Epigenetic Therapy Shows Signs of Efficacy in MYC-Expressing Solid Tumors

Omega Therapeutics has announced preliminary data from its phase 1/2 MYCHELANGELO-1 trial (NCT05497453) evaluating OTX-2002 that show specific, on-target genomic engagement and demonstrate proof-of-concept in changing the epigenetic state and downregulating expression of c-MYC in patients with hepatocellular carcinoma (HCC) and other solid tumors associated with the c-MYC (MYC) gene.¹

“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,” Mahesh Karande, president and chief executive officer, Omega Therapeutics, said in a statement.² “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.”

MYCHELANGELO-1 is a 2-part study, the first of which is assessing OTX-2002 as a monotherapy and the second of which will assess it as a combination therapy.1 So far, 4 patients have been treated in each of 2 dose level cohorts, receiving either 0.02 mg/kg or 0.05 mg/kg of OTX-2002 intravenously every 2 weeks.

OTX-2002 was generally well tolerated with no dose-limiting toxicities (DLTs) and the maximum tolerated dose was not reached. Most adverse events (AEs) were grade 1 or 2 (87%) and the most common treatment-related AEs were infusion-related reactions (26%); this finding was generally consistent with the known profile of other FDA-approved lipid nanoparticle (LNP)-delivered therapeutics.¹ There was 1 serious AE of aspartate aminotransferase elevation after the end of the DLT period with no clear cause which resolved within 4 days with minimal intervention and supportive care. There were no dose interruptions or modifications due to treatment-related AEs.

WATCH NOW: Thomas McCauley, PhD, on Treating Solid Tumors With Epigenomic Controllers

Pharmacokinetic analyses revealed that OTX-2002 was quickly cleared from systemic circulation and no accumulation was observed with repeat doses. Investigators observed low levels of immune response with no impact on pharmacokinetics and the pharmacokinetic profile of the LNP and mRNA components of the therapy were consistent between cohorts. So far, the first 2 doses are below the predicted dose range for activity based on preclinical modeling and the study is continuing dose escalation. Finally, investigators found that participants had on-target increases in cell-free DNA MYC methylation signal, which was persistent over the 2-week dosing cycle, and reductions in MYC mRNA levels in all patients.

OTX-2002, Omega’s lead mRNA therapy, is one of several Omega Epigenomic Controller (OEC) candidates in the company's pipeline. The company is also developing OTX-2101 for non-small cell lung cancer, which is currently in investigational new drug-enabling studies, and has other preclinical research programs targeting idiopathic pulmonary fibrosis, liver regeneration, corneal regeneration, SFRP1, and alopecia.

“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,” Thomas McCauley, PhD, chief scientific officer, Omega Therapeutics, said in a statement.² “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.”

REFERENCES

1. McCauley T. MYCHELANGELO™ I preliminary data overview. Presentation. September 26, 2023. https://ir.omegatherapeutics.com/static-files/19eca20b-260d-4f30-8a13-16b05a5cb26b
2. Omega Therapeutics announces promising preliminary clinical data for OTX-2002 from ongoing MYCHELANGELO™ I trial. News release. Omega Therapeutics. September 26, 2023. https://ir.omegatherapeutics.com/news-releases/news-release-details/omega-therapeutics-announces-promising-preliminary-clinical-data