Pharmacokinetics, Safety, and Tolerability of Single-Dose Dazukibart in Healthy Adults in China and Japan: Results From 2 Randomized, Double-Blind, Phase 1 Studies

Abstract

Dazukibart is a humanized monoclonal antibody selectively targeting interferon-β. The pharmacokinetics (PK), safety, tolerability, and immunogenicity of dazukibart were evaluated in 2 double-blind, randomized, placebo-controlled, single-dose, Phase 1 studies in healthy adults in China (Study 1: N = 18; dazukibart 900 mg = 15; placebo = 3) and Japan (Study 2: N = 12; Cohort 1: dazukibart 300 mg = 5, placebo = 1; and Cohort 2: dazukibart 900 mg = 5, placebo = 1). PK parameters were assessed after dosing in Study 1 and Study 2, and no significant differences were observed between PK findings among participants in both studies. A biphasic decline in dazukibart serum concentrations was observed in both studies. Exposures increased dose proportionally in Study 2. Body weight, but not race, was identified as an independent covariate of exposure using population PK modeling (including data from a Phase 1 US study [NCT02766621]). No deaths/discontinuations or serious/severe adverse events were observed, mostly mild adverse events were reported. No participants in Study 1 were antidrug antibody positive; 20.0% in Study 2 were positive for treatment-induced antidrug antibodies and neutralizing antibodies. PK parameters and immunogenicity rates were consistent with the US study, and no new safety signals were identified.

Keywords: dazukibart; ethnic sensitivity; interferon‐β; pharmacokinetics; safety.

Figure 1

(A) Study design: randomized, double‐blind, placebo‐controlled Phase 1 study in China (Study 1^*).^*Sponsor‐open study. ^#One participant from dazukibart arm was lost to follow‐up. ^ƚThe additional dose‐normalized (dn) PK end points, which include C_max (dn), AUC_last, AUC_last (dn), and AUC_inf (dn), were not evaluated as only 1 dose level (900 mg) was investigated. ^‡At the time of discontinuing from the studies (ET) an early discontinuation visit was conducted for any further evaluations that needed to be completed. (B) Study design: randomized, double‐blind, placebo‐controlled Phase 1 study in Japan (Study 2^*). ^*Sponsor‐open study. ^**Of the 13 participants, 1 was discontinued due to failure to comply with site instructions. ^‡At the time of discontinuing from the studies (ET) an early discontinuation visit should be conducted for any further evaluations that need to be completed. ADA, antibody drug development; AEs, adverse events; AUC, area under the concentration–time curve; AUC_14day, area under the concentration–time curve from time zero to 14 days; AUC_28day, area under the concentration–time curve from time 0 to 28 days; AUC_inf, area under the concentration–time curve from time zero extrapolated to infinite time; AUC_last, AUC profile from time zero to time of last quantifiable concentration; C_max, maximum serum concentration; C_last, time of last quantifiable concentration; CL, clearance; ECGs, electrocardiograms; EP, end point; Inf, infinite; ET, early termination; IRR, infusion‐related reactions; ISRs, infusion site reactions; IV, intravenous; NAb, neutralizing antibody; PK, pharmacokinetic; R, randomization; SAEs, serious adverse events. TEAEs, treatment‐emergent adverse events; t_1/2, terminal half‐life; t_max, time to reach maximum serum concentration; V_d(area), volume of distribution based on area under the concentration–time curve.

Figure 2

(A) Mean semilog serum dazukibart concentration–time profiles following single‐dose infusion in Study 1 (PK concentration analysis set). Summary statistics were calculated by setting concentration values below the LLOQ to zero. For statistics or quantities using logarithm transformation, values equal to zero were excluded during calculation. Unscheduled visit records were excluded from the plot. Five participants were excluded, and only 10 were included in Study 1 as the wrong PK collection tubes were sent by Central Lab and the first 24‐h PK samples for the first 6 participants (dazukibart 900‐mg arm = 5 and placebo arm = 1) were affected. Hence, 5 samples for the dazukibart arm were considered nonevaluable with respect to PK end points (C_max, t_max, AUC_14day, AUC_28day, AUC_inf, and t_1/2) and were excluded from concentration‐time profiles. (B) Mean semilog serum dazukibart concentration–time profiles following single‐dose infusion in Study 2 (PK concentration analysis set). Summary statistics were calculated by setting concentration values below the LLOQ to zero. For statistics or quantities using logarithm transformation, values equal to zero were excluded during calculation. Unscheduled visit records were excluded from the plot. AUC_14day, area under the concentration–time curve from time zero to 14 days; AUC_28day, area under the concentration–time curve from time 0 to 28 days; AUC_inf, area under the concentration–time curve from time zero extrapolated to infinite time; C_max, maximum serum concentration; LLOQ, lower limit of quantification; PK, pharmacokinetic; t_1/2, terminal half‐life; t_max, time to reach maximum serum concentration.

Figure 3

Dazukibart dose‐normalized PK parameter comparison graphs in US, Japanese, and Chinese participants. The boxes indicate the IQR; horizontal blue lines in the center of boxes indicate median values; whiskers extend from the box to the smallest and largest values within 1.5 times the IQR from the first quartile and third quartile, respectively; black open diamonds indicate geometric mean values; jitter blue closed dots indicate individual values of PK parameters. (A) C_max. (B) AUC_inf. AUC_inf, area under the concentration–time curve from time zero extrapolated to infinite time, C_max, maximum serum concentration, IQR, interquartile range; PK, pharmacokinetic.