Interim PK analyses from the Phase 3 ASCEND study suggest minimal systemic absorption of isotretinoin or its major metabolites in patients with moderate to severe forms CI who were treated with Timber's TMB-001 0.05% ointment.

Interim pharmacokinetic (PK) analyses from the Phase 3 ASCEND study suggest minimal systemic absorption of isotretinoin or its major metabolites in patients with moderate to severe forms of congenital ichthyosis (CI) who were treated with TMB-001 0.05% ointment, Timber Pharmaceuticals, Inc. reports.

The study will be presented during the Society for Pediatric Dermatology’s Annual Meeting to be held July 13-16, 2023, in Asheville, NC. Timber has received both Breakthrough Therapy Designation and Fast Track Status from the U.S. Food and Drug Administration for TMB-001.

“Many dermatologists are familiar with oral isotretinoin, but high-dose and chronic oral isotretinoin therapy required in the treatment of CI cannot be tolerated by many patients due to systemic toxicity,” says Alan Mendelsohn, M.D., Chief Medical Officer of Timber, in a news release. “We are advancing innovative clinical research evaluating TMB-001, a topical isotretinoin formulated using our proprietary IPEG™ delivery system that enables targeted delivery to the epidermis and dermis with the potential to minimize systemic drug absorption, which we hope will translate into better safety and lower systemic toxicity while still maintaining high degrees of efficacy.”

The Phase 3 ASCEND study (https://ichthyosistrial.com/about_ascend_study.htm) is an ongoing double-blind, vehicle-controlled randomized 12-week study followed by 12 weeks of open label treatment of patients who are greater than 6 years of age with moderate to severe X-linked recessive CI (XLRI) or autosomal recessive CI (ARCI). The primary endpoint is the difference in proportions of treated patients with 2-point Investigator's Global Assessment (IGA) scaling/fissuring score improvement from baseline at 12 weeks. A subset of patients is also participating in a 12-week open label Maximal Use Study (MuST) that includes the collection of PK data as well as safety and efficacy data.

 The interim PK analyses include the first nine patients who completed 15 days of the MuST study. The results indicate minimal absorption of isotretinoin when TMB-001 0.05% is applied to 75-90% of the body surface area. The 9 subjects (7 ARCI, 2 XLRI; ages 12-62) demonstrated mean plasma concentrations (ng/mL) of isotretinoin at Day 14 of 4.83 (range: 1.46-16.59), 4-oxo-isotretinoin of 13.71 (6.52-47.86), tretinoin of 0.08 (0-0.66) and 4-oxo-tretinoin of 0. 

“The dry, thickened, and scaling skin that people living with these rare genetic keratinization disorders must deal with can be seriously debilitating, especially in the most severe cases of XLRI and ARCI,” adds Joyce M.C. Teng, M.D., Ph.D., Professor and Director of Pediatric Dermatology, Stanford University. “If we can overcome toxicity challenges of oral treatment with a novel topical formulation of isotretinoin, we may be able to provide better care for our patients. These interim PK data are encouraging, especially when we compare the results to plasma isotretinoin concentrations that we typically see on the labels of oral therapies, which are as high as 862ng/mL with a single dose of 80mg of isotretinoin.”