GSK’s Anoro Ellipta Needs CV Postmarket Study, FDA Panel Says In Endorsement

Pulmonary-Allergy Drugs Advisory Committee votes in favor of what could become the first-approved LAMA/LABA combo for COPD but wants postmarket safety study in patients with more severe cardiovascular disease.

FDA advisors voted 11-2 in favor of approval of GlaxoSmithKline PLC’s Anoro Ellipta for chronic obstructive pulmonary disease Sept. 10, but said the novel combination treatment needs a post-market requirement to better characterize cardiac safety concerns in patients who are more severely ill than those evaluated in clinical trials.

Despite favoring the drug’s approval, many members of the Pulmonary-Allergy Drugs Advisory Committee also said the drug should come with a caution about using the drug in severe cardiovascular disease patients.

The companies are seeking approval of Anoro Ellipta, a long-acting muscarinic antagonist (LAMA)/long-acting beta 2-adrenergic (LABA) combination of umeclidinium (UMEC) 62.5 mcg and vilanterol (VI) 25 mcg inhalation powder, for the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD. Anoro Ellipta is the further along of any LAMA/LABA combination seeking U.S. approval. The drug, which has a Dec. 18 user fee goal date, will be marketed by GSK; it was developed in partnership with Innoviva Inc.

VI was approved in May as part of GSK’s fix-dosed combination with fluticason fuorate, Breo Ellipta while UMEC has not been cleared by the agency alone or in combination with another treatment (Also see "GSK’s Breo Ellipta Approved With COPD Airflow Obstruction, Exacerbation Claims" - Pink Sheet, 10 May, 2013.).

Both classes of drugs have raised safety concerns by FDA including the cardiovascular effects of LABAs and concerns about increased cardiovascular events and strokes with LAMAs (Also see "Forest Tudorza Pressair Approval For COPD Includes Post-marketing CV Safety Study" - Pink Sheet, 23 Jul, 2012.).

While efficacy data was not an issue for the advisory committee – it voted 13-0 that the efficacy data provide substantial evidence of a clinically meaningful benefit for Anoro Ellitpa’s proposed indication – unease about cardiac safety dominated Anoro’s panel review.

In briefing documents released ahead of the panel, FDA noted that in general Anoro’s cardiovascular safety analyses were mostly unremarkable, but it did find some imbalances in adverse events that favored placebo when examining subsets of data. It wanted the committee to weigh in on whether these imbalances constitute a safety signal (Also see "GSK Anoro Ellipta Appears Poised For Smooth Advisory Panel; Is First LAMA/LABA On Horizon?" - Pink Sheet, 6 Sep, 2013.).

At the Sept. 10 meeting FDA’s clinical reviewer Jennifer Pippins said Anoro’s adverse event profile was generally consistent with those of other LABAs and LAMAs, but added that the data are complex and not easily interpretable.

GSK VP C. Elaine Jones said the company does not believe the small imbalances in cardiac events seen in the clinical trials suggest a drug-effect relationship.

Positive Safety Vote Masks Committees Cardiovascular Concerns

The committee voted 10-3 that the safety of the drug was adequately demonstrated for the proposed indication, with the majority feeling comfortable with the drug’s safety in the population studied in the company’s clinical studies.

Anoro Ellipta’s NDA contained safety data from the company’s four primary efficacy trials, which included two 6-month, placebo-controlled efficacy and safety trials, two 6-month active controlled efficacy and safety trials as well as a 12-month safety trial that evaluated a higher dose of the drug than is currently up for approval.

Advisory Committee Votes

• 13-0 that the efficacy data provide substantial evidence of a clinically meaningful benefit for UMEC/VI 62.5/25 mcg once daily for the long-term, maintenance treatment of airflow obstruction in COPD
• 10-3 that the safety profile of UMEC/VI 62.5/25 mcg once daily in COPD has been adequately demonstrated for the proposed indication
• 11-2 that the efficacy and safety data provide substantial evidence to support approval of UMEC/VI 62.5/25 mcg once daily for the long-term, maintenance treatment of airflow obstruction in COPD.

These trials did not specifically exclude patients with cardiovascular disease. However, FDA’s Pippins said that patients who in any way had cardiovascular disease that would be considered unstable would not have been included.

