A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 24-Week Study to Assess the Efficacy and Safety of PPC-06 (Tepilamide Fumarate) Extended Release Tablets in Subjects With Moderate-to-Severe Plaque Psoriasis (AFFIRM)

This is a randomized, double-blind, placebo-controlled, multicenter study designed to assess the safety and efficacy of PPC-06 (tepilamide fumarate) extended release in subjects with moderate-to-severe plaque psoriasis.

开始日期2018-01-25

申办/合作机构

Dr. Reddy's Laboratories Ltd. (Russia)

NCT02173301

/ Completed临床2期

A Phase 2, Randomized, Double-Blind, Multicenter, Parallel-Group, Placebo-Controlled Study to Assess the Efficacy and Safety of Three Dose Levels of XP23829 in Subjects With Moderate-to-Severe Chronic Plaque-Type Psoriasis

The study objectives are the following:
1. To evaluate the efficacy of 3 doses of XP23829 compared to placebo for the treatment of moderate-to-severe chronic plaque-type psoriasis.
2. To evaluate the safety and tolerability of XP23829 in subjects with psoriasis.
3. To evaluate the pharmacodynamics (PD) of XP23829 through immunological analysis of peripheral blood samples.

开始日期2014-06-01

申办/合作机构

Dr. Reddy's Laboratories Ltd. (Russia)

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100 项与 Tepilamide fumarate 相关的临床结果

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100 项与 Tepilamide fumarate 相关的转化医学

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100 项与 Tepilamide fumarate 相关的专利（医药）

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项与 Tepilamide fumarate 相关的文献（医药）

2022-01-01·The Journal of clinical and aesthetic dermatology

Tepilamide Fumarate (PPC-06) Extended Release Tablets in Patients with Moderate-to-Severe Plaque Psoriasis: Safety and Efficacy Results from the Randomized, Double-blind, Placebo-controlled AFFIRM Study.

Article

作者: Mrowietz, Ulrich ; Reich, Kristian ; Lebwohl, Mark ; Munjal, Sagar ; Shenoy, Srinivas ; Kircik, Leon

Objective:

Safe, effective, long-term oral therapies are needed for plaque psoriasis. This study aimed to assess the safety and effectiveness of tepilamide fumarate (a fumaric acid ester) extended-release tablets.

Methods:

This Phase IIb, randomized, double-blind, placebo-controlled, 24-week, multicenter study treated adults with moderate-to-severe plaque psoriasis with tepilamide fumarate 400 mg once (QD) or twice daily (BID), 600 mg BID, or placebo. Coprimary endpoints were the proportion of patients achieving ≥75% reduction in the Psoriasis Area and Severity Index (PASI-75) and Investigator's Global Assessment (IGA) of clear or almost clear (≥2 points' reduction).

Results:

A total of 426 patients were randomized (mean age 49.6 [±13.0] years). There was a ≥75% PASI reduction in 39.7%, 47.2%, 44.3%, and 20.0% in the 400 mg QD, 400 mg BID, 600 mg BID, and placebo groups, respectively; IGA treatment success was 35.7%, 41.4%, 44.4%, and 22.0%, respectively. Between 50%-66% of tepilamide fumarate and 48% of placebo patients experienced ≥1 treatment-emergent adverse event. Gastrointestinal intolerance (20%-42%), infection (6%-18%), and decreased lymphocyte count (4%-9%) were more common with tepilamide fumarate.

Limitations:

High placebo response somewhat limits the utility of these findings.

Conclusion:

Patients with moderate-to-severe plaque psoriasis treated with oral tepilamide fumarate demonstrated positive response.

