Lutikizumab, a dual variable-domain immunoglobulin that inhibits interleukins (IL) 1α and 1β, was not effective as a treatment for erosive hand osteoarthritis (OA), a phase IIa study found.
At week 16, change from baseline in pain as measured on the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) was similar for patients who had been randomized to lutikizumab (−9.2, 95% CI −13.8 to −4.6) or placebo (−10.7, 95% CI −15.4 to −6), according to Margreet Kloppenburg, MD, PhD, of Leiden University Medical Center in the Netherlands, and colleagues.
The least squares mean difference between lutikizumab and placebo in change in pain was a nonsignificant 1.5 (95% CI −1.9 to 5), the researchers reported online in .
Hand OA is common, particularly among older women, and is associated with substantial disability -- yet treatments are limited and no disease-modifying agents have demonstrated efficacy.
Inflammatory cytokines including IL-1 are thought to participate in the pathogenesis of OA. "IL-1α and IL-1β bind to the IL-1 type 1 receptor, leading to the production of proinflammatory molecules, proteases and other mediators, which result in joint pain, inflammation and cartilage destruction," the researchers explained.
Blocking the two interleukins showed a decline in OA progression in a mouse model, and in a phase I trial of knee OA the treatment was associated with decreases in neutrophils, C-reactive protein (CRP) and biomarkers of synovitis, such as matrix metalloproteinase-degraded collagen types I and III.
Therefore, to see if there might be a role for this agent in hand OA, Kloppenburg and colleagues enrolled 131 adults with active inflammation of the hand joints, with pain ratings of 6 or higher on an 11-point scale, and at least one erosion of an interphalangeal joint. All underwent radiography and MRI of the hand joints at baseline and week 26. Radiographs were scored according to the Osteoarthritis Research Society International (OARSI) criteria and MRIs according to the Outcome Measures in Rheumatology/Hand Osteoarthritis MRI Scoring system (OMERACT/HOAMRIS).
Participants' mean age was 66, and most were white women. Mean duration of OA was 11 years, mean AUSCAN pain score at baseline was 39, and mean tender and swollen joint counts were 12 and 6, respectively.
They were randomized to subcutaneous placebo or lutikizumab, 200 mg every 2 weeks for 24 weeks. Rescue medication for pain with acetaminophen or ibuprofen was permitted.
As with the pain endpoint, no significant differences were seen between the two groups in change from baseline in AUSCAN function at week 16, which was −14.6 (95% CI −22.1 to −7.1) for lutikizumab and −17.2 (95% CI −24.9 to −9.4) for placebo, for a mean difference of 2.5 (95% CI −3.2 to 8.3).
Other secondary endpoints also had similar results for lutikizumab and placebo at week 26, respectively:
- Tender joints, −5.8 vs −4.7, P=0.32
- Swollen joints, −2.2 vs −1.8, P=0.64
- OARSI joint space narrowing, 0.03 vs 0.14, P=0.51
- HOAMRIS synovitis, 0.85 vs 0.92, P=0.89
- Joints with synovitis on MRI, 0.54 vs 0.46, P=0.79
With regard to pharmacodynamics, the active treatment did lead to significant declines in serum levels of IL-1α and IL-1β and in levels of neutrophils, CRP, and matrix metalloproteinase-degraded collagen type 1.
Adverse events and serious adverse events were similar in the two groups, but more patients in the lutikizumab group reported injection site reactions. Study withdrawals because of adverse events were seen in five patients receiving lutikizumab and two given placebo, and two patients receiving the active treatment withdrew from the study because of neutropenia. Low-density lipoprotein cholesterol levels increased more in the active treatment group.
"In conclusion, despite adequate systemic lutikizumab pharmacodynamic effects, lutikizumab did not significantly improve clinical outcomes or imaging outcomes in patients with erosive hand OA compared with placebo, suggesting that targeting IL-1 may be ineffective for the treatment of erosive hand OA," the authors wrote.
A limitation of the study was the possibility that 26 weeks was not long enough to detect changes in pain, function, and structure.
Disclosures
The study was funded by AbbVie.
The authors reported financial relationships with AbbVie, Pfizer, GlaxoSmithKline, Merck, Levicept, Spire Sciences, Amgen, Bristol-Myers Squibb, Regeneron, Astellas, AstraZeneca, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Roche, Sanofi, and UCB. Several are employees of AbbVie and may hold stock in the company.
Primary Source
Annals of the Rheumatic Diseases
Kloppenburg M, et al "Phase IIa, placebo-controlled, randomized study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis" Ann Rheum Dis 2018; DOI: 10.1136/annrheumdis-2018-213336.