A Phase 1, Open-label, Parallel-group Study to Assess the Pharmacokinetics, Safety, and Tolerability of BPN14770 in Participants With Mild, Moderate, and Severe Hepatic Impairment and Healthy Control Participants

The primary purpose of this study is to assess the pharmacokinetics (PK) of BPN14770 after a single oral administration of BPN14770 in participants with mild, moderate, and severe liver impairment compared with control participants with normal hepatic function.

开始日期2025-08-30

申办/合作机构

Shionogi & Co., Ltd.

NCT07012005

/ Completed临床1期

A Phase 1, Open-label, Parallel-group Study to Assess the Pharmacokinetics, Safety, and Tolerability of BPN14770 in Participants With Severe Renal Impairment and Healthy Control Participants

The purpose of this study is to assess the pharmacokinetics (PK), safety, and tolerability of BPN14770 in participants with severe renal impairment and those with normal renal function.

开始日期2025-08-25

申办/合作机构

Shionogi & Co., Ltd.

NCT07011992

/ Completed临床1期

A Phase 1, Open-label, 1-Sequence Crossover, Drug-drug Interaction Study to Assess the Effect of Repeated Doses of BPN14770 on the Pharmacokinetics of Rosuvastatin in Healthy Adult Participants

The primary objective of this study is to investigate the effects of BPN14770 on the pharmacokinetics of the breast cancer resistance protein and organic anion transporting polypeptide 1B1 substrate rosuvastatin in healthy adults.

开始日期2025-07-18

申办/合作机构

Shionogi & Co., Ltd.

100 项与 Zatolmilast 相关的临床结果

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100 项与 Zatolmilast 相关的转化医学

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100 项与 Zatolmilast 相关的专利（医药）

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项与 Zatolmilast 相关的文献（医药）

2025-05-01·LEARNING & MEMORY

Individual contribution of PDE4B and PDE4D subfamilies to the prevention of object location memory impairments induced by sleep deprivation

Article

作者: Zhao, Hongyu ; Havekes, Robbert ; Heckman, Pim R A ; Blokland, Arjan ; Meijer, Elroy L ; Prickaerts, Jos

Insufficient sleep compromises the cAMP signaling pathway in the hippocampus, negatively impacting hippocampus-dependent memory. In the current study, we explored whether selective PDE4B or selective PDE4D inhibition can improve hippocampus-dependent spatial memory in the object location test (OLT) in mice after sleep deprivation (SD). The results demonstrated that SD impaired the OLT performance, and both A-33 and zatolmilast protected against the negative consequences of SD when administered at the start and middle of the SD period. These findings suggest that both PDE4B and PDE4D subfamilies contribute to the beneficial effect of PDE4 inhibition against SD-induced memory consolidation impairment.

2024-02-11·Expert opinion on pharmacotherapy

Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence

Review

作者: Moon, Seungyoun ; Burrows, Lisa ; Tromans, Samuel ; Barwell, Julian ; Watkins, Lance V. ; Shankar, Rohit

INTRODUCTION:

Fragile X syndrome (FXS) is the most common inherited cause of Intellectual Disability. There is a broad phenotype that includes deficits in cognition and behavioral changes, alongside physical characteristics. Phenotype depends upon the level of mutation in the FMR1 (fragile X messenger ribonucleoprotein 1) gene. The molecular understanding of the impact of the FMR1 gene mutation provides an opportunity to target treatment not only at symptoms but also on a molecular level.

METHODS:

We conducted a systematic review to provide an up-to-date narrative summary of the current evidence for pharmacological treatment in FXS. The review was restricted to randomized, blinded, placebo-controlled trials.

RESULTS:

The outcomes from these studies are discussed and the level of evidence assessed against validated criteria. The initial search identified 2377 articles, of which 16 were included in the final analysis.

CONCLUSION:

Based on this review to date there is limited data to support any specific pharmacological treatments, although the data for cannabinoids are encouraging in those with FXS and in future developments in gene therapy may provide the answer to the search for precision medicine. Treatment must be person-centered and consider the combination of medical, genetic, cognitive, and emotional challenges.

