Allergy & Immunology > Asthma
FDA Committee: Is Novel Anti-IL-5 Safe in Asthma?
FDA staff raise concerns about potentially life-threatening events with new agent
by Nancy Walsh Nancy Walsh, Senior Staff Writer, MedPage Today December 08, 2015
Two new safety signals for the monoclonal antibody reslizumab are likely to dominate the discussion at an FDA advisory committee meeting on Wednesday, a briefing document prepared by the agency's technical staff suggested.
Reslizumab targets interleukin (IL)-5 and is intended to control disease exacerbations and improve lung function among patients with eosinophilic asthma not fully controlled by inhaled corticosteroids.
Sponsor Teva Pharmaceuticals has provided the agency with data from five studies in support of the proposed indication, including two multinational yearlong clinical trials.
In those two studies, with patients receiving reslizumab or placebo in addition to standard-of-care treatment, the asthma exacerbation frequency was decreased by at least half, with rate ratios of 0.50 (95% CI 0.37-0.67) and 0.41 (95% CI 0.28-0.59, P<0.0001 for both).
However, among 1,311 patients in the five placebo-controlled studies, there were five cases of anaphylaxis -- a recognized risk with biologic drugs -- three of which were considered to be related to the treatment.
"We anticipate that during the meeting, an updated and complete analysis of anaphylaxis cases will be presented. However, the ability to adjudicate these cases definitively will be limited, as necessary data (such as post-infusion vital signs) were not captured in a prospective manner in all patients," the briefing document stated.
A further concern for anaphylaxis is that patients with severe asthma are already at elevated risk for anaphylaxis because of the disease itself.
A second safety issue expected to be discussed is elevations in creatine phosphokinase (CPK) leading to muscle adverse events. "Indeed, the prevalence of potentially life-threatening CPK elevations (>10 x upper limit of normal) was double in the reslizumab arm (0.8% compared with the placebo arm (0.4%)," the document noted.
Reported muscle events included spasms, musculoskeletal pain, myalgias, extremity pain, and rhabdomyolysis.
Teva's explanation for this event was that there was an imbalance in baseline values, but CPK measurements in the 24 hours following infusion of the monoclonal antibody were lacking.
"Whether this safety signal has been adequately characterized, or requires further investigation, will be another important topic for discussion," the document indicated.
The rationale for blocking IL-5 in asthma characterized by elevated levels of eosinophils is that this cytokine is central to the regulation of eosinophils in tissue and blood. Another anti-IL-5 monoclonal antibody, mepolizumab (Nucala), was approved last month as an add-on treatment for patients with severe asthma having an eosinophilic phenotype.
The proposed indication for reslizumab is broader, and includes patients with less severe disease that is uncontrolled on inhaled steroids and is characterized by an eosinophil count of 400 cells/μL or higher.
The proposed dosing schedule for reslizumab is 3 mg/kg, given intravenously, once monthly. Only one study evaluated an additional (0.3 mg/kg) dose, finding that both doses were significantly superior for lung function compared with placebo.
FDA staff noted in the briefing document that the available data don't make it clear whether a lower dose might have been effective, and that "study of lower doses is pertinent to the safety discussion, given the safety signals that were observed in this program. Because the mechanism behind these safety findings is unclear, and could be related to dose, it will be important for the committee to consider the limitations of the dose-ranging data when reviewing the safety findings ... and whether additional dose-ranging data might be required to address the safety signals."
Another potential concern was that efficacy was less apparent for certain subgroups of patients, including adolescents, African-Americans, and, perhaps most importantly, patients residing in the U.S. This may relate to small sample sizes, but should be addressed during the meeting.
Questions that will be voted on at the meeting include whether or not the efficacy data "provide substantial evidence of a clinically meaningful benefit of reslizumab 3 mg/kg IV once every 4 weeks for the treatment of asthma" in adults 18 and older and also in children 12 to 17, and if not, what additional data are needed; and whether the safety profile is "adequate to support approval for patients with asthma."
The FDA isn't required to follow the advice of its advisory committees, but often does.
More in Allergy & Immunology
Asthma Specialists Attack Return of Primatene Mist
Targeted Asthma Support Boosts Outcomes in Older Patients
Staph Bacteria Tied To Food Allergies in Kids
Common Skin Bacterium Linked to Food Allergy Risk in Kids