Preliminary immunologic and clinical Phase 1b study outcomes from patients with ROSAH syndrome treated with the first-in-class ALPK1 inhibitor DF-003

Introduction/Rationale: ALPK1 (alpha-protein kinase 1) is a key gene and protein involved in innate immunity and inflammation. ROSAH syndrome is an autosomal dominant disorder caused by pathogenic variants in ALPK1 (e.g., T237M) and characterized by ocular inflammation, headache, anhidrosis, splenomegaly, and systemic manifestations. Elevated levels of hsCRP and inflammatory cytokines, including CCL2, CXCL10, TNFα, IL-6, IL-1β, and IL-8, have been observed in affected patients. DF-003 is a first-in-class oral ALPK1 inhibitor under development for treating the genetic root cause of ROSAH syndrome.

Methods: This Phase 1b trial (NCT06395285) is a multicenter, single-arm, open-label study evaluating the safety and tolerability of DF-003. Six patients with ROSAH syndrome (T237M ALPK1) aged 18–65 received daily oral DF-003 for 4 weeks. Serum inflammatory biomarkers and clinical outcomes including quality of life (QoL), assessment of anhidrosis and arthralgia were evaluated. Spleen changes were evaluated by CT/MRI with the Mint Lesion™ system.

Results: Four out of 6 subjects reported the reversal of anhidrosis, improvements in QoL (reduced EQ-5D scores), and improvement in arthralgia. These benefits diminished following discontinuation of therapy. Of the 2 subjects with available immunological marker data, 1 whose markers were elevated at baseline showed pharmacodynamic improvement, with reductions in IL-6, IL-8, CXCL-10, and hsCRP to within normal ranges after 28 days. In the 1 subject that did not have splenectomy, there was a ~20% reduction in spleen volume that reversed upon cessation of drug. All laboratory values remained within normal limits, with stable renal and hepatic function, and no serious or treatment-emergent adverse events were reported. Pharmacokinetic data available from 6 subjects support once-daily dosing.

Conclusion: Inhibition of ALPK1 with DF-003 demonstrated early evidence of clinical and pharmacodynamic improvements without safety concerns. These results warrant evaluation of DF-003 in a Phase 2 trial.