What Lies Beneath the Face Value of a BOX WARNING: A Deeper Look at Brodalumab

August 2018 | Volume 17 | Issue 8 | Supplement Individual Articles | 29 | Copyright © August 2018

Peter W. Hashim MD MHS,a Tinley Chen BA,a Mark G. Lebwohl MD,a Lauren B. Marangell MD,d Leon H. Kircik MDa,b,c

aThe Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, NY bIndiana University School of Medicine, Indianapolis, IN cPhysicians Skin Care PLLC, Louisville, KY dBrain Health Consultants, Houston, TX

A recent phase II clinical trial in Japanese subjects supports the lack of SIB associated with brodalumab.21 In the open label trial, 145 subjects were treated with either brodalumab 210 mg or 140 mg subcutaneously every 2 weeks. After 52 weeks, the Psoriasis Area and Severity Index (PASI)-75 rates, PASI-90 rates, and PASI-100 rates were 94.4%, 87.5%, and 55.6%, respectively, in the 210-mg group, and 78.1%, 71.2%, and 43.8% in the 140-mg group. There were no reports of suicidal ideation or suicidal behavior.Other Recent Approvals and Observations of SIBThe SIB data from other recently approved agents provides additional context for the evaluation of brodalumab. Reports of SIB have been observed among several medications, most pronounced with ixekizumab (Table 2).IxekizumabIxekizumab is a humanized IgG4 monoclonal antibody that binds with high affinity and specificity to IL-17A, therebyTable1Table2inhibiting its interaction with the IL-17 receptor. Ixekizumab was approved for the treatment of moderate-to-severe plaque psoriasis in 2016 and psoriatic arthritis in 2017.During the clinical development program of ixekizumab for psoriasis, there were 10 reports of suicide attempts in ixekizumab-treated patients, including those identified through retrospective analysis using C-CASA: 2 attempts during the induction period, 1 attempt during the maintenance period, 6 attempts during the long-term extension period, and 1 attempt during post-treatment follow-up (Table 3).22 There were additionally two reports of serious depression requiring hospitalization. There were no reports of completed suicides in patients treated with ixekizumab.All events of suicide attempts were determined by the investigator to be not related to ixekizumab due to the presence of risk factors such as undisclosed history of prior suicide attempt, depression, bipolar disorder, anxiety, alcohol/substance use or abuse, and the presence of major, acute psychosocial triggers.22 Depressive symptoms throughout the trial were captured primarily through administration of the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). An analysis of QIDS-SR16 scores demonstrated significant reductions from baseline in depressive symptoms in patients treated with ixekizumab as compared to placebo, both at the end of the induction period and at the end of maintenance period.22,23Importantly, subjects with a history of prior suicide attempts, significant uncontrolled neuropsychiatric disorders, or frequent active suicidal ideation as assessed by the QIDS-SR16 were excluded from study participation. In contrast, the brodalumab trials allowed patients with SIB risk factors at baseline to participate, thereby capturing safety data more reflective of the psoriasis population, but also impacting SIB results.Apremilast and SecukinumabClinical trials for apremilast and secukinumab have also demonstrated signals for SIB (Table 2). Among secukinumab trials, there was one completed suicide that occurred during the screening period (prior to any study drug being administered).24Among apremilast trials, one completed suicide occurred in the placebo group, with no completed suicides in the treatment group.25 There was, however, one suicide attempt with apremilast treatment (0 to ≤52 weeks).26 Post-marketing data recorded up to March 2016 showed 65 reported cases of SIB: 5 completed suicides, 4 suicide attempts, 50 cases of suicidal ideation, 5 cases of depression, and 1 case of suicidal behavior.27 In 32 of 65 cases, patients reported improvement after discontinuation of apremilast. A retrospective analysis was performed using three large patient databases (the US Food and Drug Administration Adverse Event Reporting System database, the European Medicine Agency’s EudraVigilance database, and the Northwestern Medicine EnterpriseTable3