GLAXO SALMETEROL NDA FILING PLANNED FOR MID-1991 FOLLOWING FDA OKAY ON EUROPEAN DATA; GLAXO WILL SELL ANTI-EMETIC ZOFRAN THRU HOSPITAL FORCE

Glaxo is forecasting a mid-1991 NDA filing for its twice-daily asthma inhaler product salmeterol. That filing would occur a year ahead of schedule and is due in part to FDA's willingness to accept data from European clinical trials.

Commenting on the salmeterol development during the Oct. 18 opening ceremonies for the firm's new R&D facility in Research Triangle Park, N.C., Glaxo, Inc. Exec VP Robert Ingram said FDA agreed at an Oct. 7 meeting with the company to "accept all of our foreign data" on the long-acting beta-2 agonist bronchodilator. "Hence we won't have to replicate that data here in the United States. We think that picks us up at least a year in terms of the filing; and we would expect to file, probably, mid-year next year."

Salmeterol has been in Phase III trials in the U.S. A product registration was filed overseas in March for both dry powder and aerosol formulations. The product is seen by Glaxo as a treatment for moderate to severe asthma, with an 80-90% control rate with twice-daily dosing based on foreign trial results.

FDA acceptance of Glaxo's non-U.S. clinical data for salmeterol would be an important boost for the company's effort to build a worldwide regulatory registration program. Glaxo is publicly describing the coordination of worldwide clinical trials as one of its key objectives to prepare for the post-Zantac period. If FDA does not accept data designed for multiple registrations, it would have a chilling effect on the project.

Prior to the salmeterol decision by FDA, Glaxo publicly touted a change in attitude at the agency. Glaxo Group Research Medical Director Goran Ando, MD, told an industry meeting last month that the FDA's acceptance of foreign data was showing "fantastic" progress. ("The Pink Sheet" Sept. 17, T&G-15).

At a June 1990 R&D update, Glaxo Director, Respiratory Clinical Research James Palmer described salmeterol as "not another Ventolin" (albuterol sulfate) ("The Pink Sheet" June 11, T&G-10). Salmeterol is being portrayed as an addition to the chronic therapies currently available: cromolyn sodium, steroids and theophyllines.

Glaxo is "very encouraged by the prospects for a quick review" on its other second generation asthma medication, fluticasone propionate, Ingram declared. The company has had "some discussions with FDA already on this compound," he noted. The anti-inflammatory steroid is in Phase II in the U.S. as a prophylactic inhaler formulation for moderate to severe asthma.

Meanwhile, the NDA for the albuterol formulation Volmax is still pending at FDA. Volmax had been delayed by a series of problems, including the now-discontinued use of the carcinogen methylene chloride as a solvent in the tablet-coating process. Glaxo is predicting that the drug may be approved before year-end.

Four near-term drugs in development are tops on Glaxo's highlight list as having clear therapeutic advantages over existing treatments. In addition to the two asthma products, the company continues to highlight sumatriptan for migraine and ondansetron (Zofran) for chemotherapy-induced nausea and vomiting.

The NDA for subcutaneous injectable sumatriptan, Glaxo's 5HT-1-like agonist for migraine and cluster headaches, has been on file with FDA since mid-year. The NDA for tablet form is set for filing in December. Ingram indicated that FDA may be giving sumatriptan expedited review as a significant improvement over existing migraine therapies. Noting that the sumatriptan NDA was a computerized filing, Ingram said the compound "is clearly viewed within the agency as a clear therapeutic advance, receiving a high priority." Glaxo "is very optimistic that we'll get a very efficient review of sumatriptan," Ingram said. Glaxo is putting sumatriptan marketing projections for the U.S. at the end of 1992 or early 1993.

Self-administration of the injectable does not appear to the company to be a major hurdle for clearance or market acceptance of the product. The firm projects that the subcutaneous form will be approved before the oral form. Sumatriptan tablets, which have a slower response time, are seen as more appropriate for those who can anticipate migraine attacks, have less severe attacks or do not suffer from nausea.

Glaxo told financial analysts in June that participants in its 3,000-patient trial of subcutaneous sumatriptan who had administered the drug by a pre-filled syringe auto-inject pen had a lower incidence of transient stinging that when the drug was injected by medical personnel and that there were no toxicity problems and no real potential for overdose ("The Pink Sheet" June 4, p. 8). Sumatriptan is being closely watched as a major next generation product for Glaxo after Zantac. Ranitidine, as the world's biggest selling prescription drug, had sales of $2.4 bil. for the fiscal year ended June 30.

Ondansetron and sumatriptan also represent Glaxo's effort to add a fourth major specialty to the existing GI, antibiotic and respiratory classes. The products are seen as springboards for putting Glaxo in the central nervous system area.

Ondansetron is pending at FDA as an I.V. anti-emetic and was recommended for approval by an FDA advisory committee in May. While noting the pitfalls of predicting FDA timetables, Ingram said: "We feel fairly confident that Zofran will in fact be approved this calendar year." The NDA for an oral delivery form was filed in August.

Glaxo plans to detail Zofran to oncologists using its existing hospital sales force. The company feels the market is concentrated at a relatively few cancer centers nationwide; however, as CNS drugs in its pipeline draw nearer to marketability, the company is considering creating a specialized CNS sales force. Glaxo has about 1,860 U.S. sales reps, with incremental growth to 2,000 planned by the end of the fiscal year.

Ondansetron's anti-emesis indication is but the tip of the iceberg for 5HT3 antagonists and for other CNS products. Glaxo has ondansetron and other 5HT3s in full development for a number of CNS indications, including schizophrenia (Phase II), anxiety, Alzheimer's disease and other age-related cognitive declines, alcohol, nicotine and benzodiazepine dependence. Additionally, the alpha-2 adrenoreceptor blocker fluparoxan is in clinicals as an antidepressant. Glaxo is preparing a core registration document for fluparoxan and has said it expects to file around the second half of 1993.

The Oct. 18 opening ceremonies culminated work on Glaxo's $350 mil. project to expand R&D facilities in North Carolina. The company announced recently that it is consolidating corporate discovery programs in cancer, inflammatory and metabolic diseases at the Research Triangle Park facility and shifting cardio-vascular projects to Glaxo Group Research in the U.K., which also handles respiratory and central nervous system research programs ("The Pink Sheet" Oct. 15, T&G-8).

The new facility comprises some 130 acres of Glaxo, Inc.'s 422-acre campus. The facility will eventually house 1,200 scientists and research support personnel. Currently, Glaxo has about 180 discovery and 550 development phase researchers in the U.S. The first phase of five buildings, begun in 1988, will be supplemented by another five buildings set to be completed by November 1991.

The first fruit of Glaxo's U.S. research efforts is GI87084, a painkiller supplement to general anesthesia in short- to medium-length surgical procedures, such as outpatient surgery. The compound is ready to enter Phase I and is about to be proposed for full development.