FDA Panel Backs Approval of Psoriasis Drug Brodalumab

Alicia Ault

July 20, 2016

A US Food and Drug Administration (FDA) advisory panel has backed a new biologic for psoriasis, though the panelists recommended strong warnings about the potential for suicide and self-injurious behavior (SIB) with the drug.

The FDA's Dermatologic and Ophthalmic Drugs Advisory Committee voted 18-0 yesterday to approve brodalumab (Siliq, Valeant Pharmaceuticals) for the treatment of adults with chronic, moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Most of the panel members said brodalumab should have strongly worded warnings — potentially a boxed warning — and be accompanied by an extensive risk management program. But they also voiced strong support for the drug's effectiveness.

The FDA usually follows its panels' advice.

No currently approved psoriasis drug has a warning in the label about the potential for self-injurious behaviour (SIB) or suicide. Valeant recorded six suicides in some 6200 patients who took brodalumab across all of its studies: four in psoriasis trials and one each in trials for rheumatoid arthritis and psoriatic arthritis.

"You might have expected one to two, given past experience," said Erica Brittain, PhD, deputy branch chief of the Biostatistics Research Branch at the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. "We can't say for sure there isn't a problem, but it's unknown what it means," said Dr Brittain.

Julie M. Zito, PhD, a professor of psychiatry at University of Maryland, Baltimore, said that the suicide rate is "on the order of about three and a half times greater" than with placebo. She called the suicide numbers "a signal," but Dr Zito and other panellists, along with the FDA staff, said there was not enough data to tie brodalumab to suicide or SIB.

"To me, it's a suggestion, not a signal," said Lynn A. Drake, MD, a dermatology lecturer at Harvard Medical School, Boston, Massachusetts. Dr Drake strongly advocated for approval. "We have a drug here that is hopefully at some level a bit of a game changer and could really help these patients," she said. "I'd like to see this drug out and about."

Ken Katz, MD, MSc, MCSE, a dermatologist at Kaiser Permanente, San Francisco, California, said he, too, was concerned about the higher risk for suicidal ideation and SIB, "but I don't think it should preclude moving forward with the medication."

Dr Katz called Valeant's proposal for risk mitigation "reasonable" but said he did not believe creating or joining a registry would provide any additional information. Physicians will likely steer clear of prescribing brodalumab to patients at risk for SIB, which would lead to ascertainment bias, said Dr Katz.

Valeant is proposing letters and fact sheets for physicians and patients, a patient wallet card with information on where to get help, a website, and a medication guide. It also is in discussions to join the Corrona psoriasis registry, said Tage Ramakrishna, MD, Valeant's chief medical officer.

Reasons for Suicides Debated

The FDA, Valeant and its consultants, and the panel members all discussed the potential reasons for suicidal ideation or attempts in the trials. All noted that depression and suicidality are higher in patients with psoriasis. Those at risk were not excluded from brodalumab trials. At baseline, 17% of those taking brodalumab had psychiatric disorders and 23% had moderate to severe depression or anxiety.

FDA staff said that the limited control period during the studies — 12 weeks for the three pivotal phase 3 trials — made it difficult to reach conclusions. Patients taking brodalumab who had a history of psychiatric disorders, however, had an 18-fold increase in SIB incidence compared with those without a history, said FDA reviewers.

The FDA's division of psychiatric drug products said the six suicides were higher than would be typically seen in a large psychiatric drug trial, which gave some panellists pause.

Four of those who completed suicide had a history of psychiatric problems. But two were screened — after the company began using the electronic self-rated version of the Columbia Suicide Severity Rating Scale — and showed no signs of SIB.

Most of the committee members said they did not see any biological reason why brodalumab would lead to increased suicide but that it could not be ruled out.

Effectiveness Not an Issue

The committee members were unanimous that brodalumab was highly effective and that its benefits outweighed its risks. The drug, a monoclonal antibody (IgG2) that binds to human interleukin (IL)-17 receptor A and blocks the activities of IL-17A, IL-17C, IL-17F, IL-17A/F heterodimer, and IL-25. It is to be given by subcutaneous injection at 210 mg (140 mg/mL, 1.5 mL prefilled syringe) for 3 weeks, followed by subsequent doses every 2 weeks.

In psoriasis, "there remains a significant unmet medical need," said Elaine H. Morrato, DrPH, MPH, associate professor at the Colorado School of Public Health, Aurora. "We saw evidence that many patients had dramatic effect in using the product," she said.

Data from two of the three pivotal phase 3 psoriasis studies — Study of Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Subjects (AMAGINE-2) and (AMAGINE-3) — was published in the October 1, 2015, issue of the New England Journal of Medicine, as reported by Medscape Medical News.

In those trials, slightly more than 3700 adults (mean age, 45 years; close to 70% male and about 90% white) with moderate to severe psoriasis were randomly assigned to one of three regimens: brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight of 100 kg or less and 90 mg for patients heavier than 100 kg), or placebo.

At week 12, patients given brodalumab were again randomly assigned to receive a maintenance dose every 2, 4, or 8 weeks. Those in the ustekinumab group continued to receive that drug every 12 weeks, and those in the placebo group began to receive brodalumab every 2 weeks.

At week 12, the psoriasis area and severity index (PASI) 75 (a 75% reduction in symptoms from baseline) response rates were higher with brodalumab at both doses than with placebo (86% and 67%, respectively, vs 8% in AMAGINE-2; and 85% and 69%, respectively, vs 6% in AMAGINE-3; P < .001).

Valeant emphasized the PASI 100 score — which represents total clearance — in its presentation to the committee, claiming that no other drug had approached brodalumab's efficacy. At week 12, the PASI 100 response rates with the 210-mg dose of brodalumab were 44% in AMAGINE-2, compared with 22% for ustekinumab, and 37% vs 19% in AMAGINE-3 (P < .001).

The FDA, however, reported a 41% PASI 100 rate across all brodalumab studies, compared with 38% for ustekinumab.

The agency is due to make a decision on approval by November 16, according to Valeant. The drug was recently approved in Japan.

"I am very pleased that the Advisory Committee has recommended that this life-changing treatment should be available to psoriasis patients who require a treatment with brodalumab's unique mechanism of action, and I look forward to prescribing this therapy to patients who are suffering from the devastating effect of moderate to severe plaque psoriasis," said Mark Lebwohl, MD, chairman of the dermatology department, Mount Sinai School of Medicine, New York, New York, in a statement issued by Valeant.

Dr Lebwohl was a lead investigator in the pivotal studies and also presented to the advisory committee.

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