Avanir's Reformulated Zenvia Succeeds In Confirmatory Phase III

After battling back from a crippling FDA "approvable" letter for Zenvia , its investigational treatment for the sudden and unpredictable emotional outbursts that can accompany neurologic diseases, Avanir is buoyantly predicting a 2010 launch based on positive top-line data from the Phase III confirmatory study it conducted at the agency's behest.

"I hate to admit that FDA was probably right. You can see that we maintain significant efficacy, but we have an improved safety and tolerability profile, so on balance, we have a safer drug that's better tolerated … and quite frankly will likely be a greater commercial success," CEO Keith Katkin said during an Aug. 11 analyst call. "It's been a long road to get here, but we're very pleased with the outcome."

Zenvia (dextromethorphan/quindine) treats pseudobulbar affect, a neurologic disorder triggered by neruologic diseases, such as multiple sclerosis or amyotrophic lateral sclerosis, the two patient populations Avanir tapped for the 326-patient STAR study. Pseudobulbar affect, also known as emotional lability, involves sudden, unpredictable episodes of crying, laughing or other emotional displays. Zenvia would be the first approval for the indication.

The drug combines two older medications used for other indications. The therapeutically active ingredient is dextromethorphan, while the enzyme inhibitor quinidine increases dextromethorphan's bioavailability. Dextromethorphan is an NMDA receptor antagonist and a sigma-1 receptor agonist that works to inhibit glutamate neurotransmission.

FDA sent Avanir back to try a lower dose after it was put off by safety signals from the 30/30 mg combination used in the NDA package. The company tried a 30/10 combination and a 20/10 combination, compared against placebo, in STAR; the 20/10 combo fulfills an agency requirement that the company try a least-effective dose combination.

The randomized, 60-site study was conducted in the U.S. and Latin America. It enrolled 129 MS patients and 197 patients with ALS. The 12-week double blind phase is followed by a 12-week open label study, in which 253 patients have opted to participate. It is being conducted under a special protocol assessment with FDA.

Both combinations produced a statistically significant reduction in episode rates over the course of the study (p<0.0001), cutting the number of episodes experienced by patients by as much as 88 percent, down from an average of 30 episodes per week to five per week, a result that is clinically "quite significant," the company's Chief Medical Officer Randall Kaye said. Reduction in PBA episodes from baseline was the primary endpoint in the study.

But FDA's objection was to the drug's safety profile, not its efficacy, and the new data should put those concerns to rest, Kaye said.

In STAR, which was conducted under a SPA, both doses of Zenvia demonstrated a satisfactory cardiovascular safety profile with no clinically meaningful changes in QT interval, no reported pro-arrhythmic events and no reports of cardiovascular serious adverse events. In addition, Zenvia 30/10 had no difference in adverse events from placebo, particularly in falls, headache and fatigue, all areas of FDA focus, Kaye said.

Data from an ongoing open label continuation study will be available toward the end of the year, setting up a filing in the first half of 2010 and an action date in the second half, Katkin said. "We do believe that there's a very large market opportunity - no direct competition and a significant unmet medical need."

After the approvable letter, the company ceased its commercialization build-up and retrenched, cutting its workforce and eventually closing its San Diego facility and ending collaborations with AstraZeneca and Novartis, which assumed research and development activities on Avanir's macrophage Migration Inhibitory Factor program for inflammatory diseases (¹ (Also see "Avanir Restructures After Ending Deals With Novartis, AstraZeneca" - Pink Sheet, 29 Mar, 2007.)).

In July 2007, Avanir sold off one of its two marketed products, FazaClo , an orally disintegrating formulation of clozapine, to Azur Pharma for $42 million upfront, plus another $10 million in contingency payments due in 2009 and royalties (² (Also see "Avanir Divests FazaClo To Azur Pharma To Fund Zenvia Studies" - Pink Sheet, 3 Jul, 2007.)). The other, the over-the-counter cold sore remedy Abreva , is marketed by GlaxoSmithKline.

In 2008, publicly traded Avanir turned to a private investment in public equity (PIPE) financing for operating capital. In April of that year, the Aliso Viejo, Calif., biotech closed a sale of $40 million of common stock and warrants to a group of institutional investors led by ProQuest Investments and joined by Clarus, Vivo and OrbiMed Advisors (³ (Also see "Cash Constraints Force Industry To Retool Its Opinion Of PIPEs" - Pink Sheet, 20 Nov, 2008.)).

In its July 29 quarterly earnings report, Avanir said that as of June 30 it had cash and investments in securities totaling $26.6 million, including cash and cash equivalents of $26.1 million and restricted investments in securities of $468,000.

Avanir's stock closed at $2.84, up 29.68 percent over $2.19 the day before. The stock's value had dropped to as low as 23 cents earlier in the year triggering a de-listing notice from NASDAQ, which the company overcame in June.

Zenvia, once known as Neurodex , has traveled a rocky regulatory path. Avanir resubmitted the NDA in January 2006 after FDA asked the firm to reformat the electronic application it had submitted in June 2005 as the completion of a rolling NDA. It once had a June 2006 action date, but FDA extended its review 90 days after the company submitted data from a QT study, then issued the "approvable" letter in October (⁴ (Also see "Avanir’s Zenvia Set Back Two Years, But Path Forward Is Established With FDA" - Pink Sheet, 28 Feb, 2007.)).

Avanir also is studying Zenvia in diabetic neuropathic pain, but the Phase III trial it completed in 2007 used the controversial 30/30 mg dose, and the company plans to work with FDA on an SPA testing the reformulated drug in DPN (⁵ (Also see "Avanir Reports Positive Phase III Results For Zenvia In Diabetic Neuropathic Pain" - Pink Sheet, 18 Apr, 2007.)).

- Shirley Haley ( ⁶ [email protected] )