GLAXO's ZOFRAN (ONDANSETRON) APPROVED FOR PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH "1-B" RATING AFTER 27-MONTH REVIEW AT FDA

Glaxo's Zofran I.V. (ondansetron) was approved by FDA late in the day on Jan. 4 for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy including high-dose cisplatin. FDA gave the drug a "1B" rating, denoting a new chemical entity with a modest therapeutic gain over existing therapies. FDA's review of the Zofran I.V. NDA took approximately 27 months. Zofran is the first in a new class of 5HT3 receptor antagonists to be approved by FDA. The Glaxo drug should have a sizable market lead over its nearest competitor, SmithKline Beecham's granisetron I.V. SmithKline Beecham is also pursuing an indication for prevention of chemotherapy-induced nausea and vomiting and is predicting a late-1991 target date for NDA submission in the U.S. In May 1990, FDA's Gastrointestinal Drugs Advisory Committee unanimously recommended that Zofran be approved for prevention of nausea and vomiting associated with single-day emetogenic cancer chemotherapy ("The Pink Sheet" May 28, p. 5). The committee also unanimously agreed that Zofran is more effective and has fewer side effects in prevention of nausea and vomiting caused by single-day chemotherapy than metoclopramide (Robins' Reglan), the current standard in anti-emesis. The panel concurred with Glaxo's proposed dosing regimen for Zofran of 0.15 mg/kg infused 30 minutes before chemotherapy with additional doses given four and eight hours later. A committee consultant had pointed out that Zofran's t.i.d. regimen will "most likely force hospitalization" of chemotherapy patients overnight. SmithKline Beecham is expected to pursue a once-daily dose for granisetron as an anti-emetic agent. However, Glaxo has an oral dosage form of Zofran pending at FDA that could negate SmithKline Beecham's potential dosage advantage; the NDA for oral Zofran was filed in August 1990. Although no serious side effects were seen with Zofran in clinical trials, the advisory committee recommended that elevations of liver enzyme observed in patients taking Zofran be followed in post-marketing surveillance. In prepared questions, FDA had asked the committee to discuss whether transaminase increases should be considered a safety concern. The company said that no clinical cases of hepatitis, jaundice or other renal disease had been attributed to Zofran during clinicals. The committee did not agree that Glaxo's data showed that the drug was effective for multi-day use. The panel suggested to FDA that the multi-day studies be reanalysed using a historical control of data on cisplatin-induced emesis without anti-emetic therapy to gain more information on Zofran's effectiveness over multi-day use. Zofran will enter a U.S. market of 2.5 mil. annual episodes of chemotherapy and radiotherapy emesis, according to figures discussed at a Dec. 3 analysts meeting in New York City ("The Pink Sheet" Dec. 10, p. 11). Based on these estimates by Glaxo Holdings Managing Director Franz Humer, Glaxo could receive $ 100 mil. in annual sales by capturing only 30% of the number of treatable episodes of chemotherapy emesis. Glaxo again predicted that Zofran would be approved by the end of the year.