West Coast Editor
Having previously netted positive results with Neurodex against pseudobulbar affect in patients with amyotrophic lateral sclerosis (ALS), Avanir Pharmaceuticals Inc. finished a Phase III trial in patients with multiple sclerosis who are troubled by the same complex of added symptoms.
If the data, when analyzed, back up the numbers gained earlier, they will be made part of the new drug application.
"Hopefully this trial will come out the way we want and we'll be able to make the submission by the end of this year," said Gerald Yakatan, president and CEO of San Diego-based Avanir.
The company's stock (AMEX:AVN) closed Wednesday at $1.68, up 1 cent.
Pseudobulbar affect, or PBA, is characterized by uncontrollable laughing and crying, and afflicts about 1 million patients with ALS, multiple sclerosis, Alzheimer's disease, stroke and traumatic brain injury.
Neurodex is an oral combination of dextromethorphan (DM) - long known to lessen the cough reflex and apparently effective against PBA (it's an active ingredient in Robitussin DM) - with the enzyme inhibitor quinidine sulfate, which sustains elevated levels of DM in the body.
"What makes this project so interesting is that even [DM as a cough suppressant] is only marginally effective," Yakatan said, since about 90 percent of the population falls into the "fast-metabolizer" category. "You have a hard time getting significant blood levels and therefore getting the drug to the brain, where it has to get to work," he said.
Quinidine sulfate fixes that.
"This is a kind of unique biological delivery system, where we make that 90 percent of the population into slow metabolizers," Yakatan told BioWorld Today. "Now you get 20-fold higher blood levels from the same dose, and the drug lasts a lot longer." Patients in the MS trial were given Neurodex or placebo on a 12-hour dosing schedule for 90 days. The just-completed study, done by a contract research organization, likely will yield data in about eight weeks, Yakatan said.
To determine suitability, patients were evaluated for PBA by clinical observation and a diagnostic tool called the Center for Neurologic Study Lability Scale, which measures frequency and severity of PBA episodes. The primary endpoint of the study is a comparison in the mean improvement in scores between patients treated with Neurodex and placebo.
Other endpoints in the study compared the number of PBA episodes, the improvement in quality of life, the improvement in quality of relationships and changes in pain intensity.
"For patients afflicted with it, [PBA] is pretty devastating," Yakatan said. They may be able to survive for years with their primary disease, but the social discomfort of inappropriate laughter or crying can make daily life hard.
In 2002, Neurodex proved statistical significance in a Phase III trial in 140 ALS patients with PBA, while the double-blind, placebo-controlled MS trial enrolled 150 at multiple centers. (See BioWorld Today, Nov. 20, 2002.)
The MS trial followed the ALS trial as a result of talks with U.S. regulators, Yakatan said.
"The FDA told us that if we did just ALS, we'd be getting a lot of off-label uses," he said. "The compromise was, Study two and we'll give you the broad label across all neuronal-injury diseases.'"
Neurodex has just finished a Phase II trial in neuropathic pain, and Avanir will work closely with the FDA to come up with a protocol for Phase III.
"There have been some [drugs for the indication] that failed in Phase III, even some that I think probably work, and it may have had to do with design of the study," Yakatan said.
While he didn't mention any drug by name, one failure still fresh in the minds of many is memantine, which blew up in Phase III a little over one year ago. Memantine failed in a pivotal study designed to test the drug for neuropathic pain in diabetic patients, and Richmond, Calif.-based Neurobiological Technologies Inc. lost more than 50 percent of its value that day. The drug, an orally active N-methyl-D-aspartate (NMDA) antagonist, is partnered with Forest Laboratories Inc., of New York, and in October won approval under the brand name Namenda for Alzheimer's disease. (See BioWorld Today, May 8, 2003, and Oct. 20, 2003.)
After completing analysis of the Phase III pain trial, Forest said it would continue to study memantine for the indication, since some positive results were noted. Neuropathic pain generally is a higher-profile problem than PBA, but the field is more crowded, Yakatan noted.
"When we enter [the PBA] market, it might be worth $500 million in the U.S.," he said. "Go to neuropathic pain and you may be in a $2 billion to $3 billion market, but you've got quite a bit of competition."
Avanir holds an exclusive license to develop, manufacture and market Neurodex for PBA and neuropathic pain, as well as for the weaning of drug-dependent patients from narcotics and antidepressants. A fourth indication covered by the license is chronic cough, but Avanir has no near-term plan to take on the likes of Robitussin.
"There hasn't been a new prescription cough medicine in forever, and, as a small company, we have to focus," Yakatan said.