FDA Panel Backs Reslizumab for Adults With Severe Asthma

Marcia Frellick

December 10, 2015

The monoclonal antibody reslizumab was recommended for approval by the US Food and Drug Administration's (FDA's) Pulmonary and Allergy Drugs Advisory Committee yesterday for use in treating adults aged 18 years and older with moderate to severe asthma.

The committee said safety and efficacy data weren't strong enough for it to recommend approval of the drug for children aged 12 to 17 years.

As to whether the safety and efficacy data support approval of the monoclonal antibody at a dose of 3 mg/kg by intravenous injection once every 4 weeks, the committee voted 11 to 3 in favor of treating adults and a resounding no (14 to 0) for children.

The meeting was called to discuss the biologics license application for reslizumab for injection, submitted by Teva Pharmaceutical Industries Ltd to reduce exacerbations, relieve symptoms, and improve lung function for people 12 years old and older with asthma and elevated blood eosinophils whose condition is inadequately controlled with inhaled corticosteroids.

Reslizumab is not currently marketed in the United States or any other country. If approved by the FDA, it would be the third monoclonal antibody approved for asthma, after mepolizumab and omalizumab. Reslizumab binds to human interleukin-5 (IL-5). Several cytokines can affect eosinophils, but IL-5 is the main cytokine involved in regulating blood and tissue eosinophils.

Separate Votes on Safety, Efficacy

Separate efficacy and safety votes were taken. Regarding whether the efficacy data showed clinically meaningful benefit, the vote was 13 yes and 1 no for adults; there were 14 no votes for proof that it benefits children.

As to whether the safety profile was adequate to support approval for adult patients with asthma, the committee voted yes, 11 to 3.

Lack of confidence in the data on safety and efficacy for children aged 12 to 17 years largely boiled down to the low numbers of children studied: 16 children in the placebo group and 19 in the reslizumab group.

The primary evidence of efficacy in those with moderate to severe asthma is based on findings from three phase 3, randomized, double-blind, placebo-controlled studies in the target population with elevated blood eosinophils.

In all three studies, the target population met the primary endpoints of improvement of forced expiratory volume in 1 second (FEV1) at 16 weeks and reduction in the annual rate of clinical asthma exacerbation. In addition, reslizumab consistently improved FEV1 and patient-reported asthma control.

Anaphylaxis and Muscle Toxicity

Earlier discussion of safety concerns centered on two main points: risk for anaphylaxis (3 of 1028 patients in the reslizumab group had an anaphylactic reaction attributed to the drug vs 0 patients in the placebo group) and muscle toxicity.

Kathleen M. Donohue, MD, a medical officer and clinical reviewer with the Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) for the FDA, said, "Anaphylaxis and muscle toxicity have emerged as important safety signals in the reslizumab program."

Tushar Shah, MD, senior vice president for research and development at Teva, said the safety profile was acceptable. He said that "by reducing eosinophilic inflammation, treatment with reslizumab improves asthma control. It treats both current impairments, such as symptoms and lung function, as well as future risk by reducing asthma exacerbations."

Dr Shah said anaphylactic reactions were uncommon and are designated as an adverse drug reaction of reslizumab. Because it is administered as an intravenous infusion under the supervision of a healthcare professional, any events are considered manageable, he said.

Yanling Yu, PhD, was among those voting against approval. She said, "The signal for anaphylaxis cannot be ignored." Although the number in the study who had a reaction is small, the numbers at risk in the general population would grow, she noted.

John E. Connett, PhD, also voted against approval. "I do have concerns about safety with regard to general populations," he said. "I think suggested remedies would be to conduct a systematic review or meta-analysis of data and to have fairly strong labeling that includes some warnings about what the side effects might be and postmarketing surveillance."

According to slides presented at the meeting, Teva states it is committed to informing physicians and patients on the risk through labeling.

Meeting a Need

Regardless of the outcome when the FDA makes its final decision, all agree this population needs treatment options.

Banu Karimi-Shah, MD, clinical team leader with the FDA's DPARP, said, "It is estimated about 5% of the asthma population has severe asthma with an eosinophilic phenotype despite being on maximum therapy, and many of these patients are on oral corticosteroids are still uncontrolled."

"Patients with severe uncontrolled asthma are more likely to experience frequent asthma exacerbations and hospitalizations because of asthma. Thus, development of safe and effective therapies targeted to this subpopulation is an important therapeutic step in improving asthma outcomes," Dr Karimi-Shaw said.

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