Tazarotene

Designation highlights significant regulatory milestone and provides a potential pathway to seven years of U.S. market exclusivity LA JOLLA, CA, June 18, 2026 (GLOBE NEWSWIRE) -- GRI Bio, Inc. (NASDAQ: GRI) (“GRI Bio” or the “Company”), a biotechnology company developing innovative therapies for inflammatory, fibrotic and autoimmune diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to GRI-0621 for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a progressive, irreversible and ultimately fatal lung disease affecting tens of thousands of patients in the United States. The designation represents a significant regulatory achievement for GRI-0621 and reinforces the growing recognition of the drug's potential to address significant unmet medical needs in fibrotic diseases. "Receiving FDA Orphan Drug Designation for GRI-0621 in IPF is an important validation of our development strategy and highlights the urgent need for innovative therapies capable of altering the course of this devastating disease," said Marc Hertz, Ph.D., Chief Executive Officer of GRI Bio. "We believe GRI-0621's differentiated mechanism of action has the potential to address key drivers of inflammation and fibrosis, and this designation strengthens our ability to advance the program efficiently while creating significant long-term value for patients and shareholders." Orphan Drug Designation is granted to therapies intended to treat rare diseases affecting fewer than 200,000 people in the United States. The designation provides important development and commercialization benefits, including: Potential eligibility for seven years of U.S. market exclusivity upon approvalPotential tax credits related to qualified clinical development expensesWaiver of certain FDA application feesEnhanced regulatory engagement with the FDA throughout development IPF remains one of the most challenging pulmonary diseases, characterized by progressive scarring of lung tissue that leads to declining lung function and premature mortality. Despite currently approved therapies, patients continue to face poor long-term outcomes, underscoring the need for additional treatment options. GRI-0621 an oral, RARβ/γ-selective investigational therapy designed to modulate pathways involved in inflammation and fibrosis in IPF. Emerging scientific evidence increasingly supports the role of immune dysfunction in driving fibrosis, creating opportunities for novel therapeutic approaches beyond current standards of care. GRI-0621, the Company’s once-daily oral RARβ/γ selective agonist, was evaluated in a randomized, double-blind, placebo-controlled Phase 2a trial (GRI-0621-IPF-02; NCT06331624) in 35 patients with IPF, approximately 80% of whom were on background standard-of-care (SOC) antifibrotics. The trial met its primary, secondary and exploratory endpoints, with continued analyses and positive outcomes supporting previously