Original article
Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials

https://doi.org/10.1016/j.jaad.2017.08.024Get rights and content

Background

Individuals with psoriasis are at increased risk for psychiatric comorbidities, including suicidal ideation and behavior (SIB).

Objective

To distinguish between the underlying risk and potential for treatment-induced psychiatric adverse events in patients with psoriasis being treated with brodalumab, a fully human anti–interleukin 17 receptor A monoclonal antibody.

Methods

Data were evaluated from a placebo-controlled, phase 2 clinical trial; the open-label, long-term extension of the phase 2 clinical trial; and three phase 3, randomized, double-blind, controlled clinical trials (AMAGINE-1, AMAGINE-2, and AMAGINE-3) and their open-label, long-term extensions of patients with moderate-to-severe psoriasis.

Results

The analysis included 4464 patients with 9161.8 patient-years of brodalumab exposure. The follow-up time–adjusted incidence rates of SIB events were comparable between the brodalumab and ustekinumab groups throughout the 52-week controlled phases (0.20 vs 0.60 per 100 patient-years). In the brodalumab group, 4 completed suicides were reported, 1 of which was later adjudicated as indeterminate; all patients had underlying psychiatric disorders or stressors.

Limitations

There was no comparator arm past week 52. Controlled study periods were not powered to detect differences in rare events such as suicide.

Conclusions

Comparison with controls and the timing of events do not indicate a causal relationship between SIB and brodalumab treatment.

Section snippets

Clinical studies

Psychiatric AE data were gathered from 5 psoriasis clinical trials in the brodalumab development program: a phase 2, randomized, double-blinded, placebo-controlled, dose-ranging study (ClinicalTrials.gov identifier, NCT00975637)15; an open-label, long-term extension of the phase 2 study (NCT01101100)19; and three phase 3, randomized, double-blind, controlled trials (AMAGINE-1 [NCT01708590],17 AMAGINE-2 [NCT01708603],16 AMAGINE-3 [NCT01708629])16 and their open-label long-term extensions. There

Brodalumab exposure

Through the end of the studies, 4464 patients with psoriasis received 1 or more doses of brodalumab. Most of these patients (n = 2337) received variable doses of brodalumab (without ustekinumab exposure); 1304 received overall brodalumab, 210 mg every 2 weeks (≥75% of doses were 210 mg); 256 received overall brodalumab, 140 mg every 2 weeks (≥75% of doses were 140 mg); and 567 received brodalumab, 210 mg every 2 weeks after ustekinumab exposure. Because of the nature of the study design, 4126

Discussion

Given the prevalence of SIB risk factors among individuals with psoriasis5, 6, 7, 8 and at baseline in brodalumab clinical trials, it is not surprising that SIB events occurred in the brodalumab trials and that most patients with SIB events during the brodalumab trials had a history of predisposing risk factors. The rate of SIB events with brodalumab was similar to that observed with placebo or ustekinumab during the induction phase and comparable to that with ustekinumab during the first year

References (32)

  • A. Singhal et al.

    Risk of self-harm and suicide in people with specific psychiatric and physical disorders: comparisons between disorders using English national record linkage

    J R Soc Med

    (2014)
  • M. Pompili et al.

    Suicide risk and psychiatric comorbidity in patients with psoriasis

    J Int Med Res

    (2016)
  • E. Hrehorow et al.

    Patients with psoriasis feel stigmatized

    Acta Derm Venereol

    (2012)
  • O. Arican et al.

    Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity

    Mediators Inflamm

    (2005)
  • P.S. de Oliveira et al.

    IL-17A, IL-22, IL-6, and IL-21 serum levels in plaque-type psoriasis in Brazilian patients

    Mediators Inflamm

    (2015)
  • M.H. Davami et al.

    Elevated IL-17 and TGF-beta serum levels: a positive correlation between T-helper 17 cell-related pro-inflammatory responses with major depressive disorder

    Basic Clin Neurosci

    (2016)

    • Cited by (0)

    Funding sources: None.

    Disclosure: Dr Mark Lebwohl is an employee of Mount Sinai, which receives research funds from Amgen, Anacor Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Eli Lilly, Janssen Biotech, Kadmon Corporation, LEO Pharma, MedImmune, Novartis, Pfizer, Sun Pharmaceutical Industries, and Valeant Pharmaceuticals North America LLC. Dr Papp has served as a consultant, scientific officer, or member of a speaker's bureau, advisory board, or steering committee or received research grants or honoraria from AbbVie, Akesis Pharmaceuticals, Akros, Allergan, Alza Corporation; Amgen, Anacor Pharmaceuticals, Artax Biopharma; Pharma, AstraZeneca, Baxter, Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, Can-Fite BioPharma, Celgene Corporation, Celtic Pharma, Cipher Pharmaceuticals, Dermira, Dow Pharma, Eli Lilly, Ferring Pharmaceuticals, Formycon AG, Forward Pharma A/S; Fujisawa Pharmaceuticals, Funxional Therapeutics, Galderma SA, Genentech, Genexion SA, Genzyme Corporation, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Kyowa Hakko Kirin, LEO Pharma, MedImmune, Meiji Seika Pharma, Merck (Merck Sharp and Dohme), Merck Serono, Mitsubishi Tanabe Pharma, Mylan, Novartis, NovImmune SA, Pan-Genetics Pharmaceutical Corporation, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi-Aventis US, Stiefel Laboratories, Takeda Pharmaceuticals, UCB, Valeant Pharmaceuticals North America, and Vertex Pharmaceuticals. Dr Marangell is a former employee and stockholder of Eli Lilly and a paid consultant for Valeant Pharmaceuticals North America. Dr Koo is a speaker, advisor, and consultant for Pfizer, Anacor, Novartis, Celgene, Janssen, Eli Lilly, Photomedex, Regeneron, Amgen, Sun, Valeant Pharmaceuticals North America LLC, LEO, AbbVie, and Galderma. Dr Blauvelt has served as a scientific adviser and clinical study investigator for AbbVie, Aclaris Therapeutics, Allergan, Almirall, Amgen, Boehringer Ingelheim, Celgene Corporation, Dermavant, Dermira, Eli Lilly, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, LEO Pharma, Merck, Novartis, Pfizer, Purdue Pharma, Regeneron Pharmaceuticals, Sandoz, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharmaceutical Industries, UCB, Valeant Pharmaceuticals North America, and Vidac, and he has served as a paid speaker for Eli Lilly, Janssen, Regeneron Pharmaceuticals, and Sanofi Genzyme. Dr. Gooderham has been an advisory board member, clinical investigator, and/or speaker for AbbVie, Akros, Amgen, Boehringer Ingelheim, Celgene Corporation, Dermira, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Kyowa Hakko Kirin, LEO Pharma, Eli Lilly, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Sun Pharmaceuticals Industries, Takeda Pharmaceuticals, UCB, and Valeant Pharmaceuticals North America LLC. Dr. Wu is an investigator for AbbVie, Amgen, Eli Lilly, Janssen Pharmaceuticals, Novartis, and Regeneron Pharmaceuticals. Dr Rastogi, Ms Harris, and Dr Israel are employees of Valeant Pharmaceuticals North America LLC and may hold stock and/or stock options in the company. Dr Pillai is an employee of Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals North America LLC) and may hold stock and/or stock options in the company.

    View full text
    © 2017 by the American Academy of Dermatology, Inc.