Ixekizumab Benefits Ankylosing Spondylitis Patients Who Failed to Respond to Standard Therapy, Phase 3 Study Shows

Ankylosing spondylitis (AS) patients who have failed to respond to standard therapy may benefit from treatment with ixekizumab (Taltz by Eli Lilly), Phase 3 study results show.

The study, “Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: 16 Week Results of a Phase 3 Randomized, Double-Blind, Placebo Controlled Trial in Patients with Prior Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors,” was published in Arthritis & Rheumatology.

Findings were also presented at the recent American College of Rheumatology’s annual meeting in Chicago.

Currently, the recommended treatment for AS is based on anti-TNF therapy, which targets a protein called tumor necrosis factor involved in molecular events that result in inflammation.  However, anti-TNF medicine is not indicated for all AS patients, and about 40% of individuals fail to properly respond to this type of treatment.

Evidence has suggested that interleukin-17A (IL-17A), a type of immune protein called a cytokine, plays an important role in the disease mechanisms underlying ankylosing spondylitis. Additionally, molecules targeting IL-17 have demonstrated clinical efficacy in active AS.

“However, an IL-17 [inhibitor] has not been evaluated in a population that exclusively consisted of patients with prior inadequate response or intolerance to [TNF inhibitors] in a clinical trial setting,” researchers said.

To test this hypothesis, researchers designed COAST-W (NCT02696798), a randomized, placebo-controlled Phase 3 16-week study followed by long-term evaluation of efficacy and safety of ixekizumab in AS patients who had a prior inadequate response or intolerance to one or two TNF inhibitors.

Ixekizumab is an engineered antibody that selectively inhibits IL-17A. The compound is currently indicated for the treatment of active psoriatic arthritis and plaque psoriasis, both chronic inflammatory diseases.

Patients were randomly assigned to receive subcutaneous administration of ixekizumab (80 mg or 160 mg) at the beginning of the study, followed by 80 mg given every two weeks (IXEQ2W group), every four weeks (IXEQ4W group), or matched placebo from week 0 to week 14.

The extended treatment period for each group consisted of 80 mg ixekizumab given every two (IXEQ2W) or 4 (IXEQ4W) weeks, from week 16 to week 52.

There were 316 AS adult patients enrolled in COAST-W: 98 were assigned to the IXEQ2W, 114 to the IXEQ4W and 104 to the placebo group.

All subjects had a diagnosis of AS, a history of back pain for three or more months, imaging evidence of inflammation of one or both sacroiliac joints — located where the lower spine and pelvis connect — and had previously failed to respond (90% of enrolled participants) or were intolerant (10% of study population) to one or two TNF inhibitors.

The primary outcome was ASAS40 response at week 16. c stands for Assessment in Ankylosing Spondylitis. Response criteria include patient global assessment, pain, function and inflammation. According to ASAS40 criteria, all evaluated domains must improve by at least 40 percent.

Treatment protocol was completed by 93 (89.4%) placebo, 90 (91.8%) IXEQ2W, and 99 (86.8%) IXEQ4W patients.

After the 16-week treatment, 30.6% and 25.4% of subjects in the IXEQ2W and IXEQ4W groups, respectively, achieved ASAS40 — meaning their AS signs and symptoms were significantly diminished — in comparison to only 12.5% of patients in the placebo group.

“Statistically significant improvements in disease activity, function, quality of life, and spinal MRI inflammation were observed with 16 weeks of ixekizumab treatment versus placebo,” researchers said.

Importantly, at week 1 there was already evidence of significant differences in the assessed clinical outcomes.

Adverse events were more common in both ixekizumab groups than in the placebo group and were typically due to upper respiratory tract infections and injection site reactions. One death was reported in the group being treated with the medication every two weeks.

Despite having shown an acceptable safety profile in this study’s sample, there were higher rates of adverse events across all arms (placebo included) than those reported in another ixekizumab Phase 3 study called COAST-V (NCT02696785).

However, in COAST-V, patients had never been treated with biological disease-modifying anti-rheumatic drugs.

“Many people with this chronic, debilitating disease are still searching for an effective treatment. These positive results provide support for ixekizumab as a potential treatment option for patients with AS, including those who have had an inadequate response to treatment with TNF inhibitors, a difficult-to-treat population,” Atul Deodhar, MD, Professor of Medicine at Oregon Health & Science University in Portland, and the study’s first author, said in a press release.