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GLAXO's IMITREX (SUMATRIPTAN) INJECTION IS EFFECTIVE FOR TREATMENT OF MIGRAINES, FDA ADVISORY CMTE. CONCLUDES; MORE DATA ON CLUSTER HEADACHES NEEDED

Executive Summary

Glaxo's NDA for Imitrex (sumatriptan succinate) injection supports a finding that the drug is effective in treating migraine headache, FDA's Peripheral and Central Nervous System Drugs Advisory Committee unanimously concluded at its Oct. 25 meeting. The Imitrex NDA (20-080) includes data from 10 randomized, double-blind, placebo-controlled trials. Eight of the trials evaluated the drug's effect in treating migraines, one study looked at headache associated with withdrawal from chronic analgesic use (an indication no longer being pursued by Glaxo) and one trial looked at efficacy in treating cluster headaches. The four pivotal migraine trials involved use of a 6 mg dose of sumatriptan -- the dose that Glaxo has proposed for marketing. The committee also unanimously agreed that Glaxo had submitted substantial evidence showing that the drug was safe; however, the panel agreed that Glaxo should submit results from a chronic-use study currently underway in order to demonstrate long-term safety. A recent survey presented at the Fifth International Headache Congress estimated the number of people in the U.S. experiencing migraines at about 11.2 mil. ("The Pink Sheet" July 8, T&G-8). The current perception of the market is that it is underserved by older treatments and that most migraine sufferers do not seek medical attention. Sandoz, which markets D.H.E. 45 (dihydroergotamine) injection and Cafergot (ergotamine/caffeine), has indicated that it is considering relaunching D.H.E. to take advantage of the increased awareness of migraine headache. In addition, Glaxo's oral form of sumatriptan has been pending at FDA since December 1990. David Collins, MD, a staffer from FDA's Division of Neuropharmacological Drugs, presented FDA's analyses of Glaxo's safety and efficacy studies. Two of the three main migraine studies, S2B-305 and S2B-306, were conducted in the U.S. and followed the same protocol. These were double-blind, placebo- controlled, multicenter trials that involved a total of 1,104 patients, who were randomized to one of three treatment groups: sumatriptan 6 mg, which was repeated at one hour if needed; sumitriptan 6 mg, with placebo if a second dose was needed; and placebo with a placebo followup, if needed. In S2B-305, of the 574 patients randomized, 384 received sumatriptan while 190 received placebo for their first treatment. Collins reported that "194 of the sumatriptan patients required a second dose -- of this subset, 101 got sumatriptan again and 93 got placebo." He noted that "all but 10 placebo patients required a second dose." The results of the first injection of treatment showed: "48% of sumatriptan patients were pain free at 60 minutes versus 5% of placebo patients," the FDAer said. "Another 22% of sumatriptan patients had mild pain, thus a total of 70% met the specified criteria for effective relief compared to 18% of placebo patients." In the sumatriptan-treated patients, "94% were pain free at two hours and this compares with 60%" of the placebo group, Collins noted. For patients receiving a second injection, "34% of sumatriptan patients were pain free [versus] 8% of placebo patients" 60 minutes after injection. Collins also presented data from a similar study, S2B-T29, which involved 235 patients, who self-administered their treatment with an auto-injector. Since most of the data in the Glaxo NDA were from short-term efficacy trials, both FDAers and committee members expressed concern about the lack of safety data on the 5HT[1] receptor agonist when used chronically, including whether the drug's vasoconstrictor effect might cause complications. Committee Acting Chairman Michael Brooke, MD, University of Alberta, remarked: "I think the problem ...is that the data we have seen with regard to safety looks reassuring, but the question is: 'Does it go far enough?'" Safety concerns were raised early on in the drug's development when two men, each given a high dose of I.V. sumatriptan in a clinical pharmacology trial in the U.K., experienced angina. In response to these reports, FDA put Glaxo's IND on hold. The clinical hold was later lifted when Glaxo agreed to implement a surveillance program for cardiovascular safety that included six clinical pharmacology studies, an agreement to monitor clinical study participants, and a label warning against use of sumatriptan in patients with ischemic heart disease. The committee agreed that FDA would have sufficient evidence of safety to support approval if Glaxo submits recent information from an ongoing open-label extension of study S2B-T29. Alison Pilgrim, head of international clinical development for sumatriptan, Glaxo Group Research, updated the committee on the S2B-T29 data. "We have in-house 12 months of data on nearly 300 patients who have been treating all their migraine attacks with subcutaneous sumatriptan," Pilgrim reported. She noted that "over that experience, we have found no increase in the adverse events and we found no indication of any new adverse events developing." The Imitrex NDA, which was filed with FDA on June 29, 1990, also seeks approval for the drug for use in treating cluster headaches. The committee agreed that the single study conducted for this indication was an adequate and well-controlled study demonstrating the efficacy of sumatriptan. However, the committee members asked to see a study confirming the results of the one study before recommending approval of the drug for this indication. The cluster headache trial was a double-blind, placebo- controlled, crossover study of 39 patients. Sumatriptan was effective in treating 74% of cluster headaches within 15 minutes of administration compared with a 26% reduction in cluster headaches in patients on placebo. The study was published in the Aug. 1 issue of The New England Journal of Medicine ("The Pink Sheet" Aug. 5, T&G-16). One particular concern brought up by FDA Division of Neuropharmacological Drugs Director Paul Leber, MD, was the lack of experience in treating a significant number of individuals with cluster headaches, who are mostly older males that are also at high risk of cardiovascular disease. FDA also had a problem with the design of the study. Russell Katz, MD, group leader of the Neurology Drug Group noted that "as often happens in the conduct of crossover trials ...there was a fair amount of missing data in the second period. So we chose to analyze it as a parallel study using the first period data."
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