Background/Purpose:  Duvelisib is a potent, oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ,γ being developed for hematologic malignancies, and was also explored in early phase studies in inflammatory diseases. PI3K-δ,γ isoforms are necessary for adaptive and innate immunity and have significant, non-overlapping roles in immune cell signaling. Results from several preclinical arthritis models and the inhibition of basophil activation in a healthy subject study supported duvelisib dosing between 0.5 and 5 mg twice daily (BID) in this study. The objective of this phase 2 study was to determine the safety and efficacy of duvelisib at 0.5, 1, and 5 mg BID in adults with moderate-to-severe RA while receiving background MTX.

Methods:  Adults with active RA (≥ 5 swollen and tender joints, and CRP > 7 mg/L [1.4 x ULN]) on stable background MTX were randomized to 12 weeks of double-blinded treatment with placebo or duvelisib (0.5, 1, or 5 mg BID). The primary endpoint was the proportion of subjects who achieve an ACR20 at Week 12. Immunophenotyping analysis of B- and T-cell subtypes and pharmacokinetics (PK) and safety were also assessed.

Results:Of 322 subjects enrolled, 274 completed 12 weeks of treatment. Most subjects were female (83.2%) and white (93.5%). Median age was 54.5 (21-71) years. Median time since diagnosis of RA was 78.2 (4.1-522) months; 73% of subjects had Class II RA. Mean duration of MTX prior to study entry was 54.7 (±52.1) months. The primary endpoint (ACR20 at Week 12) was not met for any of the doses of duvelisib tested in this study (Table). Although statistically significant improvements in some secondary endpoints were noted, there were no large, consistent or dose-related improvements over placebo. For example, the DAS28-CRP mean changes from baseline were greater with 0.5 and 5 mg BID than placebo after 12 weeks, but with small absolute differences (Table). Duvelisib appeared to be generally well tolerated: overall, the majority of adverse events (AEs) were Grade 1 or 2 and reversible. The most frequent AEs more common in duvelisib than placebo during treatment were anemia, elevated ALT/AST, lymphopenia, nausea, nasopharyngitis, and headache. Treatment discontinuations of 6 patients on duvelisib 5 mg BID and 1 placebo patient were required per protocol; these patients, with normal baseline ALT/AST, had reversible elevations > 3 x ULN, with no significant elevation in bilirubin. A statistically significant, but small increase from baseline in mean absolute counts of peripheral blood B-cells and T-cells (CD4+ and CD8+) at week 2 was observed at 5 mg BID. 

Table:  ACR20 and DAS28-CRP at Week 12

Conclusion:  The findings from this study indicated that in subjects with RA on background MTX duvelisib administered at 0.5, 1, and 5 mg BID had no added benefit over placebo.  No new safety signals associated with duvelisib therapy were identified.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-and-efficacy-results-of-a-phase-2-double-blind-placebo-controlled-clinical-study-of-duvelisib-with-background-methotrexate-mtx-in-adults-with-moderate-to-severe-rheumatoid-arthritis-ra/