A preliminary analysis by FDA staff has found that a potential risk of suicide with the investigational psoriasis medication brodalumab (Siliq, Valeant Pharmaceuticals) is challenging to assess because of limited data, according to a Reuters report. The review precedes a July 19 meeting of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee, which will offer an opinion on whether the drug should be approved.
Brodalumab is a monoclonal antibody (immunoglobulin G2) that binds to human interleukin-17 receptor A (IL-17RA) and blocks the biologic activities of IL-17A, IL-17C, IL-17F, IL-17A/F heterodimer, and IL-25. The product will be administered by prefilled syringe (PFS) for subcutaneous administration at 210 mg (140 mg/mL, 1.5 mL PFS) at zero, one, and two weeks, with subsequent doses administered every two weeks. Valeant is seeking approval of brodalumab for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
According to a briefing document prepared by the FDA staff, the efficacy of brodalumab for the treatment of psoriasis was supported by the three pivotal phase 3 placebo-controlled clinical trials; two of these trials also included an ustekinumab comparator arm. The studies enrolled subjects 18 to 75 years of age and older with stable moderate-to-severe plaque psoriasis diagnosed at least six months before the first dose of the investigational product. The enrolled subjects had plaque-type psoriasis with Psoriasis Area and Severity Index (PASI) scores of 12 or greater, static Physician’s Global Assessment (sPGA) scores of 3 or greater, and body surface area (BSA) involvement of 10% or greater at baseline. In all of the studies, brodalumab was superior to placebo (P < 0.001) for the coprimary endpoints (PASI 75 and sPGA of 0 or 1) as well as for the secondary endpoints (PASI 100, sPGA of 0, and Psoriasis Symptom Inventory [PSI]) at week 12.
The safety review of brodalumab presented challenges, however. Late into the clinical studies, four completed suicides occurred in the phase 3 clinical trials. A total of six completed suicides were reported in all brodalumab clinical trials (four in psoriasis, one in rheumatoid arthritis, and one in psoriatic arthritis); one of these suicides was later adjudicated as indeterminate because of possible accidental drug overdose. Valeant terminated the phase 3 studies early, thereby preventing further assessment of the drug’s safety.
In addition to the suicide issues, the increase in IL-17 that results from IL-17 receptor blockade could theoretically affect cardiovascular outcomes and major cardiovascular adverse events, the briefing document notes. It has been hypothesized that IL-17 receptor inhibition may lead to an increase in other cytokines involved in inflammation, thereby resulting in an increase in major adverse cardiac events (MACE). A review of the clinical trial data by the FDA’s Division of Cardiology and Renal Products did not support a direct association of brodalumab with MACE given the small number of events observed during the relatively brief placebo-controlled periods of the phase 3 trials. In addition, a review of the available literature was unclear with regard to the mechanistic action through which brodalumab could increase the risk of MACE.
The FDA staff concluded: “The biologic effects of the resulting increase in serum IL-17A and its interaction with other cytokines are not well understood; however, the available data raise concerns about a potential interaction with cytokines in the central nervous system and an impact on cardiovascular atherosclerosis. Limited controlled data in the brodalumab development program for these uncommon events makes the assessment of risk–benefit for brodalumab challenging.”