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Executive Summary

Parke-Davis' Neurontin was cleared by FDA's Peripheral and Central Nervous System Drugs Advisory Committee at its Dec. 15 meeting. The committee voted unanimously to recommend approval of Neurontin (gabapentin) "as an add-on [therapy] for intractable partial seizures in adults." Parke-Davis estimates that 2.5 mil. people suffer from epilepsy annually. Of those, approximately 25%-30% (about 625,000 to 750,000 epileptics) are refractory to therapy with currently- marketed anticonvulsants. As an add-on therapy, Neurontin may be promoted as having the advantage of no effect on the pharmacokinetics of other anti- epilepsy drugs. While combinations of certain anticonvulsants, for example, lower the serum levels of Tegretol (carbamazepine), gabapentin has not been found to interact with the major anti- epileptics, including carbamazepine, phenytoin, valproate, phenobarbital and diazepam. Neurontin (NDA 20-235) was not evaluated by the committee for first-line epilepsy therapy because the trials conducted by Warner-Lambert's Parke-Davis unit enrolled only patients who had failed previous therapy and continued to receive concomitant anticonvulsant medications during the trials. Parke-Davis recently initiated two monotherapy trials with Neurontin, one in the U.S. and one in Europe. Patients in those trials are receiving up to 2,400 mg of gabapentin per day. The Neurontin NDA, filed in January 1991, included three pivotal studies, two European and one U.S. In the studies, patients received either placebo or one of several doses of Neurontin. The primary endpoint in the studies was the responder rate, or the percentage of patients who experienced a greater than 50% decrease in their frequency of seizures. In the first of the three studies, conducted in the U.K., 127 patients were randomized to gabapentin 200 mg t.i.d. -- that level was increased during the treatment period to 400 mg t.i.d. -- or placebo for 12 weeks. The gabapentin-treated patients had a response rate of 23% compared to 9% for placebo-treated patients. In the second European study, patients received gabapentin 300 mg t.i.d., 400 mg t.i.d. or placebo over a three-month period. The response rates were 22%, 27% and 10%, respectively. The U.S. study, which enrolled the largest number of patients of the three trials at the highest doses, randomized 306 patients to gabapentin 200 mg, 400 mg and 600 mg t.i.d. or placebo for 12 weeks. The results of the study showed that gabapentin-treated patients were two-to-three times more likely to respond than placebo-treated patients. The percent of patients showing a response was 17% for the 200 mg t.i.d. gabapentin dose and 26% for the 600 mg t.i.d. dose. Only 8% of placebo-treated patients had a greater than 50% reduction in seizure frequency. With response rates of 17% to 26%, it is clear that Neurontin does not work for all refractory epileptic patients. About 5% to 10% of patients actually get worse on gabapentin therapy, Parke- Davis VP-Central Nervous System Clinical Research Mark Pierce, MD, told the advisory committee. FDA Medical Reviewer Cynthia McCormick, MD, pointed out that 35% of patients treated with gabapentin in the epilepsy studies withdrew from the trials because of lack of efficacy. Another 9% of patients withdrew from the studies because of adverse reactions, including convulsions and somnolence. One of FDA's major concerns regarding safety of the product involved the drug's potential for promoting pancreatic cancers. While no pancreatic cancers have been documented in humans, an increase in acinar cell carcinoma was found in studies of male rates given high gabapentin doses, FDA Neurology Drug Group Leader Russell Katz, MD, told the committee. Ongoing clinical trials with gabapentin were suspended, Katz said, and last October the data were brought before a closed session of the advisory committee, which was supplemented with other experts. At that meeting, the committee concluded that the finding represents a signal that gabapentin may be a carcinogen, but the committee could not determine whether the risk was greater for the Parke-Davis product than other anti-epileptic therapies. Although the company has conducted further animal studies since then, FDA supervisory pharmacologist Glenna Fitzgerald, PhD, said: "we still have no information about mechanism and absolutely no information about how it relates to humans." Neurontin is one of two Parke-Davis pending NDAs that FDA has continued to review since the agency discovered serious record- keeping and good manufacturing practices violations during inspections of Warner-Lambert's two Puerto Rico facilities ("The Pink Sheet" Nov. 30, p. 3). FDA exempted the anti-epileptic and the Alzheimer's disease therapy Cognex from review delays under its "integrity policy" because the drugs are intended to treat patients with life-threatening diseases. The FDA inspections have raised concerns about production of another Warner-Lambert anti-epileptic drug, Dilantin (phenytoin). The firm has received a number of reports of subpotency for its Dilantin Kapseal product ("The Pink Sheet" Dec. 14, p. 12). The company already has met once with the agency. Reportedly, the meeting was held to begin discussions regarding reformulation of the Dilantin solid-dosage line. Another meeting on the subject, originally scheduled for Dec. 17, has been moved back to January.

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