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

Abstract

To the Editor: Hyperkeratosis and widespread scaling are characteristic findings among patients with X-linked recessive or autosomal recessive lamellar (ARCI-LI) congenital ichthyosis (CI) subtypes.1Vahlquist 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 CI management predominantly includes emollients, keratolytics, and off-label retinoids.1Vahlquist 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,2Vahlquist 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 TMB-001 is a proprietary, novel, topical isotretinoin ointment formulation to treat CI using a patented IPEG™ pegylation technology isotretinoin delivery system. A phase 2a study evaluating TMB-001 in patients with CI found no concerning safety signals or evidence of significant systemic exposure to isotretinoin/tretinoin through 12 weeks while demonstrating a positive efficacy signal.3Paller A.S. Browning J. Parish L.C. Bunick C.G. 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; https://doi.org/10.1016/j.jaad.2022.02.060Abstract Full Text Full Text PDF Scopus (2) Google Scholar We report phase 2b CONTROL study (NCT04154293) efficacy and safety results for TMB-001 in participants with ARCI-LI and X-linked recessive CI. Participants ≥9 years with a clinical diagnosis of CI, 10% to 90% of total body surface area involvement, and ≥2 (of 4) assessment areas with Visual Index for Ichthyosis Severity (VIIS) score ≥3 (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1) were randomized (1:1:1) to TMB-001 0.05%:0.1%:vehicle for 12 weeks. Key efficacy end points were ≥50% VIIS scaling reduction (VIIS-50) versus baseline and ≥2-grade Investigator Global Assessment (IGA) score reduction versus baseline. Additional analyses included times to VIIS-50 and IGA success achievement. Adverse events (AEs) and local skin reactions were evaluated. Among enrolled participants (TMB-001 0.05% [n = 11], TMB-001 0.1% [n = 10], and vehicle [n = 12]), 52% had ARCI-LI and 48% had X-linked recessive (Supplementary Table I, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1). Six (18%) participants discontinued treatment. Overall, 64%/40%/33% (intent-to-treat [ITT]) and 100%/40%/40% (per protocol [PP]) of participants receiving TMB-001 0.05%/0.1%/vehicle achieved VIIS-50, respectively (nominal P = .04; TMB-001 0.05% vs vehicle; Supplementary Fig 2, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1). Median time to VIIS-50 was 28.0/54.0/63.5 days for TMB-001 0.05%/0.1%/vehicle, respectively (nominal P = .02; TMB-001 0.05% vs vehicle [ITT]; Supplementary Fig 3, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1). Improvement of ≥2-grade IGA score was observed in 55%/40%/8% (nominal P = .02; TMB-001 0.05% vs vehicle [ITT]) and 100%/60%/10% (nominal P = .002; TMB-001 0.05% vs vehicle [PP]) of participants receiving TMB-001 0.05%/0.1%/vehicle, respectively (Supplementary Fig 4, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1). Median time to ≥2-grade IGA improvement from baseline was 59.5/56.0/63.5 days for TMB-001 0.05%/0.1%/vehicle (nominal P = .04; TMB-001 0.05% vs vehicle [ITT]). A significantly greater proportion of participants who received TMB-001 0.05% achieved both VIIS-50 and ≥2-grade IGA improvement vs vehicle. Both VIIS-50 and IGA treatment success were achieved in 55%/20%/8% (ITT) and 100%/20%/10% (PP) of participants for TMB-001 0.05%/0.1%/vehicle, respectively (Figs 1 and 2; Supplementary Fig 5, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1). At week 12, a strong correlation between change from baseline in VIIS scaling and IGA scores was observed for TMB-001 0.05% (Pearson r = 0.94, P ≤ .001 [ITT]; Supplementary Table II, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1). Twenty (61%) participants reported a treatment-emergent AE, with most comprising application site reactions (Supplementary Table III, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1). Most local skin reactions were mild/moderate and were primarily reported during the first month of treatment (Supplementary Table IV, available via Mendeley at https://doi.org/10.17632/bpt5bntmpj.1).Fig 2Photograph of a participant with ARCI-LI at week 12 following treatment with TMB-001 0.05% on the arm. Participant was 21 years old with genetically confirmed ARCI-LI and had received no treatment for CI within 1 year of screening. For this participant, 42% of total BSA was treated. At week 12, IGA score was 0 (clear), with no scaling, roughness, or fissures, and VIIS-50 was met. ARCI-LI, Autosomal recessive CI-lamellar ichthyosis; BSA, body surface area; CI, congenital ichthyosis; IGA, Investigator Global Assessment; VIIS-50, ≥50% decrease in Visual Index for Ichthyosis Severity scaling score.