2024-02-01·Behavioural brain research

Treatment with the selective PDE4B inhibitor A-33 or PDE4D inhibitor zatolmilast prevents sleep deprivation-induced deficits in spatial pattern separation

Article

作者: Heckman, Pim R A ; Zhao, Hongyu ; Havekes, Robbert ; Blokland, Arjan ; Prickaerts, Jos

Sleep deprivation (SD) disrupts hippocampus-dependent memory, particularly in the dentate gyrus (DG) region, an area crucial for pattern separation. Previous research showed that non-selective phosphodiesterase type 4 (PDE4) inhibitors like roflumilast can alleviate these deficits. However, it remains unclear whether these outcomes are specific to a particular subfamily of PDE4. Hence, this study examined the specific impact of PDE4B inhibitor (A-33) and PDE4D inhibitor (zatolmilast) on spatial pattern separation in sleep deprived mice. Results demonstrated that SD impairs pattern separation, but both zatolmilast and A-33 alleviate these effects. However, A-33 impaired pattern separation in non-sleep deprived animals. The cognitive benefits of these inhibitors after SD may arise from alterations in relevant signaling pathways in the DG. This study provides initial evidence that inhibiting PDE4B or PDE4D holds promise for mitigating memory deficits due to SD.

项与 Zatolmilast 相关的新闻（医药）

2026-10-16

·高冠民医生

磷酸二酯酶 (PDE) 抑制剂研发与临床应用现状

PDE 超家族共 11 个家族 (PDE1‑PDE11)，负责水解细胞第二信使cAMP、cGMP，调控炎症、免疫、纤维化、血管张力、神经信号等多条通路。其中PDE4 家族（A/B/C/D4 个亚型）是风湿免疫、呼吸、皮肤科最受关注靶点；PDE3、PDE5 多用于心血管、肺动脉高压。早期泛亚型抑制剂受限于剂量依赖性不良反应；新一代研发核心思路：亚型高选择性、组织靶向、局部给药，分离疗效与恶心、腹泻等剂量限制性毒性。一、已上市 PDE 抑制剂（分家族）1.PDE4 家族（cAMP 特异性，炎症‑纤维化核心靶点）表格药物亚型选择性适应症科室核心特点罗氟司特 Roflumilast 泛 PDE4（A/B/C/D）重度 COPD，减少急性加重呼吸科口服；恶心腹泻、体重下降常见；肺抗炎，无抗纤维化获批《药学学报... 阿普米司特 Apremilast 泛 PDE4，轻微偏向 4B 斑块银屑病、银屑病关节炎、白塞口腔溃疡风湿免疫、皮肤科口服；无需常规实验室监测；PDE4D 抑制强，消化道不良反应突出，早期停药率高克立硼罗 Crisaborole 泛 PDE4（外用）特应性皮炎皮肤科软膏外用，几乎无全身副作用PMC 那米司特 Nerandomilast（博优维 ®）高选择性 PDE4B 特发性肺纤维化 IPF、进展性肺纤维化 PPF 呼吸科 First‑in‑class；抗炎 + 抗纤维化；PDE4D 抑制弱，消化道耐受性显著优于泛 PDE4 抑制剂；不用于皮肤病、关节炎健康界关键亚型生理： PDE4B：巨噬细胞、成纤维细胞、树突状细胞；介导炎症、纤维化，是治疗靶标； PDE4D：胃肠道上皮、中枢；抑制 PDE4D 是恶心、腹泻、呕吐主要来源； PDE4A：角质形成细胞、皮肤树突，和皮肤炎症相关。