IL-1 blockade shows promise for knee OA
medwireNews: Phase I trial results suggest that the interleukin (IL)-1 inhibitor ABT-981 is well tolerated and may give rise to an anti-inflammatory response among patients with knee osteoarthritis (OA).
Based on these findings, “ABT-981 is a viable candidate for further research,” say Jeroen Medema (AbbVie Inc., North Chicago, Illinois, USA) and fellow researchers.
In their dose-ranging study, the team randomly assigned 36 patients with mild-to-moderate knee OA to receive the dual IL-1α and IL-1β inhibitor at a dose of 0.3, 1, or 3 mg/kg every other week for four injections or 3 mg/kg every 4 weeks for three cycles, or matching placebo injections. A total of 31 participants completed the study.
In all, 53.6% of 28 patients in the ABT-981 groups and 62.5% of eight patients receiving placebo experienced treatment-emergent adverse events over the 57-day treatment period. The most frequently occurring adverse event was injection site erythema, reported in 14.3% and 0% of patients in the ABT-981 and placebo groups, respectively, and 21.4% versus 12.5% of participants experienced adverse events considered to “have a reasonable possibility of being study drug related” by the investigators.
All adverse events were mild or moderate in severity, with the exception of one incidence of grade 3 bronchitis and viral infection, which was “possibly related to ABT-981,” report Medema and colleagues in Osteoarthritis and Cartilage.
“Overall, ABT-981 was well tolerated with no observed dose-limiting toxicities,” summarize the researchers. They note that antidrug antibodies (ADA) were present in 37% of patients, but “the magnitude of ADA response was low,” and there was no association between the incidence of ADA and that of adverse events.
Mean serum IL-1α and IL-1β levels decreased from baseline to day 57 among participants in all four ABT-981 treatment groups, with 71–93% and 39–87% reductions observed from baseline values of 7.1 pg/mL 0.46 pg/mL, respectively.
Patients receiving ABT-981 also experienced a continuous decrease in high-sensitivity C-reactive protein (hsCRP) levels from baseline to week 2 regardless of dose, and those receiving the drug at a dose of 3 mg/kg had a significantly greater decrease in hsCRP over the study period compared with patients in the placebo group, “indicating a reduction in systemic inflammation,” say Medema and team.
Moreover, there were “[c]lear, dose-dependent decreases” in matrix metalloproteinase-derived type 1 and type 3 collagen levels, “indicating a dampening of inflammation-mediated joint destruction” with ABT-981 treatment.
“The safety and tolerability profile in conjunction with its effects on inflammatory biomarkers supports further investigation of ABT-981 in patients with OA,” write the study authors.
They caution that the study was limited by the small sample size of patients with limited disease activity, and that the investigation into inflammatory biomarkers should be considered exploratory.
And the team concludes: “Current phase 2 studies will address these limitations and later studies will address whether ABT-981 treatment also results in symptomatic and/or structural benefit for patients with OA.”
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