51523 The Phase 3 Vehicle-Controlled ASCEND Trial of Polyethylene Glycol Based Topical Isotretinoin (TMB-001 0.05% ointment) for Treatment of X-Linked and Autosomal Recessive Congenital Ichthyosis: Pharmacokinetic Results Compared with 80 mg Oral Isotretinoin

The ASCEND Trial [n=110] is a Phase 3, vehicle-controlled study of subjects >6 years of age with moderate-severe (IGA >3; 10-90% BSA involvement) XLRI or ARCI treated with TMB-001 0.05%. 32 substudy subjects (Maximal Use Study [MuST]) >6 years of age apply open-label TMB-001 0.05% BID to 75-90% BSA for 15 days (D) to collect pharmacokinetics (PK) of isotretinoin (ISO), 4-oxo-isotretinoin (4-O-ISO), tretinoin (TR), and 4-oxo-tretinoin (4-O-TR). Analysis of first 13 MuST subjects and contemporaneous PK in 15 healthy male volunteers (HV) administered oral isotretinoin 80 mg are compared. In HV, blood sampling was performed at multiple timepoints on D1-5 up to 120 hours (H). Blood sampling in MuST was obtained on D1 (6 timepoints), D12, D14 (6 timepoints), and D15. By D14, 13 subjects with CI (10 ARCI, 3 XLRI; mean age: 40.2 years [range 12-62]; 6 females) demonstrated mean peak plasma concentrations (ng/mL) of ISO of 5.4 (0-17.6), 4-O-ISO of 13.4 (0-41.3), TR 0.6 (0-2.6) and 4-O-TR of zero. Mean AUCt (ng/mL*hr) for topical ISO was 125. Through 120H, mean peak plasma concentrations in HV were 1164.9 for ISO (532-1950), 4-O-ISO 702 (479-1090), T 21.8 (9.8-38.8) and 4-O-T 5.3 (2.9-14.1). Mean AUCt (ng/mL*hr) for oral ISO was 16049.9. PK results from 13 adolescent and adult subjects with RXLI or ARCI treated with TMB-001 0.05% ointment on 75-90% BSA demonstrate ∼100 times lower systemic ISO concentrations, compared with plasma ISO and metabolite concentrations in HV following single dose 80 mg oral isotretinoin.