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
Authors: Amy S. Paller, John Browning, Lawrence Charles Parish, Christopher G. Bunick, Zachary Rome, Neal Bhatia
Journal: Journal of the American Academy of Dermatology (2022)

To the Editor: Clinical characteristics of congenital ichthyosis (CI) include hyperkeratosis, scaling, and erythroderma.1Oji V. Traupe H. Ichthyosis: clinical manifestations and practical treatment options.Am J Clin Dermatol. 2009; 10: 351-364Crossref PubMed Scopus (83) Google Scholar,2Vahlquist A. Gånemo A. Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies.Acta Derm Venereol. 2008; 88: 4-14Crossref PubMed Scopus (82) Google Scholar The management of CI typically involves emollients and keratolytics.2Vahlquist A. Gånemo A. Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies.Acta Derm Venereol. 2008; 88: 4-14Crossref PubMed Scopus (82) Google Scholar,3Vahlquist A. Blockhuys S. Steijlen P. et al.Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial.Br J Dermatol. 2014; 170: 173-181Crossref PubMed Scopus (23) Google Scholar Patients with lamellar or X-linked recessive CI often have considerable hyperkeratosis and scaling, for which systemic retinoids are effective but may cause dose-limiting adverse events (AEs).2Vahlquist A. Gånemo A. Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies.Acta Derm Venereol. 2008; 88: 4-14Crossref PubMed Scopus (82) Google Scholar,4Digiovanna J.J. Mauro T. Milstone L.M. Schmuth M. Toro J.R. Systemic retinoids in the management of ichthyoses and related skin types.Dermatol Ther. 2013; 26: 26-38Crossref PubMed Scopus (60) Google Scholar,5Vahlquist A. Törmä H. Ichthyosis: a road model for skin research.Acta Derm Venereol. 2020; 100adv00097Crossref Scopus (15) Google Scholar PAT-001 is a patented, novel, topical isotretinoin ointment formulation to treat CI. We present the results from a phase 2a study evaluating PAT-001 in patients with lamellar or X-linked recessive CI. This multicenter, double-blind study evaluated the safety and tolerability (primary endpoints) of PAT-001 in patients aged ≥12 years; pharmacokinetics and efficacy were the secondary endpoints. The study was conducted according to the Declaration of Helsinki principles, and all patients provided written informed consent. The patients were randomized 1:1 to PAT-001 0.1% or 0.2% and had 2 comparable contralateral lesional areas—each ≤6% of body surface area and ≥150 cm2—with identical baseline Investigator Global Assessment (IGA) scores of ≥3 (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/b4xj8wmpv9/1). One area was randomly treated with PAT-001 0.1% or 0.2% and the other was treated with vehicle twice daily for 8 weeks (Part 1). Both areas received PAT-001 0.1% or 0.2% twice daily for 4 weeks (Part 2). Safety measurements included laboratory tests and monitoring for AEs. Optional blood samples measuring isotretinoin/tretinoin levels were collected for pharmacokinetic analyses. Efficacy evaluations included changes in IGA scores and clinical signs/symptoms. Among the enrolled patients (PAT-001 0.1% [N = 10] and 0.2% [N = 9]), 10 had lamellar CI, 7 had X-linked recessive CI, and 2 had ichthyosis vulgaris (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/b4xj8wmpv9/1). Seven patients discontinued the treatment. In Part 1, 13 and 8 AEs occurred in active- versus vehicle-treated areas, respectively (Supplementary Table II, available via Mendeley at https://data.mendeley.com/datasets/b4xj8wmpv9/1); overall, 28 AEs occurred in 14 patients (Table I). Most AEs were mild; 8 patients experienced AEs that were possibly (25%), probably (3.6%), or definitely (10.7%) active treatment–related and had treatment interruptions or withdrew. Laboratory values were not clinically different from those at baseline. Systemic isotretinoin/tretinoin concentrations remained at baseline levels (Supplementary Table III, available via Mendeley at https://data.mendeley.com/datasets/b4xj8wmpv9/1).Table ISummary of treatment-emergent adverse events through 12 weeks of PAT-001 treatment∗TEAEs leading to treatment interruption or study discontinuation included rash, irritation, pruritus, folliculitis, and pain at the application site, as well as contact dermatitis. Among the 2 patients who discontinued early due to TEAEs, 1 patient experienced mild application-site folliculitis that resolved by the end of study and was considered possibly related to active treatment (PAT-001 0.1%), and the other patient experienced severe mental status changes, moderate gastroenteritis norovirus, and moderate Clostridium difficile colitis, which were considered not related to treatment (PAT-001 0.2%). Data are shown as n or n (%).PAT-001 0.1%N = 10PAT-001 0.2%N = 9No. of TEAEs1414No. of TEAEs by severity Severe11 Moderate45 Mild98No. of TEAEs by relationship to test article Definitely related21 Probably related10 Possibly related25 Not/unlikely related98No. of patients†Patients are counted only once even if an event occurs in both the treatment areas. with Any TEAE7 (70.0)7 (77.8) Any severe TEAE1 (10.0)1 (11.1) Any moderate TEAE3 (30.0)3 (33.3) Any mild TEAE5 (50.0)6 (66.7) Any definitely related TEAE1 (10.0)1 (11.1) Any probably related TEAE1 (10.0)0 Any possibly related TEAE1 (10.0)4 (44.4) Any not/unlikely related TEAE5 (50.0)5 (55.6) Any treatment-emergent SAE01 (11.1) Deaths00 Any test article related SAE00No. of patients who Discontinued due to TEAE1 (10.0)1 (11.1) Experienced a TEAE within the treatment area‡Includes both, not related and unlikely related.4 (40.0)5 (55.6)SAE, Severe adverse event; TEAE, treatment-emergent adverse event.