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

Abstract

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_1/2 ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375.

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.

Keywords: B-cell depletion; CXCR5; Efficacy; Follicular helper T cells depletion; PF-06835375; Pharmacodynamics; Pharmacokinetics; Rheumatoid arthritis; Safety; Systemic lupus erythematosus.

Fig. 1

Patient disposition in single ascending dose and multiple ascending dose cohorts. AE adverse event, IV intravenous, MAD multiple ascending dose, RA rheumatoid arthritis, SAD single ascending dose, SC subcutaneous, SLE systemic lupus erythematous

Fig. 2

Serum PF-06835375 concentration–time profiles in the A single ascending dose and B multiple ascending dose cohorts (pharmacokinetic analysis population). The PK analysis population included all patients who received at least one dose of the study treatment and had evaluable PK data. The plots presented are semi-logarithmic. IV intravenous, MAD multiple ascending dose, PK pharmacokinetic, SAD single ascending dose, SC subcutaneous

Fig. 3

Mean A, B CXCR5-positive B and C, D cTfh cell counts in the single ascending dose and multiple ascending dose cohorts (PD analysis population). The PD analysis population included all patients who received at least one dose of the study treatment and had at least one PD measurement. A single IV dose was administered in SAD cohorts (designated Day 1), and multiple SC doses were administered in MAD cohorts (Day 1 and 29); the study duration including follow-up was 4–10 months from the screening. The plots presented are semi-logarithmic. cTfh circulating follicular T helper-like, CXCR5 C-X-C chemokine receptor type 5, IV intravenous, MAD multiple ascending dose, PD pharmacodynamic, SAD single ascending dose, SC subcutaneous

Fig. 4

Geometric means of antibody responses to the A, B, C, D Tetanus/Diphtheria vaccine in the single ascending dose and multiple ascending dose cohorts and the E, F Meningococcal B vaccine in the single ascending dose and multiple ascending dose cohorts (PD analysis population). The PD analysis population included all patients who received at least one dose of the study treatment and had at least one PD measurement. Data were excluded from the plot if patients did not receive the Td or MenB vaccine at Day 4. If patients did not receive the MenB vaccine at Week 8, their Week 12 data were excluded from the plot. The lower limit of detection for anti-MenB was 4, a titer of 2 was reported in case of non-detectable MenB antibody. The plots presented are semi-logarithmic. IV intravenous, MAD multiple ascending dose, MenB Meningococcal B, PD pharmacodynamic, SAD single ascending dose, SC subcutaneous, Td tetanus/diphtheria

Fig. 5

Geometric means of BAFF over time in the A single ascending dose and B multiple ascending dose cohorts (PD analysis population). The PD analysis population included all patients who received at least one dose of the study treatment and had at least one PD measurement. The plots presented are semi-logarithmic. BAFF B-cell activating factor, IV intravenous, MAD multiple ascending dose, PD pharmacodynamic, SAD single ascending dose, SC subcutaneous

Fig. 6

B cell-related pathways in patients in the multiple ascending and single ascending dose cohorts and the pooled placebo group. ^aPatients receiving placebo in the MAD and SAD cohort were pooled into a single placebo group for analysis. Heatmap represents longitudinal modulation of gene sets upon treatment in 1, 3, 6, and 10 mg MAD and 6 mg SAD cohorts. The color scale depicts the range of change from baseline in normalized expression level for each gene set (a gene set is a group of genes represented by a gene ontology term shown to the right of the heatmap, in rows). “Day” and “Dose” legends provide column annotations for the heatmap. *FDR < 0.05. FDR, false discovery rate; MAD multiple ascending dose, PBO placebo, SAD single ascending dose

Fig. 7

Mean (95% CI) change from baseline in the expression of B and Tfh cell-specific markers over time analyzed by RNA sequencing: A CD19, B CXCR5, C IL-6, D TNFRSF17, E TNFRSF13B, and F TNFRSF13C. ^aPatients receiving placebo in the MAD and SAD cohort were pooled into a single placebo group for analysis. TNFRSF13B, TNFRSF13C, and TNFRSF17 encode transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell activating factor receptor (BAFF-R), and B cell maturation antigen (BCMA) proteins, respectively. CI, confidence interval; CXCR5 C-X-C chemokine receptor type 5, IL interleukin, IV intravenous, MAD multiple ascending dose, SAD single ascending dose, TNFRSF tumor necrosis factor receptor superfamily member. *p ≤ 0.05; **p ≤ 0.01; ***p < 0.001