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Targeting IL-1 Fails in Knee OA

<ѻý class="mpt-content-deck">— Little benefit seen for lutikizumab on scores for pain and function
MedpageToday

Inhibition of interleukin (IL)-1α and 1β with lutikizumab failed to consistently improve pain among patients with knee osteoarthritis (OA) and synovitis, an international phase II trial found.

Pain scores on the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) showed significant improvement at week 16 compared with baseline only among patients randomized to 100 mg lutikizumab every 2 weeks (-2.9, 95% CI -5.73 to 0.01, P=0.050), according to Roy M. Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues.

However, significant differences versus placebo were not seen at that time point for patients receiving 25 mg (-0.3, 95% CI -3.13 to 2.53, P=0.834) or 200 mg (-1.2, 95% CI -4 to 1.66, P=0.415), the researchers reported online in .

Knee OA has typically been considered to be a noninflammatory disease, but it's now recognized that at least half of affected patients do have synovial inflammation and are at increased risk for worse pain and a poor prognosis.

The pro-inflammatory cytokines IL-1α and 1β are thought to play a role in the development of OA, through mechanisms such as the destruction of cartilage and osteoclastogenesis. These cytokines also may mediate pain both peripherally and centrally, and in some animal models, inhibition of the IL-1 pathway has improved OA disease manifestations. Moreover, in a murine model of OA, blocking both IL-1α and 1β was associated with less pain and cartilage destruction than inhibition of either cytokine alone.

Lutikizumab is a dual variable domain immunoglobulin that binds both cytokines, and showed a decline in inflammatory markers with its use.

To examine the effects of this potential treatment in patients considered to be at risk of knee OA progression, in that they had ultrasound or MRI evidence of synovitis, Fleischmann and colleagues enrolled 347 patients from 2014 to 2016.

Participants were required to have Kellgren-Lawrence radiographic knee OA grades 2 or 3 and signs of active inflammation such as swelling and pain in the index knee, as well as scores of 4 to 8 on a numeric pain scale of 0 to 10. Rescue medications of acetaminophen and ibuprofen were permitted, as were standard-of-care medications such as nonsteroidal anti-inflammatory drugs and non-opioid analgesics.

Mean age was 60, two-thirds were women, and mean OA duration was 8 years.

Lutikizumab in one of the three doses or placebo was given subcutaneously every 2 weeks for 52 weeks.

Reductions in pain on the WOMAC scale was sustained in all groups, including placebo, from weeks 16 to 52, with no differences between the active treatment and placebo groups throughout that time period.

Change in synovitis, including synovial membrane thickness, fluid volume, and effusion scores did not differ from baseline to week 26 between the active treatment and placebo groups.

Inconsistent findings were seen on other secondary endpoints. For instance, change in WOMAC function was significantly different from placebo for the 100-mg group, but only at weeks 4 and 8. Response rates according to the criteria of the Outcome Measures in Rheumatology Clinical Trials/Osteoarthritis Research Society International group showed numerical, though not statistical, superiority for the active treatment versus placebo.

Moreover, MRI evaluations of cartilage volume, thickness, and effusion scores were "nearly identical" for all treatment groups at weeks 26 and 52. There also were no between-group differences in use of rescue medications.

Subgroup analyses did reveal greater decreases in WOMAC pain scores at weeks 26 and 52 in patients receiving the 100-mg dose whose Kellgren-Lawrence radiographic grade was 3, and for those who did not use any concomitant medications through week 26. The reason why these findings were observed only in the 100-mg group is unclear, the authors noted.

Injection site reactions were more common in the lutikizumab groups compared with the placebo group (25.2% vs 15.3%), as was the rate of neutropenia (27.5% vs 2.4%). Five cases of malignancy, three of which were basal cell carcinomas, were seen in the lutikizumab group and none in the placebo group. The reason for this observation of increased malignancies is unclear at present, but any future studies with this agent should carefully monitor this.

"The unexpected lack of an effect of IL-1 inhibition on synovitis may signify that, although the synovium is an important source of IL-1, IL-1 by itself may not be required to sustain synovitis. Other factors such as cartilage degradation products and adipokines may have a greater role in the development and maintenance of synovitis," Fleischmann's group wrote.

It's also possible that the effects of lutikizumab were masked by "strong, sustained" placebo responses ranging from 60% to 71%, they pointed out.

"The results of this study suggest that IL-1 inhibition is not an effective disease-modifying therapy in patients with knee OA," but whether certain patient subgroups might benefit "remains an open question," they concluded.

Lutikizumab also was ineffective for erosive hand OA in a recent study.

A limitation of the current study was its inclusion of patients who had generally mild radiographic changes.

Disclosures

The study was supported by AbbVie. Several co-authors are company employees.

Fleischmann and co-authors disclosed multiple relevant relationships with industry including AbbVie, Roche, Pfizer, Eli Lilly, UCB, Bristol-Myers Squibb, Bioiberica, Sanofi, GlaxoSmithKline, Janssen, Regeneron, Flexion, Merck Serono, Novartis, and Servier.

Primary Source

Arthritis & Rheumatology

Fleischmann R, et al "A phase 2 trial of lutikizumab, an anti-interleukin 1α/β dual variable domain immunoglobulin, in knee osteoarthritis patients with synovitis" Arthritis Rheum 2019; DOI:10.1002/art.40840.