Two phase 1, randomized, single-blind studies were conducted. For both studies, healthy participants aged 18–75 with body mass index of 18.0–32.0 kg/m2 were included if, in the investigator’s opinion, participating in the study would not place the person at risk following a review of the participants medical history, vital signs, ECG, and clinical laboratory tests. Female participants of child-bearing potential must have tested negative for pregnancy prior to initiation of study. Key exclusion criteria were current enrolment in a clinical study involving an investigational product or participation within the last 30 days; have previously received ixekizumab or have ever been administered other IL-17 antagonists; have known allergies to ixekizumab; have a significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, or hematologic disorder that in the investigator’s opinion poses an unacceptable risk to the subject.
Study A (I1F-MC-RHCS, ClinicalTrials.gov identifier NCT03848403) was a single-dose, subject-blind, three-period, three-formulation crossover study in healthy participants to determine the reduction in ISP for two test CF formulations compared to the original commercial formulation of ixekizumab. Participants were randomized 1:1:1 to one of three formulation sequences. Subjects received a single 1 mL SC injection administered by medical professional using a prefilled syringe of 80 mg ixekizumab commercial formulation, 80 mg ixekizumab CF formulation 1, or 80 mg ixekizumab CF formulation 2 on days 1, 8, and 15, respectively (Supplemental Fig. 1a). The three-period crossover design allowed each subject to act as their own control in comparing the effects of ixekizumab administered using the original commercial formulation to CF formulation 1 and CF formulation 2. All injections were administered in the abdomen for consistency.
CF formulation 1 (“CF formulation”) was selected as the optimal formulation to proceed on the basis of relative bioavailability results (ClinicalTrials.gov identifier NCT03848416, supplemental appendix). Study B (I1F-MC-RHCU, ClinicalTrials.gov identifier NCT04259346) was a two-arm, subject-blind, parallel-design study in healthy participants to demonstrate bioequivalence between commercial formulation and CF formulation. Participants were stratified into one of three weight categories (low, less than 70.0 kg; medium, 70.0–80.0 kg; high, more than 80.0 kg). Within the three weight categories, participants were randomized 1:1 to either 80 mg ixekizumab commercial formulation or 80 mg ixekizumab CF formulation (Supplemental Fig. 1b). Subjects in each group were sub-randomized 1:1:1 to injection site (arm, thigh, or abdomen). Participants received a single 80 mg SC dose administered by a medical professional using the autoinjector according to the randomization plan, and they returned as outpatients for pharmacokinetic sampling out to day 85.
All participants were required to give informed consent for participation in the study prior to any study-specific procedures. The protocols were approved by ethical review boards and were conducted according to International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki.
The primary objective of study A was to evaluate pain intensity on injection of ixekizumab with different formulations, as measured by visual analog scale of pain (VAS pain) scale, a well-validated tool to assess pain . VAS was presented as a 100-mm line anchored by verbal descriptors such as “no pain” and “worst possible pain.” The participant was asked to rate any ISP on the line at prespecified time points following ixekizumab administration.
The primary objective of study B was to evaluate the bioequivalence of a single 80 mg subcutaneous dose of ixekizumab CF formulation compared to the commercial formulation. Secondary and exploratory objectives include evaluation of the safety, tolerability, and immunogenicity of CF formulation compared to the commercial formulation.
VAS pain scores were summarized using standard descriptive statistics. Pain severity was categorized by VAS pain score as mild pain (30 or less), moderate pain (more than 30 and at most 70), and severe pain (more than 70). The number and percentage of the subjects in each pain severity category were summarized by formulation and time point. A mixed-effects repeated measures analysis model (MMRM) was used to analyze the continuous ISP VAS score by each time post-injection (0, 10, 20, 30, and 60 min). For measures at each time post-injection, the model included formulation, period (day 1, day 8, or day 15), formulation sequence, and formulation by formulation sequence as fixed effects. The covariance structure of the model was unstructured. The Kenward–Roger method was used to estimate the denominator degrees of freedom. Treatment least-squares means (LSM) were estimated within the framework of the MMRM using type III sums of squares. Differences in LSM between each formulation [and associated p values and 95% confidence intervals (CI)] were used for statistical inference.
For continuous data, summary statistics included the arithmetic mean, arithmetic standard deviation, median, minimum, maximum, and number of observations. For categorical data, frequency count and percentages were presented.
A number of participants’ clinical research unit visits were impacted as a result of COVID-19 restrictions, or for other reasons. Only participants who had all PK samples collected up to day 85 or participants who had one missing PK sample after day 15 were included from the primary PK statistical analysis.
Pharmacokinetic parameters were evaluated to determine the bioequivalence of CF formulation compared to the original commercial formulation. The log-transformed Cmax, AUC0–∞, and AUC0–tlast were evaluated in a linear mixed-effects model with fixed effects for formulation and a random effect for subject. The treatment differences were back-transformed to present the ratios of geometric LS means and the corresponding 90% CIs. Bioequivalence was concluded if the 90% CI was completely contained within the prespecified interval (0.80, 1.25). The tmax was analyzed using a Wilcoxon rank sum test. Estimates of the median difference based on the observed means, 90% CI, and p values from the Wilcoxon rank sum test were calculated.
All subjects who received at least one dose of study drug, whether they completed all protocol requirements or not, were included in the safety assessments. All protocol deviations that occurred were considered for their severity and impact. Safety and tolerability were assessed by clinical laboratory tests, vital sign measurements, recording of adverse events (AEs), physical examination, medical assessments, and anti-drug antibodies. All AEs were listed. Treatment-emergent AEs were summarized by formulation and severity. The frequency (the number of AEs, the number of subjects experiencing an AE, and the percentage of subjects experiencing an AE) of treatment-emergent AEs was summarized by formulation, using the Medical Dictionary for Regulatory Activities (MedDRA) version 22.1 preferred term.