AT THE EULAR 2017 CONGRESS
MADRID (FRONTLINE MEDICAL NEWS) – Treatment with the dual interleukin (IL) 1 blocker ABT-981 did not improve pain scores or erosive joint damage in patients with hand osteoarthritis (OA) in a phase 2a trial reported at the European Congress of Rheumatology.
The disappointing findings suggest that IL-1 may not be an effective target in erosive hand OA, said Margreet Kloppenburg, MD , of Leiden (the Netherlands) University Medical Center, even though the investigators obtained adequate pharmacodynamic results that suggested it was effectively blocking both IL-1 alpha and IL-1 beta.
“ABT-981 200 mg was not significantly different from placebo on primary, secondary, or exploratory endpoints,” she said. The treatment was associated with injection site reactions and neutropenia, she added, although it was otherwise well tolerated.
The phase 2a , multicenter, randomized, double-blind, placebo-controlled study she reported followed on from a phase 1 trial showing that ABT-981 could dose-dependently reduce neutrophil counts and markers of joint inflammation in patients with knee OA. So it was perhaps natural to see if it could potentially have an effect in patients with erosive hand OA.
The aim of the phase 2a trial was to evaluate the safety and efficacy of ABT-981 in the treatment of 131 patients with erosive hand OA. After screening and a 45-day washout period, patients with confirmed erosive hand OA were randomized to receive ABT-981 200 mg injected every 2 weeks or matching placebo.
The primary endpoint was the change in Australian/Canadian Hand Osteoarthritis Index ( AUSCAN ) pain from baseline to 16 weeks, but no significant difference was observed. The mean change in AUSCAN pain was –9.2 for the 64 ABT-981-treated patients and –10.7 for placebo-treated patients (P = .039).
“There were similar results with AUSCAN function and tender and swollen joint counts,” Dr. Kloppenburg said.
There were also no differences seen in radiographic or MRI endpoints, such as the number of erosive joints, Kellgren and Lawrence scores, joint-space narrowing, or the presence of osteophytes.
Nevertheless, there was evidence that ABT-981 was decreasing inflammatory markers, such as high-sensitivity C-reactive protein and neutrophils. IL-1 alpha and IL-1 beta were difficult to measure, but data suggested that IL-1 was being blocked.
Disappointing results with cytokine targeting
Hand OA affects around 11% of the OA population and erosive hand OA is a very painful phenotype that affects multiple joints, Xavier Chevalier, MD , of Henri-Mondor Hospital, Paris XII University (France), said during a separate session at the congress.
While there is a rationale for using anti-inflammatory drugs for erosive hand OA, so far there just have not been many, if any, real successes. “The effect sizes are small,” Dr. Chevalier said. “There are not a lot of drugs when compared to hip and knee OA,” he observed.
From nonsteroidal anti-inflammatory drugs to corticosteroids and disease modifying anti-rheumatic drugs such as hydroxychloroquine and methotrexate, none has been shown to have any real benefit in addressing erosive hand OA, Dr. Chevalier observed. Even biologic agents targeting IL-2, tumor necrosis factor (TNF), and now IL-1 have not lived up to their promise.
His general conclusion was that targeting cytokines in hand OA had been “disappointing” with “small effect in subgroup of clinically inflamed IP [interphalangeal] joints.”
Dr. Chevalier questioned: “Is hand OA a real OA?” There are features of the disease that imply it could be more of a ligamentous or enthesitis disease, or perhaps a subchondral bone disorder.
Is erosive hand OA even an inflammatory disease? he asked. Are TNF and IL-1 the right targets? Perhaps not, given the research presented by Dr. Kloppenburg and others, he suggested. Further research needs to look for surrogate markers and try to quantify the structural evolution of the disease, he proposed.
It is important to talk about negative studies and to not make excuses for why they might be negative, Tonia Vincent, PhD , observed during the discussion that followed Dr. Chevalier’s presentation.
“If you do proper, randomized, controlled studies in decent numbers and you don’t see effect sizes, and the only times when you see things are when they are open-label, they are not randomized, you’re looking at small numbers, it just goes to show easy it is to over interpret the results of those small studies,” said Dr. Vincent, professor of musculoskeletal biology at the Kennedy Institute of Rheumatology in Oxford, England.
“My conclusion, from my own in vivo studies and from what you’ve [Dr. Chevalier] just said, is that these are the wrong targets. Just because we are rheumatologists does not mean to say everything is about cytokines,” she said.
AbbVie funded the study. Dr. Kloppenburg acknowledged receiving research support from Pfizer and consultancy fees from AbbVie, GlaxoSmithKline, Merck, and Levicept. Dr. Chevalier disclosed working as an advisor to IBSA [Institut Biochimique SA], Sanofi, and Flexion Therapeutics; as an advisory board member for Laboratoires Genevrier and Labpharma; and receiving travel and accommodation support to attend the meeting from Nordic Pharma. Dr. Vincent did not report her disclosures.
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