Efficacy and safety of pateclizumab (anti-lymphotoxin-α) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study)

Abstract

Introduction: Tumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LTα) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin- alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LTα. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR).

Methods: Patients (n = 214) with active RA (≥ 6 swollen and tender joints, C-reactive protein ≥ 10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed.

Results: Pateclizumab reduced the DAS28(4)-ESR response (-1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (-1.54), while adalimumab (-2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AEs) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients.

Conclusions: Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients.

Trial registration: ClinicalTrials.gov NCT01225393, Registered 18 October 2010.

Figure 1

Observed versus population PK model predicted pateclizumab serum concentration-time profiles. Dose was given on study days 0, 14, 24, 42, 56, and 70. The empty symbols represent the observed individual serum concentrations at planned sampling times. The solid line represents the population PK model (built based on phase I PK data) predicted median serum concentration-time profile. The shaded band represents model predicted 90% confidence interval of the concentration-time profile for the study population. PK, pharmacokinetic.

Figure 2

B cell chemoattractant CXCL13 was decreased after treatment with pateclizumab. Mean ± SEM levels of CXCL13, a B cell chemoattractant, are presented over time after treatment with adalimumab, pateclizumab, or placebo. CXCL13 was decreased following treatment with pateclizumab, demonstrating pharmacological engagement of the LTα pathway, as observed in the phase 1 trial of pateclizumab [12]. Adalimumab also modulated CXCL13 levels to a similar degree. Significance was assessed at the efficacy endpoint (Day 85); see Methods. *P <0.05 vs. placebo. LTα, lymphotoxin alpha; SEM, standard error of the mean.