∗ TEAEs leading to treatment interruption or study discontinuation included rash, irritation, pruritus, folliculitis, and pain at the application site, as well as contact dermatitis. Among the 2 patients who discontinued early due to TEAEs, 1 patient experienced mild application-site folliculitis that resolved by the end of study and was considered possibly related to active treatment (PAT-001 0.1%), and the other patient experienced severe mental status changes, moderate gastroenteritis norovirus, and moderate Clostridium difficile colitis, which were considered not related to treatment (PAT-001 0.2%). Data are shown as n or n (%).† Patients are counted only once even if an event occurs in both the treatment areas.‡ Includes both, not related and unlikely related. Open table in a new tab SAE, Severe adverse event; TEAE, treatment-emergent adverse event. In Part 1, PAT-001 0.1% exhibited greater improvement in ≥1- and ≥2-grade IGA score versus vehicle (100% vs 66.7% and 66.7% vs 33.3%, respectively). PAT-001 0.2% demonstrated similar ≥1- and ≥2-grade IGA improvement versus vehicle (100% vs 87.5% and 50.0% vs 62.5%, respectively). By day 57, IGA score for PAT-001 0.1% and 0.2% treatment areas were ≥1-grade lower versus vehicle (66.7% and 37.5%, respectively; Fig 1). Scaling in all patients for active versus vehicle treatment areas was clear, almost clear, or mild for 0.1% and 0.2% groups (100% vs 55.6% and 100% vs 87.5%, respectively; Supplementary Fig 2, available via Mendeley at https://data.mendeley.com/datasets/b4xj8wmpv9/1). In Part 2, continued active treatment areas were clear, almost clear, or mild in 85.7% and 60% of patients for PAT-001 0.1% and 0.2%, respectively. In both treatment areas, all patients receiving PAT-001 0.1% had ≥1-grade IGA score reduction versus baseline; 80% and 60% of patients receiving PAT-001 0.2% had 1- and ≥2-grade IGA reductions, respectively. The results indicate no concerning safety signals or evidence of systemic isotretinoin/tretinoin exposure. PAT-001 0.1% appeared to have a stronger efficacy signal than PAT-001 0.2%; additional characterization is ongoing to better understand this effect. The limitations of the study include small sample size, not being powered for statistical significance, ≤12% body surface area treated, and discontinuations. These findings demonstrate that PAT-001 may be a promising alternative to oral retinoids and support ongoing investigation. Dr Paller has been an investigator without personal compensation for AbbVie, AnaptysBio, Eli Lilly, Galderma, Incyte, Krystal Biotech, LEO Pharma, Janssen, Novartis, and Sanofi-Regeneron; a consultant for and received honoraria from AbbVie, Abeona, Almirall, Amagma, AnaptysBio, Arena, Bausch, Bristol Myers Squibb, Dermavant Sciences, Dermira, Eli Lilly, Exicure, Forte, LEO Pharma, Lifemax, Pierre Fabre, Pfizer, Rapt, Regeneron, Sanofi, Sol-Gel, UCB, and Venthera; and has served on a data safety monitoring board for AbbVie and Galderma. Dr Browning has served as an investigator for Amicus, Amryt, Arcutis, Dermavant Sciences, Dermira, Eli Lilly, Forte, Galderma, LEO Pharma, Novartis, Patagonia, Pfizer, and Regeneron; a speaker for Regeneron and Pfizer; and a consultant for Dermavant Sciences, Dermira, and Novartis. Dr Parish has served as an investigator for AbbVie, Alfasigma, Amgen, Amytrx, Eli Lilly, Fibrocell, Galderma, Kiniksa, Olix, Oneness, Pfizer, Trevi, and UCB. Dr Bunick has served as an investigator for Almirall; a consultant for AbbVie, Almirall, Sanofi-Regeneron, Skinosive, and UCB; and a speaker for and received honoraria from Allergan, Almirall, and UCB. Author Rome is an employee of Timber Pharmaceuticals and part-owner of Patagonia Pharmaceuticals, LLC. Dr Bhatia has served as an advisor, consultant, and investigator for AbbVie, Almirall, Boehringer Ingelheim, Biofrontera, Bristol Myers Squibb, EPI Health, Ferndale Pharma Group, Foamix Pharmaceuticals, Galderma, ISDIN, LaRoche-Posay, LEO Pharma, Novartis, Ortho Pharmaceutical, Pfizer, Regeneron, Sanofi, Soligenix, Sun Pharmaceuticals, and Verrica Pharmaceuticals. Medical writing and editorial assistance were provided by Zehra Gundogan, VMD, of AlphaBioCom, LLC, under the direction of the authors and funded by Timber Pharmaceuticals.