Abiprubart (KPL-404) is a humanized monoclonal IgG4 antibody designed with a stabilized and functionally silent Fc region that binds to CD40. This blockage of the CD40/CD154 costimulatory interaction inhibits T-cell activation following antigen presentation. Essentially, abiprubart functions similarly to Abatacept but targets T cell activation through a different molecular interaction (CD40/CD154). 

A total of 16 patients were randomized in the pharmacokinetics lead-in phase, and 78 in the proof-of-concept (POC) phase. Demographics and baseline disease activity were consistent across all groups. In the pharmacokinetics lead-in phase, Cohort 1 (2 mg/kg SC every two weeks) and Cohort 2 (5 mg/kg SC every two weeks) showed that abiprubart was well-tolerated, leading to the initiation of Cohort 3. 

In Cohort 3, the least-squares (LS) mean change from baseline in DAS28-CRP scores at Week 12 was -2.21 points (n=27) in comparison to placebo (-1.65 points [n=26]). The LS means difference was significantly higher for the 5 mg/kg SC weekly group compared to placebo. For the 5 mg/kg SC bi-weekly group, there was a trend towards improvement, but it did not reach statistical significance (-2.00 points, n=25 vs. -1.65 points, n=26). 

Abiprubart significantly reduced rheumatoid factor, a clinical marker of disease activity and CD40 target engagement, by over 40% at both the weekly and bi-weekly 5 mg/kg dose levels in Cohort 3. 

The incidences of non-serious treatment-emergent adverse events (TEAEs) were similar across treatment groups, with no dose-related patterns, and all TEAEs were mild or moderate. One serious adverse event of monoaural deafness was not related to the drug and resolved with pulse-dose steroids.

KOL insights

“Abiprubart is an Abatacept distant relative, targeting T cell activation through a different target/molecular interaction (CD40/CD154). The trial met its primary endpoint with statistically significant reduction in DAS28-CRP at Week 12 in the 5mg/kg SC weekly dosing group, compared to placebo; with an acceptable safety profile. Another study is ongoing, definitely a compound to keep an eye on!” – Expert Opinion

Conclusion

There is an unmet need in the patient population of rheumatoid arthritis patients who show a poor response to the available biologic disease-modifying anti-rheumatic drugs (bDMARDs) or targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs). These patients have few treatment options. Kiniksa believes that disrupting the CD40-CD154 interaction is an attractive approach for multiple autoimmune diseases. Treatment with abiprubart led to a statistically significant reduction in DAS28-CRP at Week 12 for patients with refractory rheumatoid arthritis in the 5 mg/kg weekly subcutaneous dosing group compared to placebo. However, Kiniksa has prioritized abiprubart clinical development in Sjogren's disease. The company believes that these Phase II results show abiprubart to be a potentially effective and well-tolerated treatment option for a number of autoimmune diseases, including Sjogren's disease. The comparable magnitude of reduction in Rheumatoid Factor observed across weekly, biweekly, and monthly dosing and supportive post-hoc analysis of pooled efficacy data reinforce confidence that abiprubart is highly active. 

The Phase IIb study for Sjogren's disease is anticipated to begin in the second half of 2024, according to the company. Under its current operational strategy, which involves advancing abiprubart through Phase III development in Sjogren's disease, the business aims to be cash flow positive on an annual basis. It is possible that this decision is because the results from the Cohort-3 provide a clearer picture of KPL-404's effectiveness on the DAS28-CRP primary efficacy endpoint in Rheumatoid Arthritis. The drug's effectiveness was marginally superior to placebo. When compared to placebo, the results from Cohorts 1 and 2 looked promising, although the patient pools for both cohorts were small.