ABACHAI - Safety and efficacy of abatacept (s.c.) in patients with CTLA4 insufficiency or LRBA deficiency, a phase II clinical trial.

Abstract

Heterozygous germline mutations in CTLA4 (CTLA-4 insufficiency) and biallelic mutations in LRBA (LRBA deficiency) cause immune dysregulation with autoimmunity, lymphoproliferation, and immunodeficiency. For treatment, abatacept has been used successfully and is increasingly being used off-label; however, prospective clinical trial data are missing. To evaluate the safety and efficacy of abatacept in patients with CTLA-4 insufficiency or LRBA deficiency. ABACHAI was a prospective, open-label, single-arm phase IIa trial. Adult patients with genetically confirmed CTLA-4 insufficiency or LRBA deficiency and at least one clinically significant organ manifestation received 125 mg abatacept subcutaneously once weekly for 12 months. The primary endpoint was safety, defined as the number of episodes of failed infection control. Secondary endpoints included additional safety parameters, efficacy outcomes, and patient-reported quality of life. Twenty patients were enrolled (18 with CTLA-4 insufficiency and 2 with LRBA deficiency). Three patients had five severe infections during treatment (incidence rate 0.27 per patient-year), comparable to the year preceding enrolment. No EBV or CMV reactivations occurred. Abatacept reduced lymphoproliferation and immune activation and improved patient-reported quality of life and gastrointestinal symptom quality. Cytopenias and renal involvement were not sufficiently controlled. Four patients (20%) discontinued - three due to unrelated serious adverse events, one due to non-compliance. ABACHAI was the first prospective interventional trial, examining abatacept treatment in CTLA-4 insufficiency and LRBA deficiency. Abatacept demonstrated a favourable safety profile and organ-specific efficacy with strongest responses in lymphoproliferation and immune activation. Patients with refractory cytopenias or progressive organ involvement may require additional or alternative therapeutic strategies.