GSK's Nucala For COPD Faces Questions On Efficacy Results, Missing Data

US FDA advisory committee will consider impact of trial design, given that GSK did not collect asthma histories and chronic oral corticosteroid use information from its COPD study participants.

The US FDA is questioning the efficacy data and other information supporting the addition of a potentially novel COPD indication to GlaxoSmithKline PLC's Nucala (mepolizumab) in advance of a July 25 advisory committee review of the supplemental application.

Nucala is seeking a claim as an add-on treatment to inhaled corticosteroid-based maintenance treatment for reduction of exacerbations in patients with chronic obstructive pulmonary disease guided by blood eosinophil counts. The anti-interleukin-5 monoclonal antibody already approved for treatment of severe asthma in patients 12 years and older with the eosinophilic phenotype. (Also see "Birth Of A Biomarker? FDA Doesn't Define Eosinophilic Asthma, Defers To Docs On Nucala" - Pink Sheet, 21 Mar, 2016.)

Among the questions that FDA has for its Pulmonary-Allergy Drugs Advisory Committee is the validity of the biomarker; Nucala would be the first product approved for treating COPD patients based on blood eosinophil count.

FDA raised many concerns in its briefing document, including that only one of GSK's two Phase III trials showed a statistically significant reduction in moderate to severe exacerbations in patients with high eosinophil counts using the proposed dose of 100 mg subcutaneous every four weeks, compared to placebo. There also was no dose response between 100 mg and 300 mg of Nucala. The second trial did not show a statistically significant reduction in exacerbations for the 100-mg dose or a 300 mg dose.

GSK Says Data Is 'Clinically Important' To Patients 

"The lack of replication" and the fact that the higher dose did not achieve statistical significance "raises questions about the efficacy of mepolizumab for the proposed indication," the agency wrote in the briefing document.

Secondary endpoints also did not support the primary endpoint. FDA said data such as time to first moderate-to-severe COPD exacerbation showed numerical trends in favor of mepolizumab, but the differences were not consistent between the proposed dose and placebo.

GSK argued that the improvements shown are meaningful to patients. The company wrote in its briefing document that the proposed dose showed a consistent and clinically relevant reduction in moderate to severe exacerbations of 18%-20%. GSK said that the improvement is "clinically important" to the subgroup of COPD patients in the high stratum (blood eosinophil count greater than 150 cells/microliter).

"The mepolizumab-eligible COPD patient receiving [inhaled corticosteroid]-based triple therapy and who presents with an eosinophilic phenotype is likely to be severely debilitated and suffer from a poor [health-related quality of life], therefore the therapeutic efficacy demonstrated is clinically meaningful," GSK wrote in its briefing document.

The company decided to file the Nucala COPD application despite the questionable Phase III results and FDA previously acknowledging the eosinophil biomarker was challenging.  (Also see "Glaxo Set To File Nucala In COPD, Despite Mixed Phase III Results" - Pink Sheet, 12 Sep, 2017.)

Lack Of Asthma, Corticosteroid Data A Concern

Also among FDA concerns was that GSK did not collect baseline information on the asthma history and chronic maintenance oral corticosteroid use for each patient in the studies. Given Nucala already is approved for severe asthma, the agency wrote that including many subjects with severe asthma could impact the results.

FDA said asthma-related adverse events appear in the safety database, suggesting there were patients with active asthma in the trials.

"Any observed benefit of mepolizumab on exacerbations could be driven primarily or entirely by an effect in patients with concomitant asthma, given that asthma exacerbations and COPD exacerbations are not well differentiated clinically," FDA said in the briefing document.

"The lack of data collection surrounding asthma, however, does not allow further evaluation of effects within subgroups defined by asthma history," the agency added. "This raises challenges in identifying what proportion of the observed results are due to mepolizumab’s effects on asthma rather than potential effects on eosinophilic COPD, and in defining the group of patients that might benefit from mepolizumab."

FDA also said that maintenance oral corticosteroid (OCS) use raises additional challenges in interpreting the trials, in part because they can reduce peripheral blood eosinophil levels, which could influence how patients were classified in one trial and if they were included in the second.

"Because data on asthma history and maintenance OCS use were not collected, it is not possible to explore whether rates or imbalances between trial arms in either asthma history or [oral corticosteroid] use might explain observed differences in outcomes between treatment arms," the agency wrote.

GSK wrote in its briefing document that the development program's entry criteria were designed according to international guidelines for diagnosis of COPD and implemented by investigators who were experts in COPD management.

"The resultant enrollment was a COPD population similar to other COPD registration programs and different from a severe asthma population," GSK said in the document.

Committee members will discuss "the potential effect of unmeasured variables," including asthma history and oral corticosteroid use, as well the lack of statistically significant results for the primary endpoint, during the meeting.

The draft questions include votes on whether the data provide substantial evidence of efficacy, whether safety data are adequate to support approval, and whether the risk-benefit profile is adequate to support approval. If not, committee members are asked what data are needed.

Eosinophilic Phenotype In COPD To Be Discussed

FDA also wants the committee to discuss the eosinophilic COPD phenotype, including the relevance of peripheral blood eosinophils in COPD patients.

The agency wrote in its briefing document a key question is whether the entry criteria for patients into the mepolizumab studies based on baseline and historical eosinophil thresholds were appropriate to determine mepolizumab's benefit. FDA also wrote that there are no prior successful clinical programs using the IL5 pathway in COPD patients to draw from experience. The agency said the existing information in hand raises questions about the target, citing AstraZeneca PLC's Fasenra (benralizumab), which did not show efficacy in reducing COPD exacerbations in two Phase III trials among patients with the eosinophil phenotype.

In AZ's TERRANOVA trial, Fasenra did not meet its primary endpoint of a statistically significant reduction of exacerbations in patients with moderate to very severe COPD. It also failed in the similar GALATHEA trial, which had the same primary endpoint. (Also see "All Over For AZ's Fasenra In COPD With Second Trial Fail" - Scrip, 30 May, 2018.)

FDA's goal date for Nucala is Sept. 7 or earlier.