Once feared for potentially harmful cardiovascular effects, Avanir Pharmaceuticals Inc.’s Nuedexta has become the first drug to gain FDA approval for treatment of the involuntary emotional disorder “pseudobulbar affect,” with no black box warning.

The company announced the approval of Nuedexta, which combines two known ingredients, Oct. 29. One half of the combo is dextromethorphan, an NMDA receptor antagonist and a sigma-1 receptor agonist that inhibits glutamate neurotransmission. The other component is the metabolic inhibitor quinidine, which helps increase bioavailability of dextromethorphan.

Patients with pseudobulbar affect, also known as emotional lability or emotional incontinence, suffer sudden, unpredictable episodes of crying, laughing and/or other displays. The condition is linked to neurological disorders such as multiple sclerosis and amyotrophic lateral sclerosis. It is also thought to be a common co-morbidity in many other neurological disorders including traumatic brain injury and stroke. The label does not restrict use to particular diseases and the company is planning to cast its sales net very widely.

Approval had been a long time coming seeing as the first filing for the combination had been submitted in 2005. The company is aiming to launch the treatment during the first quarter of 2011.

Finding The Winning Combination

Formerly called Zenvia and Neurodex, the drug had been battling for years to get approval, but safety signals stood in the way.

The company had initially tested a 30 mg dose of dextromethorphan with a 30 mg dose of quinidine. But concerns arose about dose-dependent prolongation of the QT interval, which is linked to a rare and life-threatening arrhythmia called torsades de pointes. After discussions with FDA, the company tested two combinations with lower doses (20 mg dextromethorphan/10 mg quinidine and 30 mg dextromethorphan/10 mg quinidine) to improve the safety profile ([A#14070228007]).

FDA cleared Nuedexta with the lowest dosing combination studied – 20 mg dextromethorphan and 10 mg of quinidine.

Avanir may submit a supplemental NDA for a higher dose down the line.

Both of the lower combinations achieved primary endpoint of reduction in emotional lability and secondary endpoint of reduction in the CNS lability scale, with a similar magnitude of clinical effect (Also see "Avanir's Struggle Was Worth It: Reformulated Zenvia Succeeds In Confirmatory Phase III" - Pink Sheet, 11 August, 2009.).

The adverse events were a little bit higher for the 30/10 combination in terms of dizziness – probably the main reason the agency cleared the 20/10 combination alone, explained Randall Kaye, chief medical officer, said during a Nov. 1 investors’ call.

The company said it still believes the 30/10 dosing might offer additional benefits and may pursue a supplemental NDA for this dose combination down the line. But market research suggests that doctors would have a tough time distinguishing between the two combinations and having one dosing option is simpler.

Many Warnings, But No Black Box

In the end, the agency did not require a risk evaluation and mitigation strategy, did not require mandatory safety monitoring except in patients with underlying cardiac risk factors, and did not impose a boxed warning, Kaye said.

“Our thanks go to the many dedicated professionals at the FDA, who worked so diligently over the many years on this program with us and spent untold hours after our NDA and Complete Response Submissions to ensure that they would meet this PDUFA date,” Kaye said.

The label does include extensive warnings about cardiovascular risks, hypersensitivity reactions, dizziness, drug-drug interactions, and serotonin syndrome if used on top of antidepressants.

“Safety considerations are clearly described, well-characterized, and we believe are manageable,” Kaye said.

The label allows any patient with PBA to be a candidate for Nuedexta, regardless of underlying neurologic disease or injury, executives noted during the call.

“Our goal is to ensure that clinicians make the correct diagnosis of PBA and that irrespective of underlying neurologic disease or injury that they are aware that there is now the first and only approved FDA treatment for PBA,” said CEO Keith Katkin.

However, the label makes it clear that while emotional lability is common in a range of disorders, such as Alzheimer’s and other dementias, the drug has only been proven safe and effective in randomized trials for patients with ALS and MS. Efficacy in ALS and MS was demonstrated in the 326-patient Phase III STAR study.

The label points out that patients with underlying neurologic diseases other than ALS and MS may experience other adverse reactions not described in the prescribing information.

While the label specifically highlights the effectiveness of the drug in multiple sclerosis and ALS patients, off-label usage in a broader patient pool is likely, say some analysts.

The lack of restrictions on patient population and no black box warning bode well, in the view of Jefferies International analyst Andrew Fein.

“While the label specifically highlights the effectiveness of the drug in multiple sclerosis and ALS patients, we believe off-label usage in a broader patient pool is likely,” he wrote.

Avanir has not set a price yet for Nuedexta but did indicate a range of $3,000 to $5,000 per year. Jefferies is projecting sales of $255 million in 2013.

Casting A Wide Sales Net

The company had cash and cash equivalents of $39.4 million at the end of its fiscal year in September 2010, and said it has enough funds for the initial launch of Nuedexta in early 2011.

Prior to the approval, Avanir had already been actively recruiting a sales force of 75 reps. Seven professionals have already been hired and another 68 have accepted conditional offers of employment.

At launch, the sales force is going to cast a very wide net to reach different specialists treating the various disorders linked with involuntary emotional expression. This would include neurologists, geriatric psychiatrists, geriatricians, and physical medicine and rehabilitation specialists.

Each sales rep will be given a target list of 200 physicians, reaching a total of 15,000 physicians across the U.S.

Avanir plans to promote the treatment at upcoming medical conferences and to work with patient advocacy groups to increase awareness of emotional liability.

Execs also said that getting the drug approved outside the U.S. will be an important strategic focus in the next year. For example, it plans to consult with the European Medicines Agency, though Katkin acknowledged it may need more data beyond the trials used to support the U.S. application to get cleared in Europe.

“Certainly, before approval there were a number of companies that were contacting us, interested in both U.S. and ex-U.S. partnerships,” Katkin said. “So it is our expectation that, given the great news on Friday, we would just expect to see that interest increase.”

By Emily Hayes

The Winning Combination: Avanir’s Nuedexta Finally Cleared For Emotional Incontinence

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