Investigational Agent Vatiquinone Fails to Establish Efficacy in Mitochondrial Disease Associated Seizures


While results of the study do not support the advancement of vatiquinone for the treatment of mitochondrial disease associated seizures, PTC Therapeutics continues to plan to advance the agent in Friedreich ataxia.

Matthew Klein, chief executive officer of PTC Therapeutics

Matthew Klein

According to a recent announcement from PTC Therapeutics, the drug makers of vatiquinone, the agent failed to achieve its primary end point of reduction in observable motor seizures in a placebo-controlled study of pediatric patients with genetically confirmed mitochondrial disease and associated refractory seizures (MDAS). The company still plans to discuss how to proceed with the agent as a potential treatment for Friedreich ataxia (FA).1

The parallel-arm, double-blind, placebo-controlled study comprised of 68 individuals with MDAS, with the primary end point of reduction in observable motor seizures over a 24-week placebo-controlled phase. While the trial failed to meet its primary end point, investigators did observe overall reductions in seizure frequency, with the largest changes seen in a subgroup of children with Leigh syndrome, in whom benefit was also observed in the key secondary end points of occurrence of status epilepticus and disease-related hospitalizations.

"We are incredibly grateful to the patients, their families and our investigators who participated in this important study,” Matthew Klein, chief executive officer of PTC Therapeutics, said in a statement.1 “While we are disappointed with the results of the study, we hope that there are learnings that can benefit the development of other therapies for patients with mitochondrial disease, who remain without approved treatments for this highly morbid and fatal set of diseases."

In the trial, patients received 15 mg/kg of vatiquinone orally if body weight was less than 13 kg, and 200 mg if body weight was greater than 13 kg, 3 times per day or up to 72 weeks. The study was comprised of a 24-week double-blind phase, followed by an open-label phase of 48 weeks for individuals who completed the double-blind phase. Those included had genetic confirmation of either inherited mitochondrial disease with associated epilepsy phenotype (Alpers/polymerase subunit gamma, Leigh syndrome, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), or other genetically confirmed mitochondrial disease secondary to mitochondrial mutations (Pontocerebellar hypoplasia type 6, nuclear DNA RARS2 mutation) or myoclonic epilepsy with ragged reg fibers (MERRF, mitochondrial DNA mitochondrially encoded tRNA lysine mutation).

READ MORE: AI Model SCORE-AI Shows Clinical Utility in Reading Abnormal EEGs, Distinguishing Seizure Types

Vatiquinone, an investigational agent, specifically targets 15-lipoxygenase, a regulator of key energetic and oxidative stress pathways. Most recently, in May of this year, the therapy failed to meet its primary end point in a phase 3 study (NCT04577352) study of patients with FA; however, it did show positive benefit on other key disease subscales and secondary end points.

Otherwise known as MOVE-FA, the randomized, placebo-controlled trial included 146 pediatric and adult individuals with FA, most of which were under 18 years of age. Over a 72-week period, treatment with vatiquinone resulted in a placebo-corrected change of 1.6 (P = .14) on Friedreich Ataxia Rating Scale (mFARS) score, the primary end point. Despite this, patients on the agent showed significant benefits in the bulbar and upright stability subscales (P = .044 and P = .021), considered reflective of key aspects of disease morbidity and predict loss of time to loss of ambulation.2

Prior to MOVE-FA, vatiquinone previously demonstrated a statistically significant effect on disease severity in a phase 2 trial (NCT01962363). The small-scale study, which featured 4 individuals with FA, showed that after 6 months of treatment, total FARS score improved by an average of 9%. While all subscales improved, bulbar and upper limb coordination subscales were most improved, by 80% and 53%, respectively. Mean improvements persisted at 18 months from baseline, although these findings were attenuated.3

1. PTC Therapeutics announces results from the MIT-E clinical trial of vatiquinone for the treatment of mitochondrial disease associated seizures. News release. June 29, 2023. Accessed July 11, 2023.
2. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. News release. May 23, 2023. Accessed July 11, 2023.
3. Sullivan K, Freeman M, Shaw J, et al. EPI-743 for Friedreichs ataxia patients with point mutations. Neurology. 2016;86(16 supplement).
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