Two investigational bronchodilators stemming from the Beyond Advair collaboration between GlaxoSmithKline and Theravance will move forward in clinical development after they were shown to improve bronchodilation in patients treated once daily at levels similar to GSK's Serevent (salmeterol) twice daily in Phase IIb studies released April 2.

The long-acting beta2 agonist compounds are GSK642444, discovered by GSK, and GSK159797, discovered by Theravance.

In an April 3 conference call elaborating on the Phase IIb study results, Theravance CEO Rick Winningham said, "In particular, we were very pleased with the results of '444 dosed once daily, which demonstrated greater 24-hour bronchodilator activity than salmeterol dosed twice daily and was well tolerated."

GSK/Theravance plan to pursue '444 as the lead compound in the program and will initiate 28-day studies in a larger patient population in asthma later this year and in chronic obstructive pulmonary disease next year. The companies will pursue dose-ranging studies of '797 as a backup compound.

Phase III trials are currently targeted for the latter half of 2008, Winningham said.

Salmeterol is the LABA used in GSK's corticosteroid combination drug Advair (salmeterol/fluticasone). The goal of the Beyond Advair collaboration - dating back to 2002 - is to develop a once-daily inhaled combination LABA and corticosteroid for the treatment of asthma and COPD (¹ Also see "Theravance IPO Would Fund Phase III Telavancin Antibiotic Trials" - Pink Sheet, 28 September, 2004.).

The randomized, crossover, double-blind, placebo- and active-controlled trials evaluated the safety and efficacy of three inhaled doses each of '444 and '797 over 14 days in approximately 55 patients controlled on inhaled corticosteroids. The studies evaluated improvement in FEV1 (forced expiry volume in one second) over baseline corticosteroid therapy with once daily doses of the compounds compared to salmeterol, given twice daily.

All doses of '444 (25, 100 and 400 micrograms) showed greater broncodilator activity than salmeterol dosed twice a day on day 14. All doses of '797 demonstrated comparable bronchodilator activity to salmeterol on day 14.

The two lower doses of '444 also produced smaller changes in placebo-adjusted, weighted mean heart rate over salmeterol over the first four hours after dosing on day 14. The heart rate effect was comparable to salmeterol for the lowest dose of '797, the company reported.

"Regarding safety, I am pleased to report that both compounds exhibited pharmacodynamic profiles similar to other inhaled long-acting beta agonists with little impact on heart rate at selected doses," Theravance Senior VP-Development Michael Kitt said.

Schering-Plough and Novartis are also racing to develop the first once-daily, fixed-dose combination asthma treatment combining a LABA and oral corticosteroid. The drug makers signed a deal to develop and commercialize a combination of Novartis' investigational LABA indacaterol and Schering-Plough's marketed corticosteroid Asmanex (mometasone) for asthma and COPD last year (² Also see "Schering/Novartis To Develop Once-Daily Inhalation Combination For Asthma, COPD" - Pink Sheet, 14 August, 2006.).

In 2005, FDA issued a public health advisory stating that long-acting beta agonist bronchodilators such as Serevent, Advair and Novartis/Schering's Foradil should be used as a second-line treatment for asthma patients due to a potential for asthma-related deaths (³ Also see "Serevent, Advair, Foradil Relegated To Second-Line For Asthma Patients" - Pink Sheet, 18 November, 2005.).

-Jessica Merrill (j.merrill@elsevier.com)

GSK/Theravance Target 2008 Phase III Start For Next-Gen Bronchodilators

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