Efficacy and safety of brodalumab in patients with psoriasis who had inadequate responses to ustekinumab: subgroup analysis of two randomized phase 3 trials R.G. Langley,1 A.W. Armstrong,2 M.G. Lebwohl,3 A. Blauvelt,4 S. Hsu,5 S. Tyring,6 S. Rastogi,7 R. Pillai8 and R. Israel9 1Dalhousie University, Halifax, Nova Scotia, Canada; 2University of Southern California, Los Angeles, CA, USA; 3Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Oregon Medical Research Center, Portland, OR, USA; 5Temple University School of Medicine, Philadelphia, PA, USA; 6University of Texas Health Science Center, Houston, TX, USA; 7Ortho Dermatologics, Bridgewater, NJ, USA; 8Dow Pharmaceutical Sciences, Petaluma, CA, USA; 9Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA British Journal of Dermatology. DOI: 10.111/bjd.17318

Robert G. Langley

Introduction What’s already known? Among biologics used to treat psoriasis, brodalumab has a unique mechanism of action by antagonizing interleukin-17 receptor A In the AMAGINE-2/-3 randomized controlled trials, brodalumab demonstrated superior skin clearance efficacy and safety compared with ustekinumab as induction therapy in patients with psoriasis Brodalumab is approved for the treatment of moderate-to-severe psoriasis in adults who have experienced treatment failure or loss of response on other systemic therapies 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 65-70 (What is already known about this topic?)

Objective To evaluate the efficacy and safety of brodalumab through week 52 in patients who had inadequate responses to ustekinumab 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 160-163 (Second to last paragraph in Study Design)

Methods (1) AMAGINE-2 and AMAGINE-3 are two phase 3 trials comparing the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to-severe plaque psoriasis1 Inclusion criteria: aged 18 to 75 years Psoriasis area and severity index ≥12 static physician’s global assessment score ≥3 involvement of ≥10% of body surface area In this post hoc analysis, the groups analyzed were patients who remained on brodalumab or ustekinumab for the full 52-week study duration and those who switched treatment at 16 weeks because of nonresponse (see following slide for study design) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 135-136 (first paragraph in Study Design) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 136-139 (first paragraph in Study Design) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 146-148 (second paragraph in Study Design) 1. Lebwohl et al. N Engl J Med 2015;373:1318-1328.

Methods (2) Study design for AMAGINE-2/-3.1 Treatment arms in grey boxes were not included in this analysis. aPatients who were not rescued because of adequate response at week 16. bPatients who continued on brodalumab 210 mg Q2W following inadequate response after week 16. cPatients who were not rescued because of adequate response at week 16. dPatients who continued on ustekinumab following inadequate response after week 16. ePatients who were rescued with brodalumab 210 mg Q2W following inadequate response at week 16. Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks 6687 Efficacy in Ustekinumab Failures -12-2.docx – Figure 1 + Legend 1. Lebwohl et al. N Engl J Med 2015;373:1318-1328.

Methods (3) The primary efficacy objective of this post hoc analysis was to compare the efficacy of brodalumab rescue treatment at week 52, in patients with inadequate response to ustekinumab at week 16 versus ustekinumab continuation in patients with inadequate responses to ustekinumab after week 16, using rates of improvement in psoriasis area and severity index score of at least 75% (PASI 75), 90% (PASI 90) and 100% (PASI 100) from baseline Patient-reported health outcomes were also assessed using Dermatology life quality index (DLQI) Psoriasis symptom inventory (PSI) responses Efficacy analyses were adjusted for baseline total body weight, prior biologic use, geographic region, and baseline value group 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 160-165 (third paragraph in study design) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 200-204 (statistical analysis)

Results (1) At week 12, PASI 75, PASI 90 and PASI 100 response rates for brodalumab and ustekinumab were lower in patients who were eventually rescued or who remained on maintenance therapy after week 16 following inadequate responses compared with response rates in those who were not rescued Among patients who experienced inadequate response to ustekinumab, those rescued with brodalumab had PASI 75, PASI 90 and PASI 100 response rates of 72.6%, 58.1% and 36.3%, respectively, at week 52 compared with 61.7%, 25.5% and 5.4%, respectively, in patients who continued ustekinumab (see figure on next slide) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 233-235 (Efficacy at Week 12) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 94-97 (Abstract results)

Results (2) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Figure 3 and legend Proportions of responders with PASI 75, PASI 90 and PASI 100 responses by study visit week through week 52. Shaded areas indicate the response rates at week 12, week 16 and week 52. No patients rescued with brodalumab 210 mg Q2W following inadequate response to ustekinumab at week 16 achieved PASI 100 at week 12 or week 16

Results (3) PASI 75, PASI 90 and PASI 100 responses were approximately 1.5-, 1.5- and 1.6-fold higher, respectively, in patients without prior biologic use compared with those with prior biologic use among ustekinumab-treated patients rescued with brodalumab DLQI and PSI response rates decreased by 16.2% and 32.4%, respectively, from week 12 to week 52 in ustekinumab-treated patients who continued ustekinumab following inadequate responses after week 16, while DLQI rates increased by 3.6% and PSI rates increased by 76.5% over the same period in ustekinumab-treated patients who were rescued with brodalumab The exposure-adjusted rate of treatment-emergent adverse events was generally similar between those who were rescued with brodalumab and those who remained on ustekinumab 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 262-264 (Effiacy by prior biologic use) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 256-260 (Efficacy at week 52) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 273-274 (Safety)

Discussion The skin clearance efficacy associated with switching to brodalumab was greater than that associated with continued ustekinumab treatment among patients with inadequate response to ustekinumab Rescue with brodalumab in ustekinumab-treated patients was efficacious in both those with and without prior biologic use, although higher response rates were observed in those without prior biologic use The overall exposure-adjusted adverse event rate was similar between treatment groups 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 296-298 (Discussion second paragraph) 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 326-329 (Discussion fourth paragraph)

Conclusions What does this study add? The results demonstrate that brodalumab is efficacious in treating moderate-to-severe psoriasis in patients who do not achieve adequate responses with ustekinumab Brodalumab may be effective in patients who have inadequate responses to ustekinumab These results may be useful to clinicians seeking alternatives to ustekinumab therapy for efficacy-related reasons 6687 Efficacy in Ustekinumab Failures -12-2.docx – Lines 71-77 (What does this study add?)

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