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Trial Shows Positive Results With Isotretinoin Treatment in Congenital Ichthyosis


Alan Mendelsohn, MD, presented captivating Phase 3 TMB-001 PK Data in a poster session.

Phase 3 ASCEND (NCT05295732) trial results show that interim PK analyses indicate minimal systemic absorption of isotretinoin or its major metabolites in patients with moderate to severe forms of congenital ichthyosis (CI) with TMB-001 0.05% ointment. Alan Mendelsohn, MD, chief medical officer of Timber Pharmaceuticals, presented the full data set in a poster session at the 2023 Society for Pediatric Dermatology Meeting in Asheville, North Carolina, July 13-16.

He spoke exclusively with Dermatology Times® at the meeting and pointed out key endpoints met in the trial, showcased photos of treatment progress, and expressed optimism in the future of CI treatment in the video below.

"Congenital ichthyosis is a difficult disease to treat," said Mendelsohn. Investigators leading this study know the quality of life, especially for pediatric patients, is affected by hyperkeratinization of the skin.

The ASCEND Phase 3 Trial (n=142) is an ongoing double-blind, vehicle-controlled randomized 12-week study followed by 12 weeks open label treatment of subjects >=6 years of age with moderate to severe (IGA >=3; 10-90% involved body surface area [BSA]) X-linked (RXLI) and lamellar ichthyosis (ARCI) treated with TMB-001 0.05%, a proprietary topical isotretinoin ointment. Mendelsohn shared that investigators are currently enrolling patients 6 and older, and up to this date, they have included patients as young as 4 and as old as 90.

The primary endpoint of the study was the difference at week 12 in proportions of treated subjects with 2-point IGA scaling/fissuring score improvement from baseline. An additional subset of 32 participants >=6 years of age are being evaluated in a distinct open-label study arm applying TMB-001 0.05% BID to 75-90% involved BSA for 15 days to collect pharmacokinetics of isotretinoin (ISO), 4-oxo-isotretinoin (4-O-ISO), tretinoin (TR), and 4-oxo-tretinoin (4-O-TR) concentrations, followed by 10 weeks of continued application of TMB-001 0.05% BID for safety and efficacy.

Investigators said in their poster presentation, "Protocol driven interim pharmacokinetic analyses in the first 9 adolescents and adults who completed day 15 of MuST are reported. Blood sampling was obtained on day 1 pre-dose and at 1, 2, 4, 6 and 12 hours (H) post dose, day 12 pre-AM dose, day 14 pre-AM dose and at 1, 2, 4, 6 and 12H post dose, and day 15 24H post day 14 dose. Through day 15, 7 subjects with ARCI (median age: 42.6 years [range 24-62]; 5 females) demonstrated median maximum plasma concentrations (ng/mL) of ISO of 4.92 (range 1.5-18.1), 4-O-ISO of 18.0 (range BQL-56) and TR below limit of quantification [BQL] (range BQL-2.7). Two subjects with RXLI (ages 12, 31; 2 males) demonstrated maximum concentrations (ng/mL) of ISO of 2.03-5.03, 4-O-ISO of 4.6-26.1, and TR BQL in both subjects. All 9 subjects had 4-O-TR levels that were BQL. Peak values were variably achieved by days 12-14. Historically, mean isotretinoin plasma Cmax was 862 ng/mL when single dose oral isotretinoin 80 mg was taken by 74 healthy, fed volunteers."

Mendelsohn pointed out photos of a 12-year old boy's results on the poster. "You can clearly see the differences particularly on his thigh, on his abdomen and on the back of his arm in terms of improvement. This is achieved with a peak plasma concentration of only 5 as opposed to...800 or 1000," he said. Adverse events included skin reactions. No significant oral isotretinoin toxicity were noted.

In the conclusion of the ASCEND trial, results of 9 participants including adolescent and adult subjects with RXLI and ARCI indicate minimal systemic ISO absorption when TMB-001 0.05% is applied to 75-90% BSA, particularly compared with labelled plasma ISO concentrations with oral isotretinoin.

"Our hope is that in fact, this may be in negotiations with the FDA," Mendelsohn said in his final thoughts. Timber has received both breakthrough therapy designation and fast track status from the US Food and Drug Administration for TMB-001.


1. Teng J, Wine Lee L, Song E, et al. The Phase 3 vehicle controlled ASCEND trial for treatment of x-linked and autosomal recessive congenital ichthyosis: interim analysis of pharmacokinetic results of xaximal use study. Poster presented at the 2023 Society for Pediatric Dermatology Meeting, July 13-16; Asheville, NC.

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