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GLAXO’s ZOFRAN IS MORE EFFECTIVE, HAS FEWER SIDE EFFECTS THAN METOCLOPRAMIDE FOR CHEMOTHERAPY-INDUCED NAUSEA, FDA ADVISORY COMMITTEE CONCLUDES

Executive Summary

Glaxo's Zofran (ondansetron) is more effective and has fewer side effects in prevention of nausea and vomiting caused by single-day chemotherapy than metoclopramide (Robins' Reglan), FDA's Gastrointestinal Drugs Advisory Committee unanimously agreed at its May 24 meeting. In response to prepared questions from FDA, the committee concurred that injectable Zofran "has been shown by substantial evidence to be more efficacious and safer than metoclopramide injection," the current standard therapy, and that "promotion of a superiority claim to metoclopramide should be permitted." The committee unanimously recommended that FDA approve Zofran for "prevention of nausea and vomiting associated with single-day emetogenic cancer chemotherapy." The committee also supported Glaxo's proposed dosing regimen for the anti-emetic, set at 0.15 mg/kg infused 30 min. before chemotherapy with two additional doses four and eight hours later. Zofran is likely to be the first of a new class of 5-HT[3] receptor antogonists to be approved by FDA. SmithKline Beecham recently projected a second quarter of 1990 NDA submission date for once-daily granisetron I.V., its own 5-HT[3] antagonist, for prevention of chemotherapy-induced nausea and vomiting ("The Pink Sheet" April 9, p. 9). Granisetron is being studied for a once-daily dose as an anti-emetic; ondansetron has a t.i.d. regimen. Committee consultant David Ahmann, MD, pointed out that the t.i.d. regimen will "most likely force hospitalization" of chemotherapy patients overnight. Further back in the pipeline, Glaxo has an oral formulation of Zofran in Phase III studies. The company is also in early clinicals with an anti-schizophrenia indication for the drug. "Zofran is the first significant breakthrough in control of the side effects of chemotherapy to come along in a while," the committee reviewer of the ondansetron NDA, Kermit Speeg, MD, University of Texas, declared. Summarizing what he called Zofran's "remarkably low" adverse effect profile, Glaxo's director of clinical research, William Jenkins, MD, reported that mild headache and constipation were the most common side effects reported in safety data from 2,500 patients in the U.S. and Europe. No serious adverse events have been attributed to Zofran. Serious side effects associated with metoclopramide include hypertensive crises, severe depression and extrapyramidal symptoms such as facial spasms. However, the committee recommended that elevations of liver enzyme levels observed in patients taking ondansetron be followed in post-marketing surveillance. In its list of prepared questions, FDA asked the committee to consider whether transaminase increases in the clinical data should be considered a safety concern. Glaxo's Jenkins reported that no clinical cases of hepatitis, jaundice or other renal disease had been attributed to Zofran during the studies and that in 85% of study subjects with unusual increases, transaminase levels returned to baseline within three weeks. The advisory panel also recommended further study in pediatric patients. FDA Division of Gastrointestinal and Coagulation Drug Products Director Stephen Fredd, MD, told the committee that the agency "would be uncomfortable at putting in the pediatric [warning] clause -- that 'safety and efficacy has not been shown in children.'" The drug, he said, "is going to be used in children and we would like to work with the company to get sufficient labeling information." The advisory panel did not agree that Glaxo's data demonstrated that the drug was effective for multi-day use. The FDA medical reviewer for the NDA, Hugo Gallo-Torres, MD, maintained that Glaxo's study data failed to make clear whether ondansetron administered over several days had additive effectiveness, or whether the anti-emetic's initial effect merely "spilled over" from the first day into subsequent days of therapy. The advisory committee suggested to FDA that Glaxo's multi-day studies be reanalysed using a historical control of data on cisplatin-induced emesis without anti-emetic therapy in order to gain more information on Zofran's effectiveness over multiple-day use. The three U.S. pivotal trials used by Glaxo to support approval for the product included roughly 300 patients receiving ondansetron. The cancer patients in the studies underwent single-day chemotherapy regimens with the majority receiving cisplatin (Bristol-Myers' Platinol), which results in severe vomiting in 95% of patients. In the first study, a double-blind, single-center study of 48 patients, subjects received either ondansetron 0.15 mg/kg or placebo. Out of 24 patients receiving ondansetron, 17 had complete or major reduction of vomiting, compared to none on placebo. A second trial, used by Glaxo to support its proposed dosage, was a randomized, double-blind comparison of high dose (0.30 mg/kg), intermediate dose (0.15 mg/kg) and low dose (0.015 mg/kg) ondansetron in 112 patients receiving cisplatin. All strengths of the drug were found to limit emesis, with the intermediate dose achieving a statistically significant higher rate of complete response, 46% vs. 15%, than the low dose. The highest dose in the study did not improve the response rate significantly over the 0.15 mg/kg dose. Glaxo's largest single-day treatment study compared Zofran with metoclopramide in 307 cisplatin-treated patients. The ondansetron group acheived 40% complete supression, compared to 30% on metoclopramide. The failure rate (no reduction of emesis) of patients on metoclopramide was 36% compared to 21% on ondansetron. Median time to onset of vomiting following chemotherapy for those who did experience emesis was 20.5 hours with ondansetron, compared to 4.3 hours with metoclopramide. "If used as an index of efficacy, this difference indicates that ondansetron protected the patient more than four times as long as metoclopramide," Glaxo Director of Clinical Development Andrew Finn noted. Glaxo's NDA package also contained results of two foreign trials, in France and in Holland, where Zofran is already approved and on the market. Glaxo's attempt to gain a multi-day indication was based on two U.S. studies in patients receiving cisplatin over five days. In a study of 79 patients receiving high, low or intermediate t.i.d. ondansetron, 28% of patients achieved complete control of emesis on all days. In a second multi-day study completed after the NDA and submitted to FDA within the last month, ondansetron was matched against metoclopramide in patients receiving a less toxic cisplatin regimen. Approximately 57% of the ondansetron patients gained complete response, versus 50% on the metoclopramide. Ondansetron received a boost rom the medical journal literature two months ago, when a French study reported in the March 22 New England Journal of Medicine found that ondansetron stopped vomiting in 75% of patients versus 42% on metoclopramide in 108 cancer patients ("The Pink Sheet" March 24, T&G-8). The U.S. market for ondansetron may be as high as $100 mil., Charles Sanders, CEO of Glaxo U.S., said earlier this year ("The Pink Sheet" Jan. 22, p. 8). Sanders estimated an annual potential patient population of 500,000. Glaxo filed the NDA nineteen months ago, a relatively short period until advisory committee review. The company has scheduled major back-to-back presentations on its research activity with financial analysts in London and New York on May 30-31. The successful FDA review provides a good backdrop for these sessions to reassure analysts about post- Zantac activities.
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