Secukinumab re‐initiation achieves regain of high response levels in patients who interrupt treatment for moderate to severe plaque psoriasis

Dear Editor, Clinical trials of biologics in psoriasis usually evaluate fixed‐dosing regimens. However, patients may need to interrupt therapy for reasons such as surgery, travel, changes in healthcare coverage or pregnancy.1 Consequently, dermatologists need to know whether interrupting biological therapy might correlate with diminished response on retreatment. We analysed data from a randomized withdrawal trial of secukinumab in patients with moderate to severe plaque psoriasis to ascertain the effects of retreatment. Eligibility criteria and design of the original studies up to 52 weeks were previously published.2 In this double‐blind withdrawal study (NCT01544595), patients who exhibited Psoriasis Area and Severity Index (PASI) 75 response at Week 52 of treatment with secukinumab 300 mg or 150 mg, administered subcutaneously once every 4 weeks during maintenance, were randomized 2 : 1 either to continue the same regimen or receive placebo every 4 weeks until relapse. Relapse was defined as loss of > 50% of maximum PASI improvement compared with pretreatment baseline. Patients who experienced relapse at any visit received secukinumab (300 mg or 150 mg) at Weeks 0 (week of relapse), 1, 2, 3, and 4, then every 4 weeks, thereby restarting secukinumab. Recapture of PASI 75/90/100 response was assessed by determining the proportion of patients who experienced ≥ 75%/≥ 90%/100% PASI improvement from baseline of the original studies. Of 181 patients treated with secukinumab 300 mg for 52 weeks who were randomized to treatment withdrawal, 63·0% had previously received systemic therapies and 83·4% were naïve to biologics. PASI data for the study patients (all PASI 75 responders) at randomization indicate the high degree of psoriasis control achieved during secukinumab therapy (Table 1). Baseline demographics and clinical characteristics in subjects randomized to withdrawal of secukinumab 300 mg BMI, body mass index; PASI 90, ≥ 90% improvement in baseline Psoriasis Area and Severity Index score. Baseline demographics and clinical characteristics in subjects randomized to withdrawal of secukinumab 300 mg BMI, body mass index; PASI 90, ≥ 90% improvement in baseline Psoriasis Area and Severity Index score. Twenty‐nine patients (16·0%) maintained response over 52 weeks of placebo administration and did not require retreatment, 16 (8·8%) withdrew for various reasons, and the 136 (75·1%) relapsed. Median time to relapse was 28·0 weeks [95% confidence interval (CI) 24·14–32·00]. Mean PASI at relapse was 15·6 (range 4·5–65·1). Over 90% of patients regained PASI 75 by Weeks 12–16 of retreatment (Fig. S1a; see Supporting Information). In subgroups who had exhibited PASI 90 and PASI 100 prior to withdrawal, rates of PASI 75 recapture were even higher (Fig. S1a–c). Recapture rates for PASI 90 (78·8%) and PASI 100 (48·1%) were also high in prior PASI 90 responders, as well as in prior PASI 100 responders (PASI 90: 86·3%; PASI 100: 67·3%). In the overall analysis population (prior PASI 75 responders), the Kaplan–Meier estimate of median time to regain of response was 4·0 weeks (95% CI 3·29–4·14) for PASI 75 and 8·1 weeks (95% CI 8·14–8·43) for PASI 90. Mean PASI at Week 16 after restart of treatment was 1·6 (range 0·0–13·8). Consistent with previous studies, efficacy of the 150 mg dose was lower across all time‐ and endpoints (data not shown). Secukinumab exposure in the 300 mg group during 1 year of follow‐up was 100·2 patient‐years, with a mean exposure per patient of 202·2 days. Adverse events were consistent with those observed in registration studies and presented no unexpected safety findings.2,3 Blood samples were assessed for possible secukinumab immunogenicity, as previously described.4 No subjects in the 300 mg treatment withdrawal arm tested positive for antisecukinumab antibodies, including after re‐exposure. Historically, treatment withdrawal regimens for biologics have been inferior to fixed‐interval dosing. Rates of PASI 90 response at 1 year with fixed‐interval vs. as‐needed dosing were 60% vs. 14% in a study of secukinumab5 and 34–52% vs. 10–12% in two infliximab studies.6,7 A 24‐week study of etanercept found that fixed‐interval dosing was associated, on a Physician's Global Assessment, with a 70% response rate vs. 60% for as‐needed dosing.8 Thus, preferred dosing per secukinumab label is 300 mg every 4 weeks. However, patients in real‐world settings face challenges in fully adhering to fixed‐interval dosing. The results presented here provide reassurance that, when dosing interruption is necessary, patients who have achieved good results (e.g. PASI 75) with secukinumab have a 94% probability of regaining response after resuming treatment. Median time to relapse after secukinumab withdrawal was > 6 months. When relapse did occur, retreatment delivered a fast regain of response. The majority (> 78%) of patients who exhibited the highest response levels (PASI 90, PASI 100) regained PASI 90 after treatment interruption and resumption; recapture of PASI 100 was somewhat lower (67%) among patients who were initially PASI 100 responders. Re‐initiation of secukinumab included a reloading schedule of once‐weekly dosing followed by maintenance dosing every 4 weeks. The lack of anti‐secukinumab antibodies observed during this study is consistent with the known low immunogenic potential of secukinumab.4 A potential study limitation is the enrolment of patients who were treated with secukinumab for only 1 year, who thus might experience higher recapture rates than patients who had been treated longer. In summary, results of this analysis confirm efficacy among the commonly encountered subgroup of patients who cannot maintain unbroken fixed‐interval dosing. The authors received writing and editorial support from Andrew Horgan, PhD (BioScience Communications, New York, NY), which was supported by Novartis. Funding sources: Funding for the trial and its publication was provided by Novartis Pharma AG. Conflicts of interest: A.B. has served as a scientific consultant and clinical study investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, UCB, and Valeant, and as a paid speaker for Eli Lilly, Regeneron and Sanofi Genzyme. K.R. has served as a consultant and/or paid speaker for, and/or participated in clinical trials sponsored by, companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Biogen Idec, Celgene, Centocor, Covagen, Eli Lilly, Forward Pharma, GSK, Janssen‐Cilag, LEO Pharma, Medac, MSD, Novartis, Pfizer, Vertex, Takeda and XenoPort. R.B.W. acted as a consultant and/or speaker and/or received research grants for AbbVie, Almirall, Amgen, Celgene, Eli Lilly, Medac, Novartis, Pfizer, Janssen and XenoPort. J.C.S. has served as advisor and/or received speaker honoraria and/or participated in clinical trials for Abbott/AbbVie, Actavis, Amgen, BASF, Astellas, Berlin‐Chemie/Menarini, Biogenetica International Laboratories, Centocor, Fresenius, Janssen, LEO Pharma, Mitsubishi Tanabe, Novartis, Pierre‐Fabre, Takeda, Toray Industries, Inc. and Vichy.