And both the primary efficacy studies and the safety study included exclusion criteria that prohibited patients with a significant abnormal ECG finding on the 12-lead ECG obtained at visit 1 in the study and prohibited patients with a significant abnormal finding on the 24-hour Holter monitoring conducted at visit 1.

The safety study was also designed to enroll a more stable COPD patient population than the primary efficacy studies, FDA said.

The overall low rate of cardiac events in the clinical trials, combined with the exclusion criteria, led nearly all committee members – not just those voting no on safety – to express concerns about the applicability of the safety data to sicker patients.

“I would feel a little uneasy based on the data presented that if I had a patient with uncontrolled congestive heart failure that I could necessarily generalize these data to include those patients,” Panel Chair David Jacoby, division of pulmonary and critical care medicine at Oregon Health and Science University, said. “It seems to me if [congestive heart failure patients] were included in all these [study] groups we would be seeing higher numbers of cardiac events,” in all of the treatment groups, including placebo, Jacoby said.

Jacoby, who did ultimately vote in support of the safety data, said he questioned whether patients with more severe cardiovascular disease were underrepresented or whether the reporting procedures for cardiac events were inadequate. He recommended post-marketing studies to look more closely at adverse events in patients with severe cardiovascular disease as well as labeling that warns about the drug’s use in such patients.

GSK said they would expect sicker patients to have more cardiac events, but also noted those patients would have lots of spontaneous events that are not necessarily related to the therapy. Studies with sicker patients would be very noisy, the company added.

GSK also said that about 60% of the patients studied had cardiovascular risk factors and were taking a cardiovascular medication. It did acknowledge only about 5% of patients had a history of myocardial infarction and the company said it didn’t have numbers on the percent of patients studied who had congestive heart failure.

Trial Criteria Gave “Illusion” Of Studying CV Patients

James Stoller, who voted no on safety and also no on the drug’s approval, said the trials’ inclusion/exclusion criteria was contradictory and that given the high prevalence of cardiac mortality in patients with COPD it will be imperative to better characterize cardiovascular patients studied with the drug.

Stoller said he was troubled that the study included patients at cardiovascular risk, but excluded patients with ECG abnormalities at baseline. “While it gives the illusion of being inclusive it provides a backstop such that one cannot include the very population at risk.”

He said patients should have a very careful characterization of cardiac risk at baseline of every parameter possible in order to make an intelligent statement about a cardiovascular risk signal with the drug.

Stoller also requested further study of patients with more severe COPD, such as those who meet the Gold IV criteria and patients on oxygen. More severe COPD patients he said were clearly underrepresentated because the studies restricted patients who used oxygen for more than 12 hours a day. According to FDA, about 10% percent of patients studied were classified as Gold IV while the rest were Gold II or III.

Further, Stoller raised concerns that Anoro data showed cardiovascular safety imbalances with the lower dose of UMEC, but not the higher dose. “There’s certainly little evidence that makes a definitive statement about the absence of a safety risk, nor is there definitive evidence of a clear cut safety risk. So I’m struggling in this no-man’s land of inadequate data to assuage the concern,” he said.

Unlike the majority, Stoller believes additional data should be acquired prior to marketing approval because he said that when drugs have been withdrawn from the market due to safety signals it has usually taken a long time and exposed many patients to risk.

Francis McCormack, University of Cincinnati School of Medicine’s Director of the Division Of Pulmonary, Critical Care And Sleep Medicine, also supports approval “within the context of appropriate labeling and post-marketing studies.” He said would like to see post-marketing safety studies focus on U.S. patients as a large fraction of patients in the clinical trials were from other countries that have difference incidents of cardiovascular events compared to the U.S.

Erik Swenson, a pulmonary and critical care specialist at the University of Washington, voted no on safety, but for approval because he trusted the agency and sponsor would deal with the concerns in post-marketing; he also wanted studies to address COPD patients with concomitant renal problems.

The advisory committee meeting came at a critical time for GSK, as FDA just released draft bioequivalence guidelines for generic manufacturers looking to copy the company’s blockbuster asthma and COPD treatment Advair Diskus (fluticasone/salmeterol) (Also see "Advair Bioequivalence Guidance Falls Short of GSK’s Requests" - Pink Sheet, 9 Sep, 2013.).