2.PDE5 家族（水解 cGMP）西地那非、他达拉非、伐地那非：勃起功能障碍、肺动脉高压 PAH；改善血管内皮，结缔组织病相关指端溃疡临床也有超说明书使用；头痛、面部潮红、低血压为主要不良反应。3.PDE3 家族米力农、氨力农：静脉，心衰短期正性肌力；西洛他唑：外周动脉病，抗血小板、扩血管。4. 非选择性 PDE 茶碱：老药，COPD、哮喘，治疗窗窄，心律失常风险大，现已少用。二、新一代 PDE4 抑制剂研发管线（2026）研发大方向：避开 PDE4D 强抑制，优先靶向 PDE4B/PDE4A，降低消化道不良反应，分为肺纤维化、自身免疫皮肤病、中枢三大方向。 Orismilast：PDE4B 优先，Ⅱb 期银屑病、特应性皮炎；Ⅱ 期数据 PASI‑75 接近阿普米司特，胃肠道耐受优于阿普米司特，推进 Ⅲ 期皮肤适应症，不开发肺纤维化。 Zatolmilast：PDE4B 选择性，中枢渗透，开发神经退行性疾病。 Namir‑α(NAM‑08)：PDE4A 高选择性，专注银屑病；主要作用角质形成细胞，全身免疫抑制弱；对关节病变预期疗效有限，Ⅱ 期，尚未上市。吸入型 PDE4 抑制剂（Tanimilast）：肺部局部给药，降低全身暴露，规避消化道副作用，用于哮喘、COPD，减少全身不良反应。研发痛点历史：大量早期 PDE4 候选药物临床失败，剂量‑毒性矛盾是最大瓶颈：提高剂量获得抗炎疗效，同时抑制 PDE4D 触发恶心腹泻；泛 PDE4 抑制剂存在天花板剂量，限制疗效上限。解决路径：①亚型选择性；②局部给药；③组织偏向分子设计。三、不同疾病领域应用现状1. 风湿免疫病阿普米司特：PsA、斑块银屑病、白塞口腔溃疡，口服小分子，介于传统 DMARD 与生物制剂之间；优势：无骨髓抑制、肝肾功能无需频繁监测；短板：消化道不良反应，关节改善力度弱于生物制剂；对 ILD 无适应症。 PDE5 抑制剂：结缔组织病肺动脉高压、雷诺 / 指端溃疡辅助治疗。在研：高选择性 PDE4B/A 分子，探索银屑病、PsA；那米司特不开发风湿皮肤适应症。2. 间质性肺病 / 肺纤维化那米司特 Nerandomilast里程碑：首个 PDE4B 选择性抑制剂获批 IPF/PPF；Ⅲ 期证实可延缓 FVC 下降，兼具抗炎 + 抑制肌成纤维细胞活化、胶原沉积；生存模型提示可显著延长生存期；不良反应以食欲下降、乏力为主，恶心腹泻发生率低；和尼达尼布、吡非尼酮作用通路不同，未来可探索联合方案。3. 皮肤科外用克立硼罗已成熟；口服方向期待新一代亚型选择性 PDE4，希望达到接近阿普米司特疗效，同时降低消化道不耐受，解决阿普米司特早期停药率高的临床痛点。4. 呼吸系统（COPD、哮喘）罗氟司特用于 COPD 慢性支气管炎表型，减少急性加重；吸入 PDE4 在研，规避全身副作用。5. 中枢神经系统 Ibudilast（异丁司特），非选择性 PDE，用于多发性硬化等神经炎症；多个脑穿透 PDE4 亚型抑制剂处于早期临床，神经领域转化成功率偏低。四、研发范式转变：从泛抑制到亚型精准靶向旧范式：泛 PDE4 抑制（阿普米司特、罗氟司特）同时抑制 4A/4B/4C/4D；疗效来自抑制 PDE4B，副作用来自 PDE4D；疗效‑毒性互相捆绑，剂量天花板明显。新范式：亚型选择性 PDE4B 选择性（那米司特）：主攻巨噬细胞、成纤维细胞，纤维化‑肺部炎症，降低 PDE4D 介导胃肠道毒性。 PDE4A 选择性（Namir‑α）：主攻角质形成细胞，皮肤局部炎症，对全身免疫、关节作用有限。重要局限：亚型不是绝对开关，选择性只是抑制倍数差异；依然会有少量脱靶，不良反应无法完全归零。五、现存挑战与未来方向毒性问题仍未完全解决：即便高选择性，高剂量下仍会有 PDE4D 微弱抑制，部分患者依旧出现胃肠道反应；组织分布差异：PDE4B 在肺、免疫细胞高表达；PDE4A 富集皮肤；因此药物选择性决定适用疾病谱，不能简单互相替代：那米司特治肺不治皮肤；Namir‑α 侧重皮肤，关节获益有限；新策略探索：吸入给药、PROTAC 降解技术、变构抑制剂，进一步分离疗效与毒性；拓展适应症：CTD‑ILD、系统性硬化纤维化、慢性炎症皮肤病，是未来重要拓展方向。六、临床思维小结泛 PDE4 抑制剂（阿普米司特）：风湿皮肤科成熟用药，兼顾皮肤、关节，但消化道不良反应是主要短板； PDE4B 高选择性（那米司特）：肺纤维化领域突破，抗炎 + 抗纤维化，消化道耐受性提升，但对皮肤关节炎症疗效不足；下一代 PDE4A 选择性分子瞄准银屑病，目标解决阿普米司特不耐受人群，但关节病变疗效有限； PDE 抑制剂不是一类药，亚型选择性决定靶组织、适应症、不良反应谱，不能互相等同替换。