reported findings. The FDA's decision to grant Orphan Drug Designation underscores the seriousness of IPF and highlights the potential importance of developing differentiated therapies capable of targeting underlying disease mechanisms. The Orphan Drug Designation adds another important catalyst to GRI Bio's broader strategy of advancing innovative therapies for diseases driven by immune dysregulation and fibrosis. The Company continues to execute on key development objectives while exploring opportunities to maximize the value of its proprietary platform. "We are committed to advancing GRI-0621 with urgency and discipline," added Dr. Hertz. "This designation further strengthens our regulatory foundation and supports our mission of delivering innovative therapies for patients with severe diseases while building a biotechnology company positioned for sustainable long-term growth." Idiopathic Pulmonary Fibrosis is a chronic, progressive lung disease characterized by irreversible scarring of lung tissue. The disease leads to declining respiratory function, reduced quality of life, and shortened survival. Current treatment options remain limited, and significant unmet medical need persists for therapies capable of improving outcomes and slowing disease progression. About GRI Bio, Inc. GRI Bio is a clinical-stage biopharmaceutical company focused on developing innovative therapies for inflammatory, fibrotic and autoimmune diseases. The Company's lead program, GRI-0621, is an oral RARβ/γ-selective agonist being developed for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive and life-threatening fibrotic lung disease with significant unmet need. GRI-0621 is designed to modulate pathways associated with inflammation, fibrosis and tissue repair and is being evaluated as a potential novel oral therapeutic for patients with IPF. In addition to GRI-0621, the Company is also developing a pipeline of novel type 2 diverse NKT (“dNKT”) agonists for the treatment of systemic lupus erythematosus. Additionally, with a library of over 500 proprietary compounds, GRI Bio has the ability to fuel a growing pipeline. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words such as “anticipate,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “intend,” “seek,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “target,” “aim,” “should,” “will,” “would,” or the negative of these words or other similar expressions. These forward-looking statements are based on the Company’s current beliefs and expectations. Forward-looking statements include, but are not limited to, statements regarding: the Company’s expectations with respect to development and commercialization of the Company’s product candidates, the timing of initiation or completion of clinical trials and availability of resulting data, the potential benefits and impact of the Company’s clinical trials and product candidates and any