2001-02-01·Transplantation proceedings4区 · 医学

Methyl hydrogen fumarate inhibits acute and chronic rejection in rat kidney transplantation models

4区 · 医学

Article

作者: J Lutz ; M Lehmann ; K Asadullah ; H.-D Volk ; H.P Strebel ; J Brock ; K Risch ; R.K Joshi

The immunosuppressive effect of Me hydrogen fumarate (MHF) using calcium methylfumarate (CaMF) in rat transplantation models of acute (AR) and chronic rejection (CR) was studied.Orthotop kidney transplantation (T_x) was combined with contralateral nephrectomy using the strain combination WF(RT1u) to BDIX (RT1dv1) (AR model) and F344 (RT1lv1) to LEW (RT1l) (CR model).Recipients were treated per os (stomach tube) prophylactically or therapeutically with 33.3 mg/kg per day CaMF.In the CR model, rats were treated also with 1.5 mg/kg cyclosporin A for 10 days.Anal. of the immune state of rats surviving the observation period of 100 days by donor specific retransplantation showed that the tested immunosuppressive protocol did not induce tolerance.Comparing two different schedules of CaMF-treatment in the CR model F344 to LEW, prophylactic administration resulted in more effective inhibition of CR than seen for the therapeutical administration.The clin. onset of chronic graft injury about 12 wk after T_x is preceded by rising cellular graft infiltration by macrophages from week eight which peaks between week 12 and 16.

Viruses-Basel

Tepilamide Fumarate as a Novel Potentiator of Virus-Based Therapy

Article

作者: Spinelli, Marcus M. ; Arulanandam, Rozanne ; Maznyi, Glib ; Wong, Boaz ; Diallo, Jean-Simon ; Gilchrist, Victoria H. ; Chen, Andrew ; Alain, Tommy ; Alwithenani, Akram

Oncolytic virotherapy, using viruses such as vesicular stomatitis virus (VSVΔ51) and Herpes Simplex Virus-1 (HSV-1) to selectively attack cancer cells, faces challenges such as cellular resistance mediated by the interferon (IFN) response. Dimethyl fumarate (DMF) is used in the treatment of multiple sclerosis and psoriasis and is recognized for its anti-cancer properties and has been shown to enhance both VSVΔ51 and HSV-1 oncolytic activity. Tepilamide fumarate (TPF) is a DMF analog currently undergoing clinical trials for the treatment of moderate-to-severe plaque psoriasis. The aim of this study was to evaluate the potential of TPF in enhancing the effectiveness of oncolytic viruses. In vitro, TPF treatment rendered 786-0 carcinoma cells more susceptible to VSVΔ51 infection, leading to increased viral replication. It outperformed DMF in both increasing viral infection and increasing the killing of these resistant cancer cells and other cancer cell lines tested. Ex vivo studies demonstrated TPF’s selective boosting of oncolytic virus infection in cancer cells without affecting healthy tissues. Effectiveness was notably high in pancreatic and ovarian tumor samples. Our study further indicates that TPF can downregulate the IFN pathway through a similar mechanism to DMF, making resistant cancer cells more vulnerable to viral infection. Furthermore, TPF’s impact on gene therapy was assessed, revealing its ability to enhance the transduction efficiency of vectors such as lentivirus, adenovirus type 5, and adeno-associated virus type 2 across various cell lines. This data underscore TPF’s potential role in not only oncolytic virotherapy but also in the broader application of gene therapy. Collectively, these findings position TPF as a promising agent in oncolytic virotherapy, warranting further exploration of its therapeutic potential.