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The safety and tolerability profile of TMB-001 remained consistent with phase 2a reported AEs and with the known safety profile of topical retinoids.3Paller A.S. Browning J. Parish L.C. Bunick C.G. 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; https://doi.org/10.1016/j.jaad.2022.02.060Abstract Full Text Full Text PDF Scopus (2) Google Scholar, 4Wagner N. Benkali K. Alió Sáenz A. Poncet M. Graeber M. Clinical pharmacology and safety of trifarotene, a First-in-Class RARγ-selective topical retinoid.J Clin Pharmacol. 2020; 60: 660-668Crossref PubMed Scopus (12) Google Scholar, 5Zaenglein A.L. Levy M.L. Stefanko N.S. et al.Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents.Pediatr Dermatol. 2021; 38: 164-180Crossref PubMed Scopus (13) Google Scholar Interestingly, TMB-001 0.05% demonstrated improved efficacy versus 0.1%; additional characterization is needed to explain this finding. Limitations include the small sample size and that only post hoc nominal P values were calculated at week 12. These results support ongoing TMB-001 efficacy and safety investigation as a promising alternative to oral retinoids for patients with CI. Teng has served as an investigator for Castle Creek Pharmaceuticals, LEO Pharma, Novartis, Pfizer Inc, Palvella Therapeutics, Regeneron, and Timber Pharmaceuticals and a consultant for Abeona Therapeutics, AFT Pharma, Amryst, BridgeBio, Castle Creek Pharmaceuticals, KrystalBio, LEO Pharma, Menlo Therapeutics, Nobelpharma Ltd., Novartis, Pfizer Inc, Palvella Therapeutics, Regeneron, and Timber Pharmaceuticals. Bunick has served as an investigator for Almirall; a consultant for AbbVie, Almirall, LEO Pharma, Sanofi-Regeneron, Skinosive, and UCB; and a speaker for and received honoraria from Allergan, Almirall, and UCB. Guenthner and Eads have served as scientific advisers and/or clinical study investigators for AbbVie, Aclaris, Almirall, Amgen, AOBiome, Anaptys Bio, Arcutis, Asana, Atacama, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Cassiopeia, Celgene, Concert Pharmaceuticals, Crown Therapeutics, Cutanea, Dermavant, Dermira, Edesa, Eli Lilly and Company, Foamix, Forte, Gage, Galderma, Glenmark, Incyte, Janssen, LEO Pharma, Novan, Novartis, Novum, Pfizer Inc, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, Timber Pharmaceuticals, Vanda, Verrica, Vidac, and UCB Pharma. Murrell has served as an investigator and advisor for AbbVie, Amgen, ArgenX, Dermira, Eli Lilly and Company, Galderma, Janssen, LEO Pharma, Novartis, Pfizer Inc, Principia Biopharma, Roche, Sanofi, and Sun Pharmaceuticals Inc, and served on an advisory board for Eli Lilly and Company, Immune Pharmaceuticals, and Principia Biopharma. Marathe has no conflicts of interest to declare. Kempers served as a consultant for Arcutis Biotherapeutics and a clinical trial investigator for AbbVie, Amgen, Arcutis Biotherapeutics, Brickell Biotech, Bristol Myers Squibb, Candesant Biomedical, Concert Pharmaceuticals, Dermira, Edesa Biotech, Eli Lilly and Company, Forte Biosciences, Galderma, Incyte Corporation, NFlection Therapeutics, Novan, Novartis, Palvella Therapeutics, and Timber Pharmaceuticals. Mendelsohn and Raiz are employees of Timber Pharmaceuticals, and Tavakkol is a former employee of Timber Pharmaceuticals. Castelo-Soccio received honoraria from and served on an advisory panel for Pfizer Inc and served as clinical study investigator for Timber Pharmaceuticals. Medical writing and editorial assistance were provided by Zehra Gundogan, VMD, of AlphaBioCom, LLC, under the direction of the authors, and was funded by Timber Pharmaceuticals. The authors thank Keith Choate, MD, PhD, for his guidance in study design and for testing the use of the VIIS scale.