Further Mixed Results For GSK/Theravance’s Relovair Have Investors Holding Breath

GSK and Theravance released preliminary results of two Phase III studies for their COPD drug Relovair that could serve to help differentiate the drug from Advair.

Investors have been waiting with bated breath for the NDA filing of GlaxoSmithKline Inc. and Innoviva Inc.’s chronic obstructive pulmonary disease drug Relovair, which may serve as a follow-on to the blockbuster Advair. The completion of the Phase III trials brings the NDA one step closer, but mixed trial results have investors worried that approval is not a sure thing.

The British pharma and its biotech partner released further data for their Phase III program on March 23, while also reaffirming their plans to file for approval of Relovair (fluticasone furoate/vilanterol) for the treatment of COPD in the U.S. and EU by mid-year. GSK added that it will seek approval in the asthma setting in the EU this year, but is still discussing the asthma program with FDA. The news reassured some investors who were concerned that GSK had decided not to pursue the asthma indication at all after some potential safety issues and mixed efficacy results were brought to light.

The latest results released from the late-stage program of Relovair were two non-pivotal studies that compared the drug to Advair (fluticasone propionate/salmeterol) in patients with COPD. The identical 500 patient, 12-week studies evaluated 24-hour lung function through a FEV1 (forced expiratory volume in one second) breathing test. One study showed the once-daily Relovair to be statistically superior to the twice-a-day Advair (p≤0.001); the other failed to show statistically significant superiority (p=0.267), but did demonstrate improvement in breathing for Relovair patients. Further results will be released at an upcoming medical meeting.

The mixed results add to what is already a mixed bag of trials. In mid-January, results were announced from two Phase III 52-week exacerbation studies each enrolling 1,620 patients and comparing three doses of fluticasone/vilanterol (200/25 mcg, 100/25 mcg and 50/25 mcg) to vilanterol alone in a step-wise manner. In both studies, all doses of the combination demonstrated reductions in the annual rate of moderate to severe exacerbations compared to vilanterol monotherapy, but the highest dose was not statistically significant in the second study, causing the Theravance stock to tank. The stock is still down 15% this year. There were also concerns about fatal pneumonia in the COPD studies, which GSK said it is investigating. Most of the cases, however, were in the highest dose, which will not be submitted to regulatory authorities (Also see "Relovair Data Raises Respiratory Stakes For GSK And Theravance" - Pink Sheet, 16 Jan, 2012.).

Theravance stock increased slightly on the news of the non-pivotal trials, adding almost 5% to close at $19.47. Meanwhile GSK’s American depository receipts that trade on the New York Stock Exchange slid less than a percentage point to $45.12.

“We believe that superiority to Advair is a high hurdle and success in even one of these studies is a meaningfully positive data point,” said Brean, Murray, Carret & Co. analyst Brian Skorney. “We believe Relovair has now demonstrated two advantages to Advair: greater improvement in lung function and better dosing.”

Bernstein analyst Ronny Gal suggested in a March 23 research note that the “significant gap” between the results of the two studies would help to further illustrate how difficult it is to conduct trials in the disease setting and would help make a positive approval case for Relovair with FDA.

Like Advair, Relovair is a long-acting beta2 agonist/corticosteroid combination. Advair brings in sales of more than $8 billion annually, but could face generic competition in coming years now that its active ingredient has lost patent protection. GSK has been successful in staving off the hordes of generic companies that would like a piece of the Advair market due to the uncertainty surrounding bioequivalence standards for inhaled respiratory drugs. The device patents for the popular Diskus inhalation device used with Advair have been extended to 2016, helping to keep companies like Teva Pharmaceutical Industries Ltd. and Novartis AG’s Sandoz International GMBHunit from coming up with a viable generic alternative for the drug (although Teva could have a candidate up for approval as early as 2014).

The two studies just announced will not be used to support the regulatory filings of Relovair, but will likely be used to help differentiate Relovair further from Advair in the marketplace. “The idea is that gaps in the data elsewhere may be overcome by arguing that there is cumulative evidence Relovair is clinically more efficacious. We note that the current trial follows on an earlier one which showed numerically better (p=0.28) Relovair efficacy versus the high dose of Advair (500/50) on FEV at 12 weeks,” wrote Gal.

Relovair In Asthma

Further data meant to support the asthma program was also announced on March 23. The Phase III registrational study of 330 patients with persistent asthma evaluated the steroid in Relovair, fluticasone furoate (FF), versus the steroid in Advair, fluticasone propionate (FP), and placebo. The 24-week study showed that both demonstrated statically significant efficacy compared to placebo when measuring trough evening FEV1.

“We strongly suspect GSK will submit the steroid as a standalone for first line treatment in asthma,” wrote Gal. “We note Theravance will not get royalties on the FF alone, but presumably patients stepping up from FF to combination therapy will preferentially use Relovair.”

FDA is broadly concerned about the safety of LABAs for the treatment of asthma after data linked the products to severe asthma exacerbations, hospitalizations and death. Last year, the agency announced it would require clinical trials for existing LABAs approved for asthma (Also see "FDA Supersizes Its Order For LABA Safety Studies" - Pink Sheet, 15 Apr, 2011.).

GSK and Theravance are working together to develop two additional respiratory products, vilanterol in combination with GSK’s long-acting muscarinic antagonist GSK573719, and a bifunctional long-acting inhaled bronchodilator that combines both muscarinic antagonist and beta2 antagonist activities in one agent.

The two companies have been closely tied since entering into a collaboration in 2002 for the LABA development. The relationship was later expanded in 2004 when GSK paid $129 million upfront and increased its stake in the company from 6% to 19% in exchange for the right to license any new medicines that the biotech develops. While GSK’s stake in the company has fluctuated over the years, it currently stands as Theravance’s largest investor with 15.7 million shares, or about 19% (Also see "GSK Boosts Stake In Theravance, An Apparent Nod To The Biotech's Respiratory Portfolio" - Pink Sheet, 29 Nov, 2010.).