Topical isotretinoin for ichthyoses: Striving for an “A” grade

By Warren R. Heymann, MD, FAAD
Nov. 20, 2024
Vol. 6, No. 47

Two meaningful events changed my life in 1982 — my marriage and the introduction of isotretinoin. Forty-two years later, both remain front and center. Attending the focus session “Think like an expert about ichthyosis” at the AAD in San Diego rejuvenated my enthusiasm for isotretinoin when I learned of a new topical formulation that is reportedly safe and effective.

In a commentary devoted to retinoids in ichthyosis, I wrote, “The cornerstone of topical ichthyosis management incorporates hydration and lubrication, with the addition of keratolytics and modulators of keratinocyte differentiation, depending on scale severity. Creams or ointments with low concentrations of salt, urea, or glycerol assist with hydration. Petroleum jelly is effective for lubrication. The keratolytics include α-hydroxy acids (lactic acid and glycolic acid), salicylic acid, N-acetylcysteine, propylene glycol, and high-dose urea. The keratinocyte differentiation modulators include retinoids (tretinoin, adapalene, and tazarotene) and calcipotriol. Lifestyle considerations (a daily bathing routine with water and a mild cleanser) and refraining from environments and activities that exacerbate the disorder should be emphasized. For patients with severe ichthyoses (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, or other disorders of cornification [DOC]), oral retinoids (isotretinoin and acitretin) are essential. Retinoic acid plays a significant role in transcription regulation by binding retinoic acid response elements that are located proximally to numerous genes integral to organ development.” (1)

Systemic retinoids for ichthyoses and DOC require long-term, potentially lifelong, use. The adverse effects of prolonged use of systemic retinoids include bone abnormalities (osteoporosis, osteophyte formation, ligamentous ossification, and premature closure of epiphyses), ophthalmologic complications, cardiovascular health related to hyperlipidemia, potential hepatic dysfunction, and teratogenicity. (1,2,3) Teratogenicity is estimated to have a 20-35% risk to infants exposed to isotretinoin in utero, manifested by congenital defects such as craniofacial defects, cardiovascular and neurological malformations, or thymic disorders. (3) This commentary will focus on using a newly formulated topical isotretinoin for managing severe, recalcitrant ichthyoses.

According to Marathe et al., TMB-001 is a proprietary, novel, topical isotretinoin ointment formulation with a patented polyethylene glycol (IPEG^™) technology isotretinoin delivery system designed to improve skin hydration and reduce scaling in participants with congenital ichthyosis (CI). (4)

A 12-week phase 2a study of patients (with lamellar CI n=10, X-linked recessive CI n=7, and ichthyosis vulgaris n=2) demonstrated a favorable safety profile with no significant systemic exposure to isotretinoin. All patients receiving the 0.1% ointment had ≥1-grade IGA score reduction versus baseline; 80% and 60% of patients receiving the 0.2% formulation had 1- and ≥2-grade Investigator Global Assessment (IGA) reductions, respectively. Seven patients discontinued treatment for mild adverse reactions. (5)

In the 12-week Phase 2b study, 33 CI patients at least nine years old (lamellar CI n=17, X-linked recessive CI n=16) were enrolled the primary and key secondary efficacy endpoints — a 50% improvement in Visual Index for Ichthyosis Severity scaling scores (VIIS-50) and ≥ 2-grade improvement in IGA scores from baseline, respectively — were achieved by 64%, 40%, and 33% (VIIS-50) and 55%, 40%, and 8% (IGA success) of participants receiving TMB-001 0.05%, TMB-001 0.1%, and vehicle, respectively. The reason for the milder formulation being more effective than the higher concentration awaits explanation. Twenty (61%) participants reported a treatment-emergent adverse event, with most comprising application site reactions. Six (18%) participants discontinued treatment. (6) No clinically significant laboratory abnormalities were observed in this study. (4)

The ongoing Phase 3 ASCEND (NCT05295732) trial results demonstrated 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. The data was presented in a poster session at the 2023 Society for Pediatric Dermatology Meeting in Asheville, North Carolina, July 13-16, 2023. (7)

As most ichthyoses are genodermatoses, the future lies in therapies that target specific mutations rather than those that rely on broad pharmacologic strokes of retinoids. Inevitably, retinoid use — oral or topical — in patients with ichthyoses will become passé. For now, their utilization is the standard of care. (1) The potential for a topical isotretinoin formulation that is safe and effective would be a positive therapeutic step on the road to personalized, specific, targeted therapy.