implication that the data or results observed in preclinical trials or earlier studies, topline or interim data or trials will be indicative of results of later studies or clinical trials or final data, the Company’s beliefs and expectations regarding potential shareholder value and future financial performance, the Company’s beliefs about the timing and outcome of regulatory approvals and potential regulatory approval pathways, the Company’s expected future milestones, shareholder value and the length of time the Company’s current resources will fund its planned operations (which current estimate assumes only initial preparatory activities for GRI-0621 as substantial additional capital or resources will be required to fund a Phase 2b clinical trial of GRI-0621). Actual results may differ from the forward-looking statements expressed by the Company in this press release and consequently, you should not rely on these forward-looking statements as predictions of future events. These forward-looking statements are subject to inherent uncertainties, risks and assumptions that are difficult to predict, including, without limitation risks related to: (1) the Company’s inability to maintain the listing of the Company’s common stock on The Nasdaq Capital Market and to comply with applicable listing requirements; (2) changes in applicable laws or regulations; (3) the inability of the Company to raise financing in the future; (4) the success, cost and timing of the Company’s product development activities; (5) the inability of the Company to obtain and maintain regulatory clearance or approval for its respective products, and any related restrictions and limitations of any cleared or approved product; (6) the inability of the Company to identify, in-license or acquire additional technology; (7) the inability of the Company to compete with other companies currently marketing or engaged in the development of products and services that the Company is currently developing; (8) the accuracy of the estimated size and growth potential of the markets for the Company’s products and services, and its ability to serve those markets, either alone or in partnership with others; (9) that later data or clinical trials may be inconsistent with or contrary to data and observations to date, including that later data may not indicate a patient benefit, modulate toxicities or validate a mechanism of action; (10) inaccuracy in the Company’s estimates regarding expenses, future revenue, capital requirements and needs for and the ability to obtain additional financing; (11) the Company’s ability to protect and enforce its intellectual property portfolio, including any newly issued patents and its ability to obtain any expected patent term extensions, adjustments, exclusivities or disclaimers; and (12) other risks and uncertainties indicated from time to time in the Company’s filings with the U.S. Securities