.05 mg/kg (n=4) of OTX-2002 once every two weeks. Changes in MYC DNA methylation and mRNA levels were analyzed through measurements of cell-free DNA and exosomal mRNA, respectively. As of the data cut-off date of September 18, 2023, one HCC patient in the 0.05 mg/kg dose level cohort remained on treatment.

Key Highlights:


  • Highly specific on-target engagement and intended epigenetic changes at the target genomic loci were observed for all eight patients across both dose levels, as evidenced by a robust increase in cell-free DNA MYC methylation signal following administration with OTX-2002. The increased methylation signal persisted throughout the two-week dosing interval.
  • Epigenetic modulation of MYC translated to rapid, robust and durable downregulation of MYC expression in all eight patients, with mean reductions across both dose levels of approximately 55% observed 7 days following administration with OTX-2002.
  • The increase in methylation and corresponding downregulation of MYC expression observed clinically are within the ranges that led to anti-tumor activity in preclinical xenograft models.


  • Consistent pharmacokinetic (PK) data across both dose levels with rapid clearance and minimal variability observed within and between patients.
  • No accumulation was observed following repeat administration, and low, transient levels of immune response were observed with no related adverse events or impact on PK observed.
  • Both initial dose levels are below the predicted threshold for anti-tumor activity based on preclinical models.

Safety and Tolerability:

  • At both dose levels, OTX-2002 was generally well tolerated, with no dose-limiting toxicities.
  • The majority of adverse events observed in the trial were grade 1 or 2.
  • The most common treatment-related adverse events were infusion-related reactions (26%) including fever and chills, generally consistent with the known profile of other FDA-approved LNP-delivered therapeutics.

Gerard Evan, Ph.D., Principal Group Leader of the Francis Crick Institute in London and Professor of Cancer Biology, King’s College London, added, “While MYC’s role and importance in cancer progression has been long established, no clinical approach to date has effectively controlled its expression directly at its source. These new data, while early, are incredibly promising and highlight the potential of programmable epigenomic mRNA therapeutics to provide a groundbreaking new strategy to pre-transcriptionally control gene regulation. If successful, this approach could be applied broadly to a vast range of MYC-driven cancers where immense patient need remains.”

Based on these encouraging data, OTX-2002 continues to advance in monotherapy dose escalation. Following the identification of a recommended dose, the Company expects to initiate expansion cohorts in monotherapy and in combination with standard of care therapies.

Company Investor Webcast and Conference Call

Omega will host a webcast and conference call for analysts and investors to review these data today, Tuesday, September 26, 2023, at 8:00 a.m. ET. The webcast will feature members of Omega’s leadership team along with guest speaker, Gerard Evan Ph.D., Principal Group Leader of the Francis Crick Institute in London and Professor of Cancer Biology, King’s College London. The live webcast can be accessed under “News & Events” on the investors section of Omega’s website at To participate in the live call, please register using this link. It is recommended that participants register at least 15 minutes in advance of the call. Once registered, participants will be informed of the dial-in numbers, including PIN. The archived webcast will be available on Omega’s website for approximately 90 days following the event.

About OTX-2002

OTX-2002 is an mRNA therapeutic delivered via lipid nanoparticles (LNPs) designed to downregulate MYC expression pre-transcriptionally through epigenetic modulation while potentially overcoming MYC autoregulation. MYC is a master transcription factor that regulates cell proliferation, differentiation and apoptosis and plays a significant role in more than 50% of all human cancers. OTX-2002 has demonstrated the ability to control MYC expression pre-transcriptionally in multiple preclinical studies, including the successful downregulation of MYC in non-human primates. Additionally, OTX-2002 has shown robust anti-tumor activity alone and in combination with standard of care therapies in vivo in multiple preclinical models of HCC. Currently, OTX-2002 is being evaluated as a potential treatment for HCC and other solid tumors associated with MYC. 

About Omega Therapeutics

Omega Therapeutics is a clinical-stage biotechnology company pioneering the development of a new class of programmable epigenomic mRNA medicines to treat or cure a broad range of diseases. By pre-transcriptionally modulating gene expression, Omega’s approach enables controlled epigenomic modulation of nearly all human genes, including historically undruggable and difficult-to-treat targets, without altering native nucleic acid sequences. Founded in 2017 by Flagship Pioneering following breakthrough research by world-renowned experts in the field of epigenetics, Omega is led by a seasoned and accomplished leadership team with a track record of innovation and operational excellence. The Company is committed to revolutionizing genomic medicine and has a diverse pipeline of therapeutic candidates derived from its OMEGA platform spanning oncology, regenerative medicine, multigenic diseases including immunology, and select monogenic diseases.

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SOURCE: Omega Therapeutics