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ONDANSETRON IN FULL DEVELOPMENT AS ANXIOLYTIC, WITH SCHIZOPHRENIA PHASE II UNDERWAY; ZANTAC-BISMUTH CITRATE IN PHASE III FOR PEPTIC DISEASE

Executive Summary

Ondansetron (GR38032F) has "entered the full development program" in the "last few months" as an anxiolytic and is being looked at for a number of CNS indications, Glaxo Group R&D Director Richard Sykes, PhD, announced at an R&D development update to securities analysts in New York City on May 31. In recently-completed, double-blind, placebo-controlled trials of ondansetron for generalized anxiety, patients "showed improvement similar to that with diazepam, both being superior to placebo," Sykes said. Four weeks of ondansetron treatment is "significantly more effective" than placebo and patients show "no rebound anxiety" or sedation in contrast to diazepam, Sykes told the gathering. Ondansetron, like sumatriptan, is another compound coming out of Glaxo's 5HT receptor work. The NDA for sumatriptan for migraine is slated for June (see preceding story). The NDA for ondansetron for the anxiety indication is slated for the "first half of 1993," according to the company. Another 5HT[3]-antagonist is "on track" in the exploratory development phase, Sykes said. The drug is being developed for gastrointestinal indications, "particularly nausea and vomiting and irritable bowel syndrome," he elaborated. Results on Phase II double-blind, placebo-controlled trials for ondansetron in schizophrenia are expected to be available "later this year," analysts were told. Glaxo also has clinicals underway for the 5HT[3] antagonist for nicotine, alcohol and benzodiazepine dependence and for memory loss-associated cognitive disorders, the company disclosed. The company also recently moved ondansetron into full development for post-operative nausea and vomiting. Large-scale, multinational trials are underway, Glaxo said, with the drug being tested at a dosage of 16 mg b.i.d. Worldwide filings for this indication are forecast for the "first half of 1991." Ondansetron's first indication is as an anti-emetic. FDA's Gastrointestinal Drug Advisory Committee on May 24 unanimously recommended that ondansetron (Zofran) be approved as a treatment for chemotherapy-induced nausea and vomiting and deemed Zofran superior to metoclopramide ("The Pink Sheet" May 28, p. 5). Zofran has been approved for the cancer treatment anti-nausea indication in the U.K., France, Belgium, Holland and New Zealand. Also in development for CNS indications is the alpha-2 adrenoreceptor blocker fluparoxan (GR50360) as an antidepressant. Sykes said the filing data has been delayed from what analysts were told last year, until "hopefully" around the second half of 1993, because Glaxo has rationalized its worldwide development programs "so that we can use one core registration dossier for the U.S. and all over the world at the same time." Also highlighted by Sykes is the move into full clinical development of ranitidine bismuth citrate (GR19065AM) as a therapy for peptic ulcer diseases. The compound is now moving into Phase III studies. Ranitidine bismuth citrate (RBC) is being evaluated for its potential to heal ulcers and maintain healing longer than currently available drugs. Clinicals are also planned to look at ranitidine bismuth citrate's effect on Helicobacter pylori, a bacterium that may contribute to gastrointestinal disease, Glaxo said, with initial registration filings worldwide forecast for 1993-1994. RBC is "antisecretory" and has been shown in animal studies to be cytoprotective, presumably because of bismuth's coating action and also its ability to induce prostaglandin synthesis, Sykes said. The compound is also a potential inactivator of Pepsin I, the enzyme "responsible for boring holes in the stomach wall," Sykes noted. Reporting comparative human clinicals trials of RBC and De-Nol, Rhone-Poulenc Rorer's prescription Pepto-Bismol cousin colloidal bismuth subcitrate, Sykes suggested that Glaxo's product is safer. In measurements of bismuth plasma levels, Glaxo found that De-Nol's plasma levels peak and also show an accumulation over time, whereas plasma levels in the volunteers taking RBC did not. "This...could prove important for the safety of the compound," Sykes noted. In the U.S., Glaxo is also studying higher-dose ranitidine (Zantac). The ulcer drug has been approved at higher doses in the U.K. and Italy for duodenal ulcer and reflux esophagitis treatment. The company expects to file for an NSAID-induced duodenal ulcer prevention indication in the latter half of the year here in the U.S. During Q&A, Sykes hinted that ranitidine has a better safety profile for the duodenal ulcer prevention indication than omeprazole, citing omeprazole's "potential genotoxicity. We're concerned about omeprazole's potential safety problems," Sykes said. Merck's Losec was recommended for approval for two new duodenal ulcer indications at a May 25 FDA Gastrointestinal Drugs Advisory Committee meeting. Underscoring the continued importance of Zantac to Glaxo's coffers, the company outlined a number of line extensions planned for 1990-92. These include higher dose regimens for reflux esophagitis and maintenance; 300 mg b.i.d for healing duodenal ulcers and 300 mg nocturnally for maintenance; a gastric ulcer maintenance indication; co-administration with NSAIDs and new formulations such as effervescent tablets and granules and suspensions. The company expects to file in the U.S. for a Zantac soft gelatin capsule shortly. Updating Glaxo's recent pipeline changes, Sykes said several candidates dropped during the past year include fluticasone propionate for inflammatory bowel disease; Bioleukin (IL-2) and GM-CSF; carbovir, Glaxo's first transcriptase inhibitor, and AH13205, a prostaglandin (EP2) agonist for respiratory disease. "On track" in the exploratory phase (Phase I/II), according to Sykes, are 10 compounds (see chart). Additionally, there are six new additions to the exploratory development phase in the last 12 months, the analysts were told. These include: squalene synthase inhibitor, which is being developed as a selective inhibitor of cholesterol biosynthesis; reverse transcriptase inhibitor, an anti-AIDS drugs licensed from IAF Biochem in Canada that is potentially less toxic and acts longer than AZT. It is in toxicology studies now and hopefully will be in human studies "later this year," Sykes noted. DNA polymerase inhibitor, which Sykes said is "orders of magnitude more potent that acyclovir" for herpes simplex and shingles; an ultra short-acting opioid now going into Phase I; 5HT[1]-like agonist; 5-lipoxygenase inhibitor, a potential treatment for inflammatory bowel disease and possibly for the inflammatory aspects of respiratory disease. Sykes noted that Glaxo has had two new drug registrations worldwide so far this year. The once-a-day calcium antagonist lacidipine (GR43659) was filed in February worldwide outside the U.S. and Japan for mild to moderate hypertension; in March, registrations were filed outside the U.S. and Japan for the long-acting beta-2-agonist salmeterol for asthma.

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