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Clinical Trial
. 2024 Jun 17:15:1380975.
doi: 10.3389/fimmu.2024.1380975. eCollection 2024.

Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia

Jason Lickliter  1 , Xin Yang  2 , Jiawang Guo  2 , Wubin Pan  2 , Zheng Wei  2   3
Affiliations
Clinical Trial

Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia

Jason Lickliter et al. Front Immunol. .

Abstract

Background: Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR1. In this first-in-human study, icanbelimod was investigated in healthy men in Australia.

Methods: Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort.

Results: Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (Tmax 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions.

Conclusion: Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts.

Clinical trial registration: ClinicalTrials.gov, identifier NCT02280434.b.

Keywords: CBP-307; Sphingosine-1-phosphate receptor modulator; icanbelimod; lymphocyte reduction; pharmacodynamics; pharmacokinetics; safety.

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Conflict of interest statement

Author JL was employed by company Nucleus Network. Authors XY, JG, WP, and ZW were full-time employees of Connect Biopharma at the time of the study. The authors declare that this study received funding from Connect Biopharma. The funder was involved in the trial design.

Figures

Figure 1
Figure 1
Study design. Participants were randomized 3:1, double-blind, per cohort to orally receive icanbelimod or placebo (with approximately 240 mL of non-carbonated water), all administered in the study center. All participants were required to fast from 10 hours predose to 4 hours postdose and all patients received standardized meals whilst in the study center. Cohort 3 participants returned after one week of washout, for an additional 0.5 mg dose administered 30 minutes after a high-fat breakfast (preceded by fasting overnight and for 4 hours postdose). Participants in Cohorts 1–4 were discharged from the study center on Day 4, and returned for final assessments on Day 7. QD, once daily.
Figure 2
Figure 2
Dose-dependent increases were observed in mean icanbelimod concentration after (A) single dosinga–c (B) and multiple (once daily) dosing,c–e (C) with Ctrough reaching steady state by Day 14 of multiple dosingc–e. aIn Cohorts 1 (C1), 2 (C2), and 3 (C3), participants were randomized to single dose icanbelimod 0.1 mg, 0.25 mg, and 0.5 mg (n=6), respectively, or placebo (n=2). bIn Cohort 4 (C4), participants were randomized to single dose icanbelimod 2.5 mg (n=4) or placebo (n=1). cAll treatments were administered after fasting, except for C3 participants who received a 0.5 mg dose after fasting and returned after one week of washout for an additional 0.5 mg dose administered following a high-fat breakfast. dIn Cohort 5 (C5), participants were randomized to icanbelimod 0.1 mg for one day, followed by 0.25 mg once daily (n=6), or placebo (n=2). eIn Cohort 6 (C6), participants were randomized to icanbelimod 0.15 mg once daily (n=6) or placebo (n=2).
Figure 3
Figure 3
Mean lymphocyte counts decreased in a dose-dependent manner (A) after single dosesa–c (B) and multiple (once daily) doses of icanbelimod, reached steady state by Day 14, and returned to baseline levels one week after the final dose was administeredc–e. Time is not shown uniformly in either panel. aIn Cohorts 1 (C1), 2 (C2), and 3 (C3), participants were randomized to single dose icanbelimod 0.1 mg, 0.25 mg, and 0.5 mg (n=6), respectively, or placebo (n=2). bIn Cohort 4 (C4), participants were randomized to single dose icanbelimod 2.5 mg (n=4) or placebo (n=1). cAll treatments were administered after fasting, except for C3 participants who received a 0.5 mg dose after fasting and returned after one week of washout for an additional 0.5 mg dose administered following a high-fat breakfast. dIn Cohort 5 (C5), participants were randomized to icanbelimod 0.1 mg for one day, followed by 0.25 mg once daily (n=6), or placebo (n=2). eIn Cohort 6 (C6), participants were randomized to icanbelimod 0.15 mg once daily (n=6) or placebo (n=2).
Figure 4
Figure 4
Mean heart rate decreased (A) after single doses of icanbelimod in Cohorts 1–4a–c and (B), in Cohort 5, the decreases during the initial 3 hours after 0.1 mg and 0.25 mg doses (0–3 and 24–27 hours, respectively) were attenuated by up-titration, relative to decreases observed with the 0.15 mg once daily dose in Cohort 6c–f. aIn Cohorts 1 (C1), 2 (C2), and 3 (C3), participants were randomized to single dose icanbelimod 0.1 mg, 0.25 mg, and 0.5 mg (n=6), respectively, or placebo (n=2). bIn Cohort 4 (C4), participants were randomized to single dose icanbelimod 2.5 mg (n=4) or placebo (n=1). cAll treatments were administered after fasting, except for C3 participants who received a 0.5 mg dose after fasting and returned after one week of washout for an additional 0.5 mg dose administered following a high-fat breakfast. dIn Cohort 5 (C5), participants were randomized to icanbelimod 0.1 mg for one day, followed by 0.25 mg once daily (n=6), or placebo (n=2). eIn Cohort 6 (C6), participants were randomized to icanbelimod 0.15 mg once daily (n=6) or placebo (n=2). fAdministration of icanbelimod 0.1 mg on Day 1, followed on subsequent days by icanbelimod 0.25 mg once daily in C5, was associated with less pronounced reduction in heart rate during the first 2 days of dosing than following administration of icanbelimod 0.15 mg once daily in C6.
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