Glaxo Relenza Program Will Address Diskhaler Ease of Use, Drug Efficacy

Glaxo plans to monitor patient experience with its Relenza Diskhaler through an "active" Phase IV program for the inhaled antiviral influenza treatment. FDA approved Relenza July 27.

Glaxo will develop and implement "an active program for detecting consumer problems with the drug/Diskhaler delivery device in the potentially broader, though less systematically monitored, population of patients using the Diskhaler as actually marketed," FDA said in its approval letter for Relenza.

Glaxo plans to gather feedback from patients and doctors who have experience with Relenza (zanamivir), asking subjects how easy the device was to use and if the whole course of medication was completed. The company will also assess drug efficacy in treating the flu in the general population.

In clinical trials, the first dose of Relenza was administered under supervision and instruction. Correct use of the device from the initial dose is essential as Relenza has been proven effective only when administered within 48 hours of symptom onset, labeling notes.

Labeling, which recommends two inhalations twice daily for five days, includes a bolded statement emphasizing that patients should be instructed in the use of the diskhaler, including a demonstration whenever possible.

Glaxo will begin tracking the diskhaler's performance this winter. Patient and physician monitoring data, as well as information obtained through a post-marketing study of patient instructions for using the diskhaler, will be the basis of further revisions to Relenza labeling "to improve clarity of instructions and effective use," FDA said.

Glaxo's Phase IV commitments include the development of a plan for providing educational materials to healthcare providers. The company says it will provide sample diskhalers as well as leaflets, booklets and training videos to healthcare providers to assist them in training patients.

During the Relenza review by FDA's Antiviral Drugs Advisory Committee Feb. 24, committee members and FDA Medical Officer Barbara Styrt, MD, questioned whether Relenza might demonstrate lower efficacy in practice than in clinical trials due to the challenge of correctly operating the diskhaler device.

Since correct delivery within two days of symptom onset is essential to Relenza's efficacy, "even a short learning curve could have a substantial impact on treatment effect," Styrt told the committee (¹ (Also see "Provision Of Relenza Placebo Inhalers To Doctors, Pharmacists Planned" - Pink Sheet, 1 Mar, 1999.)).

FDA's approval of Relenza runs contrary to the advisory committee's recommendation, which ended in a 13-4 vote against approval of the flu treatment.

Many committee members expressed "reluctance" as they voted against approval, suggesting that Relenza's efficacy could probably be more clearly shown in studies targeting specific high-risk populations or in studies evaluating the drug in other aspects of flu care such as prophylaxis.

FDA took the unusual step of publicly disseminating a memo explaining its approval rationale when it cleared Relenza for marketing (² (Also see "Relenza Cmte. Concerns Addressed In Labeling & Phase IV - FDA's Jolson" - Pink Sheet, 2 Aug, 1999.)).

Following the committee meeting, FDA extended Relenza's six-month priority review deadline from late April to late July to give Glaxo an opportunity to respond to the advisory committee review. FDA stipulated specific additional information in a March 17 letter to the company.

The first neuraminidase inhibitor to receive FDA approval, Relenza is slated for launch this fall in time for the 1999-2000 flu season.

The drug may have competition in its first season on the market, however: Roche and Gilead are projecting an autumn launch for the flu pill Tamiflu (oseltamivir, GS 4102), which is under priority review at FDA with a user fee deadline of October 29. Roche said it was using the Relenza review as a roadmap to avoid pitfalls in its submission (³ (Also see "Roche Oseltamivir Flu Pill Heads To September Advisory Committee" - Pink Sheet, 21 Jun, 1999.)).

Relenza is indicated for treatment of uncomplicated acute illness due to influenza virus in adults and adolescents 12 years and older who have been symptomatic for no more than two days. Labeling notes that "this indication is based on studies in which the predominant influenza infections were influenza A, and a limited number of patients with influenza B were also enrolled."

FDA advisory committee members had expressed concern about the small number of influenza B patients in the Relenza trials. Clinical trials of Relenza included 1,036 patients with influenza A and 128 with influenza B. Labeling indicates that despite the difference in the number of patients in each subgroup, "there was no consistent difference in treatment effect."

Glaxo will provide "additional information on the safety and efficacy of zanamivir in treatment and prevention of influenza B, as well as influenza A, and comparisons between types and subtypes" under its Phase IV commitments. Since influenza B represented approximately 25%-40% of the flu circulating in the U.S. in the last season, Glaxo expects more information on Relenza and influenza B to be available after data analysis is complete.

Glaxo plans to file for supplemental use of Relenza for prevention of influenza in the fourth quarter of 1999, based on an 800-subject study of influenza transmission among families and a study of transmission among 1,107 individuals.

In the latter study, reported in the July 7 issue of the Journal of the American Medical Association, zanamivir 10 mg inhaled once daily for 28 days was 67% efficacious in preventing laboratory-confirmed clinical influenza. Glaxo said it is still evaluating what it will do promotionally with the JAMA reprint.

The availability of Relenza for flu treatment will not obviate the need for immunization with the traditional flu vaccines, and "use of zanamivir should not affect the evaluation of individuals for annual influenza vaccination," labeling cautions.

If Relenza labeling is amended in the future to carry a prophylaxis indication, it will likely include a prominent statement emphasizing the importance of influenza vaccination as recommended by the Center for Disease Control's Advisory Committee on Immunization Practices, Glaxo indicated.

The two flu therapies currently available, Forest's Flumadine (rimantadine) and Endo's Symmetrel (amantadine), are both labeled for treatment and prophylaxis but are only indicated for influenza A. Labeling for both products notes that annual vaccination remains the "method of choice" for prophylaxis.

Glaxo's clinical trials of Relenza utilized the endpoint of time to improvement in major symptoms, defined as an absence of fever and self-assessment of "none" or "mild" for headache, myalgia, cough and sore throat.

Glaxo's Phase III Southern Hemisphere trial in 321 influenza-positive patients demonstrated a 1.5-day difference in median time to symptom improvement among patients on Relenza compared to placebo. A Phase II and Phase III study in North America in over 600 influenza positive patient suggested an up to one-day reduction in median time to symptom improvement, "although statistical significance was not reached in either of these studies," labeling notes.

Advisory committee members questioned why Relenza's North American study did not demonstrate statistical significance. Labeling refers to the discrepancy between results in Relenza's three Phase III trials, noting that the variation in treatment effect between studies may be associated with "population-related factors including amount of symptomatic relief medication used."

In Relenza's Phase IV studies, FDA requested further information on the safety and efficacy of zanamivir in North American patients from ongoing Relenza trials as well as a "presentation of results in North American subpopulations of other ongoing studies with sufficient North American enrollment."

In the memo explaining FDA's rationale for approving Relenza, Division of Antiviral Drug Products Director Heidi Jolson, MD, maintained "I do not believe that the lack of a conclusive finding in the North American study negates the robust demonstrations of efficacy in the European and Southern Hemisphere studies, particularly given the inherent difficulties in conducting trials for this indication." The European study found a 2.5 day difference in symptom duration between Relenza and placebo.

Jolson pointed out that although she agreed that the North American trial results were "inconclusive in providing definitive evidence of efficacy...this modest treatment benefit, approximately one-day on average, is likely to be clinically relevant when viewed within the context of an illness that lasts approximately 6-7.5 days among placebo recipients." She said that because European results were not replicated elsewhere, those findings are likely to be "an overestimate of the treatment effect that providers can reasonably expect."

Glaxo submitted NDA 21-036 for Relenza Oct. 27, 1998. Relenza is licensed from Melbourne, Australia-based Biota Holdings.