Adv Ther https://doi.org/10.1007/s12325-022-02126-0 ORIGINAL RESEARCH Ixekizumab Citrate-Free Formulation: Results from Two Clinical Trials Sanjay Chabra . B. J. Gill . Gaia Gallo . Danting Zhu . Celine Pitou . Christopher D. Payne . Ana Accioly . Luis Puig Received: February 15, 2022 / Accepted: March 11, 2022 Ó The Author(s) 2022 ABSTRACT visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the begin- Introduction: Subcutaneous (SC) injection is a ning to three possible treatment sequences and common route of drug administration; how- received a 1 mL SC injection of the three for- ever, injection site pain (ISP) might create a mulations sequentially in the abdomen on negative patient experience. We evaluated ISP, days 1, 8, and 15, respectively. A mixed-effects bioequivalence, and overall safety of the citrate- repeated measures analysis model was used to free (CF) formulation of ixekizumab, a high- analyze VAS score by time post-injection. affinity monoclonal antibody that selectively Study B (NCT04259346) evaluated the bioe- targets interleukin-17A. quivalence of a single 80 mg dose of CF for- Methods: Two phase 1, single-blind studies mulation compared to the original commercial were conducted in healthy participants. The formulation. Subjects (N = 245) were random- crossover study A (NCT03848403) evaluated ized 1:1 to either commercial or CF formulation pain intensity on injection as measured by 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 Supplementary Information The online version contains supplementary material available at https:// formulation (n = 63) was - 21.7 (p \ 0.0001), doi.org/10.1007/s12325-022-02126-0. indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence S. Chabra (&) of the CF formulation was established as Texas Arthritis Center, El Paso, TX, USA 90% CIs for the ratio of geometric LSM e-mail: schabra@hotmail.com AUC0–tlast, AUC0–?, and Cmax between treatments B. J. Gill were contained within the prespecified limits of Complete Dermatology, Houston, TX, USA 0.8 and 1.25. Except for less ISP in the CF for- mulation, overall safety profile was comparable. G. Gallo  D. Zhu  C. Pitou  C. D. Payne  A. Accioly Conclusion: Ixekizumab CF formulation Eli Lilly and Company, Indianapolis, IN, USA proved to be bioequivalent, was associated with less ISP, and had no other notable differences in L. Puig Hospital de La Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain Adv Ther the safety profile compared to the original patient adherence to treatment, and even lead to commercial formulation. treatment discontinuation [1]. Factors such as Trail Registration: ClinicalTrials.gov identifier needle sizes, volume injected, injection site loca- NCT03848403, NCT04259346. tion, viscosity, and the buffers used in the for- mulation have been reported as possible causes of Keywords: Ixekizumab; Injection site pain; pain upon administration of a SC injection [2–5], Bioequivalence; Citrate-free whereas speed of injection does not appear to influence pain sensation [6, 7]. Ixekizumab, a high-affinity monoclonal Key Summary Points antibody that selectively targets interleukin (IL)-17A, is administered via subcutaneous Injection site pain (ISP) is a common injection [8, 9]. Injection site reactions (ISRs) adverse event for subcutaneously are among the most common treatment-emer- administered medications and may create gent adverse events (TEAEs) with an incidence a negative patient experience rate per 100 patient-years between 15 and 20 Citrate is an excipient previously during the first year of ixekizumab administra- identified to contribute to pain perception tion [9]. Among the ISRs, injection site pain (ISP) and erythema occur most frequently [9] Two test formulations of citrate-free and can be bothersome for some patients. ixekizumab were developed, and one Exploratory studies were conducted and showed formulation was selected to proceed in the that the citrate buffer and the sodium chloride bioequivalence study with the original tonicity agent were the main cause of ISP in the commercial formulation original commercial formulation. Citrate-free formulation of ixekizumab Two test formulations of citrate-free (CF) proved to