A Phase 1 first-in-human study of the safety, tolerability, and pharmacokinetics of the ROBO2 fusion protein PF-06730512 in healthy participants

Abstract

Proteinuria associated with podocyte effacement is a hallmark of focal segmental glomerulosclerosis (FSGS). Preclinical studies implicated ROBO2/SLIT2 signaling in the regulation of podocyte adhesion, and inhibition of this pathway is a novel target to slow FSGS disease progression. This first-in-human dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of PF-06730512, an Fc fusion protein that targets the ROBO2/SLIT2 pathway, in healthy adults. In this Phase 1, double-blind, sponsor-open study, single ascending dose (SAD) cohorts were randomized to receive up to 1000 mg or placebo intravenously (IV); multiple ascending dose (MAD) cohorts were randomized to receive up to 400 mg subcutaneous (SC) doses, 1000 mg IV dose, or matching placebo. Safety evaluations were performed up to 71 (SAD) and 113 (MAD) days after dosing; blood samples were collected to measure serum PF-06730512 concentrations and antidrug antibodies (ADA) to PF-06730512. Seventy-nine participants (SAD, 47; MAD, 32) were enrolled. There were 108 mild (SAD, 46; MAD, 62) and 21 moderate (SAD, 13; MAD, 8) treatment-emergent adverse events (TEAEs); no deaths, treatment-related serious AEs, severe TEAEs, or infusion reactions were reported. PF-06730512 exposure generally increased in an approximately dose-proportional manner; mean t1/2 ranged from 12-15 days across 50-1000 mg doses. Immunogenicity incidence was low (SAD, 0 ADA+; MAD, 2 ADA+). In conclusion, single IV doses of PF-06730512 up to 1000 mg and multiple IV and SC dosing up to 1000 and 400 mg, respectively, were safe and well tolerated in healthy participants. Further trials in patients with FSGS are warranted. Clinical trial registration: Clinicaltrials.gov: NCT03146065.

Keywords: Phase 1; ROBO2; first-in-human; focal segmental glomerulosclerosis; pharmacokinetics.

Conflict of interest statement

Chay Ngee Lim, Donal Gorman, and Stephen Berasi are employees of and stockholders in Pfizer Inc. Constantino Kantaridis and Isabelle Huyghe are employees of and stockholders in Pfizer N.V. – S.A. Gabriele E. Sonnenberg was an employee of Pfizer Inc at the time of the study.

© 2021 Pfizer Inc. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.

Figures

FIGURE 1

Median serum PF‐06730512 concentration–time profiles. (A) SAD (B) MAD. Summary statistics were calculated by setting concentration values below the LLOQ to 0. The LLOQ was 0.025 µg/ml. IV, intravenous; LLOQ, lower limit of quantification; MAD, multiple ascending dose; Q2W, once every 2 weeks; QW, once weekly; SAD, single ascending dose; SC, subcutaneous; SD, single dose