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.

BACKGROUND: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF­06835375, 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 t1/2 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.

Relationship Between Paraoxonase-1 Genotype and Activity, and Major Adverse Cardiovascular Events and Malignancies in Patients With Rheumatoid Arthritis Receiving Tofacitinib.

OBJECTIVE: This posthoc analysis investigated the relationship between paraoxonase-1 (PON1) genotype and activity, and risk of major adverse cardiovascular events (MACE) and malignancies in clinical studies of tofacitinib in patients with rheumatoid arthritis (RA). METHODS: Data were pooled from 9 phase II/III studies and the associated long-term extension studies (all completed by October 2017). PON1 activities in plasma were measured using paraoxon (paraoxonase activity), dihydrocoumarin (lactonase activity), and phenylacetate (arylesterase activity) as substrates. PON1 Q192R genotype effect on baseline PON1 activity was assessed using linear regression for each study, with fixed-effects metaanalysis across studies. MACE and malignancy risk by time-varying enzyme activity was determined using Cox proportional hazards regression. RESULTS: The analysis included 1969 patients with RA. Compared with the QQ genotype, the RR genotype had a significant positive association with baseline paraoxonase activity and a significant negative association with baseline lactonase and arylesterase activity (all P < 0.001). Time-varying models demonstrated a significant association of increased paraoxonase activity over time with lower risk of MACE (P < 0.001) and malignancies (excluding nonmelanoma skin cancer [NMSC]; P ≤ 0.05), even after controlling for risk factors identified in univariate analysis and RA disease activity. A similar trend was observed for lactonase and arylesterase for MACE. CONCLUSION: Higher paraoxonase activity over time was associated with significantly reduced risk of future MACE and malignancies (excluding NMSC), but not NMSC, in patients with RA receiving tofacitinib. Further investigation of PON1 as a novel functional lipid biomarker of MACE/malignancy risk in patients with RA is warranted. (ClinicalTrials.gov: NCT01059864, NCT00550446, NCT00687193, NCT00960440, NCT00814307, NCT00856544, NCT00853385, NCT00847613, NCT01039688, NCT00413699, NCT00661661).

Higher Seroprevalence of Anti-Adeno-Associated Viral Vector Neutralizing Antibodies Among Racial Minorities in the United States.

Anti-adeno-associated viral vector (AAV) neutralizing antibodies (NAbs) can ablate efficacy of transgene expression following intravenous vector administration. This observation in both preclinical and clinical trials has led to exclusion of NAb-positive patients from receiving AAV gene therapy. AAV drug development includes selection of capsids with lower NAb seroprevalence that also possess other favorable traits. Often a limited number of healthy volunteers are screened to gauge NAb seroprevalence. However, limited data sets can be biased leading to inaccurate estimates of NAb incidence. In this study, we evaluated AAV NAbs against a panel of vectors among healthy donors within the United States. While the overall seroprevalence against most AAVs was lower, we did observe increased NAb incidence among black and Hispanic donors. These findings of increased NAb seroprevalence among the minority races were confirmed in a second set of donors who also demonstrated higher seroprevalence among these races. Interracial- and intraracial differences within genders were also observed among donors. The increased incidence of AAV NAb among racial minorities was unexpected. Our findings underscore the need for removing bias in sample data sets and evaluating seroprevalence within the patient population while selecting capsids.