be bioequivalent, was associated ixekizumab were assessed in the clinical pro- with less ISP, and had no other gram to address pain associated with injection. notable differences in the safety profile On the basis of the relative bioavailability compared to the original commercial results of the test formulations, one formulation formulation was selected for the pivotal bioequivalence study. The active ingredient in the CF formu- lation remains ixekizumab 80 mg/ml but differs from the original commercial formulation in that there is no citrate buffer, an excipient pre- viously identified to contribute to pain percep- DIGITAL FEATURES tion [2–4]. In addition, the tonicity agent was changed from sodium chloride to sucrose This article is published with digital features, (Supplementary Table 1). Here, we report the including a video abstract, to facilitate under- results of two phase 1 studies that assessed ISP, standing of the article. To view digital features bioequivalence, and safety of the original com- for this article go to https://doi.org/10.6084/ mercial formulation versus the CF formulation. m9.figshare.20377029. METHODS INTRODUCTION Study Design Subcutaneous (SC) injection is a common route of drug administration for biologic products given Two phase 1, randomized, single-blind studies its potential for high bioavailability and rapid were conducted. For both studies, healthy par- onset of action. However, pain at the injection site ticipants aged 18–75 with body mass index of may create a negative patient experience, limit 18.0–32.0 kg/m2 were included if, in the Adv Ther investigator’s opinion, participating in the medium, 70.0–80.0 kg; high, more than 80.0 kg). study would not place the person at risk fol- Within the three weight categories, participants lowing a review of the participants medical were randomized 1:1 to either 80 mg ixekizumab history, vital signs, ECG, and clinical laboratory commercial formulation or 80 mg ixekizumab CF tests. Female participants of child-bearing formulation (Supplemental Fig. 1b). Subjects in potential must have tested negative for preg- each group were sub-randomized 1:1:1 to injection nancy prior to initiation of study. Key exclusion site (arm, thigh, or abdomen). Participants criteria were current enrolment in a clinical received a single 80 mg SC dose administered by a study involving an investigational product or medical professional using the autoinjector participation within the last 30 days; have pre- according to the randomization plan, and they viously received ixekizumab or have ever been returned as outpatients for pharmacokinetic sam- administered other IL-17 antagonists; have pling out to day 85. known allergies to ixekizumab; have a signifi- All participants were required to give cant history of or current cardiovascular, respi- informed consent for participation in the study ratory, hepatic, renal, gastrointestinal, prior to any study-specific procedures. The endocrine, or hematologic disorder that in the protocols were approved by ethical review investigator’s opinion poses an unaccept- boards and were conducted according to Inter- able risk to the subject. national Conference on Harmonization Good Study A (I1F-MC-RHCS, ClinicalTrials.gov Clinical Practice guidelines and the Declaration identifier NCT03848403) was a single-dose, sub- of Helsinki. ject-blind, three-period, three-formulation crossover study in healthy participants to deter- Objectives mine the reduction in ISP for two test CF for- mulations compared to the original commercial The primary objective of study A was to evalu- formulation of ixekizumab. Participants were ate pain intensity on injection of ixekizumab randomized 1:1:1 to one of three formulation with different formulations, as measured by sequences. Subjects received a single 1 mL SC visual analog scale of pain (VAS pain) scale, a injection administered by medical professional well-validated tool to assess pain [10]. VAS was using a prefilled syringe of 80 mg ixekizumab presented as a 100-mm line anchored by verbal commercial formulation, 80 mg ixekizumab CF descriptors such as ‘‘no pain’’ and ‘‘worst possi- formulation 1, or 80 mg ixekizumab CF formu- ble pain.’’ The participant was asked to rate any lation 2 on days 1, 8, and 15, respectively (Sup- ISP on the line at prespecified time points fol- plemental Fig. 1a). The three-period crossover lowing ixekizumab administration. design allowed each subject to act as their own The primary objective of study B was to control in comparing the effects of ixekizumab evaluate the bioequivalence of a single 80 mg administered using the original commercial for- subcutaneous dose of ixekizumab CF formula- mulation to CF formulation 1 and CF formula- tion compared to the commercial formulation. tion 2. All injections were administered in the Secondary and exploratory objectives include abdomen for consistency. evaluation of the safety, tolerability, and CF formulation 1 (‘‘CF formulation’’) was immunogenicity of CF formulation compared selected as the optimal formulation to proceed on to the commercial formulation. the basis of relative bioavailability results (Clini- calTrials.gov identifier NCT03848416, supple- Statistical Analyses mental appendix). Study B (I1F-MC-RHCU, ClinicalTrials.gov identifier NCT04259346) was a two-arm, subject-blind, parallel-design study in VAS pain scores were summarized using standard healthy participants to demonstrate bioequiva- descriptive statistics. Pain severity was catego- lence between commercial formulation and CF rized by VAS pain score as mild pain (30 or less), formulation. Participants were stratified into one moderate pain (more than 30 and at most 70), of three weight categories (low, less than 70.0 kg; and severe pain (more than 70). The number and Adv Ther percentage of the subjects in each pain severity the median difference based on the observed category were summarized by formulation and means, 90% CI, and p values from the Wilcoxon time point. A mixed-effects repeated measures rank sum test were calculated. analysis model (MMRM) was used to analyze the continuous ISP VAS score by each time post-in- Safety Analyses jection (0, 10, 20, 30, and 60 min). For measures at each time post-injection, the model included All subjects who received at least one dose of formulation, period (day 1, day 8, or day 15), study drug, whether they completed all proto- formulation sequence, and formulation by for- col requirements or not, were included in the mulation sequence as fixed effects. The covari- safety assessments. All protocol deviations that ance structure of the model was unstructured. occurred were considered for their severity and The Kenward–Roger method was used to esti- impact. Safety and tolerability were assessed by mate the denominator degrees of freedom. clinical laboratory tests, vital sign measure- Treatment least-squares means (LSM) were esti- ments, recording of adverse events (AEs), phys- mated within the framework of the MMRM ical examination, medical assessments, and using type III sums of squares. Differences in anti-drug antibodies. All AEs were listed. Treat- LSM between each formulation [and associated ment-emergent AEs were summarized by for- p values and 95% confidence intervals (CI)] were mulation and severity. The frequency (the used for statistical inference. number of AEs, the number of subjects experi- For continuous data, summary statistics encing an AE, and the percentage of subjects included the arithmetic mean, arithmetic stan- experiencing an AE) of treatment-emergent AEs dard deviation, median, minimum, maximum, was summarized by formulation, using the and number of observations. For categorical Medical Dictionary for Regulatory Activities data, frequency count and percentages were (MedDRA) version 22.1 preferred term. presented. Pharmacokinetics Analyses RESULTS A number of participants’ clinical research unit Baseline Characteristics visits were impacted as a result of COVID-19 restrictions, or for other reasons. Only partici- Demographics at baseline for both studies are pants who had all PK samples collected up to listed in Table 1. Baseline characteristics were day 85 or participants who had one missing PK similar overall between groups and between sample after day 15 were included from the studies. primary PK statistical analysis. Pharmacokinetic parameters were evaluated