Isotretinoin

随着生物科学技术的进步，各种类型创新疗法不断涌现并在临床研究得到验证，展现出了巨大的临床潜力。新技术、新靶点药物的早期临床研究与注册性临床研究（Pivotal Trial）的价值在整个药物研发中日益显著。其中，试验结果对于适应症拓展与后续研究的方案制定具有举足轻重的作用，因而对结果的解读很有必要。医药魔方NextPharma & TrialCube数据库围绕行业现状及未来趋势，将早期临床研究与注册性临床研究的结果进行筛选，并对其中关键结果进行可视化呈现，以期赋能医药伙伴（可于文章后免费申请数据库试用）。医药魔方数据库现建立“临研速递”专栏，定期发布精选的早期临床研究与注册性临床研究的可视化结果，敬请期待。本期筛选的两项注册性临床研究分别是 PHOENIX和ASCEND ，可视化结果如下。 注册性临床研究 ▌PHOENIX(NCT05021536)推荐理由：复方疗法AMX0035（苯丁酸钠+牛磺熊去氧胆酸）治疗ALS的III期注册性临试验PHOENIX研究未达到预设主要终点及次要终点。AMX0035上市之路充满争议，尽管早期临床显示出积极疗效，但在此次III期试验中遭遇重大挫折，也让这款药物前景黯淡。▌ASCEND(NCT05295732)推荐理由：微创新疗法TMB-001用于X联锁和常染色体隐性遗传先天性鱼鳞病的III期注册性临试验ASCEND研究结果积极，患者IGA综合评分具有显著意义的降低，其中82%患者达到临床意义的改善。目前这一领域尚无有效疗法获批上市，TMB-001的积极结果有望给这一罕见病群体带来希望。▌NextPharma & TrialCube如何获得？免费申请试用方式如下：1、  扫描下方二维码2、点左下方“阅读原文”，直接跳转申请链接Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

MADISON, N.J.--( BUSINESS WIRE )-- NOT FOR UK USE – NOT INTENDED FOR UK MEDIA Timber Pharmaceuticals, Inc., a LEO Pharma company, today presents preliminary results from the ASCEND trial in a late-breaking session at the 2024 American Academy of Dermatology (AAD) Annual Meeting. 1 The results offer a first look at the safety, efficacy and pharmacokinetic (PK) data from 17 adult and adolescent participants (aged 12-64 years) enrolled in the open-label maximum use arm of the phase 3 ASCEND trial. 1 These late-breaker results are part of a wide-ranging data program from LEO Pharma at AAD, with eight abstracts accepted in total for the meeting, showcasing an ongoing commitment to advancing the standard of research in medical dermatology. ASCEND is a clinical trial of TMB-001, a polyethylene glycol (iPEG™) based investigational topical isotretinoin being developed for the treatment of moderate-to-severe X-linked and autosomal recessive congenital ichthyosis (CI). 3 CI is a group of rare genetic keratinization disorders that leads to dry, thickened, and scaling skin. 4-7 Currently, no specific treatments are approved by the U.S. Food and Drug Administration (FDA) to treat CI. 2 Patients enrolled in the open-label maximum use arm of the ASCEND trial with 75-90% body surface area involvement and moderate-to-severe disease on the Investigator Global Assessment (IGA) scale (IGA scores ≥3) were included in this analysis. 1 TMB-001 results showed that, from baseline to Week 12, the mean total Investigator Global Assessment (IGA) composite scaling and fissuring score decreased from 3.2 to 1.6 (p=0.0001). In the same timeframe, 59% of patients achieved a ≥2 point decrease in IGA scores from baseline, while 82% demonstrated a clinically significant (≥1 point) improvement in IGA scores from baseline. 1 No serious adverse events (SAEs) were reported. 1 65% of participants experienced at least 1 adverse event (AE), with a total of 35 events. 1 The top three treatment-emergent AEs were erythema (N=7), pruritus (N=4), and stinging/pain (N=2). 1 “ The preliminary findings from the ASCEND trial are encouraging and indicate the potential of TMB-001 to provide hope for those living with X-linked and autosomal recessive CI,” said Kreesten Meldgaard Madsen, Chief Development Officer, LEO Pharma. “ We know that the management of this disease can be incredibly challenging and, given the limited treatment options available, we remain focused on pushing the development of TMB-001 forward with the goal of helping to address this considerable unmet need.” The results were taken from participants in the open-label maximal use arm of the ASCEND trial. This arm aimed to analyze the PKs of TMB-001 by determining the level of systemic exposure of isotretinoin and metabolites. 1 To do this, the change from baseline of isotretinoin (ISO), 4-oxo-isotretinoin (4-O-ISO), tretinoin (TR), and 4-oxo-tretinoin (4-O-TR) after 14 days of twice-daily application of TMB-001 was assessed. 1 The data demonstrated low systemic concentrations across all four molecules examined after 14 days of twice-daily application of TMB-001. 1 The steady-state mean peak plasma concentrations (ng/mL) in the 17 participants were 4.5 for ISO, 9.0 for 4-O-ISO, and low to not calculable for TR and 4-O-TR. 1 “ X-linked and autosomal recessive CI can be incredibly challenging to live with, and in my experience patients are often impacted both psychically and psychologically by a host of symptoms,” said Dr. Christopher Bunick, Lead Author and Associate Professor of Dermatology, Yale School of Medicine. “ With no specific treatment currently available, CI patients are currently having to deal with their condition with minimal support. I hope that the data and insights presented today can help provide new knowledge and support for this patient community.” In January 2024, LEO Pharma finalized the