PI-106 - SAFETY AND PHARMACOKINETICS OF DF-003, A TARGETED, FIRST-IN-CLASS ALPHA-KINASE 1 INHIBITOR FOR TREATMENT OF THE RARE GENETIC DISEASE, ROSAH SYNDROME.

R. Guttendorf¹, V. Mahajan², Y. Kim³, C. Cook⁴, S. Parker⁴, J. Fan⁵, D. Liu⁵, Z. Zhao⁵, T. Xu⁵, C. Xu⁵, H. Lichenstein⁴, J. Yogaratnam⁴; ¹Aclairo Pharmaceutical Development Group, Inc., Sterling, VA, USA, ²Molecular Surgery Laboratory, Byers Eye Institute, Stanford University, Palo Alto, CA, USA, ³Altasciences Clinical Research Services, Lost Angeles, CA, USA, ⁴Drug Farm USA LLC, Guilford, CT, USA, ⁵Shanghai Yao Yuan Biotechnology Ltd (Drug Farm), Shanghai, China.

Background: ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome is a rare genetic disease driven by a gain-of-function ALPK1 T237M mutation with no approved drug treatment. Patients go blind from retinal degeneration, retinal inflammation, and optic atrophy. We developed a first-in-class ALPK1 kinase inhibitor, DF-003, as a precision medicine to target the root cause of ROSAH syndrome. This first-in-human study assessed safety and pharmacokinetics (PK) in healthy volunteers (HVs) after single and multiple doses, including food effect, to support a Phase 2 study in ROSAH patients.

Methods: This randomized, double-blind, placebo (PBO)-controlled study was conducted in 48 normal HVs meeting inclusion/exclusion criteria. HVs were randomized 6:2 to receive oral DF-003 or matching PBO in 5 single ascending dose (SAD) cohorts (3 to 150 mg) and a 14-day once-daily multiple dose (MD) cohort (50 mg QD) under fasted conditions. Food effect (high-fat meal) was evaluated after a single 20 mg dose in a crossover fashion. Safety and tolerability were assessed by adverse event (AE) monitoring, clinical laboratory/hematology testing, physical exams, vital signs, ECGs, and eye exams. Plasma samples were collected for PK analyses. DF-003 was quantified with a validated LC-MS/MS assay.

Results: DF-003 was well tolerated in all cohorts; no serious AEs were reported. Single-case AEs were mild (fatigue, headache) and single-case lab abnormalities (creatine kinase, ALT, AST, and LDH) resolved without intervention. Median time to Cmax ranged from 7 to 24 h postdose from 3 to 150 mg in SAD and on Days 1 and 14 in MD. Sampling intervals were extended in SAD cohorts 4 and 5 and in MD to enable determination of terminal t½ (mean: 120-150 h). SAD Cmax and AUC0-96h increased dose proportionally from 3 to 150 mg; geometric mean (CV%) ranged from 1.0 (31) to 55 (48) ng/mL and 76 (27) to 3520 (36) ng∙h/mL, respectively. Food increased Cmax and AUC0-96h by approximately 30%. Accumulation was 10x to 12x after 14 days of QD dosing.

Conclusion: ALPK1 kinase inhibition with DF-003 was found to be safe without any systemic or ocular complications. PK characterization provided valuable data to inform selection of a once-daily dose regimen for the continued study of DF-003 to prevent vision loss in ROSAH syndrome.