Primary Objectives to determine the bioequivalence of CF formu- lation compared to the original commercial The primary endpoint was achieved in both formulation. The log-transformed Cmax, studies. In study A, LSM pain VAS score AUC0–?, and AUC0–tlast were evaluated in a (0–100 mm) for the CF formulation at the time linear mixed-effects model with fixed effects for of injection was 3.5 mm versus 25.2 mm for the formulation and a random effect for subject. original commercial formulation, with LSM The treatment differences were back-trans- difference of - 21.7 (p \ 0.0001) (Fig. 1). Ten formed to present the ratios of geometric LS minutes after the injection, the difference in means and the corresponding 90% CIs. Bioe- LSM VAS score was - 4.5 (p \ 0.0001). In quivalence was concluded if the 90% CI was study B, bioequivalence was demonstrated completely contained within the prespecified between CF formulation and the original com- interval (0.80, 1.25). The tmax was analyzed mercial formulation. The 90% confidence using a Wilcoxon rank sum test. Estimates of intervals for the ratio of geometric least-squares Adv Ther Table 1 Baseline demographics Study A Study B Parameter Overall (N = 70) IXE80 original commercial (N = 126) IXE80 CF (N = 119) Age, years (mean, SD) 44.5 (13.5) 42.9 (12.8) 46.8 (13.5) Gender (n, %) Male 33 (47.1) 59 (46.8) 59 (49.6) Female 37 (52.9) 67 (53.2) 60 (50.4) Weight, kg (mean, SD) 74.9 (12.8) 76.2 (12.3) 76.3 (12.9) 2 BMI, kg/m (mean, SD) 25.9 (3.2) 26.7 (2.9) 26.8 (3.2) Race (n, %) American Indian/Alaska Native 2 (2.9) 0 0 Asian 6 (8.6) 0 1 (0.8) Black 20 (28.6) 32 (25.4) 19 (16.0) White 41 (58.6) 93 (73.8) 98 (82.4) Multiple 1 (1.4) 1 (0.8) 1 (0.8) Includes all enrolled participants BMI body mass index, CF citrate-free, IXE ixekizumab, SD standard deviation mean AUC0–tlast, AUC0–?, and Cmax between formulation. Geometric least-squares mean of treatments were entirely contained within the Cmax was 9.66 lg/mL and 9.97 lg/mL for the prespecified limits of 0.8 and 1.25 (Table 2). commercial formulation and CF formulation, Between-subject pharmacokinetic variability respectively. Geometric least-squares mean of estimates were moderate and consistent AUC was 207 lg/day/mL and 219 lg/day/mL for between the commercial formulation and CF the commercial and CF formulations, Fig. 1 VAS injection-site pain score at the time of VAS pain score = 0; mild pain, VAS pain score [ 0 injection in study A. Significantly less pain was reported and B 30; moderate pain, VAS pain score [ 30 and with the citrate-free formulation than with the original B 70; severe pain, VAS pain score [ 70. LSM least- commercial formulation at the time of injection squares means, N number of subjects, VAS visual analog (***p \ 0.0001). Pain categories were defined as no pain, scale Adv Ther Table 2 Statistical summary of definitive bioequivalence data in study B Parameter IXE80 CF IXE80 original commercial Ratio of geometric LSM 90% CI (lower, (units) (N = 110) (N = 112) (CF/commercial) upper) AUC0–tlast 219 207 1.06 (0.990, 1.13) (lg day/mL) AUC0–? 227 213 1.07 (0.995, 1.14) (lg day/mL) Cmax (lg/mL) 9.97 9.66 1.03 (0.960, 1.11) AUC0–? area under the concentration versus time curve from time zero to infinity, AUC0–tlast area under the concentration versus time curve from time zero to time t, where t is the last time point with a measurable concentration, CF citrate-free formulation, CI confidence interval, Cmax maximum observed drug concentration, IXE ixekizumab, LS least square means, N number of observations Table 3 Statistical summary of tmax definitive bioequivalence data in study B Parameter IXE80 CF IXE80 original Median of differences 90% CI (lower, P value (units) (N = 110) commercial (N = 112) (test 2 commercial) upper) tmax (day) 4.04 4.99 0 (- 0.02, 0.03) 0.7592 CF citrate-free formulation, CI confidence interval, IXE ixekizumab, N number of observations, tmax time of maximum observed drug concentration 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 respectively. There was no statistically signifi- Safety cant difference in tmax between the CF formu- lation and original commercial formulation In study B, 35.5% participants (N = 245) repor- (Table 