Ixekizumab Citrate-Free Formulation: Results from Two Clinical Trials

Abstract

Introduction: Subcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A.

Methods: Two phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh.

Results: Primary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was - 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC0-tlast, AUC0-∞, and Cmax between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable.

Conclusion: Ixekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation.

Trail registration: ClinicalTrials.gov identifier NCT03848403, NCT04259346.

Keywords: Bioequivalence; Citrate-free; Injection site pain; Ixekizumab.

© 2022. The Author(s).

Figures

Fig. 1

VAS injection-site pain score at the time of injection in study A. Significantly less pain was reported with the citrate-free formulation than with the original commercial formulation at the time of injection (***p < 0.0001). Pain categories were defined as no pain, VAS pain score = 0; mild pain, VAS pain score > 0 and ≤ 30; moderate pain, VAS pain score > 30 and ≤ 70; severe pain, VAS pain score > 70. LSM least-squares means, N number of subjects, VAS visual analog scale

Fig. 2

Mean serum concentrations of citrate-free formulation vs. original commercial formulation to 85 days post-injection in study B. Errors bars represent the standard of deviation. IXE ixekizumab

Fig. 3

Number of injection site pain events in study B. For the original commercial formulation, there were eight cases of moderate injection site pain and one case of severe pain. No severe injection site pain was reported for the CF formulation group