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GLAXO HAS TWO NDAs ON TAP: ZOFRAN FOR POST-OPERATIVE NAUSEA AND SEREVENT FOR ASTHMA; FLIXOTIDE NDA JUST FILED, VOLMAX IS "APPROVABLE"

Executive Summary

Glaxo submitted its NDA for Flixotide "a few weeks ago" and plans to file two other NDAs by January, Glaxo Holdings R&D Director Richard Sykes, PhD, told analysts Dec. 11 at the company's annual R&D update. Glaxo will file an NDA "over the next few weeks" for a new indication for Zofran (ondansetron) for the prevention and treatment of post-operative nausea and vomiting at a 4 mg dose for both uses. Sykes said there is a 50% incidence of post-operative nausea and vomiting across all classes of adult and pediatric surgery. Zofran I.V. has been on the U.S. market since January 1991 for the prevention and treatment of chemotherapy- and radiotherapy- induced emesis in a multidose regimen. Outside the U.S., ondansetron has been approved as single-injection nausea preventative prior to chemotherapy. The company noted that efficacy is improved when Zofran is administered in combination with dexamethasone. SmithKline Beecham's anti-nausea product Kytril (granisetron) was recently approved in the U.K., and the company plans to file an NDA in the U.S. by year end. Kytril is also approved in South Africa and France. SmithKline Beecham filed a patent infringement case against Glaxo over the sale of Zofran in the spring ("The Pink Sheet" May 6, T&G-5). The second NDA filing planned by Glaxo is for the beta-2 adrenergic agonist Serevent (salmeterol) for the treatment of adult chronic asthma in a metered-dose inhaler formulation. The filing should happen "in two to three weeks time," Sykes said. Glaxo submitted its first international registration, for pediatric use, outside the U.S. in September. Glaxo defended the role of beta agonist therapy for chronic asthma treatment before FDA's Pulmonary-Allergy Drugs Advisory Committee at its Dec. 12-13 meeting (see related story, p. 15). While the advisory committee recommended that FDA needs additional data on the safety of beta-2 agonist bronchodilators, it is unclear how FDA will interpret that recommendation. Calling salmeterol the "most highly studied beta-2 agonist," Sykes told the analysts that studies to date in nearly 6,300 patients have shown there is "no attenuation" in effectiveness of salmeterol over time as measured by forced expiratory volume (FEV[1]), peak flow rates (PEFR) or exacerbations of asthma leading to hospitalization. He noted that 835 of the nearly 6,300 patients in worldwide clinical trials of salmeterol have been receiving the drug for 12 months or more. He said the data show that the "asthma has been stabilized and it stays stabilized" under treatment with salmeterol. Glaxo is predicting the publication of most of the large Serevent clinical studies "by the end of 1991/first quarter 1992." Sykes said the company also will make available the "Serevent Surveillance Study" of approximately 24,000 patients from the U.K. where the drug has been on the market for about a year. The study data is currently being analyzed and will be out "in the next three months," Sykes said. The NDA for intranasal fluticasone propionate (Flixotide), an anti-inflammatory steroid, was filed with FDA for perennial rhinitis, Sykes reported. Fluticasone is marketed outside the U.S. for seasonal rhinitis (under the name Flixonase), and topical fluticasone is marketed in the U.S. as Cutivate cream and ointment for inflammation and pruritis associated with corticosteroid- responsive dermatoses. The topicals were approved in December 1990 ("The Pink Sheet" Dec. 24, 1990, T&G-1). An inhaled formulation of fluticasone for asthma is slated for its first overseas filing in the first quarter 1992. Sykes said the NDA filing in the U.S. should happen "by the end of 1993." Glaxo's long-pending, twice-daily oral albuterol sulfate anti- asthma medication Volmax is "approvable" at FDA. The company received the approvable letter on Oct. 31, but the product had not been approved as of Dec. 13. FDA approval of the oral version, which employs Alza's OROS oral controlled-release delivery system, has been delayed by a series of problems, including FDA's review of the now-discontinued use of methylene chloride, a carcinogen, as a solvent in the Volmax tablet-coating process. Moving to a general review of Glaxo's pipeline, Sykes highlighted three compounds in "full development": the antiretroviral 3TC; the "ultra short-acting" parenteral opioid analgesic GI 87084; and ranitidine bismuth citrate. He also spotlighted extensions to the migraine drug sumatriptan (Imitrex). The antiretroviral GR 109714 (3TC), licensed from IAF Biochem in Canada, is a potential oral treatment for asymptomatic and symptomatic HIV. Glaxo materials prepared for the analysts meeting describe 3TC as a "potent and selective inhibitor of viral reverse transcriptase" with "activity against AZT-resistant isolates." Glaxo said the drug also possesses a "potentially improved toxicity profile" compared to AZT and ddI, and has the "potential for improved dosing frequency (b.i.d.)." 