The U.S. FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee voted unanimously for the approval of Valeant Pharmaceuticals’ Siliq (brodalumab). The full FDA is expected to make a decision on approval of the drug by mid-November this year.
Support for the psoriasis treatment drug was accompanied by strongly worded warnings about the drug’s connection to potential for suicide and self-injurious behavior (SIB), as well as recommendations for an extensive risk management program.
The drug, recently approved in Japan, is a monoclonal antibody that binds to human interleukin (IL)-17 receptor A and blocks the activity of several forms of this molecule and also IL-25. IL-17 is a pro-inflammatory cytokine that has been previously implicated in the development of psoriasis.
Siliq was shown to be highly effective and beneficial in several clinical trials, observations that led the FDA committee to agree that the drug’s benefits outweigh its risks.
“There remains a significant unmet medical need,” said Elaine H. Morrato, DrPH (doctorate in public health), MPH, associate professor at the Colorado School of Public Health, about the state of research in psoriasis. “We saw evidence that many patients had a dramatic effect in using the product,” she said.
Siliq, to be given by subcutaneous injection at 210 mg (140 mg/mL, 1.5 mL prefilled syringe) for three weeks, followed by subsequent doses every two weeks, was studied in three pivotal Phase 3 studies, the AMAGINE clinical program.
Data from two of them, 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 New England Journal of Medicine in October 2015.
Such studies compared the efficacy of the drug to Stelara (ustekinumab), also a monoclonal antibody that is an FDA-approved treatment for psoriasis.
About 3,700 adults with moderate to severe psoriasis were randomly assigned to one of three treatment regimens: Siliq (210 mg or 140 mg every two weeks), Stelara (45 mg for patients with a body weight of 100 kg or less and 90 mg for patients heavier than 100 kg), or a placebo.
The company was especially confident with the efficacy results due the psoriasis area and severity index (PASI) 100 score, which represents total clearance or 100 percent reduction in symptoms from baseline. According to Valeant, no other drug has approached this efficacy. At week 12 of treatment, the PASI 100 response rates with Siliq were 44 percent in AMAGINE-2, compared with 22 percent for Stelara, and 37 percent vs 19 percent, respectively, in AMAGINE-3.
The concern regarding potential dangerous side effects comes from the six suicides reported among the 6,200 participants across all studies of the drug: four in psoriasis trials and one each in trials for rheumatoid arthritis and psoriatic arthritis. This rate of suicide, higher than that typically observed in clinical trials for psychiatric drugs, generated discussions among committee members.
It is important to note that depression and suicide are higher in patients with psoriasis. Before the trials, 7 percent of those taking Siliq had psychiatric disorders and 23 percent had moderate to severe depression or anxiety. Two of the patients who committed suicide were screened and presented no signs of SIB. The short duration of the studies also makes it difficult for conclusions to be drawn.
“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 Dr. Tage Ramakrishna, MD, Valeant’s chief medical officer.
“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 Dr. Mark Lebwohl, MD, lead investigator of the pivotal studies and chairman of the dermatology department at Mount Sinai School of Medicine, in a statement issued by Valeant.