Robust results of COAST-X trial prompted approval

The FDA recently approved ixekizumab (Taltz) in the 80 mg IV dose for the treatment of non-radiographic axial spondyloarthritis in patients with objective signs of inflammation.

The approval was based on the 52-week, randomized, double-blind, placebo-controlled, parallel-group COAST-X trial that showed that the IL-17 inhibitor was superior to placebo in improving signs and symptoms of the disease, showing it to be an effective treatment for patients who are intolerant to NSAIDs or for whom NSAIDs are ineffective.

“This study is the first to demonstrate the efficacy of an IL-17 inhibitor in non-radiographic axial spondyloarthritis,” Atul Deodhar, MD, from the Division of Arthritis & Rheumatic Diseases, Oregon Health & Sciences University, Portland, and colleagues wrote about the COAST-X trial in The Lancet. “Treatment with ixekizumab showed significant improvement in [Assessment of SpondyloArthritis international Society-40] ASAS40 responses as early as week 1, and responses did not differ based on the ixekizumab starting dose (160 mg or 80 mg) or continued dosing regimen (80 mg [every 2 weeks] Q2W or [every 4 weeks] Q4W).”

Pedro M. Machado, from the Centre for Rheumatology & Department of Neuromuscular Disease, University College of London, wrote in an editorial accompanying the study, “Following on from the demonstration of efficacy of secukinumab and ixekizumab in radiographic axial spondyloarthritis, this study represents another step towards the unifying concept of axial spondyloarthritis as it extends evidence of efficacy of IL-17 inhibition to the non-radiographic axial spondyloarthritis subgroup, fulfilling an unmet clinical need in this subgroup of patients.”

In the COAST-X trial, which took place at 107 sites in 15 countries, patients were eligible to participate if they were 18 years or older and had active axial non-radiographic axial spondyloarthritis, “objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs),” Deodhar and colleagues explained.

The trial had three arms to which patients were randomized — subcutaneous 80 mg ixekizumab every 4 weeks (Q4W), subcutaneous 80 mg ixekizumab every 2 weeks (Q2W), or placebo. The participants were allowed to change background medications, switch to open-label izekizumab Q2W, or both after week 16 at investigator discretion, the study authors noted. The primary endpoints were, at weeks 16 and 52, an ASAS40 response, 40% or more improvement and an absolute improvement of 2 or more units over baseline (range 8-10) in three of four domains, patient global, spinal pain, function, and inflammation, and no worsening in the domain not showing improvement.

“Patients who switched to open-label ixekizumab were imputed as nonresponders in logistic regression analysis,” Deodhar and colleagues wrote.

Patients were enrolled in the trial from Aug. 2, 2016 to Jan. 29, 2018. Out of 781 screened patients, 303 patients were ultimately enrolled — 105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W. Most of the patients, 290 (96%) completed the first 16 weeks of the study and 265 (87%) completed the full 52 weeks. This included the patients that switched to open label ixekizumab Q2W. At randomization, the patients in the ixekizumab groups were given either 80 mg (47 in the Q4W group, 50 in the Q2W group) or 160 mg (49 in the Q4W group and 52 in the Q2W group).

The average age of the trial participants was around 40, they were evenly split between male and female, most of the participants were white, and most were from European study sites.

“At week 52, 34 (32%) of 105 patients in the placebo group had completed the full 52-week period on their originally assigned study medication, versus 52 (54%) of 96 in the ixekizumab Q4W group and 52 (51%) of 102 in the ixekizumab Q2W group,” Deodhar and colleagues wrote.

The study authors noted that both primary endpoints of the trial were met.

  • ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, P=0.0094 versus placebo; ixekizumab Q2W: 41 [40%] of 102, P=0.0016; placebo: 20 [19%] of 105).
  • ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, P=0.0045; ixekizumab Q2W: 32 [31%] of 102, P=0.0037; placebo: 14 [13%] of 105).
  • There was at least one treatment adverse event in each arm of the trial — 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group.
  • Nasopharyngitis and injection site reaction were the most common treatment-related adverse event.
  • The frequency of serious adverse events was low at 1% across all trial arms; there were no malignancies or deaths, nor were there any new safety concerns.
  • There was one case of serious infection in the ixekizumab Q4W arm.

Interestingly, Deodhar and colleagues noted that “A higher ASAS40 response rate was seen in each ixekizumab treatment group versus placebo as early as week 1 (13 [14%] of 96, P=0.0077 for ixekizumab Q4W and 12 [12%] of 102, P=0.0123 for ixekizumab Q2W versus one [1%] of 105 for placebo. The starting dose (80 mg or 160 mg at week 0) did not affect the primary outcome results at weeks 16 or 52.”

“The long-term efficacy of ixekizumab is supported by the observation that most of the patients who switched to open-label ixekizumab (127 [88%] of 144) remained on open-label ixekizumab treatment until week 52, indicating that most physicians and patients chose to remain on the drug, the study authors wrote. “Only five (3%) patients went on to open-label TNF inhibitors, despite sponsor-provided access to TNF inhibitors.”

The study authors noted that a limitation of the study was an absence of a predefined rescue criteria to guide treatment changes and noted that “substantial proportions of patients who achieve ASAS40 response or had ASDAS low disease activity were switched from their masked ixekizumab treatment to open-label ixekizumab and, thus, were considered non-responders.” This, they wrote, “might have affected the treatment effect size…”

  1. The FDA recently approved ixekizumab (Taltz) in the 80mg IV dose for the treatment of non-radiographic axial spondyloarthritis in patients with objective signs of inflammation.

  2. The approval was based on robust results from the COAST-X trial, which showed that ixekizumab is superior to placebo for patients who are intolerant to NSAIDs or for whom NSAIDs are ineffective.

Candace Hoffmann, Managing Editor, BreakingMED™

Eli Lilly and Company funded the study.

Deodhar reports relevant relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.

Muchado disclosed relevant relationships with AbbVie, Novartis, and UCB, Eli Lilly, the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre.

Cat ID: 158

Topic ID: 90,158,438,730,192,158,68,925