Point to Remember: Retinoids are standard therapy for patients with severe ichthyoses and disorders of keratinization. Dermatologists are familiar with the mucocutaneous and systemic adverse effects of oral isotretinoin. The promise of a safe and effective topical isotretinoin would be a welcome therapeutic advance.

Our expert’s viewpoint

Denise Gass
Board Member, Foundation for Ichthyosis & Related Skin Types, Inc. (FIRST)

I was enrolled in Phase 2 and Phase 3 trials of TMB-001. Like many others in the study, I found the cream to be extremely effective at reducing scaling throughout my body, with minimal side effects. I have moderate ARCI-CIE, manifesting as fine scaling and redness all over, with extremely thick scaling on the palms and soles. I saw positive changes in several areas: less shedding on clothing and my environment, less time spent on manual exfoliation, more days of typical-looking skin. The cream is very strong — where I applied too much, I did occasionally develop abrasions. (It was later confirmed I was on the highest percentage of active ingredient, which is not going forward.) Ichthyosis is highly variable, and I believe getting the dosage just right will involve a period of trial and error for each patient. This personalized experimentation will be a welcome step forward after a lifetime with this disease and zero FDA approved treatments to this point.

1. Heymann WR. Retinoids in ichthyosis and disorders of cornification: Tipping the scales toward optimal use. J Am Acad Dermatol. 2022 Jan;86(1):44-45. doi: 10.1016/j.jaad.2021.10.022. Epub 2021 Oct 23. PMID: 34699911.

2. Doolan BJ, Paolino A, Greenblatt DT, Mellerio JE. Retinoid-induced skeletal hyperostosis in disorders of keratinization. Clin Exp Dermatol. 2022 Dec;47(12):2273-2276. doi: 10.1111/ced.15382. Epub 2022 Sep 27. PMID: 35988035; PMCID: PMC10087317.

3. Draghici CC, Miulescu RG, Petca RC, Petca A, Dumitrașcu MC, Șandru F. Teratogenic effect of isotretinoin in both fertile females and males (Review). Exp Ther Med. 2021 May;21(5):534. doi: 10.3892/etm.2021.9966. Epub 2021 Mar 23. PMID: 33815607; PMCID: PMC8014951.

4. Marathe K, Teng JMC, Guenthner S, Bunick CG, Kempers S, Eads K, Castelo-Soccio L, Mendelsohn AM, Raiz J, Murrell DF. Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not Result in Clinically Relevant Laboratory Abnormalities in Participants with Congenital Ichthyosis in the Phase 2b CONTROL Study. Dermatol Ther (Heidelb). 2023 Jun;13(6):1255-1264. doi: 10.1007/s13555-023-00923-1. Epub 2023 May 11. PMID: 37170057; PMCID: PMC10264299.

5. Paller AS, Browning J, Parish LC, Bunick CG, Rome Z, Bhatia N. Safety, tolerability, and efficacy of a novel topical isotretinoin formulation for the treatment of X-linked or lamellar congenital ichthyosis: Results from a phase 2a proof-of-concept study. J Am Acad Dermatol. 2022 Nov;87(5):1189-1191. doi: 10.1016/j.jaad.2022.02.060. Epub 2022 Mar 7. PMID: 35271936.

6. Teng JMC, Bunick CG, Guenthner S, Murrell DF, Marathe K, Kempers S, Eads K, Mendelsohn AM, Raiz J, Tavakkol A, Castelo-Soccio L. The CONTROL study: A randomized, double-blind vehicle-controlled phase 2b study of novel topical isotretinoin formulation demonstrates improvement in recessive X-linked and autosomal recessive lamellar congenital ichthyosis. J Am Acad Dermatol. 2022 Dec;87(6):1455-1458. doi: 10.1016/j.jaad.2022.07.028. Epub 2022 Jul 21. PMID: 35872261.

7. Buchanan L, Mendelsohn A. Trial shows positive results with isotretinoin treatment in congenital ichthyosis. Dermatology Times, July 15, 2023. Trial Shows Positive Results With Isotretinoin Treatment in Congenital Ichthyosis. https://www.dermatologytimes.com/view/trial-shows-positive-results-with-isotretinoin-treatment-in-congenital-ichthyosis

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