Neuropsychiatric Adverse Events in Brodalumab Psoriasis Studies Mark Lebwohl,1 Kim A. Papp,2 Jashin J. Wu,3 Andrew Blauvelt,4 Alan Menter,5 Shipra Rastogi,6 Radhakrishnan Pillai,7 Robert Israel8 1Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Probity Medical Research, Waterloo, Ontario, Canada; 3Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA; 4Oregon Medical Research Center, Portland, OR, USA; 5Baylor University Medical Center, Dallas, TX, USA; 6Ortho Dermatologics, Bridgewater, NJ, USA; 7Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals North America LLC), Petaluma, CA, USA; 8Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA 2017 Fall Clinical Dermatology Conference® • October 12-15, 2017 • Las Vegas, NV INTRODUCTION • Psoriasis has profound psychosocial implications that can affect the ability of patients to socialize with family members, interact with coworkers, and make friends1 • Psychiatric comorbidities, such as depression and anxiety, are common in patients with psoriasis2,3 • Suicidal ideation has been reported in as many as 17.3% of patients with psoriasis compared with 8.3% of healthy controls4 • Brodalumab is a monoclonal antibody that targets interleukin-17 (IL-17) receptor A and is indicated for the treatment of psoriasis5 • Brodalumab has demonstrated efficacy in the treatment of plaque psoriasis5,6 • Reports of suicide in patients with psoriasis enrolled in clinical trials for brodalumab led to concerns that brodalumab may be linked to psychiatric adverse events (AEs)6,7 OBJECTIVE • To assess psychiatric AEs and improvements in depression and anxiety in patients with psoriasis treated with brodalumab in clinical trials METHODS Clinical studies • Efficacy and safety of brodalumab (140 or 210 mg every 2 weeks [Q2W]) were investigated in one phase 2 trial and in three phase 3, multicenter, randomized trials of patients with moderate-to-severe plaque psoriasis (AMAGINE-1/-2/-3)5,6 • In the phase 3 studies, more than 80% of patients were being treated with brodalumab 210 mg Q2W by the end of the week 52 controlled period • There were no specific exclusion criteria for psychiatric disorders or substance abuse Endpoints • The hospital anxiety and depression scale (HADS), which determines anxiety and depression on a 21-point scale each, was measured in AMAGINE-1 • The dermatology life quality index (DLQI) assesses the socio-psychological impact of the skin disease8 on patients’ lives and was measured in AMAGINE-1/-2/-3 • Data on psychiatric AEs were pooled for all trials and were summarized as follow-up time–adjusted event rates – The follow-up time–adjusted event rate is the total number of events reported during the follow-up observation time divided by total patient-years of observation; this includes gaps and interruptions in exposure and time beyond the exposure period RESULTS • Mean HADS anxiety and depression scores significantly improved with brodalumab compared with placebo by 12 weeks (Figure 1) • Mean DLQI significantly improved with brodalumab compared with placebo by 12 weeks (Figure 2) • Rates of psychiatric adverse events were comparable between treatments at week 52 and did not increase with long-term treatment (Table 1) • There were 22 suicidal ideations (follow-up time–adjusted rate, 0.24), 6 suicide attempts (0.07), 3 completed suicides (0.03), and 1 additional suicide adjudicated as indeterminate (Table 2) • Two suicidal ideation and behavior (SIB) events (suicide attempts) were reported in 1 patient treated with brodalumab during the 12-week induction phase (0.03%; 1/3066) • Follow-up time–adjusted rates of SIB were greater in patients with a history of depression compared with those without (1.42 and 0.21 per 100 patient-years, respectively) • Follow-up time–adjusted rates of SIB were greater in patients with a history of suicidality compared with those without (3.21 and 0.20 per 100 patient-years, respectively) • Of the 3 completed suicides, all patients were receiving brodalumab 210 mg, had baseline risk factors, and had demonstrated clinical responses (PASI ≥73; Table 3) – Time-to-event from first dose ranged from 140 to 845 days. Follow-up time–adjusted SIB rates through week 52 were lower in the brodalumab group compared with the ustekinumab group, with overlapping CIs (0.20 [0.08, 0.41] vs 0.60 [0.12, 1.74]) – Long-term rates of SIB with brodalumab were slightly higher (0.37 [0.26, 0.52]) compared with those through week 52, with no increase in the completed suicide rate (0.04 [0.01, 0.11] vs 0.06 [0.01, 0.20]) Table 2. Integrated Analysis of Follow-up Time–Adjusted Patient Incidence Rates of SIB Events Through Week 52 and in Long-term Follow-up 52-week poola Long-term poolb Ustekinumab (N=613; pt-yr = 503.6) n (r) [95% CI] Brodalumab (N=4019; pt-yr = 3545.7) n (r) [95% CI] Brodalumab (N=4464; pt-yr = 9161.8) n (r) [95% CI] Suicidal ideation adverse event 1 (0.20) [0.01, 1.11] 3 (0.08) [0.02, 0.25] 22 (0.24) [0.15, 0.36] Suicidal behavior adverse event Completed suicidec Intentional self-injury Suicide attempt Suicidal behavior 1 (0.20) [0.01, 1.11] 0 (0.00) [0.00, 0.73] 0 (0.00) [0.00, 0.73] 1 (0.20) [0.01, 