OTX-2002 Shows Encouraging Safety in Small Hepatocellular Carcinoma Cohort

The FDA granted orphan drug designation to OTX-2002 for managing HCC in November 2022.

The investigational mRNA therapeutic OTX-2002 demonstrated encouraging safety, tolerability, and pharmacokinetics in a small population of patients with hepatocellular carcinoma (HCC) and other solid tumors related to the c-MYC (MYC) oncogene, according to a press release on findings from the phase 1/2 MYCHELANGELO I trial (NCT05497453).¹

Investigators reported highly specific on-target engagement and epigenetic changes among all 8 patients receiving 0.02 mg/kg (n = 4) or 0.05 mg/kg of OTX-2002 (n = 4) every 2 weeks. The agent’s modulation of MYC rapidly and durably downregulated MYC oncogene expression in all 8 patients; investigators highlighted a mean reduction of 55% at 7 days following treatment.

Treatment with OTX-2002 also produced consistent pharmacokinetic data at both dosing levels, as investigators observed little variability and quick clearance within patients. Additionally, there was no accumulation after additional doses of OTX-2002, and the agent produced low and transient levels of immune response with no adverse effects (AEs) impacting pharmacokinetics. Investigators reported that both initial dose levels of the agent demonstrated anti-tumor activity below the predicted threshold established by preclinical models.

OTX-2002 was well tolerated among patients, and investigators observed no dose-limiting toxicities. Patients mostly experienced grade 1 or 2 AEs, the most common of which included infusion-related reactions (26%) such as fever and chills. These toxicities appeared to be comparable with the known profiles of other FDA-approved agents administered via lipid nanoparticles.

“We are thrilled to see that all 8 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 at Omega Therapeutics, said in the press release. “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.”

In the ongoing open-label MYCHELANGELO I trial, investigators are assessing the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of OTX-2002 on its own in part 1 and with standard-of-care treatments in part 2 among those with relapsed/refractory HCC and other solid tumor types associated with MYC oncogene expression. Investigators are conducting the trial at clinical sites in the United States and Asia. As of the data cutoff point of September 18, 2023, a single patient with HCC remained on treatment in the 0.05 mg/kg cohort.

The trial’s primary end points are dose-limiting toxicities, treatment-emergent AEs, overall response rate, and duration of response.

Patients 18 years and older with metastatic, advanced, or recurrent solid tumors that have progressed following standard-of-care therapy and intermediate or advanced stage, Child-Pugh A HCC not amenable to locoregional therapy or curative treatment approaches are able to enroll on the study. Having an ECOG performance status of 0 or 1 is another requirement for enrollment.

The FDA granted orphan drug designation to OTX-2002 for managing HCC in November 2022.²

“We look forward to continuing to work with clinical investigators, patients, and the FDA as we advance our MYCHELANGELO clinical program and evaluate the potential of OTX-2002 to bring a new treatment option to the community [of patients with liver cancer],” Mahesh Karande, president and chief executive officer at Omega Therapeutics, said in a press release at the time of the orphan drug designation.²

References

1. Omega Therapeutics announces promising preliminary clinical data for OTX-2002 from ongoing MYCHELANGELO™ I trial. News release. Omega Therapeutics. September 26, 2023. Accessed September 26, 2023. https://shorturl.at/hmqNZ
2. Omega Therapeutics receives orphan drug designation for OTX-2002 for the treatment of hepatocellular carcinoma. News release. Omega Therapeutics. November 2, 2022. Accessed September 26, 2023. http://bit.ly/3fqiafd