An Open-Label Tolerability and Actual-Use Human Factors Study of Etrolizumab Autoinjector in Healthy Volunteers.

INTRODUCTION: Etrolizumab is a novel, dual-action, anti-ß7 integrin antibody in development for patients with moderate to severe ulcerative colitis or Crohn's disease. Phase 3 studies use a prefilled syringe (PFS) for etrolizumab administration. In parallel, an autoinjector (AI) is being developed to increase delivery options for patients if etrolizumab is approved. Here we describe the overall development strategy and detail the first-in-human study of this AI. METHODS: This open-label study of healthy volunteers evaluated the tolerability and usability of the etrolizumab AI under development. The primary endpoint was the proportion of participants with greater than mild pain following injection. Adverse events (AEs) and usage errors were also assessed. Results were reported by injection site (thigh vs abdomen) and needle training (experienced vs naive). Pharmacokinetic (PK) variability between participants was an exploratory endpoint. RESULTS: Thirty participants completed the study; 97% of them did not experience any pain greater than mild, and 50% did not experience any pain at all. Three usage errors were observed, one of which resulted in delivery of a partial dose of etrolizumab. No patterns of usage errors were observed. Mild injection site reactions (ISRs) were reported; all resolved by the end of the study. Participants injecting into the abdomen reported more ISRs than those injecting into the thigh; needle training did not influence AE incidence or severity. CONCLUSIONS: Results from this first-in-human study demonstrate that single injections of etrolizumab 105 mg using an AI were well tolerated in healthy volunteers, with transient, mild pain and minimal usage errors. Results from this study also informed the design of a subsequent PK comparability study evaluating exposure of etrolizumab administered by either the PFS or the AI. Overall, the availability of an AI may provide an attractive option for patients desiring a convenient, easy-to-use delivery mechanism for etrolizumab. TRIAL REGISTRATION: NCT02629744.

Comparable Pharmacokinetics, Safety, and Tolerability of Etrolizumab Administered by Prefilled Syringe or Autoinjector in a Randomized Trial in Healthy Volunteers.

INTRODUCTION: Etrolizumab is a novel, dual-action anti-ß7 integrin antibody studied in phase 3 trials in patients with inflammatory bowel disease. An autoinjector (AI) is being developed in parallel to complement the prefilled syringe with needle safety device (PFS-NSD) for subcutaneous (SC) administration in these trials. Here we demonstrate the comparable pharmacokinetics, tolerability, and safety of both devices. METHODS: This randomized, open-label, two-part study in healthy participants evaluated the comparability of etrolizumab exposure between the AI and the PFS-NSD. Part 1 (pilot) involved a small number of participants, and initial results were used to finalize the design of the larger part 2 (pivotal) study. In both parts, participants were randomly assigned to receive a single SC dose of etrolizumab 105 mg by AI or PFS-NSD. Randomization was stratified by body weight. Primary pharmacokinetic outcomes were Cmax, AUClast, and AUC0-inf. RESULTS: One hundred and eighty healthy participants (part 1, n = 30; part 2, n = 150) received a single SC dose of etrolizumab by AI or PFS-NSD. Primary pharmacokinetic results from part 1 supported modification of the part 2 study design. Results from part 2 demonstrated that etrolizumab exposure was equivalent between devices, with geometric mean ratios (GMRs) between AI and PFS-NSD of 102% (90% confidence interval [CI] 94.2-111) for Cmax, 98.0% (90% CI 89.3-107) for AUClast, and 97.6% (90% CI 88.6-107) for AUC0-inf. Median tmax and mean terminal t1/2 were also similar between devices. GMRs and 90% CIs of all primary pharmacokinetic parameters were fully contained within the predefined equivalence limits (80-125%). CONCLUSION: This pharmacokinetic study demonstrated that single SC injections of etrolizumab 105 mg using an AI or a PFS-NSD resulted in equivalent etrolizumab exposure and similar safety and tolerability in healthy participants. Taken together, these results support the use of an AI for etrolizumab administration. TRIAL REGISTRATION: NCT02996019.