2025-12-22

·EndPoints

Shionogi to pay $2.5B to acquire one of the only approved ALS drugs

Japanese drugmaker Shionogi announced Monday that it will be taking ownership of one of the only approved ALS drugs in a multibillion-dollar deal, with implications for its broader ambitions in rare disease. The company will pay $2.5 billion to acquire both the oral and IV formulations of Radicava, also known as edaravone, from Bain Capital-owned Tanabe Pharma. As part of the deal, Tanabe will spin out a newco for all Radicava operations, which will operate as a subsidiary of Shionogi. For Shionogi, the deal represents a significant investment in the rare disease space. The company is researching drugs for rare genetic disorders, most of which are in early- or mid-stage testing. But it also has zatolmilast, a PDE4D inhibitor that is in Phase 3 for the inherited developmental disorder known as fragile X syndrome. The acquisition of Radicava suggests Shionogi may want to build out its commercial infrastructure in rare disease ahead of zatolmilast’s first pivotal readouts. A Shionogi spokesperson declined to comment directly on its future plans, but said in an emailed statement that the deal “will solidify our strategic focus in rare disease and immediately add capabilities to ensure long term success.” As part of the transaction, Tanabe may receive royalties on future sales, the companies said in the announcement . Intravenous Radicava costs about $160,000 per year, and the oral formulation costs about $175,000. ALS is universally fatal. For years, it has been one of drug development’s most difficult fields, with most efforts failing. Radicava is one of the only exceptions, reaching the market in Japan in 2015 before an FDA approval in 2017. It is one of two FDA-approved drugs for all forms of ALS, along with riluzole, an oral drug from the French drugmaker Rhône-Poulenc (later acquired by Sanofi) that was approved in the 1990s. But both treatments provide only modest benefits, typically slowing ALS progression by a few months. Biogen and Ionis also got their drug Qalsody approved in 2023, but only for a genetic form of ALS making up about 2% of all diagnoses. There remains a significant demand for new ALS treatments, and the patient community is highly organized. A first-of-its-kind basket study for experimental ALS drugs is ongoing at Massachusetts General Hospital, but it’s seen limited success . Additionally, in 2022, multiple advocacy groups successfully put pressure on the FDA to be more flexible for ALS treatments, as the agency granted a full approval to Amylyx Pharmaceuticals’ Relyvrio despite an ongoing Phase 3 study. However, that trial ultimately failed , and Relyvrio was withdrawn.

上市批准临床3期并购

2025-12-11

·新浪医药

肺纤维化突破性疗法，获批上市

当地时间 12 月 10 日，勃林格殷格翰宣布，其口服磷酸二酯酶 4B（PDE4B）抑制剂那米司特（Nerandomilast）新适应症获 NMPA 批准上市，用于治疗成人进展性肺纤维化（PPF）。新闻稿指出，该疗法的获批标志着五年多来，PPF 患者迎来了首个新的治疗选择。对数百万受这种危及生命的肺部疾病影响的患者来说，无疑是一项突破。截图来源：企业官网那米司特是勃林格殷格翰在研的新型 PDE4B 抑制剂，其通过抑制 PDE4B 酶发挥作用，该酶在肺部高度表达，并与纤维化和炎症过程密切相关。通过抑制这些通路，那米司特展现了抗纤维化和抗炎的双重效果，有望为 IPF 患者带来临床获益。 2022 年，美国 FDA 曾授予那米司特突破性疗法认定，凸显了其在 IPF 治疗中的潜力。2025 年 10 月，该药在中美同步获批，标志着 IPF 治疗格局在十多年来首次迎来变革。在中国获批上市是基于那米司特关键性 III 期临床试验 FIBRONEER™-IPF 的积极结果。这是十年来首个达到主要终点的 IPF III 期临床试验。 FIBRONEER™-IPF 是一项双盲、随机、安慰剂对照试验，旨在评估至少接受 52 周治疗，那米司特对 IPF 患者的疗效和安全性。主要终点是第 52 周时用力肺活量（FVC，mL）较基线的绝对变化。治疗第 52 周时的关键疗效结果已发布于《新英格兰医学杂志》，包含：截图来源：企业官微关键次要复合终点（首次出现急性 IPF/ILD 加重、首次因呼吸系统原因住院或死亡时间）未达到。最常见的不良事件是腹泻：安慰剂组发生率 16.0%，那米司特 9 mg 组发生率 31.1%、18 mg 组发生率 41.3%。腹泻是最常见的导致试验方案终止的不良事件，因腹泻导致停药的比例在那米司特9 mg、18 mg 和安慰剂组分别为 1.8%、6.1%、0.5%。其他不良事件在各治疗组之间发生率均衡，尤其是血管炎、抑郁、自杀倾向或药物性肝损伤等特定关注的不良事件，在那米司特组与安慰剂组发生率相当。在各治疗组中，接受基础抗纤维化治疗的患者因不良事件导致试验方案终止的发生率均更高。接受安慰剂、那米司特 9 mg 和 18 mg 治疗的患者中，严重不良事件的发生率分别为 33%、31% 和 30%，致死性不良事件的发生率分别为 5%、4% 和 2%。值得一提的是，除了本次获批上市的适应症以外，那米司特还于 25 年 5 月在国内递交了进行性肺纤维化适应症的上市申请（受理号：JXHS2500057/8）。作为一种严重的致死性肺部疾病，IPF的典型症状为肺纤维化程度持续增加、肺功能持续下降、呼吸症状加重，严重影响患者生存质量。IPF的自然病程多变且无法预测，预后不佳，患者在确诊后的中位生存期约为3年，5年生存率更是低于多种常见癌症，因而常被称为"不是癌症的癌症"。目前，IPF直接的致病途径尚不明确，治疗手段一直十分有限。 2025年5 月 15 日，勃林格殷格翰 1 类新药那米司特片（BI 1015550）新适应症在中国上市申请获受理。除了那米司特，目前在研发中的PDE4B 抑制剂还有Zatolmilast和Orismilast。 Zatolmilast：最初由Tetra Therapeutics发现，后被Shionogi收购。它是一种选择性PDE4D抑制剂，目前主要用于治疗脆性X综合征（FXS），这是一种遗传性智力障碍。 Orismilast：由LEO Pharma开发，后被UNION therapeutics获得。2021年，信达生物与UNION达成合作，获得该药物在中国的独家开发和商业化权益。Orismilast主要用于治疗中重度特应性皮炎和银屑病新浪医药综合加入读者交流群： —精彩回顾— 我国启动全球最大规模尿液HPV筛查研究针对红斑狼疮！阿斯利康首创生物制剂 III 期成功恒瑞乙肝「突破性疗法」来袭 ADC之后，ABC来了全球首例！中国医生体内CAR-T成功治疗狼疮商务合作：杨小雨 15210041717