3), and the overall PK profile remained ted a total of 135 AEs (Table 4). Most were mild the same (Fig. 2). to moderate in severity, and no AEs were serious Adv Ther Table 4 Summary of treatment-emergent AEs in study B, all causalities Treatment-emergent AEs IXE80 original commercial (N = 126) IXE80 CF (N = 119) Total (N = 245) Participants with TEAE (n, %) 55 (43.7) 32 (26.9) 87 (35.5) Any TEAE (n) 85 50 135 Mild 83 43 126 Moderate 2 7 9 Severe 0 0 0 SAE (n) 0 0 0 Discontinuation due to AE (n) 1 1 2 AE adverse event, CF citrate-free formulation, IXE ixekizumab, n number of observations, SAE serious adverse event, TEAE treatment-emergent adverse event Table 5 Summary of injection-site reactions in study B: pain, pruritis, erythema Treatment-emergent AEs IXE80 commercial (N = 126) IXE80 CF (N = 119) Participants reporting ISRs (n, %) 30 (23.8) 11 (9.2) Number of reported ISRs (n) 58 25 Pain severity (n, %) Mild 5 (8.6) 2 (8.0) Moderate 8 (13.8) 0 Severe 1 (1.7) 0 Pruritus severity (n, %) Mild 6 (10.3) 2 (8.0) Moderate 0 0 Severe 0 0 Erythema severity (n, %) Noticeable but mild 11 (19.0) 7 (28.0) Clearly red 4 (6.9) 2 (8.0) Bright red 7 (12.1) 1 (4.0) Unknown 1 (1.7) 0 Percentages are based on number of reported ISRs by treatment. Only the maximum severity of each adverse event is reported AEs adverse events, CF citrate-free formulation, IXE ixekizumab, ISR injection-site reaction, n number of observations or severe. One participant from each group compared with those who received the CF for- discontinued because of COVID-19 infection. mulation (Table 5). Of participants reporting an More ISRs were reported in subjects who ISR, more moderate and severe levels of pain received the original commercial formulation and erythema were observed in participants of Adv Ther Fig. 3 Number of injection site pain events in study B. pain. No severe injection site pain was reported for the CF For the original commercial formulation, there were eight formulation group cases of moderate injection site pain and one case of severe the original commercial formulation group mean VAS pain score for pain was 37 mm, with compared to the milder levels reported in CF 43% of subjects reporting moderate pain and group. Eight cases of moderate ISP and one case 12% reporting severe pain. With the citrate-free of severe pain were reported for the original adalimumab formulation, the VAS was 12 mm commercial formulation group. No moderate or and the percentages for moderate and severe severe ISP was reported for the CF formulation pain were 12% and 2%, respectively [14]. A group (Fig. 3). retrospective cohort study evaluating patient After receiving the commercial formulation, adherence and persistence with citrate-free 9.8% of subjects were positive for treatment- adalimumab found that adherence and persis- emergent anti-drug antibodies (TE-ADA); 3.4% tence are significantly improved with citrate- of subjects were TE-ADA positive following the free adalimumab compared to adalimumab- CF formulation. containing citrate [15]. In our studies, there was a reduction of ISP based on mean VAS pain score from 25.2 mm DISCUSSION with the original formulation to 3.5 mm with the CF formulation. Bioequivalence with the Efficacy and safety of ixekizumab have been commercial formulation was clearly estab- demonstrated across its indications from almost lished. When statistical analyses were con- 21,000 patient-years of exposure [9]. ISRs were ducted on the data from the pharmacokinetic the second most common TEAE of special population for each injection site separately, interest across psoriasis, psoriatic arthritis, and the 90% CIs for all comparisons were again axial spondyloarthritis studies, and ISP is one of completely contained within the confidence the most common ISRs [9]. The CF formulation limits of 0.80 and 1.25. This result had an added was developed to improve overall patient benefit as it suggested that the two formulations experiences. Studies of other compounds have were interchangeable at the injection site level. demonstrated that changing the buffer reduced The safety data showed that there were no injection site pain, which may have implica- reports of moderate or