title: 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: BACKGROUND
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01225393, Registered 18 October 2010.
authors.forename: William P
authors.initials: WP
authors.lastname: Kennedy
authors.forename: J Abraham
authors.initials: JA
authors.lastname: Simon
authors.forename: Carolyn
authors.initials: C
authors.lastname: Offutt
authors.forename: Priscilla
authors.initials: P
authors.lastname: Horn
authors.forename: Ann
authors.initials: A
authors.lastname: Herman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Townsend
authors.forename: Meina T
authors.initials: MT
authors.lastname: Tang
authors.forename: Jane L
authors.initials: JL
authors.lastname: Grogan
authors.forename: Frank
authors.initials: F
authors.lastname: Hsieh
authors.forename: John C
authors.initials: JC
authors.lastname: Davis
mesh_terms: D000068879:Adalimumab; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007279:Injections, Subcutaneous; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D010612:Pharyngitis / Q000139:chemically induced; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D008233:Lymphotoxin-alpha; D002097:C-Reactive Protein; D000068879:Adalimumab; C576689:pateclizumab