项与 Tepilamide fumarate 相关的新闻（医药）

2023-02-11

·生物制品圈

“不死的癌症”——银屑病研发进展最新汇总

前言银屑病作为一种免疫介导的慢性皮肤病，对患者的生活质量有重大影响。银屑病的治疗主要依据发病程度，轻度至中度疾病主要依赖局部治疗，中度至重度疾病通常需要全身给药。近年来生物制剂如TNF-α抗体、IL-17A抗体、IL-12/23抗体，以及小分子化药PDE4抑制剂，JAK抑制剂等均在中重度的银屑病患者中表现出较好的治疗效果。本文概述了银屑病治疗的主要药物类型，并对目前处于研发前沿的药物进行了汇总。图1 银屑病的发病机制01银屑病银屑病是一种以青壮年为主要发病人群的自身免疫性疾病，全球发病率在2-3%。有多种发病类型，包括斑块型银屑病（寻常型银屑病），滴状银屑病，脓疱状银屑病和红皮病型银屑病等。银屑病病人常伴随多种并发症，如银屑性关节炎、淋巴癌、心血管疾病、高血压，糖尿病以及忧郁症等。银屑病常易复发，且目前尚不能完全治愈，长期的疾病折磨会让多数患者存在较大的心理压力和经济负担。银屑病的病理特征是角质形成细胞增生和T细胞、树突状细胞、巨噬细胞和中性粒细胞的浸润，目前被认可的发病机制是以IL-23/Th17为轴的慢性炎症反应。髓系树突状细胞释放IL-23和IL-12，激活产生IL-17的T细胞、Th1细胞和Th22细胞，产生丰富的银屑病细胞因子IL-17、IFN-γ、TNF和IL-22。这些细胞因子介导角质形成细胞的过度增殖和趋化因子的释放，参与银屑病炎症反应[1]。02治疗现状银屑病是一种慢性复发性疾病，通常需要长期治疗。治疗方法的选择取决于疾病的严重程度。根据银屑病患者病变的临床严重程度（PASI评分）、受影响体表面积的百分比（BSA评分）和患者的生活质量，常分为轻度或中度，重度银屑病。● 轻度至中度银屑病一般可以进行局部涂抹治疗。a.糖皮质激素根据激素效果不同，一般用于轻中度银屑病患者的糖皮质激素为弱效和中效糖皮质激素。常用的弱效激素有地奈德和氢化可的松等。中效激素包括糠酸莫米松、丁酸氢化可的松和丙酸氟替卡松等。长期使用激素膏剂会产生多种不良反应，如皮肤萎缩、烧灼和瘙痒感、毛细血管扩张、诱发或加重局部感染、银屑病皮损加重及皮损反跳等不良反应。b.口服视黄醇阿维A酸和其他类视黄醇是用于减少皮肤细胞产生治疗银屑病的药物，副作用包括皮肤干燥和肌肉酸痛。c.维生素D类似物卡泊三醇、骨化三醇和他卡西醇等合成形式的维生素D抑制细胞的增殖，促进角质细胞分化，可减缓皮肤细胞的生长。可单独使用，也可与外用糖皮质激素联用。皮肤刺激是导致停药的常见副作用。d.钙调磷酸酶抑制剂他克莫司（Protopic）和吡美莫司（Elidel）等钙调磷酸酶抑制剂通过抑制IL-2和干扰素-γ的合成来阻断T细胞的激活，可缓解皮疹并减少鳞屑形成。长期使用可能增加患皮肤癌和淋巴瘤的风险。e.芳香烃受体(AHR)抑制剂银屑病患者中角质形成细胞表达的一种配体依赖性转录因子：AHR表达增加，AHR抑制剂的外用药本维莫德乳膏可以使皮肤细胞分化正常化，改善皮肤屏障。毛囊炎和接触性皮炎是最常见的副作用。f.磷酸二酯酶4(PDE-4)抑制剂银屑病的发病与PDE-4的过度表达有关，抑制PDE4能够增加cAMP水平，导致参与银屑病病理生理的免疫调节因子下调。外用药罗氟司特于2022年7月被美国FDA批准治疗斑块状银屑病（尚未进入中国市场），目前报道最多的副作用是高血压、头痛、腹泻和鼻咽炎。图2 银屑病的评估治疗方案[2]● 中度至重度银屑病通常需要全身治疗a.光疗法治疗银屑病的光疗最常用的是窄谱中波紫外线和PUVA（紫外线UVA 与光敏剂联合疗法），作用机制包括细胞凋亡和免疫抑制。最适合光疗的银屑病主要有点滴型银屑病和斑块型银屑病。常用的窄谱中波紫外线对于皮肤深层和内脏没有任何影响，但常产生一定的副作用，如皮肤发炎、瘙痒，干燥，甚至是恶心和头痛。b.超强糖皮质激素和强效糖皮质激素超强效糖皮质激素有丙酸卤倍他索、丙酸氯倍他索和卤米松。强效糖皮质激素包括氯氟舒松和倍他米松二丙酸酯。长期使用或过度使用强效皮质类固醇可能会使皮肤变薄，而且随着时间的推移，外用糖皮质激素可能会变得无效。c.免疫抑制剂甲氨蝶呤和环孢素等免疫抑制剂减少皮肤细胞的产生和抑制免疫系统来缓解银屑病，但副作用较大，长期服用需要接受健康检查。d. Nrf2刺激剂Almirall SA的Nrf2刺激剂富马酸二甲酯于2017年被欧盟批准治疗斑块状银屑病，目前尚未进入中国市场。e. PDE4抑制剂安进（Amgen）的PDE4抑制剂阿普斯特是2021年12月被获批用于治疗斑块状银屑病的口服小分子药物，治疗效果显著，大多数不良事件的严重程度为轻度至中度。