3TC is in dose-escalation trials in the U.S. and is expected to enter Phase III trials by the middle of 1992, Sykes reported. Cautioning against too high expectations, he told analysts "the drug looks good . . . but has a long way to go yet." Merck and Boehringer Ingelheim both recently have reported resistance problems with some of their monotherapy reverse transcriptase inhibitors, and it appears that resistance may be a problem with the entire class ("The Pink Sheet" Dec. 2, T&G-7), although Janssen has not yet reported any viral resistance to its TIBO- derived compounds. The opioid analgesic GI 87084 is in full development for inducting and maintaining anesthesia. The compound, which is metabolized by blood esterases, has a rapid onset and offset of action with a half-life of 10 minutes, according to the Glaxo materials. Sykes predicted that the compound may be suitable for outpatient use, induction of anesthesia in hospital patients or as an "alternative" to other inhaled analgesics. Discussing the future of the 5HT, receptor agonist sumatriptan, Glaxo noted that it is developing several line extensions that include suppositories, an intranasal formulation, effervescent tablets and new auto-injector devices. Injectable sumatriptan currently uses an autojector from Owen Mumford, but Glaxo's new inhouse autoinjector will go on the market in some countries in January 1992, Sykes said. Injectable sumatriptan was recommended for approval in the U.S. by FDA's Peripheral & Central Nervous System Drugs Advisory Committee on Oct. 25. Glaxo filed the NDA for oral sumatriptan on Dec. 17, 1990. Sykes noted that six-month double-blind and one- year open label studies of the oral version have shown the same response rate, with "no attenuation" in efficacy over time. Glaxo continues to study sumatriptan for the extended indications of severe tension headache and pediatric migraine. Glaxo estimated before analysts in December 1990 that 2 bil. tension headaches occur each year. Sykes said Glaxo usually tries to have about 16 compounds in its "exploratory development" program (Phase I and Phase II trials). In the program now, Glaxo has two angiotensin A-2 antagonists for hypertension and congestive heart failure: GR 117289 and GR 138950, a "back-up" compound. Sykes commented that the angiotensin A-2 inhibitor class "could well replace ACE inhibitors," noting that these drugs have "a different target" and "different profiles." During Q&A, Sykes said the company's "hope is that A-2 will be once-a-day treatments with maybe a better safety profile than ACE inhibitors." Also in exploration is Glaxo's adenosine type-1 agonist GR 79236 for type II diabetes, which Sykes called a "completely novel" orally active compound. Explaining the adenosine type-1 agonist's mechanism of action during Q&A, Sykes said: "we're targeting type II diabetes by telling the cell to not break down fatty acids, stop sending more energy into the bloodstream, let the body use the energy that's already there so it can preferentially [use] glucose and reduce the glucose level. That's the theory." Sykes noted that the theoretical mechanism of action "could be used in reducing fat levels as an antihypolipedemic." Fat cells, he explained, "contain on their surfaces receptors for adenosine to . . . block the cell from glycolysis," which is the breakdown of "fatty acids inside the cell to liberate free fatty acids so they can be used for an energy source." Glaxo noted in its recently-released fiscal 1991 annual report that diabetes is one of several new R&D areas it is investigating. To strengthen its diabetes program, Glaxo entered into a collaboration with Amylin Corp. to develop chemical blockers of the hormone amylin for diabetes and obesity ("The Pink Sheet" Nov. 4, T&G-1). Sykes explained that amylin is believed to be a "control mechanism" that overrides insulin in type II diabetes. Therefore, the idea would be to develop amylin antagonists. In type II diabetics, Sykes reminded the audience, "it's not insulin ruling. [The diabetics are] not depleted of insulin, they're just becoming sensitive in some way. Their glucose metabolism is deranged, so although there's lots of glucose available, the cell still gets the message to produce more energy." Glaxo's serotonin 5-HT program, begun with sumatriptan and ondansetron, continues in full swing with six compounds in the exploratory phase, that is, Phase I/II trials, Sykes reported. The three 5-HT[3] compounds -- GR 81225, GR 87442 and GR 68755 -- are being studied for central nervous system indications, emesis control and irritable bowel syndrome, respectively. Glaxo has two 5-HT [1]-like agonist follow- ons to sumatriptan for migraine -- GR 85548 and GR 127607 -- that have different pharmacokinetic and pharmacodynamic properties. The company also is looking at a 5-HT[4] antagonist for irritable bowel syndrome. The CNS 5-HT[3] has been under full development for schizophrenia and the company plans to submit its first international registration in 1997. Ondansetron also continues to be investigated for two CNS indications -- age-associated memory impairment and generalized anxiety. Sykes presented data on a U.S. ondansetron study in age- associated memory impairment that used the name-face association test as a measure of efficacy. Ondansetron 1 mg twice-daily "saved six years of memory loss over three months" of treatment in a 12- week trial, Sykes said. Glaxo is predicting a first registration filing outside the U.S. for the memory impairment indication during the first half of 1993. For generalized anxiety, Phase II trial results of ondansetron 1 mg and 4 mg, diazepam 2 mg ("the standard dose in the U.K.," Sykes noted) and placebo found response rates of 59%, 57%, 58% and 45%, respectively among 50-60 patients per treatment arm. The ondansetron treatment arm showed "significant effects but no rebound and no dependency," Sykes said. The studies are ongoing and Glaxo hopes to file for marketing approval overseas by the end of 1993. Other compounds in exploratory development are GV 104326, an injectable tribactam, and GV 118819, an oral tribactam, both developed by Glaxo in Italy and both set to enter Phase I in 1992; GR 108359, a third generation oral cephalosporin; two antivirals, GR 95168 for herpes simplex-1 and varicella zoster virus, and GR 85478 for herpes simplex-1 and herpes simplex-2, both set for Phase I in 1992; GF 120918, a multi-drug resistance inhibitor out of Glaxo France for drug resistant tumors; and fluparoxan, an alpha-2 adrenoreceptor antagonist. Fluparoxan had been in Phase III trial for depression but showed no improvement in efficacy over existing therapies so was discontinued. The drug remains under study for male sexual dysfunction.

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