100 项与 Zatolmilast 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D12173	-	-	DB14790

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
脆性X综合征	临床3期	美国	Tetra Therapeutics, Inc.	2022-11-01
Jordan 综合征	临床2期	美国	Shionogi & Co., Ltd.	2025-02-04
Jordan 综合征	临床2期	美国	Jordan's Guardian Angels	2025-02-04
阿尔茨海默症	临床2期	日本	Shionogi & Co., Ltd.	2021-05-14
认知功能障碍	临床1期	美国	Tetra Therapeutics, Inc.	2017-01-01

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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


NCT03817684 (CTgov)	临床2期	阿尔茨海默症	255	BPN14770 (BPN14770 10mg Bid)	鹹醖鬱夢膚選遞憲醖廠(顧積襯衊餘餘襯範廠鏇) = 鑰築夢鏇夢餘衊選遞蓋衊糧積衊壓獵夢醖顧選 (簾網壓夢齋鹽遞願窪蓋, 1.71) 更多	-	2025-02-18
				BPN14770 (BPN 14770 25mg Bid)	鹹醖鬱夢膚選遞憲醖廠(顧積襯衊餘餘襯範廠鏇) = 網夢鹹積獵糧糧積襯憲衊糧積衊壓獵夢醖顧選 (簾網壓夢齋鹽遞願窪蓋, 1.67) 更多
NCT03569631 (CTgov)	临床2期	脆性X综合征	30	BPN14770 (BPN14770)	獵醖壓夢艱獵鹽製築積 = 構鑰窪壓衊顧醖簾糧鏇餘觸網醖遞窪淵鹹繭遞 (製餘蓋壓觸構構觸網鏇, 鏇積膚遞顧願獵鑰廠艱 ~ 鹹築蓋鑰獵願選夢餘鬱) 更多	-	2024-12-19
				Placebo (Placebo)	獵醖壓夢艱獵鹽製築積 = 齋築鹽廠鏇淵糧廠膚窪餘觸網醖遞窪淵鹹繭遞 (製餘蓋壓觸構構觸網鏇, 顧願壓觸獵範獵醖齋觸 ~ 鬱構簾齋構壓膚憲顧齋) 更多
NCT03569631 (Pubmed) 人工标引	临床2期	脆性X综合征	30	BPN14770	窪鬱鑰網糧獵艱憲衊網(觸醖繭顧遞簾壓顧糧鹽): difference = 5.31, P-Value = 0.0018 更多	积极	2021-05-01
				Placebo