f.JAK抑制剂百时美施贵宝（BMS）的TYK2抑制剂Deucravacitinib（氘可来昔替尼）于2022年9月在日本被批准用于治疗红皮病性银屑病、寻常性银屑病和脓胞型银屑病。g.生物制剂TNF-α抑制剂、IL-12/23抑制剂、IL-17抑制剂和IL-23抑制剂等注射用药在银屑病的治疗中表现出较好的效果，但可能增加严重感染风险，因此仅供短期使用，可与其他治疗方法交替使用。表1 治疗银屑病的生物制剂上市现状03药物研发前沿目前针对银屑病的药物研发，仍是抗体类的生物制剂为主，不过也不乏PDE4抑制剂的身影(详见表2)。利用IL-12和IL-23共有的p40亚基研发的IL-12/IL-23抗体药物在银屑病方面的研究正如火如荼的开展，目前AVT-04已在美国提交申请上市，而且全球有10种药物处于临床3期研发阶段。IL-23抗体也有2款药物进入针对银屑病治疗的临床3期阶段。TNF-α单克隆抗体在银屑病治疗领域的研发工作仍不减热度，北京神州细胞的SCT-630已经在国内申请上市，另外有3款国内机构研发的药物和一款美国机构研发的药物处于临床3期阶段。在银屑病治疗领域，IL-17A抗体药物的研发热度也高涨不下，目前有5款IL-17A抗体药物处于临床3期阶段。其中有4款是国内机构所研发，分别为三生国健、恒瑞医药、智翔医药和百奥泰生物科技有限公司。PDE4抑制剂在银屑病领域逐渐崭露头角，近两年分别有外用药和口服药被审批上市。目前大部分PDE4抑制剂处于临床2期研发阶段，另外Pefcalcitol已在美国申请上市，或许成为用于治疗银屑病的下一个PDE4外用药。表2 临床3期和申请上市阶段的银屑病领域药物除了上述已经进入临床3期阶段的靶点药物外，临床2期阶段的药物有PDE4抑制剂如HPP-737、LEO-29102、ME-3183、Orismilast、PF-07038124、QY101、DC-591042和KPG-612等，JAK抑制剂如泽璟生物的盐酸杰克替尼、辉瑞的Brepocitinib、诺诚健华的ICP-332和LEO Pharma A/S的Delgocitinib等，Nrf2刺激剂如ALZ-001和Tepilamide fumarate。此外还有研究发现IL-2通过诱导T细胞激酶，以及MicroRNAs均在银屑病病程中发挥作用，也有望是未来银屑病治疗的新方向。04总结银屑病是一种免疫相关的慢性皮肤疾病，由于发病周期长，容易复发，而且无法痊愈，严重影响患者的生活质量。目前针对银屑病的治疗主要是依据患者的发病程度，轻中度患者一般使用外用药物，中重度患者通常需要全身治疗。目前银屑病的药物研发方向主要是IL-12/23 p40抗体，IL-17A抗体，TNF-α抗体等生物制剂，以及PDE4抑制剂，JAK抑制剂，Nrf2刺激剂等小分子化药。随着对银屑病发病机制的深入，也不断涌现有望发展为治疗银屑病的新靶点和新方向。参考资料：1.Lowes, Michelle A et al. “Immunology of psoriasis.” Annual review of immunology vol. 32 (2014): 227-55. doi:10.1146/annurev-immunol-032713-1202252.Nast, Alexander et al. “S3 Guideline for the treatment of psoriasis vulgaris, update - Short version part 1 - Systemic treatment.” Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG vol. 16,5 (2018): 645-669. doi:10.1111/ddg.135163.Lé, Ana Maria, and Tiago Torres. “New Topical Therapies for Psoriasis.” American journal of clinical dermatology vol. 23,1 (2022): 13-24. doi:10.1007/s40257-021-00649-w3．Mayoclinic官网4. 智慧芽官网5. 新视界官网6. 其他公开信息在抗体圈微信公众号回复“JPM23”可下载60 家药企PPT合集。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

