By Matt Olszewski
Pictured: Adult holding child's hand/gorodenkoff/iStock

Biopharma company Chimerix announced Wednesday positive results from two early-stage clinical trials for its first in-class small molecule imipridone, a potential treatment for an incurable and aggressive type of pediatric brain tumor which demonstrated longer survival in this subset of patients.
The data, published Wednesday in the journal Cancer Discovery, showed that Chimerix’s ONC201 nearly doubled survival for patients with H3K27M-mutated diffuse midline gliomas (DMG), as compared to previous patients.
Diffuse midline gliomas with the H3K27M mutation are aggressive, with a survival rate of 11 months to 15 months. However, the median overall survival was nearly 22 months for tumors that had not recurred at the time of enrollment in the trial. In addition, almost a third of those patients lived longer than two years.
“These data further elucidate the underlying novel mechanism of action for ONC201 in a patient population which has very limited treatment options,” Chimerix CEO Mike Andriole said in a statement. “While these results require validation in prospectively designed studies, such as the Phase III ACTION study, they nevertheless provide ongoing confidence and rationale for ONC201’s monotherapy treatment effect.”
According to Chimerix, the Phase III ACTION trial is actively recruiting patients in 11 countries and will enroll 450 patients shortly after completion of front-line radiation therapy—the standard of care—who will receive ONC201 at one of two dosing frequencies or placebo.
H3K27M-DMG tumors are typically found in children and young adults and the only available treatment is radiation. However, these tumors are in critical regions of the brain which makes treatment challenging.
“H3K27M-DMG represents one of the most difficult tumors to treat,” co-author Carl Koschmann, clinical scientific director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine, said in a statement. “Prior to this study, there have been more than 250 clinical trials that have not been able to improve outcomes. These results are potentially a major crack in the armor.”
Although efficacy has been demonstrated in early-stage trials, the mechanism behind the drug candidate is still unclear.
ONC201 was originally intended to target dopamine receptors, but researchers noticed that this drug passes the blood-brain barrier–a critical challenge to overcome when developing drugs for brain tumor treatment.
The first few trials in glioblastoma were unsuccessful, but some patients with DMG that carried the H3K27M mutation had more desirable results. Researchers decided to conduct a Phase I trial in children and young adults with this H3K27M-mutated DMG. At the same time, they aimed to learn more about what was occurring in these tumor cells. Cerebrospinal fluid was collected from specific patients. After further research, ONC201 was found in tumor cells and affected mitochondria.
Along with the survival analyses of 71 patients with H3 K27M-DMG who were treated with ONC201, the study supported mechanistic findings that showed the ability of the drug candidate to interrupt metabolic pathways and reverse the epigenetic consequence of the H3K27M mutation.
Other clinical trials are underway, including testing ONC201 simultaneously with other therapies. Researchers also hope to discover how to overcome resistance to ONC201 by using a variety of drug combinations.
“We are really excited about this study and envision ONC201 becoming standard of care for these patients in the near future,” co-author Sriram Venneti, scientific research director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine, said in a statement.