Safety and Tolerability of Ixekizumab: Integrated Analysis of Injection-Site Reactions from 11 Clinical Trials
February 2018 | Volume 17 | Issue 2 | Original Article | 200 | Copyright © February 2018
Neil H. Shear MD FRCPC,a Carle Paul MD PhD,b Andrew Blauvelt MD MBA,c Melinda Gooderham MD MSc FRCPC,d Craig Leonardi MD,e Kristian Reich MD PhD,f Mamitaro Ohtsuki MD PhD,g Beth Pangallo RN,h Wen Xu PhD,h Susan Ball PhD,h Terri Ridenour MBA BSN,h Hitoe Torisu-Itakura MD PhD,i Noah Agada, MD MPH,h and Lotus Mallbris MD PhDh
aSunnybrook Health Sciences Centre, Dermatology, Clinical Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada bCHU and Paul Sabatier University, Toulouse, France cOregon Medical Research Center, Portland, OR dSKIN Centre for Dermatology, Queen’s University and Probity Medical Research, Peterborough, ON, Canada eSt. Louis University School of Medicine, St. Louis, MO fDermarologikum Hamburg and SCIderm Research Institute, Hamburg, Germany gJichi Medical University, Tochigi, Japan hEli Lilly and Company, Indianapolis, IN iEli Lilly Japan KK, Hyogo, Japan
reported injection-site reactions. Consistent with the 12-week induction period of the UNCOVER studies, the most common injection-site reactions across all 11 studies were classified as nonspecified (9.5%), erythema (3.1%), and pain (1.7%). After the first 2 weeks of treatment, the frequency of injection-site reactions decreased and then remained stable (≤4.2%) out to week 156 (Figure 3). A similar pattern was reported for pain and erythema. The incidence of injection-site pain was stable at 0.1% and injection-site erythema remained below 0.3% from week 36 to week 156.There were no serious adverse events related to injection-site reactions.Relationship Between Injection-Site Reaction, Previous Exposure to Biologic Agents, Race, and Development of ADAOf the 1167 patients treated with IXE Q2W in the 12-week induction period of the UNCOVER studies, 13.7% of those who had previously used biologic therapy reported injection-site reactions relative to 18.0% of patients who had never used biologic therapy. In a subgroup analysis of injection-site reactions by race, the frequency of injection-site reactions among White, Asian, and Other races was comparable with the global population during the 12-week induction period (Figure 1). No association of injection-site reactions and TE-ADA against ixekizumab was established (Table 3).
In clinical trials demonstrating the efficacy and safety of ixekizumab as a treatment for moderate-to-severe psoriasis, injection-site reactions were among the most commonly reported adverse events. This report details the injection-site reactions reported in ixekizumab psoriasis trials to provide more comprehensive information for patients and clinicians. While injection-site reactions were not reported by all patients who received ixekizumab, it is important that patients be informed of the possibility and reported pattern of injection-site reactions.Typically, injection-site reactions were reported within the first 2 weeks of treatment. In addition, longer-term safety data, summarized by 2 week intervals through 156 weeks of treatment, demonstrate a decrease in the rate with longer durations of ixekizumab exposure. The frequencies of the injection-site reactions tapered off rapidly and over time. The reactions were generally mild-to-moderate in severity, nonserious, resolved spontaneously without concomitant treatment, and did not usually lead to treatment discontinuation. The most typically described injection-site reaction was characterized as a clearly red papule, but there were cases (13% to 15%) in which the reaction was of greater magnitude (ie, bright red [1 patient had a dark scar] or ≥2 mm papule). In subgroup analyses, no relationship between injection-site reactions and previous exposure to biologic agents, race, or development of TE-ADA were identified. Consistent with the findings that a few injection-site reactions were characterized as more remarkable, a case study reported a 47-year-old female whose injection-site reaction resulted in significant coverage and discontinuation of treatment.17
Apart from this case report, recall injection-site reactions have been reported postmarketing, although such a phenomenon was not reported during clinical trials.In general, the etiology of injection-site reactions is multifactorial and may be associated with both immunologic and non-immunologic