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Executive Summary

Carter-Wallace's Felbatol (felbamate) is safe and effective for use in controlling certain seizures associated with adult epilepsy and Lennox-Gastaut syndrome, FDA's Peripheral and Central Nervous System Drugs Advisory Committee concluded at its Dec. 14 meeting. In separate votes, the committee unanimously agreed that felbamate has been shown to be effective in reducing seizures associated with Lennox-Gastaut syndrome, which affects children, partial onset seizures in adult epileptics and secondary generalized clonic-tonic seizures in adult epileptics. The committee based its votes on six pivotal trials conducted by Carter-Wallace and the National Institutes of Health using doses up to 3,600 mg/day. "Because there are no recent precedents for the approval of antiseizure medications, it is not entirely clear what the standard should be in deciding whether or not they should be approved for marketing," FDA Neurology Drug Group Leader Russell Katz, MD, said in his introductory remarks to the committee. Katz noted that Felbatol and Warner-Lambert's Neurontin (gabapentin) represent "the first NDAs for novel antiseizure medications to be submitted to FDA in well over 10 years." Neurontin was reviewed by the committee Dec. 15. Antiseizure drugs, however, are likely to be an important part of the Neuropharmacological Drug Division's work in coming years. In addition to Felbatol and Neurontin, Burroughs Wellcome's Lamictal (lamotrigine) could be reviewed by the committee early next year ("The Pink Sheet" Dec. 7, T&G-3). Other seizure drugs under development include Marion Merrell Dow's Sabril (vigabatrin), for which the company has said it expects to file an NDA in 1993. One unsettled regulatory issue the committee was asked to address Dec. 14 was whether a general anti-epilepsy claim was appropriate for Felbatol, or whether the label should simply indicate its use in specific seizure types. The committee ultimately agreed on the latter approach. Currently-marketed epilepsy drugs carry two types of indications. Warner-Lambert's Dilantin (phenytoin), for example, is indicated for specific types of seizures. Ciba-Geigy's Tegretol (carbamazepine) is labeled as "an anticonvulsant" with a subsequent listing of seizures for which it has been studied. Committee member Antonio Delgado-Escueta, MD, Veterans Affairs Medical Center, Los Angeles, commented that "epilepsy" includes "more than one syndrome. I think we'd better stick to seizure types" in labeling. FDA's Katz praised the novel study designs used in the felbamate development program. In particular, he cited two trials that compared felbamate directly to low-dose valproic acid as "one of the first attempts to evaluate a novel antiseizure medicine as monotherapy." He noted that Carter-Wallace's study of Lennox-Gastaut syndrome "is one of the first -- if not the first -- controlled trial in this population." Lennox-Gastaut is a condition characterized by seizures and mental retardation that strikes children under eight years of age. Finally, Katz praised a study conducted in pre- surgery epilepsy patients who were being taken off other drugs, thereby allowing a direct comparison of felbamate to placebo. The two other Felbatol trials were traditional add-on, cross-over designs. Felbatol's clinical results were presented to the committee by FDA medical reviewer Janeth Rouzer-Kammeyer, MD. The two add-on trials (studies 13 and 16) showed a mean reduction in seizure counts favoring felbamate versus placebo, Rouzer-Kammeyer said. The pre-surgery trial (study 20) showed a statistically- significant advantage of felbamate over placebo in reducing time to fourth seizure in 65 patients, Rouzer-Kammeyer said. In the two monotherapy trials (studies 4 and 5), felbamate was compared to the lowest labeled dose of valproic acid (Abbott's Depakene and generics). Felbamate showed a significant reduction in the number of patients withdrawn from medicine due to worsening symptoms (a defined study endpoint) in both trials. Finally, in the 46-patient Lennox-Gastaut trial (study 10), Felbatol demonstrated a trend toward reduction of telemetry- monitored seizures and a statistically-significant improvement in parental global assessments of the patient's condition. Carter-Wallace's safety database included 960 adults and 324 children. In controlled monotherapy trials enrolling a total of 58 felbamate patients and 43 placebo patients, there was "little difference between the incidence of [adverse drug reactions]" in the two groups, Rouzer-Kammeyer said. Reactions seen in a total of 366 monotherapy patients included headache (25%), insomnia (19%), nausea (18%), anorexia (12%), dizziness and vomiting (11%), and somnolence and fatigue (7%). "The drug has a favorable toxicity profile," she said. Felbatol does interact with other anticonvulsants, Rouzer- Kannemeyer noted. Carter-Wallace estimated that felbamate patients see an 18%-30% increase in valproic acid blood levels, a 30%-45% increase in phenytoin levels and a 25%-30% decrease in carbamazepine levels. One safety issue with the drug is a possibility of urethane contamination in the final product, FDA's Katz told the committee. The carcinogen is a by-product of one of the steps in synthesizing the drug. However, it has not been detected in the final product. The committee agreed with Katz' assessment that the sponsor's willingness to use an assay sensitive enough to detect .2 parts per million of urethane was adequate. By a six-to-two vote, the committee rejected an indication for seizures in children other than Lennox-Gastaut patients. Committee members were divided as to whether felbamate's demonstrated efficacy against epileptic seizures in adults should be extrapolated to children. They key issue in the committee's rejection of the pediatric indication, however, appeared to be a safety issue raised by committee member Dennis Choi, MD/PhD, Washington University School of Medicine. Carter-Wallace said felbamate may act by binding to the glycene site of the N-methyl-D-asparate (NMDA) receptor. Choi noted that NMDA antagonists have been associated with CNS developmental disorders in animal models. He suggested that felbamate should be studied for such an effect prior to granting a pediatric indication. Committee member Sid Gilman, MD, University of Michigan, called felbamate "an agent that is very promising in the adult population and also in one terrible disease in children." However, he said, "we have essentially no other information on this agent in children. We hear just today that this agent may be effective at the NMDA receptor. That gives me significant pause." While felbamate's mechanism of action is not clear, its NMDA activity could suggest other indications Carter-Wallace may explore for the drug. The company told the committee that it has done animal studies demonstrating a neuroprotective effect of felbamate in models of ischemia. Carter-Wallace filed the felbamate NDA (20-189) in September 1991 ("The Pink Sheet" Oct. 7, 1991, p. 18). The firm is seeking approval for 400 mg and 600 mg tablets as well as a 600 mg/ml suspension for doses up to 3,600 mg per day. Felbamate was synthesized in 1955, but clinical development began only in 1982 under the auspices of the National Institute of Neurological Disorders and Stroke's epilepsy drug development program. Carter- Wallace filed a second IND in 1988 for Lennox-Gastaut syndrome, which was designated an orphan indication. Felbamate is licensed to Schering-Plough outside of North America ("The Pink Sheet" April 13, T&G-15). Carter-Wallace's collaboration with NINDS pre-dates NIH's recent use of "reasonable price" clauses in drug company agreements such as the Bristol-Myers Squibb Taxol deal. However, in the current political atmosphere, any drug whose development was partially funded by the government is likely to face price scrutiny. At the committee meeting, the father of a Lennox-Gustaut patient ended a plea for felbamate's approval with a call for it to be priced affordably.

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