Ovation’s Sabril Visual Defect Is Topic Of FDA Meeting; Is End To Longest Review In Sight?

FDA’s Peripheral and Central Nervous System Drugs Advisory Committee will evaluate vigabatrin for two epilepsy indications at a meeting rescheduled for Jan. 7-8.

A key discussion point during FDA's advisory committee review for Ovation Pharmaceuticals' Sabril on Jan. 7-8 will be whether the benefits of the anti-epileptic in two different indications outweigh the risk of irreversible vision loss among vigabatrin patients.

During the two-day meeting, FDA's Peripheral & Central Nervous System Drugs Advisory Committee will consider a series of questions about the risk of central and peripheral vision loss with Sabril, a GABA-transaminase inhibitor, and whether Ovation's proposed Risk Evaluation & Mitigation Strategy is adequate to address the risk.

On Jan. 7, the committee will discuss Sabril for the treatment of refractory complex partial seizures in adults. The following day, the panel will evaluate the use of the drug in the treatment of infantile spasms.

In its briefing documents, Ovation says that any visual loss can be detected before it becomes clinically meaningful and that discontinuation of Sabril treatment halts any progression. Moreover, Ovation asserts that vigabatrin does not cause central visual loss.

In one Ovation study of Sabril (study 4020), 36.5 percent of adults and 20 percent of children had at least one occurrence of progressive bilateral concentric peripheral constriction (BCPC) of visual fields, and 24.6 percent of adults and 15.3 percent of children had at least two BCPC occurrences.

Ovation has proposed a REMS program that includes an ophthalmologic monitoring schedule: for CPS patients, every six months; for patients with infantile spasms, every three months for the first 18 months, then every six months thereafter.

The company also proposes that its REMS include restricting Sabril distribution through specialty pharmacies and to prescribers that have received education about and attested to understanding its risks and monitoring protocol.

A litany of questions

But vision loss is just one of a litany of issues that the advisory committee will consider during the two-day meeting.

On the first day, the panel will discuss nine questions, many with multiple parts, culminating in whether approval is recommended for the treatment of refractory CPS in adults. The list is even longer for the second day, with 13 questions on the treatment of infantile spasms.

FDA acknowledges the length of the discussion points in its briefing documents to the committee. "The question list for the meeting is unusually long and complex..... Of course, as the meetings progress, we may determine that it might be not necessary to take a formal vote on all of the (sub-parts of the) questions posed."

The first day should be easier on Ovation, as FDA has concluded Sabril is efficacious for the treatment of refractory CPS in adults - a determination it has not made for the infantile indication.

But it will be up to the panel to determine whether that efficacy is offset by safety concerns, the largest being irreversible visual loss.

Long, complex regulatory history

Despite the daunting list of issues to be addressed by the advisory committee, the meeting is a major milestone for vigabatrin in what has been a lengthy and bumpy road to approval.

The initial IND for Sabril for the adult CPS indication was submitted in 1980 by Merrell Dow, then placed on clinical hold in 1983 when a unique histopathologic finding - intrameylinic edema - was seen in animals given vigabatrin at doses similar what would be given to humans.

Testing resumed in 1989, and the NDA was submitted in 1994. FDA denied approval of the drug three times (1995, 1997 and 1998); the final time after the agency became aware of the unique visual field defect associated with use of vigabatrin.

Ovation submitted an NDA for the treatment of infantile spasms in late December 2007, and received a priority review designation, setting the six-month user fee deadline at June 27. The adult CPS indication had been the subject of an earlier "complete response" letter, and the new user fee date also was June 27.

FDA missed the user fee deadline, but initially was able to schedule a review for Aug. 6-7. That meeting, however, was cancelled after FDA could not find a pediatric neurologist to replace Dartmouth Medical School's Greg Holmes, who was disqualified due to a conflict of interest (¹ (Also see "The Longest Review: Inside Ovation’s Wait For Sabril" - Pink Sheet, 27 Aug, 2008.)).

-Jamie Hammon ([email protected])