ABT-981 disappoints in hand osteoarthritis trial
The experimental drug ABT-981 fails to show significant improvements in pain and joint symptoms compared with placebo in patients with hand osteoarthritis (OA), according to a phase IIa trial presented at the European League Against Rheumatism (EULAR) Annual Congress 2017 held in Madrid, Spain.
“In the study, 131 patients with hand OA were randomized to receive placebo or subcutaneous injection of ABT-981 200 mg every 2 weeks for 26 weeks,” said investigator Dr Margreet Kloppenburg of the Leiden University Medical Center, Leiden, the Netherlands. “All patients had hand OA as defined by the American College of Rheumatology criteria, along with ≥3 inflamed interphalangeal joints, patient-rated hand pain score ≥6 [on a scale of 0–10], and radiographic evidence of ≥1 erosive interphalangeal joint.” [EULAR 2017, abstract OP0168]
The study failed to meet its primary endpoint of improvement in Australian/Canadian (AUSCAN) pain score after 16 weeks of treatment with ABT-981 vs placebo (least squares [LS] mean change, -9.2 vs -10.7; p=0.39). Similarly, LS mean changes in AUSCAN function (-16.4 vs -14.3; p=0.49), tender joint count (-5.8 vs -4.7; p=0.32) and swollen joint count (-2.2 vs -1.8; p=0.64) at week 26 were comparable between the two groups.
“Likewise, no significant differences were observed with ABT-981 vs placebo at 26 weeks in X-ray endpoints such as osteophytes and erosive joints, and MRI endpoints such as synovitis, cartilage space loss and erosive damage,” reported Kloppenburg.
In terms of pharmacodynamics, treatment with ABT-981 was associated with significant reductions in levels of high-sensitivity C-reactive protein, neutrophils and the collagen degradation biomarker C1M at weeks 16 and 26. “We also found a low incidence of immunogenicity associated with ABT-981,” added Kloppenburg.
ABT-981 was generally well tolerated. Infection was reported by 51 percent of patients in the placebo group and 41 percent of patients in the ABT-981 group, but none of the patients had serious infections. However, ABT-981 was associated with higher rates of injection-site reaction (36 vs 16 percent), grade 2 neutropenia (14 vs 0 percent), and grade 3 neutropenia (5 vs 0 percent).
Five patients in the ABT-981 group and two patients in the placebo group discontinued treatment due to adverse events.
“In OA, interleukin [IL]-1α and IL-1β bind to IL-1 type 1 receptor, resulting in pain, inflammation, cartilage destruction and bone resorption. Therefore, IL-1 inhibition represents a potential treatment for OA,” explained Kloppenburg. [Cytokine 2014;70:185-193; Rheumatology (Oxford) 2003;42 (Suppl 2):ii3-ii10; Nat Rev Rheumatol 2011;7:33-42; Nat Rev Rheumatol 2016;12:14-24] “ABT-981 is a novel human immunoglobulin that simultaneously binds and inhibits IL-1α and IL-1β. A previous phase I study in patients with knee OA showed that ABT-981 reduced neutrophil counts and synovitis markers in a dose-dependent manner.” [Osteoarthritis Cartilage 2015;23 (Suppl 2):A398-A399]
“However, the results of our present study suggest that targeting IL-1 may be ineffective in erosive hand OA, as ABT-981 failed to translate the pharmacodynamic improvements into better outcomes,” she concluded.