Safety results of ixekizumab with 1822.2 patient-years of exposure: an integrated analysis of 3 clinical trials in adult patients with psoriatic arthritis

Abstract

Background: The long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3).

Methods: Integrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥ 1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3 years for adverse events.

Results: Total exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6).

Conclusions: The findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis.

Trial registration: SPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).

Keywords: Inflammatory bowel disease; Ixekizumab; Major adverse cardiovascular events; Psoriatic arthritis; Safety.

Conflict of interest statement

B. Combe received grant/research support from Pfizer, MSD, and Roche-Chugai; is a consultant for Pfizer, UCB, Bristol-Myers Squibb, Janssen, Eli Lilly and Company, MSD, Roche-Chugai, AbbVie, Sanofi, and Gilead; and is on Speakers bureau for Pfizer, Bristol-Myers Squibb, Gilead, Eli Lilly and Company, Roche-Chugai, and MSD.

P. Rahman has received consulting fees or other remuneration and is on Speakers bureau for AbbVie, Eli Lilly and Company, Janssen, Pfizer, Novartis, and UCB and received grant/research support from Janssen.

H. Kameda has received consulting fees or other remuneration and is on Speakers bureau for AbbVie, Asahi Kasei Pharma, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe Pharma, Novartis, Chugai, and Pfizer.

J.D. Cañete has received consulting fees or other remuneration from Janssen, Novartis, Mylan, Eli Lilly and Company, Pfizer, and UCB and is on Speakers bureau for Janssen, and Novartis.

G. Gallo, N. Agada, and W. Xu are employees and shareholders of Eli Lilly and Company.

M.C. Genovese received grant/research support and is a consultant for Eli Lilly and Company, and Novartis.

Figures

Fig. 1

Study design. All patients treated with IXE had a loading dose of 160 mg at week 0. ADA dose was 40 mg Q2W unless stated otherwise. aPatients determined to be inadequate responders by blinded criteria given adjustments to their background/existing therapy. Inadequate responders in the non-IXE groups randomized to IXE Q2W or IXE Q4W with washout for ADA inadequate responders. bResponders in ADA or PBO groups re-randomized to either IXE Q2W or IXE Q4W. cPatients randomized to IXE Q2W or PBO if they met the randomized withdrawal (RW) criteria (i.e., those who met Coates criteria for MDA for ≥ 3 consecutive months across ≥ 4 consecutive visits) at week 36 or later up to week 64. dPatients who had not met RW criteria at week 64 were given IXE Q2W; patients who relapsed (no longer met MDA criteria) during the double-blind withdrawal period were switched to, or continued, IXE Q2W. ADA Q2W: 40 mg of adalimumab every 2 weeks; IXE Q2W: 80 mg of ixekizumab every 2 weeks; IXE Q4W: 80 mg of ixekizumab every 4 weeks; LTE: long-term extension; MDA: minimal disease activity; PBO: placebo; Wk: week

Fig. 2

Number of patients by treatment duration. The number of patients exposed to ixekizumab over a period of 3 years. Total N = 1118; total exposure = 1822.2 patient-years

Fig. 3

Treatment-emergent adverse events per 100 patient-years by years of treatment. AE: adverse event; D/C: discontinuation; IXE: ixekizumab; NMSC: non-melanoma skin cancer; PY: patient-years; SAE: serious adverse event

Fig. 4

Exposure-adjusted incidence rate of TEAEs at 1-year intervals to year 3. The data points on the graph are the IR (95% CI)/100 PY at successive 1-year interval to year 3 for all ixekizumab-treated dataset (SPIRIT-P1, SPIRIT-P2, SPIRIT-P3) for a serious infections, b MACE (CEC-adjudicated), c NMSC, d other malignancies (excluding NMSC), e depression, and f IBD related. The CIs for the IRs are from likelihood ratio test of treatment effect from the Poisson regression model. The AEs were coded using MedDRA Version 19.1. *95% CI was not evaluated for IBD. AE: adverse event; CEC: Clinical Events Committee; CI: confidence interval; IBD: inflammatory bowel disease; IR: incidence rate; IXE: ixekizumab; MACE: major adverse cardiovascular events; MedDRA: Medical Dictionary for Regulatory Activities; Ns: number of patients entered in each time interval; n: number in group; PBO: placebo; PY: patient-years; Q2W: every 2 weeks; Q4W: every 4 weeks; TEAEs: treatment-emergent adverse events