1.11] 0 (0.00) [0.00, 0.73] 4 (0.11) [0.03, 0.29] 2 (0.06) [0.01, 0.20] 1 (0.03) [<0.01, 0.16] 1 (0.03) [<0.01, 0.16] 0 (0.00) [0.00, 0.10] 15 (0.16) [0.09, 0.27] 4 (0.04) [0.01, 1.11] 1 (0.01) [0.00, 0.06] 6 (0.07) [0.02, 0.14] 4 (0.04) [0.01, 1.11] Overall suicidal ideation and behavior 2 (0.40) [0.05, 1.44] 7 (0.20) [0.08, 0.41] 34 (0.37) [0.26, 0.52] SIB, suicidal ideation and behavior. aCumulative events through the 52-week, controlled treatment period. bIncludes events in the 52-week treatment period and the uncontrolled open-label extension. cIncludes fatal event reported as intentional overdose that was adjudicated as indeterminate. Table 1. Incidence of Psychiatric Adverse Events Occurring in ≥0.1% of Patients Treated With Brodalumab During the Initial Placebo-Controlled Study Perioda Preferred term, n (%) Placebo (N=879) Ustekinumab (N=613) Brodalumabb (N=3066) Psychiatric disorders SOC 16 (1.8) 12 (2.0) 61 (2.0) Insomnia 6 (0.7) 4 (0.7) 17 (0.6) Depression 5 (0.6) 3 (0.5) 14 (0.5) Anxiety 2 (0.2) 2 (0.3) 13 (0.4) Libido decreased 0 (0) 0 (0) 5 (0.2) Depressed mood 1 (0.1) 2 (0.3) 3 (0.1) Mood swings 0 (0) 0 (0) 3 (0.1) Stress 1 (0.1) 0 (0) 3 (0.1) SOC, system organ class. aIncludes data from the placebo-controlled phase 2 study, AMAGINE-1, AMAGINE-2, and AMAGINE-3. bAll brodalumab dose groups combined. Table 3. Summary of Completed Suicides (Known and Unknown Cause) Age, y/Sex Brodalumab dose Clinical response (PASI score) Clinical information 59/Male 210 mg 100 • 329 days after first dose of brodalumab • History of financial stressors (lost disability due to brodalumab response and unable to find work) 39/Male 210 mg 73 • 140 days after first dose of brodalumab • Informed investigator he had legal difficulties and was likely to be incarcerated • Family reported he killed himself, means unknown 56/Male 210 mg 100 • 845 days after first dose of brodalumab • Ongoing treatment for depression and anxiety • Described recent stress and isolation due to relocation Indeterminate case 56/Male 210 mg 100 • History of depression; on antidepressant and benzodiazepine • 97 days after first dose of brodalumab • Toxic levels of mixed opiates compatible with ingestion of poppy seed tea and methadone; therapeutic level of citalopram, elevated alprazolam, and alcohol • HADS baseline depression and anxiety score decreased from 15 to 2 and 14 to 6, respectively, 2 weeks before the event • Ruled indeterminate by C-CASA adjudication C-CASA, Columbia classification algorithm of suicide assessment; HADS, hospital anxiety and depression scale; PASI, psoriasis area and severity index. Figure 1. Shifts in HADS severity for (A) depression and (B) anxiety at week 12 in patients who scored moderate or severe at baseline in the AMAGINE-1 trial. Improve Improve to normal Stay the same Worsen Pa tie nt s w ith s hi ft s in se ve ri ty g ro up s, % * 60 0 40 20 80 100 A B Placebo Brodalumab 140 mg Q2W Brodalumab 210 mg Q2W Depression Pa tie nt s w ith s hi ft s in se ve ri ty g ro up s, % * 60 0 40 20 80 100 Placebo Brodalumab 140 mg Q2W Brodalumab 210 mg Q2W Anxiety HADS, hospital anxiety and depression scale; Q2W, every 2 weeks. Shifts in HADS severity at week 12 in patients who scored “moderate” or “severe” at baseline. *Data are shown as observed; percentages do not add up to 100%. Figure 2. DLQI 0/1 response rate at week 12 in patients from the AMAGINE-1, -2, and -3 trials. Placebo Ustekinumab Brodalumab 140 mg Q2W Brodalumab 210 mg Q2W R es po ns e ra te , % 30 0 20 10 50 70 40 60 AMAGINE-1 5% 5% 44% 44% 7% * 43% * 56% * 47% * 43% * 59% * 61% NA AMAGINE-2 AMAGINE-3 DLQI 0/1 response to treatment DLQI, dermatology life quality index. DLQI response = score 0/1. *P<0.001 vs placebo. Acknowledgments: This study was sponsored by Ortho Dermatologics. Medical writing support was provided by MedThink SciCom and funded by Ortho Dermatologics. References: 1. Krueger et al. Arch Dermatol. 2001;137:280-284. 2. Dowlatshahi et al. J Invest Dermatol. 2014;134:1542-1551. 3. Kurd et al. Arch Dermatol. 2010;146:891-895. 4. Dalgard et al. J Invest Dermatol. 2015;135:984-991. 5. Lebwohl et al. N Engl J Med. 2015;373:1318-1328. 6. Papp et al. Br J Dermatol. 2016;175:273-286. 7. Danesh and Kimball. J Am Acad Dermatol. 2016;74:190-192. 8. Lewis and Finlay. J Investig Dermatol Symp Proc. 2004;9:169-180. CONCLUSIONS • Mean HADS anxiety and depression scores were reduced from baseline in patients with moderate- to-severe plaque psoriasis receiving brodalumab • A higher patient satisfaction and quality of life was observed with brodalumab compared with placebo, as determined by DLQI response rate • Rates of SIB at week 52 in patients treated with brodalumab were similar to those treated with the active comparator ustekinumab, and SIB rates did not increase with long-term treatment • No pattern emerged between timing of the events and the initiation or withdrawal of brodalumab • Controlled data do not suggest a causal relationship between brodalumab treatment and SIB © 2017. All Rights Reserved. 7407_FCDC SIB encore poster_M1-2.indd 1 10/2/17 4:51 PM FC17PosterValeantLebwohlNeuropsychiatricAdverseEffectsPsoriasis.pdf