A Double-Blind, Phase I, Single Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BOS161721 in Healthy Subjects

Azra Hussaini, Rajat Mukherjee, Dina M Berdieva, Christen Glogowski, Richard Mountfield, Peter T C Ho, Azra Hussaini, Rajat Mukherjee, Dina M Berdieva, Christen Glogowski, Richard Mountfield, Peter T C Ho

Abstract

The purpose of this study was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BOS161721, a humanized immunoglobulin G1 triple mutation (M252Y/S254T/T256E) monoclonal antibody that inhibits interleukin-21 (IL-21) bioactivity. This randomized, single-center, double-blind, placebo-controlled study randomized healthy volunteers 3:1 to single ascending intravenous and subcutaneous doses of BOS161721 (range 1-240 mg) or placebo. BOS161721 and placebo groups had similar rates of adverse events, mostly mild; none led to study discontinuation. There were no clinically significant findings in physical examination, vital signs, or laboratory assessment. In the pooled BOS161721 population, four subjects (8.5%) tested antidrug antibody-positive predose, and seven (14.9%) postdose. Absolute CD4+ lymphocyte count remained normal throughout follow-up. BOS161721 administered subcutaneously was absorbed slowly, with a median time to maximum concentration (Tmax ) of 144 hours across doses (range 1-15 days) and a mean apparent terminal elimination half-life of 80-87 days for doses ≥ 30 mg. Area under the concentration-time curve from time zero to infinity (AUC0-inf ) and maximum observed concentration (Cmax ) were linear across doses > 10 mg. Subcutaneous bioavailability was 64%. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) decreased dose-dependently with threshold characteristics at doses of ≥ 10 mg. Downregulation in BATF, IL6, LAG3, and SOCS3 genes caused by IL-21 stimulation was reversed dose-dependently. BOS161721 was well-tolerated across doses, suppressed IL-21-induced pSTAT3 dose-dependently, and reversed downregulation of genes critical to tolerance induction and T-cell exhaustion induced by IL-21. Further clinical studies are ongoing in patients with systemic lupus erythematosus, in which IL-21 has a pathogenetic role.

Trial registration: ClinicalTrials.gov NCT03036865.

Conflict of interest statement

During this clinical trial, P.T.C.H., D.M.B., and Ri.M. were paid employees of Boston Pharmaceuticals, the study sponsor, and have equity holdings in Boston Pharmaceuticals. A.H., Ra.M., and G.G. were directly compensated by Boston Pharmaceuticals for their contributions. D.M.B. is currently affiliated with The Bill & Melinda Gates Medical Research Institute.

© 2019 Boston Pharmaceuticals. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Dose escalation schematic. *One subject dosed with active and one subject dosed with placebo in a sentinel subcohort first. **For each cohort, the decision to escalate to the next higher dose level was made after all subjects were administered either BOS161721 or placebo and were followed for at least 7 days.
Figure 2
Figure 2
Median BOS161721 plasma concentration vs. time following s.c. dosing.
Figure 3
Figure 3
Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) Cmin vs. BOS161721 dose. CI, confidence interval, Cmin, minimum percentage of pSTAT3 positive lymphocytes. Simple linear regression predicted natural log of parameter with 95% CI on the predicted mean.
Figure 4
Figure 4
Phosphorylated signal transducer and activator of transcription 3 AUC0-last vs. BOS161721 dose. AUC0-last = area under the plasma concentration time curve from predose (time = 0) to last quantifiable concentration.
Figure 5
Figure 5
In vivo BOS161721 reverses ex vivo interleukin (IL)‐21‐induced downmodulation of BATF, IL6, LAG3, and SOCS3 expression. Blood from subjects treated with placebo or single dose of BOS161721 by s.c. or i.v. routes were collected as assessed for gene expression in a stepwise manner. First, predose samples from subjects were evaluated for differential gene expression resulting from IL‐21 stimulation in presence and absence of BOS161721. A total of 29 genes were identified for further analysis using a P < 0.025 level of significance with a Benjamini‐Hochberg adjustment for testing of multiple genes. BOS1617821 dosing‐related differential expression of these 29 genes was assessed in a second step by comparing baseline and postdose (day 60) samples from subjects. Only four genes demonstrated a statistically significant (P > 0.01) after adjusting for multiplicity as in the first step. Data are expressed as threshold cycle (Ct) values and the absolute differences in the means of gene expression are determined in comparison to unstimulated (saline treated) negative control samples. Error bars reflect 95% confidence intervals around the expression estimates.

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