The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis

This is a randomized, double-blind and vehicle-controlled Phase III study to evaluate the safety and efficacy of topical TMB-001 0.05% ointment for the treatment of congenital ichthyosis (CI) in subjects with either the RXLI or ARCI subtypes. In addition, a subset of preselected centers will recruit subjects in parallel with either the RXLI or ARCI subtypes for enrollment into an Optional Maximal Use arm for evaluation of the systemic exposure and safety of topical TMB-001 0.05% ointment for the treatment of CI. The Phase III Study is designed in three periods: \- Period 1 - Induction (3 weeks): At the beginning of the 3-week Induction Period, eligible subjects will be randomized (2:1 ratio) to either TMB-001 0.05% once-a-day (QD) or Vehicle QD treatment, with use of mandatory standardized bland emollient (Cetaphil™) provided by the Sponsor. \- Period 2 - Treatment (9 weeks): The dosing frequency in the 9-week treatment period will be increased in each treatment group to TMB-001 0.05% BID or Vehicle BID. Mandatory bland emollient will be discontinued. \- Period 3 - Maintenance (12 weeks): At Week 12, eligible subjects in the TMB-001 treatment group will be randomized (1:1 ratio) to an open-label treatment with TMB-001 0.05% BID or TMB-001 0.05% QD. To be eligible, subjects must have achieved a ≥1-point reduction in IGA score from Baseline. Subjects with less than a 1-point reduction in IGA score from Baseline will be discontinued from the study. Vehicle-treated subjects who achieved \<1-point reduction in IGA score from Baseline are eligible to cross over to the TMB-001 0.05% BID treatment group. Subjects with a ≥1-point reduction in IGA score from Baseline on vehicle will be discontinued from the study. Subjects at the end of the study or subjects discontinued from the study at any time will be followed-up for additional 2 weeks for AEs.

This is a multicenter, randomized, double-blind, vehicle-controlled Phase III study to evaluate the efficacy and safety of TMB-001 0.05% topical ointment in the treatment of CI. Subjects will be selected according to predefined entry criteria. The study treatment duration is 24 weeks and expected to be sufficient to show a treatment effect. Isotretinoin is an approved active pharmacological ingredient with a long history of safe use in humans. However, isotretinoin is a known teratogen with an extremely high risk for severe birth defects if pregnancy occur while taking oral isotretinoin in any amount, even for a short period of time. Therefore oral, systemic isotretinoin requires an iPLEDGE program (iPLEDGE 2012), which is a risk management distribution program mandated by the FDA. To minimize pregnancy risks, women of childbearing potential (WOCBP) will only be enrolled if they agree to use highly effective methods of contraception consistently and correctly and undergo regular pregnancy testing. To minimize bias, subjects will be blinded and randomly assigned to treatment with TMB-001 0.05% or Vehicle, additionally subjects who had previously been treated with TMB 001 will be excluded from this study but can be enrolled in the optional Maximal Use arm (in a subset of preselected centers). The use of a vehicle control group is consistent with FDA's standard for generating valid scientific evidence to definitively support safety and efficacy. The vehicle group accounts for the effects of treatment that do not depend on the test treatment. The study is designed to mitigate safety risks by using an initial 2:1 randomization (active treatment to vehicle), along with frequent clinic visits over the 12-week treatment period. The subsequent 1:1 randomization of eligible TMB-001 0.05% treated subjects to two dosing regimen (QD or BID) allows for assessment of the optimal TMB-001 0.05% maintenance therapy as well as provides additional safety data for 12 weeks. The cross-over of eligible subjects from the vehicle control group will also provide additional safety data. Overall, the study design is considered to be scientifically robust and clinically relevant for evaluating TMB-001 0.05% treatment for the safe and effective treatment of CI.