acquisition of Timber Pharmaceuticals, a clinical-stage biopharmaceutical company focused on the development and commercialization of treatments for rare and orphan dermatologic diseases. Upon completion, the Timber Pharmaceuticals lead investigational product candidate, TMB-001, was added to LEO Pharma’s pipeline. TMB-001 is under investigation and has not been evaluated by any health authority. About the ASCEND Trial An ongoing, multicenter phase 3 study to evaluate the efficacy and safety of TMB-001 0.05% topical ointment in the treatment of congenital ichthyosis (CI) in subjects (aged ≥6 years) with either the autosomal recessive congenital ichthyosis (ARCI) or X-linked recessive ichthyosis (XLRI) subtypes. 3 The clinical trial is divided into two parts. The first is a randomized, double-blind, vehicle-controlled phase III study. Its objective is to ascertain the efficacy of TMB-001 0.05% topical ointment as a treatment for CI compared with vehicle during 12 weeks of treatment. 3 In the second part of the trial, a subset of preselected centers will recruit subjects in parallel with either the ARCI or XLRI subtypes for enrollment into an Optional Maximal Use arm. The primary objective of this part of the trial is to determine systemic exposure of isotretinoin and metabolites after single or multiple applications of TMB-001 0.005% ointment. Its primary endpoint is an assessment of individual concentrations of 4-oxo-isotretinoin (4-O-ISO), tretinoin (TR), 4-oxo-tretinoin (4-O-TR) and change from baseline. 3 About Congenital Ichthyosis Congenital ichthyosis (CI) is a group of rare genetic keratinization disorders that can lead to dry, thickened, and scaling skin. 4-7 Most cases of ichthyosis are inherited, but some types develop in association with genetic syndromes or diseases, such as Hodgkin's Lymphoma. 8,9 People living with CI may have limited range of motion, chronic itching, an inability to sweat normally, high risk of secondary infections, and impaired eyesight or hearing. 4-7 About TMB-001 TMB-001, topical isotretinoin in the company’s investigational patented polyethylene glycol (IPEG™) delivery system, is being developed for the treatment of moderate-to-severe subtypes of congenital ichthyosis (CI). During Q4 2021, the positive topline results for its Phase 2b CONTROL Study were announced. In Q1 2022, TMB-001 received both Breakthrough Therapy Designation and Fast Track Status from the U.S. Food and Drug Administration (FDA). The Phase 3 ASCEND clinical trial was initiated in Q2 2022. About LEO Pharma LEO Pharma is a global company dedicated to advancing the standard of care for the benefit of people with skin conditions, their families and society. Founded in 1908 and majority owned by the LEO Foundation, LEO Pharma has devoted decades of research and development to advance the science of dermatology, and today, the company offers a wide range of therapies for all disease severities. LEO Pharma is headquartered in Denmark with a global team of 4,400 people, serving millions of patients across the world. In 2022, the company generated net sales of DKK 10.6 billion. References Bunick CG, et al. Efficacy, Safety and Pharmacokinetics of First 17 Adult and Adolescent Subjects in Maximal Use Portion of Vehicle Controlled ASCEND Trial of Polyethylene Glycol (iPEG™)-Based Topical Isotretinoin 0.05% (TMB-001) for Treatment of Congenital Ichthyosis. Presented at American Academy of Dermatology (AAD) 2024 Annual Meeting, San Diego, Ca., March 8-12, 2024. Hernández-Martin A, Aranegui B, Martin-Santiago A, Garcia-Doval I. A systematic review of clinical trials of treatments for the congenital ichthyoses, excluding ichthyosis vulgaris. J Am Acad Dermatol . 2013;69(4):544-549.e8. ClinicalTrials.gov. National Library of Medicine (U.S.). The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis (ASCEND). Identifier: NCT05295732. https://classic.clinicaltrials.gov/ct2/show/NCT05295732 Oji V, Traupe H. Ichthyosis: clinical manifestations and practical treatment options. Am J Clin Dermatol. 2009;10(6):351-364. Takeichi T, Akiyama M. Inherited ichthyosis: Non-syndromic forms. J Dermatol. 2016;43(3):242-251. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm Venereol. 2008;88(1):4-14. Lilly E, Bunick CG. Congenital Ichthyosis: A Practical Clinical Guide on Current Treatments and Future Perspectives. Clin Cosmet Investig Dermatol. 2023;16:2473-2479. Haber R, Feghali J, Nadir U, Yi MD, Cahn BA. Acquired ichthyosis: a clinical review. Arch Dermatol Res. 2023;315(9):2529-2543. Mishra K, Jandial A, Gupta K, Prakash G, Malhotra P. Ichthyosis: A Harbinger of Lymphoma. BMJ Case Rep. 2018;2018:bcr2018224229. MAT-71602 March 2024