Chimerix Sees Promise to Treat Brain Tumors With Imipridone Platform
By Alex Keown
May 11, 2023
Chimerix Inc. is highly confident in the outcomes of the Phase III ACTION study assessing its lead imipridone asset ONC201 in patients with H3 K27M-mutant glioma.
The Durham-based company’s prediction is backed by positive Phase II data shared at the American Association for Cancer Research Annual Meeting in March. That data showed ONC201 (dordaviprone) is able to reverse the H3 K27M mutation, the epigenetic signature of the disease. Such a reversal is believed to result in significant antitumor effects and prolongation of survival in these patients, Chimerix Chief Executive Officer Mike Sherman said during a quarterly earnings call. He added this is the first known instance of any therapy reversing the H3 K27 trimethyl loss typically seen in H3 K27M-mutant glioma patients.
“This is a characteristic, which you may know has been linked to tumor growth and poor prognosis. So on top of the durable tumor responses observed in the Phase II data set, the overall survival advantage reported by multiple nonrandomized analysis of patients treated with ON201 compared to all others. This provides additional confidence in the outcome of the (Phase III) ACTION trial,” Sherman said.
Joshua Allen, chief technology officer at Chimerix said the data presented at AACE “bolsters our confidence” in the probability of success in the Phase III ACTION Study.
“These findings suggest both in lab models and in patients’ tumors that ONC201 reverses would have thought to be the H3K27M mutations pathogenic hallmark… said another way, the H3K27M mutation found in tumors caused global loss of H3K27 trimethylation to drive oncogenic gene expression,” he said during the call. “This new finding demonstrates a reversal of the direct consequence of the mutation as a whole new mechanistic layer and gives us additional confidence in the potential utility of ONC201 in the ACTION study patient population.
Allen added that the reversal of the H3K27 trimethyl loss seen in patients treated with ONC201 was “consistent, persistent, and pervasive” across patients in their tumors.
Key results demonstrated that H3 K27M-mutant glioma patients treated with ONC201 experienced a statistically significant reversal of the H3 K27me3-loss epigenetic signature throughout their tumor compared to patients who were not on the Chimerix-developed drug candidate. The company noted that consistent findings were also reported in preclinical models that were “mechanistically linked to specific metabolic changes induced in tumors by ONC201.”
Additional ONC201 pharmacological data compiled by Chimerix combined with the clinical data will support a potential New Drug Application upon the completion of the ACTION study, pending positive results, Sherman said.
ONC201 is the first member of Chimerix’s imipridone class of anti-cancer small molecules which selectively targets Dopamine Receptor D2 (DRD2) and ClpP. In addition to ONC201, Chimerix is also developing ONC206, a second generation imipridone that has demonstrated anti-cancer activity in pre-clinical models of various central nervous system (CNS) tumors and other malignancies. ONC206 is a ClpP agonist and DRD2 antagonist that has enhanced in vitro potency relative to ONC201. ONC206 is currently being evaluated in Phase I dose escalation clinical trials for adults with recurrent primary central nervous system tumors.
Sherman said the company is making “good progress” in advancing the Phase 1 dose escalation studies for ONC206. He expressed hope that company researchers will be able to identify additional signals of activity later this year ahead of the completion of dose-escalation, which is expected to be completed in the first half of 2024. In March, the company reported an investigator-assessed response that emerged during dose escalation. The responder is a patient with recurrent glioblastoma without the H3K27M-mutation who received ONC206 as a monotherapy treatment. Sherman said this signals the potential for this drug candidate in a patient population nearly six-times as large as the H3K27M glioma indication.
- About the Author
- Latest Posts
Alex Keown is a freelance journalist who writes about a variety of subjects including the pharma, biotech, and life science industries. Prior to freelancing, Alex has served as a staff writer and editor for several publications.