and Exchange Commission (the “SEC”), including the risks and uncertainties described in the “Risk Factors” section of the Company’s most recent Annual Report on Form 10-K filed with the SEC on January 30, 2026 and subsequently filed reports. Forward-looking statements contained in this announcement are made as of this date, and the Company undertakes no duty to update such information except as required under applicable law.Investor Contact:JTC Team, LLCJenene Thomas(908) 824-0775GRI@jtcir.com

原文题目：HowDoes the Food and Drug Administration Approve Topical Generic Drugs AppliedtotheSkin? 文章作者：Priyanka Ghosh, Sam G Raney, Markham C Luke 刊发期刊：Dermatol Clin 发表时间：2022年07月 作者单位：美国FDA 原文链接：DOI: 10.1016/j.det.2022.02.003 核心要点 ·皮肤外用药物在美国是规模达数十亿美元的产业，广泛用于治疗痤疮、银屑病、光化性角化病、基底细胞癌等各类皮肤疾病。 ·皮肤外用药物剂型丰富，主要包括溶液剂、凝胶剂、乳膏剂、洗剂、软膏剂等。 ·1984 年《药品价格竞争与专利期补偿法案》（俗称《哈奇-韦克斯曼修正案》）为外用皮肤仿制药开辟了审批通道，提升了患者用药可及性。 ·获批的仿制药需与原研药药学等同且生物等效，按照说明书规定使用时，二者临床疗效与安全性保持一致。 ·外用仿制药的生物等效性评价方案，主要取决于药物作用部位、作用机制以及剂型复杂程度。 引言 皮肤外用药物即直接涂抹于皮肤表面、用于治疗皮肤疾病的药品，是皮肤科临床治疗的重要组成部分。Pastore等人梳理了油脂、膏霜、香膏等制剂自古用于治病及美妆的历史；Bender 和Thom在 1966 年发表的文献中介绍了古代冷霜配方，其工艺与如今市面在售的乳膏制剂十分相似。尽管配方渊源久远，但现代皮肤外用药物均经过精密研发，由一种或多种活性药效成分（活性成分）与辅料配比制成，可保证单位皮肤面积获得稳定给药量。从古罗马盖伦冷霜这一经典配方发展至今，皮肤外用药物的配方研发与生产工艺已实现巨大革新。 皮肤外用制剂属于靶向给药剂型，可将药物精准作用于身体局部，既能实现局部治疗，又能减少药物全身吸收，降低全身性毒副作用。部分外用药物除局部皮肤起效外，还会产生全身药理效应；部分药物用于破损、病变皮肤，而病变皮肤的角质层（皮肤渗透的主要屏障）已受损或缺失，药物渗透规律也随之改变。还有部分外用制剂用于杀灭皮肤表面寄生虫。对于部分局部作用药物，为规避全身毒性风险，还需评估其体内吸收程度。 美国外用药品监管法规发展历程 1906 年《纯净食品和药品法》是美国国会最早出台的消费者保护法案之一，旨在打击疫苗标签乱象，该法案催生了美国化学局，该局后续发展为如今的美国食品药品监督管理局（FDA）。 1932 年磺胺酏药害事件发生后，美国国会颁布《联邦食品、药品和化妆品法案》，授权 FDA 有权否决未证实安全性的药品上市申请。1938 至 1962 年间，FDA 收到约 4500 份新药上市申请（NDA），多款皮肤外用药品获批上市，例如曲安奈德外用软膏，用于缓解皮质类固醇应答性皮肤病引发的炎症与瘙痒症状。 欧洲反应停惨剧发生后，美国于 1962 年出台《联邦食品、药品和化妆品法案》（又称《基福弗-哈里斯修正案》），要求所有上市药品（含皮肤外用制剂）均需完成上市前审批。该修正案最核心的要求是：药品上市必须提供严谨、规范的临床试验数据，同时证明安全有效。1932—1968 年间已上市的药品，也需重新补充有效性数据，接受 FDA 复核，这一专项工作被称为药品有效性研究执行计划，曲安奈德软膏等多款外用药品均通过了本次有效性核查。 1984 年，为简化仿制药审批流程、降低药价、提升患者用药可及性，美国国会颁布《药品价格竞争与专利期补偿法案》（又称《哈奇-韦克斯曼修正案》）。该法案允许药企提交简化新药申请（ANDA）申报仿制药，无需像原研药 NDA 申请那样开展全套安全性与有效性研究。仿制药申请以 FDA 对参照原研药的安全有效性认定为基础，核心要求是证明仿制药与参照上市药品（RLD）具备生物等效性。《美国联邦法规》第 21 篇第 320 部分，明确了仿制药生物等效性的评价数据要求。 本文聚焦小分子化学类皮肤外用仿制药的 ANDA 审批路径与评价方法，评价方案会结合外用剂型的复杂程度制定。近十年来，生物制剂在银屑病等皮肤病治疗领域取得重大突破，但生物制剂多为动植物、微生物来源的复杂混合物，依照《公共卫生服务法》第 351 条申报，不在本文讨论范围内。 常见皮肤外用剂型 外用制剂的历史可追溯至古希腊与古代中国，早期冷霜、药贴等膏剂便用于皮肤局部病症治疗。目前美国市场主流外用剂型共十大类：凝胶剂、溶液剂、乳膏剂、混悬剂、软膏剂、洗剂、喷雾剂、泡沫剂、洗发剂、贴剂。各类剂型对应不同皮肤病治疗需求： ·抗寄生虫洗剂：含马拉硫磷、苯甲醇等成分，涂抹于头皮治疗头虱； ·抗真菌溶液：如艾沙康唑、他伐硼罗溶液，用于治疗甲癣； ·维A酸类、抗生素类凝胶/乳膏：维 A 酸、他扎罗汀、克林霉素制剂治疗寻常痤疮，甲硝唑制剂用于玫瑰痤疮； ·维生素D₃衍生物软膏/乳膏：如卡泊三醇，治疗银屑病； ·钙调磷酸酶抑制剂：吡美莫司、他克莫司制剂，用于特应性皮炎。 剂型选择主要取决于活性成分的制剂适配性、患者使用体验与便捷性。例如：封闭性强的软膏适用于特应性皮炎，易挥发的凝胶、乳膏则更受面部痤疮患者青睐。各类剂型技术特点： ·溶液剂：活性成分完全溶解于基质中； ·混悬剂：活性成分部分悬浮于分散介质，需先溶解才能穿透皮肤角质层； ·凝胶剂：添加胶凝剂制成，分为水基、醇基单相凝胶，也存在少量乳剂型凝胶（如双氯芬酸钠凝胶）； ·乳液、乳膏剂：通常为双相乳化基质，活性成分可溶解于单一或双相基质中； ·软膏剂：以凡士林、聚乙二醇为基质，涂抹后会形成密闭保护膜，适合角质层受损的皮肤疾病； ·泡沫剂、喷雾剂：由溶液/乳液添加抛射剂，或搭配气压泵制成； ·洗发剂：含表面活性剂的溶液/乳液，专门用于头皮疾病（如脂溢性皮炎）； ·贴剂：药物负载于胶黏基质或水凝胶中，可长时间贴附于皮肤并持续释药。 