Avanir Pharmaceuticals announced positive results in its pivotal Phase III clinical trial evaluating the safety and effectiveness of Neurodex in the treatment of pseudobulbar affect (PBA) in patients with multiple sclerosis (MS). In the double-blind study, 150 patients at 22 clinical sites were randomized to receive either placebo or Neurodex on a 12 hour dosing schedule for 90 days.
The Centre for Neurologic Study Lability Scale (CNS-LS), a validated instrument that assesses frequency and severity of PBA episodes, was utilized as the primary efficacy endpoint. A minimum CNS-LS score was required for inclusion in the study. For the primary endpoint, Neurodex patients had a statistically significant greater reduction in CNS-LS than those receiving placebo (p<0.0001). The four secondary endpoints evaluated in the trial were also statistically significant in favour of Neurodex: number of PBA episodes (p=0.0003); quality of life (p<0.0001); quality of relationships (p<0.0001); and pain reduction (p=0.026).
Overall, Neurodex was well tolerated in this patient population. The majority of reported side effects were mild or moderate. Of the side effects reported in 5 per cent or more of the patients, a statistically significant difference between Neurodex and placebo was observed only for dizziness. In the Neurodex group, 14.5 per cent of patients withdrew from therapy due to adverse events, compared to 12.3 per cent discontinuing in the placebo group, release from Avanir says.
"The robustness of the efficacy data in this trial with MS patients parallels the results obtained in our previous trial with ALS patients. The 90 day study time period validates the durability of the drug's effect in the treatment of PBA," said James E Berg, vice president of Clinical and Regulatory Affairs at Avanir. "Through the treatment of PBA we can eliminate or reduce patients' anxiety about controlling their emotions in social and business settings, thus improving their quality of life," he added.
Pseudobulbar affect is a symptom complex that is characterized by uncontrollable laughing or crying, and afflicts patients with neurological conditions such as ALS or Lou Gehrig's disease, Alzheimer's disease, MS, stroke and traumatic brain injury. Except for the addition of a pain endpoint, the primary and secondary efficacy endpoints used in the MS study were the same as those in the previous pivotal trial in which ALS was the underlying disease.
"Patients with PBA have no FDA-approved treatment option, and our pivotal trial results represent an important step forward in the treatment of these patients," said Avanir president and chief executive officer Gerald J Yakatan. He added, "The results of our two successfully completed Phase III trials will form the basis for the first new drug application seeking regulatory marketing approval for the treatment of PBA."
Neurodex is a patented, orally administered combination of dextromethorphan and an enzyme inhibitor, quinidine, which sustains elevated levels of dextromethorphan in the human body. Results of Phase I studies have demonstrated that the combination of dextromethorphan and a low dose of quinidine results in elevated and prolonged dextromethorphan blood levels (Clinical Pharmacology & Therapeutics, 1992; 51: 647-55; 1999; 39: 984). Dextromethorphan has activity as both a sigma-1 receptor agonist and an NMDA receptor antagonist.
Neurodex is the first drug product in clinical development specifically intended to treat PBA. The first Phase III trial of Neurodex for PBA in ALS patients was completed in June 2002. The double blind, controlled, multi-center clinical trial had three treatment arms and compared Neurodex to each of its two components, dextromethorphan and quinidine. With statistically significant data achieved in two patient populations, patients with ALS and patients with MS, Avanir intends to seek an indication to treat PBA associated with any neurological condition.