severe pain with the CF tions for improving patient compliance [11, 12]. formulation. In addition, reports of ISRs were In the etanercept reformulation study, the less frequent and less severe following the CF mean VAS pain score for the original formula- formulation compared to the commercial for- tion was 23.1 mm versus the phosphate-free mulation in study B. With the exception of ISP, formulation VAS pain of 19.1 mm [13]. With the safety profile of ixekizumab across the two the original formulation of adalimumab, the formulation was consistent. Adv Ther Conducting the clinical program in healthy contributions to the pharmacokinetics aspects volunteers bears both strengths and limitations. of the paper. As healthy participant studies, there were fewer confounding factors that could impact the Funding. Eli Lilly and Company funded the results (e.g., concomitant medications, pain studies, the Rapid Service Fee, and/or the Open related to disease state). In addition, the Access fee. recruitment of healthy participants made it possible to collect intensive PK samples over a Medical Writing and/or Editorial Assis- long period of time (nearly 3 months) after a tance. Nancy Tan, PharmD, Eli Lilly and Com- single dose. Furthermore, the injections were pany, provided writing and editorial assistance. administered by trained professionals, which also decreased potential confounders. For Author Contributions. Study conception study A, an important strength is the compara- and design: Danting Zhu, Celine Pitou, tive nature of its crossover study design. As all Christopher D Payne, Ana Accioly; Data collec- subjects received all three injections, absolute tion: Sanjay Chabra, BJ Gill; Statistical Analysis: perception of pain by patients may vary but this Danting Zhu; All authors contributed to the was diminished by the design of the study. For analysis and interpretation of the results and study B, a key strength was its large sample size. drafting of the manuscript. All authors reviewed It is important to keep in mind that studies the manuscript and approved the final version conducted in healthy participants should not of the manuscript. be compared with studies conducted with actual patients. Measurements of clinical effi- Prior Presentation. The data from these cacy were not collected; however, the equiva- studies were presented in part at the 2022 lent pharmacokinetics demonstrated in this Society of Investigative Dermatology congress study suggest the CF formulation would be in Portland. equally clinically effective. Moreover, other than the absence of citrate and change in Disclosures. Dr. Sanjay Chabra reports par- tonicity agent, the CF and original commercial ticipation in company sponsored speaker’s formulations are comparable. The stability and bureau for Eli Lilly and Company. Dr. BJ Gill bio-immunological features are the same, and reports participation as speaker for educational the binding affinity is not expected to be programming for Eli Lilly and Company and affected in any way. Post-marketing surveillance Journey Medical Corporation. Dr. Gaia Gallo, activities would monitor and evaluate any Danting Zhu, Celine Pitou, Christopher D potential new safety signals. Payne, and Ana Accioly are employees and minor shareholders of Eli Lilly and Company. Dr. Luis Puig reports grants to institution from CONCLUSION Abbvie, Almirall, Amgen, Boehringer Ingel- heim, Celgene, Janssen, Leo-Pharma, Lilly, Ixekizumab CF formulation proved to be bioe- Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB; quivalent, was associated with less ISP, and had consulting fees or honoraria from Abbvie, no other notable differences in the safety profile Almirall, Amgen, Baxalta, Biogen, Boehringer compared to the original commercial Ingelheim, Celgene, Gebro, Janssen, Leo- formulation. Pharma, Lilly, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Samsung-Bioepis, Sanofi, UCB; participation in company sponsored speaker’s bureau for Cel- ACKNOWLEDGEMENTS gene, Janssen, Lilly, MSD, Novartis, Pfizer. The authors thank the participants and inves- Compliance with Ethics Guidelines. All tigators for the studies. 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