Secukinumab Successful in Spondylitis, Psoriatic Arthritis

Alice Goodman

November 24, 2014

BOSTON — The human monoclonal antibody secukinumab (Novartis), which selectively neutralizes interleukin (IL)-17A, is safe and effective for patients with ankylosing spondylitis and psoriatic arthritis, according to two sets of pivotal phase 3 studies.

Results from the MEASURE 1 and MEASURE 2 trials of patients with ankylosing spondylitis and the FUTURE 1 and FUTURE 2 trials of patients psoriatic arthritis were presented here at the American College of Rheumatology (ACR) 2014 Annual Meeting.

"This new antibody targeting IL-17A shows efficacy in ankylosing spondylitis, and many of these patients failed on TNF inhibitors. This agent also is effective in psoriatic arthritis," said Richard Loeser, MD, chair-elect of the ACR program committee.

IL-17A is a cytokine that plays an important role in driving the immune response in inflammatory arthritic diseases. Of all the IL-17 inhibitors in development, secukinumab is the furthest along and the only one for which phase 3 data exist for spondyloarthritis, which encompasses, among other conditions, ankylosing spondylitis and psoriatic arthritis. The agent is also the first non-tumor necrosis factor (TNF) biologic to show benefits in ankylosing spondylitis.

"In the MEASURE 1 and MEASURE 2 trials, we saw rapid, significant sustained responses in the signs and symptoms of ankylosing spondylitis," said lead author Dominique Baeten, MD, from the Academic Medical Center at the University of Amsterdam. "Responses were seen in both TNF-exposed and non-TNF-exposed patients," he added.

Ankylosing Spondylitis

"Although anti-TNF agents are used to treat ankylosing spondylitis, not all patients respond to those drugs. It is important to have other effective drugs for ankylosing spondylitis," he explained.

The phase 3 MEASURE trials compared secukinumab with placebo in patients with ankylosing spondylitis.

In MEASURE 1 (NCT01358175), the secukinumab regimen was an intravenous loading dose of 10 mg/kg at baseline and weeks 2 and 4, followed by monthly subcutaneous doses of either 75 mg or 150 mg up to week 52.

In MEASURE 2 (NCT01649375), the secukinumab regimen was subcutaneous once-weekly doses (either 75 mg or 150 mg) at baseline and weeks 1, 2, 3, and 4, followed by monthly subcutaneous doses of either 75 mg or 150 mg up to week 52.

Dr. Baeten presented week 16 and week 52 efficacy and safety results from MEASURE 1 in 482 patients with active ankylosing spondylitis. Patients had been exposed to 1 TNF inhibitor (27%) or no TNF inhibitor (73%).

At week 16, the study met the primary end point of a 20% improvement in signs and symptoms, measured with Assessment of Spondyloarthritis International Society (ASAS) criteria.

Table. Week 16 MEASURE 1 Outcomes

ASAS Improvement Secukinumab 75 mg, % Secukinumab 150 mg, % Placebo, % P Value
20% 59.7 60.8 28.0 <.0001
40% 33.1 41.6 13.1 <.001

 

In addition, the secondary end points were met in the two secukinumab groups, including improvements in high-sensitivity C-reactive protein levels, Bath Ankylosing Spondylitis Disease Activity Index, physical function assessed with the 36-item Short Form Health Survey, the Ankylosing Spondylitis Quality of Life Questionnaire, and an increase in ASAS partial remission.

At week 16, patients in the placebo group who achieved a 20% improvement were randomized to either 75 mg or 150 mg secukinumab. At week 24, nonresponders in the placebo group were randomized to either dose of secukinumab. From week 24 to week 52, all patients were on open-label secukinumab.

"For all comparisons, responses at 52 weeks were sustained in both treatment arms," said Dr. Baeten. "The data seem to favor the 150 mg dose."

A subanalysis of patients exposed and not exposed to TNF inhibitors showed that all patients benefited, but the magnitude of benefit was slightly less in previously exposed patients, he said.

Secukinumab was well tolerated and there were no unexpected safety signals.

There were more adverse events and serious adverse events in the placebo group than in either of the secukinumab groups during the 52-week treatment period.

However, no serious infections were reported, and immunogenicity was low.

In MEASURE 2, the efficacy and safety of secukinumab was similar. Again, the 150 mg dose appeared to be superior.

Psoriatic Arthritis

First results from the phase 3 FUTURE 1 and FUTURE 2 trials were similarly positive for secukinumab in more than 1000 patients with psoriatic arthritis.

In FUTURE 2 (NCT01752634), patients with psoriatic arthritis were treated with subcutaneous secukinumab (75 mg, 150 mg, or 300 mg) or placebo at baseline and at weeks 1, 2, 3, and 4, and monthly thereafter.

"FUTURE 2 demonstrated the critical efficacy of selective IL-17 inhibition in patients with psoriatic arthritis. The 300 mg and 150 mg doses achieved rapid clinically significant improvement in psoriatic arthritis, including signs and symptoms, physical function, and quality of life," said lead author Iain McInnes, MD, from the University of Glasgow in the United Kingdom.

Responses were observed regardless of previous exposure to TNF inhibitors or concurrent methotrexate.

The researchers identified the 150 mg dose as the best one for psoriatic arthritis; the 75 mg dose was not effective.

Secukinumab was well tolerated, and the adverse-event profile was similar to that in MEASURE 1 and MEASURE 2.

Results from FUTURE 1 (NCT01392326) were also positive in patients with psoriatic arthritis; improvements in signs and symptoms, physical function, and quality of life at week 52 were rapid and sustained.

Targeting the IL-17 Pathway

"These results are very exciting," said Eveline Wu, MD, from UNC Health Care in Durham, North Carolina.

"The IL-17 pathway is known to be involved in the pathogenesis of disease, particularly spondyloarthritis. It is ideal to have a drug that targets this pathway. Secukinumab is the only IL-17 antagonist that has met the primary end point in phase 3 trials in these diseases, and it is closest to approval," she said.

This evidence comes on the heels of the approval of secukinumab by the US Food and Drug Administration for the treatment of psoriasis.

On the basis of these four trials, Novartis expects to file for global regulatory approval for these indications in 2015, according to a news release. If approval is granted, this will be a blockbuster drug, with $1 to $1.5 billion in annual sales, according to a report published in the Wall Street Journal.

Other IL-17 antagonists in development include brodalumab (Amgen and AstraZeneca), which is directed to the IL-17 receptor, and ixekizumab (Lilly). Both drugs have demonstrated efficacy in phase 2 trials of psoriasis.

Dr. Baeten reports financial ties with Novartis, Boehringer Ingelheim, Jannsen, MSD, Pfizer, AbbVie, BMS, Eli Lilly, Roche, and UCB. Dr. Innes reports receiving financial support from Novartis, Pfizer, UCB, BMS, Amgen, Janssen, AbbVie, Celgene and Lilly. Dr. Wu has disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2014 Annual Meeting: Abstract 819, presented November 17, 2014; Abstract LB1, presented November 18, 2014.

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