Chimerix, a biopharmaceutical company committed to enhancing and extending the lives of patients grappling with severe diseases, has unveiled significant findings endorsing its pioneering small molecule, ONC201, in the treatment of H3 K27M-mutant diffuse midline gliomas (H3K27M-DMG). This groundbreaking research, featured in the esteemed peer-reviewed journal Cancer Discovery by the American Association for Cancer Research, sheds light on the potential of ONC201 as a transformative therapeutic solution.
In the manuscript titled “Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways,” the study probes the survival rates of 71 patients afflicted by H3 K27M-DMG who were administered ONC201. Impressively, this treatment exhibited promising outcomes within a patient group often facing limited options and a challenging prognosis. Beyond assessing clinical responses, the investigation aligns laboratory findings with results from treated patients, establishing ONC201’s capacity to dismantle metabolic pathways and reverse the epigenetic repercussions linked to the H3 K27M mutation.
“The survival analyses published today in Cancer Discovery reported that ONC201 frontline treatment, administered post radiation therapy, demonstrated a statistically significant increase in mOS from diagnosis versus historical controls (21.7 months mOS vs. 12 months mOS, p<0.0001). These data are particularly relevant given that enrollment in the ongoing ACTION study occurs in a similar population. Additionally, these data further elucidate the underlying novel mechanism of action for ONC201 in a patient population which has very limited treatment options. 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 and offer hope to the patients, families and caregivers facing this challenging and life-threatening cancer.”
– Mike Andriole, Chief Executive Officer of Chimerix
“H3K27M-DMG represents one of the most difficult tumors to treat. 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.”
– Carl Koschmann, M.D., Associate Professor of Pediatric Neuro-Oncology and Clinical Scientific Director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine
Patients stricken by H3K27M-mutant diffuse midline glioma (DMG) are currently bereft of effective therapies. ONC201, however, has recently displayed efficacy in these cases, though the underlying mechanism remained elusive. The study delved into clinical outcomes, genetic profiling of tumors, and correlated samples from multi-site clinical trials. Those administered ONC201 post initial radiation but pre-recurrence showcased a notable median overall survival of 21.7 months. Meanwhile, individuals treated after recurrence recorded a median overall survival of 9.3 months. Encouragingly, a radiographic response correlated with heightened expression of pivotal genes associated with the tricarboxylic acid cycle, as identified in the baseline tumor sequencing.
Further investigations demonstrated that ONC201 treatment led to elevated 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient cerebrospinal fluid samples. This coincided with an increase in repressive H3K27me3 both in vitro and within human tumors. This epigenetic modulation correlated with the downregulation of genes involved in cell cycle control and neuro-glial differentiation. Collectively, the study underscores ONC201’s potential in tackling H3K27M-DMG by disrupting intertwined metabolic and epigenetic pathways, ultimately reversing the telltale reduction in H3K27me3.
These findings illuminate a promising avenue for addressing a critical medical need, offering renewed hope for patients and paving the way for novel treatment strategies in the realm of oncology.
