Abstract Body (Do not enter title and authors here):
Background: Pulmonary arterial hypertension (PAH) remains a disease with a poor prognosis despite currently available pulmonary vasodilator therapies. Enhanced interleukin-6 (IL-6) signaling has been suggested to contribute directly to pulmonary vascular remodeling in PAH. However, previous studies have shown that anti-IL-6 receptor antibodies are effective only in a subset of patients, indicating heterogeneous treatment responses. This study is the first to validate a precision medicine approach for PAH. Using a nationwide patient registry, comprehensive cytokine analysis, and AI-driven clustering, we identified a subgroup of patients with an "activated immune-responsive phenotype," characterized by high serum IL-6 levels and thus expected to respond to treatment.

Methods: The SATISFY-JP trial was a multicenter, single-arm, open-label, Phase 2 clinical trial to evaluate the efficacy and safety of satralizumab, an anti-IL-6 receptor antibody, in patients with PAH. The study enrolled 20 PAH patients with serum IL-6 levels of 2.73 pg/mL or higher. Satralizumab (120 mg) was administered subcutaneously at weeks 0, 2, and 4, and every 4 weeks thereafter. The primary endpoint was the percent change in pulmonary vascular resistance (PVR) from baseline to week 24.

Results: Of 110 PAH patients screened for high-sensitivity IL-6, 43 (39.1%) met the inclusion criterion of IL-6 ≥ 2.73 pg/mL. A total of 20 patients from 9 centers were enrolled and constituted the Full Analysis Set (FAS). The baseline characteristics of the FAS population were as follows: mean age at enrollment was 59.3-yo, 13 patients (65.0%) were female, and 9 (45.0%) had a history of smoking. The distribution by WHO Functional Class was 5 patients (25.0%) in Class II and 15 (75.0%) in Class III. The underlying etiologies of PAH were Idiopathic/Heritable PAH (I/HPAH) in 9 patients (45.0%), PAH associated with connective tissue disease (CTD-PAH) in 9 patients (45.0%), and PAH associated with congenital heart disease (CHD-PAH) in 2 patients (10.0%). The primary endpoint was evaluated in 17 patients. The results showed improvement in the primary endpoint, the 17.4% percent reduction in pulmonary vascular resistance (PVR), from baseline to week 24.

Conclusion: In a subgroup of PAH patients identified by high serum IL-6 levels, the anti-IL-6 receptor antibody satralizumab improved PVR at 24 weeks. The results of this trial support the validity of a novel precision medicine strategy.