临床结果免疫疗法临床终止临床研究

2016-03-28

·BioSpace

Bay Area’s XenoPort Snags Psoriasis and MS Deal Worth $490 Million+ from Dr. Reddy’s Laboratories Ltd.

March 28, 2016 (Last Updated: 5:50pm PT) By Mark Terry , BioSpace.com Breaking News Staff Hyberabad, India-based Dr. Reddy’s Laboratories , announced today that it had inked a licensing deal with Santa Clara, Calif.-based XenoPort worth more than $490 million. Dr. Reddy’s Laboratories will gain exclusive U.S. rights to develop and market XP23829 for all indications, including moderate-to-severe chronic plaque psoriasis and potentially for relapsing forms of multiple sclerosis (MS). Dr. Reddy’s will pay an upfront payment of $47.5 million to XenoPort and an extra $2.5 million for specific clinical trial materials. XenoPort is also eligible for up to $190 million in various regulatory milestones, and $250 million in possible commercial milestones. Royalties up to the mid-teens have also been negotiated. “XP23820 complements our internal development efforts, which have primarily focused on the mild-to-moderate psoriasis segment to date,” said Raghav Chari , executive vice president, Proprietary Products Group , for Dr. Reddy’s Laboratories, in a statement. “In other markets, fumarates have been used as first line choices of treatment prior to initiation of biologic therapies in patients with moderate-to-severe psoriasis. We intend to initiate the registration program for XP23820 as soon as feasible so that we can accelerate the availability of this important treatment choice for moderate-to-severe psoriasis patients in the U.S. market.” XP23820 is an oral fumaric acid ester that acts as a prodrug for monomethyl fumarate (MMF). Biogen ’s blockbuster drug, Tecfidera, for MS, and Fumaderm, for psoriasis, are based on another MMF prodrug, dimethyl fumarate (DMF). Cambridge, Mass.-based Biogen (BIIB) has dominated the MS market, but has made some shifts toward the even higher-risk areas of Alzheimer’s drugs. It has initiated enrollment in two identical Phase III clinical trials for its drug aducanumab, with a total combined 2,700 patients. Analysts project the trial costs to exceed $1 billion. Data is expected through 2020, with completion in 2022. Its MS franchise has been facing stiff competition, pricing pressures, and a decreasing number of untreated patients. The company’s 2015 second quarter financials showed softer sales of Tecfidera than as expected, although they improved in the third quarter. In January, there were reports that XenoPort might be up for sale. The company’s main focus has been drugs for restless leg syndrome, but was rumored to be working with investment banks and contacting potential buyers. In October 2015, XenoPort announced it was restructuring to maximize its HORIZANT (gabapentin encarbil) drug for restless leg syndrome. It was cutting 25 jobs and its chief executive officer and director, Ronald Barrett , was retiring immediately. He was replaced by Vincent Angotti , who was previously executive vice president and chief operating officer. But on Sept. 15, the company announced positive results in its Phase II clinical trial of XP23820 for psoriasis. It met its primary endpoint in both the 800 mg daily dosage and 400 mg twice daily dosage, demonstrating statistically significant improvement. It had also terminated its XP23820 program for plaque psoriasis. The drug showed significant gastrointestinal-related side effects that caused almost a third of its 200 subjects to drop out of its psoriasis study. Side effects included nausea, vomiting and stomach ache. Eric Schmidt , an analyst with Cowen & Co. , told Reuters at the time, “XenoPort should stop spending limited resources on a drug that, while active, appears to be inferior to the standard of care in psoriasis.” Which apparently they did, selling it to Dr. Reddy’s Laboratories. Dr. Reddy’s has a big interest in generics and biosimilars. In the U.S. market, its focus is on dermatology and neurology.

