Introduction
Eosinophilic esophagitis (EoE) is a chronic and progressive Type 2 inflammatory disease with a significant unmet need for effective and safe long-term targeted therapy. Cendakimab (CEN) is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody that binds to interleukin 13 (IL-13) thereby blocking interaction with its receptors, IL-13Rα1 and IL-13Rα2. CEN is currently under clinical development for the treatment of EoE. Here, we present the results of 2 phase 1, randomized, single-center, single-dose trials assessing the pharmacokinetics (PK), safety, and tolerability of CEN in healthy Chinese (NCT05638282) and US (NCT05337345) populations.
Aims & Methods
In the China study (NCT05638282), healthy participants (age, 18–55 years; body mass index [BMI], 18.0–28.0 kg/m2; weight, ≥50.0 kg) were sequentially assigned to 2 groups. Participants in each group were randomized 5:1 to receive: group 1, single-dose CEN 360 mg subcutaneous (SC) via 1 injection (n=10) or placebo (n=2), and group 2, single-dose CEN 720 mg SC via 2 injections (n=10) or placebo (n=2). All doses were administered in the abdomen using an autoinjector (AI). In 1 of 4 groups of the US study (NCT05337345), healthy participants (age, 18–55 years; BMI, 18.0–30.0 kg/m2; weight, ≥40.0 kg) received single-dose CEN 360 mg SC via 1 injection in the abdomen using an AI (n=32). Data from groups that received CEN via AI are presented here. The PK parameters assessed in both studies were maximum observed serum concentration (Cmax), time of Cmax (Tmax), area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUC0-T), AUC from time 0 to infinite time (AUC∞), terminal elimination half-life (T1/2), apparent total body clearance (CL/F), and apparent volume of distribution of terminal phase (Vz/F). Safety and tolerability were also evaluated.
Results
Demographic characteristics were generally similar in the China and US studies, eg. median BMI was 23 and 26 kg/m2, respectively. In the China study, following SC doses of 360 and 720 mg, the absorption of CEN was slow, with a median Tmax of 96 and 143 hours; mean T1/2 was 565 and 535 hours, and Vz/F was 11.8 and 10.7 liters, respectively (Table). The geometric mean Cmax, AUC∞, and AUC0-T increased in a dose-proportional manner between the 360 and 720 mg CEN doses. Antidrug antibodies (ADAs) were detected in 50% of participants in each of the 360 and 720 mg CEN groups, with a low titer in most of them. Results for the 360 mg AI group from the China study were consistent with those of the 360 mg AI group in the US study. ADAs were detected in 16% of the participants in the US study. In both studies, the ADA response did not impact the safety or PK of CEN, and CEN (360 mg or 720 mg) was well tolerated with no deaths, serious adverse events (AEs), or discontinuations due to an AE.
Conclusion
Single-dose 360 mg or 720 mg SC CEN was safe and well tolerated in all healthy participants. CEN PK was generally dose-proportional for Cmax and AUC from 360 mg to 720 mg. Overall, the PK, tolerability, and safety profiles of a single dose of 360 mg SC CEN in the China study were consistent with those observed in the US study, supporting the use of similar doses across both populations.
Table. Summary of serum pharmacokinetic parametersa
| Study | Cendakimab doseb | AUC∞, hours*µg/mL | AUC0-T, hours*µg/mL | Cmax, µg/mL | Median Tmax, hours (range) | Mean T1/2, hours (SD) | CL/F, L/h | Vz/F, L |
| China study | 360 mg (n=10) | 24,300 (22) | 23,000 (23) | 29.4 (38) | 96 (72–312) | 565 (116) | 0.015 (22) | 11.8 (30) |
| 720 mg (n=10) | 51,200 (26) | 49,300 (25) | 66.5 (25) | 143 (48–311) | 535 (108) | 0.014 (26) | 10.7 (23) |
| US study | 360 mg (n=32) | 25,187 (35) | 23,908 (34) | 29.8 (34) | 144 (8–314) | 506 (114) | 0.014 (36) | 10.2 (33) |
aValues are geometric mean (% geometric coefficient of variation), except where otherwise noted.
bAdministration in the abdomen using an AI.
SD, standard deviation. |
Disclosure
YC and SP have nothing to disclose; CX, SB, BW, YQ, KY, BM, and PZ are employees of Bristol Myers Squibb; LL, JR, WK, BY, CDO, MT, JM, PZ are employees and stockholders of Bristol Myers Squibb