外用仿制药治疗等效性的评价方法 仿制药若要与原研药实现治疗等效，必须同时满足药学等效与生物等效。美国《治疗等效性评价批准药品目录》（俗称《橙皮书》）定义：药学等效指仿制药与原研药活性成分种类、含量、剂型、给药途径完全一致。 经审批的仿制药，若被证实与原研药药学等效且生物等效，即可临床替代使用，在说明书规定的使用条件下，疗效与安全性与原研药完全一致。外用仿制药的生物等效性评价方式，由药物作用部位、作用机制及剂型复杂程度决定。 根据《美国联邦法规》第 21 CFR 320.24 条款，以下体内、体外方法均可用于生物等效性评价： ·人体体内试验（血液）：测定全血、血浆、血清或其他适宜生物体液中活性药物成分/活性基团以及其活性代谢产物（如必要）的浓度随时间的变化情况； ·人体体内试验（尿液）：测定活性成分及其活性代谢产物（如必要）随时间变化的尿液排泄量； ·人体体内药效学试验：精准、可重复地测定药物产生的药理效应随时间变化情况； ·对照临床终点试验：通过临床试验证实生物等效性； ·FDA 认可的体外试验：可有效反映药物体内吸收特征； ·FDA 认定的其他等效性评价方法。 生物等效性研究的核心目的：判断仿制药与原研药的配方差异，是否会改变活性成分在作用部位的释放速度与释放量。 对于全身作用药物，通常依靠血药浓度开展药代动力学评价；但皮肤外用药物以局部作用为主，一般不采用全身药代动力学试验评价生物等效性。 （1）临床终点生物等效性试验 这是传统局部外用药物生物等效性的主流评价方法。试验周期长达数周甚至数月，需招募数百至数千名对应适应症患者，试验同时设置安慰剂对照组，要求受试药与原研药疗效均显著优于安慰剂。 该方法应用成熟，但成本高、耗时长，且灵敏度有限，难以精准区分仿制药与原研药在药物释放、吸收上的细微差异。 （2）药效学生物等效性试验 仅有限应用于糖皮质激素类外用制剂，通过检测药物引发的血管收缩反应评价等效性。近十年来，FDA 持续研发更高效的外用制剂生物等效性评价技术。 （3）外用溶液剂：豁免体内生物等效性试验 依据 21 CFR 320.22 (b)(3) 条款，满足以下条件的皮肤外用溶液剂，可豁免体内生物等效性试验：仿制药与原研药活性成分、浓度、剂型完全一致，且辅料及配方未对活性成分的局部 / 全身吸收造成显著影响。 （4）凝胶、乳膏、洗剂、软膏：基于理化表征的评价方法 FDA 针对各类外用制剂发布专项指导原则，推荐理化表征分析法，可作为临床终点试验的补充方案，部分情况下可直接替代临床试验，独立用于生物等效性评价。 该方法的核心逻辑：保证仿制药与原研药配方组成、微观结构高度一致，二者差异控制在原研药不同批次产品的正常波动范围内。适用前提：仿制药与原研药辅料、配方无显著差异，不会改变活性成分的吸收特性。 配方一致可规避辅料差异引发的皮肤刺激、过敏，以及病变皮肤对药物吸收的影响；同时保证活性成分的稳定性、溶解度、存在形态统一，确保药物渗透、分配规律一致。 剂型复杂度越高（溶液剂＜凝胶剂＜乳膏剂），生物等效性失效风险越高。FDA 会根据剂型特点，制定针对性的理化与结构表征（Q3）检测项目及体外释放试验（IVRT）、体外透皮试验（IVPT）研究，主要包含： ·外观与微观结构：多倍显微镜观察，对比二者微观形态差异； ·粒径与晶型：针对含悬浮颗粒的制剂，颗粒大小、晶型会直接影响溶解度与溶出速度，进而改变药物吸收； ·乳滴粒度分布：针对乳膏、乳液等双相乳液剂型，液滴大小会影响涂抹干燥过程及药物吸收； ·流变特性：半固体制剂的黏度、流变性，不仅影响患者使用感受，还会改变给药剂量与药物扩散速度； ·比重/密度检测：控制生产过程中夹带气泡量，避免因装药量差异影响实际给药量； ·pH 值检测：pH 会影响活性成分溶解度、稳定性，也是引发皮肤刺激的重要因素； ·水分活度与干燥速率：针对双相剂型，对比游离水含量与涂抹后干燥速度； ·体外释放试验（IVRT）：检测活性成分的体外释放速率，可发现微观结构、生产工艺带来的细微差异； ·体外透皮试验（IVPT）：模拟药物涂抹皮肤后的渗透过程，多用于复杂双相乳剂型制剂。 （5）结合药代动力学的体内试验 多数局部外用药物无需检测全身吸收，但兼具局部与全身作用的制剂，需开展交叉体内药代动力学试验，评价药物全身吸收的速度与程度。典型案例：双氯芬酸钠凝胶，主要用于缓解骨关节炎疼痛，药物作用靶点为关节滑液，可被吸收入血，因此需检测血药浓度。 （6）多项体内试验联合应用 在少数情况下，当仿制药与相应的参比制剂在处方上存在差异时，可采用以药代动力学（PK）为终点的生物等效性研究和以对比性临床终点为终点的生物等效性研究进行评估。例如，就双氯芬酸钠凝胶而言，尽管该药物可在血浆中检测到，但仍存在一些潜在争议，因外用本品后，双氯芬酸钠的生物利用度偏低。即便仿制药与参比制剂在给药局部的药物递送量存在明显差异，二者在体内的全身药物暴露水平也可能相差甚微。与此同时，双氯芬酸钠治疗骨关节炎的确切作用机制尚未阐明，其作用部位也无明确界定，目前普遍认为靶点为关节周围组织或关节滑液。因此，该类产品除开展药代动力学终点生物等效性研究外，还需同步开展对照临床终点生物等效性研究，综合判定其生物等效性。 因此，皮肤局部外用仿制药可采用一种或多种方法进行生物等效性研究。许多外用仿制药均可采用体内生物等效性方法，包括开展含对比临床终点的生物等效性研究，或针对皮质类固醇产品开展体内血管收缩试验（无论仿制药与参比制剂存在何种差异），因为采用上述体内研究，可降低生物等效性各类潜在失效风险，且该评价方式不受受试制剂处方差异的影响。不过，基于表征的生物等效性方法则适用于部分仿制药品种，这类产品的Q1/Q2与参比制剂无差异，且这些差异不会显著影响活性成分的局部或全身生物利用度。除配方无差异外，基于表征的生物等效性方法中的建议还可能包括以下研究，以支持生物等效性的验证，具体取决于剂型的复杂程度以及药品的作用机制/作用部位：受试制剂与参比制剂的Q3表征、体外释放率（IVRT）研究、体外透皮试验研究，以及含药代动力学（PK）终点的生物等效性研究。 总结 美国政府问责局数据显示：2010—2015 年，57% 的皮肤外用药品价格涨幅超100%，2015 年外用仿制药均价较此前上涨 276%。因此，建立高效、科学的外用仿制药生物等效性评价体系，对提升市场竞争、降低药价、保障患者用药可及性至关重要。本文系统梳理了美国主流皮肤外用剂型、监管法规演变，以及当下外用仿制药生物等效性的全套评价体系。目前用于评估拟上市仿制药等效性的方法，涉及通过一项或多项研究对药品进行系统且严格的比较评估，均是确保候选仿制药与原研药中活性成分在作用部位的生物利用度（吸收速率与吸收程度）保持一致。 临床关注要点 合规获批的外用仿制药，按说明书使用时，临床疗效与安全性和原研药完全等同； 仿制药等效性评价需通过多项严谨试验综合判定； FDA 持续优化审批标准，保障临床医师与患者可便捷获取优质外用仿制药。 参考文献 见原文。