临床3期引进/卖出临床2期临床结果财报

100 项与 Tepilamide fumarate 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11335	-	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
斑块状银屑病	临床2期	美国	Dr. Reddy's Laboratories Ltd. (Russia)	2014-06-01
斑块状银屑病	临床2期	美国	XenoPort, Inc.	2014-06-01
多发性硬化症	临床1期	美国	XenoPort, Inc.	-
帕金森病	临床前	美国	XenoPort, Inc.	-

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适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02173301 (CTgov)	临床2期	斑块状银屑病	200	XP23829 400 mg QD (XP23829 400 mg QD (Once Daily))	廠膚鹹窪衊衊網範築膚(壓願襯積選蓋鹹壓夢壓) = 鑰遞觸醖醖鑰鏇夢壓淵壓衊醖製廠積糧廠製齋 (觸鹹鹹鬱夢壓網製簾範, 5.07) 更多	-	2022-04-12
				XP23829 400 mg BID (XP23829 400 mg BID (Twice Daily))	廠膚鹹窪衊衊網範築膚(壓願襯積選蓋鹹壓夢壓) = 齋願鏇壓鬱積鏇築蓋願壓衊醖製廠積糧廠製齋 (觸鹹鹹鬱夢壓網製簾範, 5.50) 更多
NCT03421197 (CTgov)	临床2期	斑块状银屑病	426	PPC-06 400 mg QD (PPC-06 400 mg QD)	糧範網顧餘餘餘餘廠獵 = 鑰遞繭壓鏇獵廠獵淵顧遞範餘襯積鑰鏇膚衊鹽 (築積鏇廠鹽夢簾構襯顧, 築膚壓築憲憲蓋願積繭 ~ 鏇範遞艱鏇選鬱遞鏇廠) 更多	-	2021-05-11
				PPC-06 400 mg BID (PPC-06 400 mg BID)	糧範網顧餘餘餘餘廠獵 = 艱鏇窪構鹽膚積壓鬱齋遞範餘襯積鑰鏇膚衊鹽 (築積鏇廠鹽夢簾構襯顧, 醖襯艱糧蓋憲網膚選淵 ~ 顧衊築膚積壓鬱糧積憲) 更多
AAN2014	临床1期	-	-	XP23829 Formulation 1 (200 mg BID)	醖淵淵選夢鑰願膚顧襯(膚鹽淵夢夢齋膚窪構繭) = 獵築鑰鑰鏇襯願獵遞壓構製遞積襯鑰願淵餘鹹 (夢糧鹽窪簾鏇簾廠鹹顧 ) 更多	-	2014-04-08
				XP23829 Formulation 1 (400 mg BID)	醖淵淵選夢鑰願膚顧襯(膚鹽淵夢夢齋膚窪構繭) = 簾憲築壓願簾壓範蓋窪構製遞積襯鑰願淵餘鹹 (夢糧鹽窪簾鏇簾廠鹹顧 ) 更多