A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis.
| Autor: | Cohen S; Internal Medicine, University of Texas Southwestern Medical School Metroplex Clinical Research Center, 8144 Walnut Hill Lane, Suite 800, Dallas, TX, 75231, USA. SCohen@dfwra.com., Beebe JS; Pfizer Inc, Cambridge, MA, USA., Chindalore V; Pinnacle Research Group, LLC, Anniston, AL, USA., Guan S; Pfizer Inc, Cambridge, MA, USA., Hassan-Zahraee M; Pfizer Inc, Cambridge, MA, USA., Saxena M; Pfizer Inc, Cambridge, MA, USA., Xi L; Pfizer Inc, Cambridge, MA, USA., Hyde C; Pfizer Inc, Cambridge, MA, USA., Koride S; Pfizer Inc, Cambridge, MA, USA., Levin R; Clinical Research of West Florida, Clearwater, FL, USA., Lubaczewski S; Pfizer Inc, Collegeville, PA, USA., Salganik M; Pfizer Inc, Cambridge, MA, USA., Sloan A; Pfizer Inc, Cambridge, MA, USA., Stevens E; Pfizer Inc, Groton, CT, USA., Peeva E; Pfizer Inc, Cambridge, MA, USA., Vincent MS; Pfizer Inc, Cambridge, MA, USA., Martin DA; Pfizer Inc, Cambridge, MA, USA., Chu M; Pfizer Inc, Collegeville, PA, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Arthritis research & therapy [Arthritis Res Ther] 2024 Jun 06; Vol. 26 (1), pp. 117. Date of Electronic Publication: 2024 Jun 06. |
| DOI: | 10.1186/s13075-024-03337-2 |
| Abstrakt: | Background: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Methods: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. Results: In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t Conclusions: These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. Trial Registration: ClinicalTrials.gov identifier: NCT03334851. (© 2024. The Author(s).) |
| Databáze: | MEDLINE |
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