A Phase IIa Trial to Evaluate the Safety, Tolerability, and Biological Activity of LAM-002A (Apilimod Dimesylate Capsules) in C9ORF72-Associated Amyotrophic Lateral Sclerosis

This is a clinical trial to evaluate the safety, tolerability, and biological effect of LAM-002A in adults with C9ORF72-associated ALS (C9ALS).

开始日期2021-12-23

申办/合作机构

OrphAI Therapeutics, Inc.

NCT04446377 / Completed临床2期

A Phase II Randomized, Double-Blind, Placebo-Controlled Study of LAM-002A for the Prevention of Progression of COVID-19

This is a clinical trial to evaluate the efficacy of LAM-002A compared to placebo treatment in adults with a confirmed SARS-CoV-2 infection who are receiving standards supportive care in an outpatient setting.

开始日期2020-07-15

申办/合作机构

Yale University

NCT02594384 / Completed临床1期

A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of LAM-002A (Apilimod Dimesylate Capsules) Administered Orally in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

This is a Phase 1 dose-exploration study of LAM-002A administered by mouth in patients with relapsed or refractory B-cell NHL. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD),and preliminary anti-tumor activity will be evaluated.

开始日期2015-10-01

申办/合作机构

OrphAI Therapeutics, Inc.

100 项与 Apilimod Dimesylate 相关的临床结果

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100 项与 Apilimod Dimesylate 相关的转化医学

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100 项与 Apilimod Dimesylate 相关的专利（医药）

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项与 Apilimod Dimesylate 相关的文献（医药）

2024-09-03·Brain : a journal of neurology

Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial

Article

作者: Sampognaro, Paul J ; Swenson, Andrea ; Prudencio, Mercedes ; Gendron, Tania F ; Fandrick, Keith ; Macklin, Eric A ; Rothstein, Jeffrey D ; Edwards, Joan ; Young, Peter R ; Babu, Suma ; Nkrumah, Esther ; Pant, Pravin ; Paganoni, Sabrina ; Nicholson, Katharine A ; Landrette, Sean ; Spruill, Susan ; Petrucelli, Leonard ; Nix, Darrell

Abstract:

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated.This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured.Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism.Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

2023-07-20·bioRxiv : the preprint server for biology

Complete Protection from SARS-CoV-2 Lung Infection in Mice Through Combined Intranasal Delivery of PIKfyve Kinase and TMPRSS2 Protease Inhibitors.

作者: Balistreri, Giuseppe ; Kirchhausen, Tom ; Lesnikova, Angelina ; Sirnonen, Tarja ; Ojha, Ravi ; Saber, Saber Hassan ; Kuivanen, Suvi ; Kareinen, Lauri ; Joensuu, Merja ; Vapalahti, Olli ; Strandin, Tomas ; Kipar, Anja ; Kant, Ravi

Emerging variants of concern of SARS-CoV-2 can significantly reduce the prophylactic and therapeutic efficacy of vaccines and neutralizing antibodies due to mutations in the viral genome. Targeting cell host factors required for infection provides a complementary strategy to overcome this problem since the host genome is less susceptible to variation during the life span of infection. The enzymatic activities of the endosomal PIKfyve phosphoinositide kinase and the serine protease TMPRSS2 are essential to meditate infection in two complementary viral entry pathways. Simultaneous inhibition in cultured cells of their enzymatic activities with the small molecule inhibitors apilimod dimesylate and nafamostat mesylate synergistically prevent viral entry and infection of native SARS-CoV-2 and vesicular stomatitis virus (VSV)-SARS-CoV-2 chimeras expressing the SARS-CoV-2 surface spike (S) protein and of variants of concern. We now report prophylactic prevention of lung infection in mice intranasally infected with SARS-CoV-2 beta by combined intranasal delivery of very low doses of apilimod dimesylate and nafamostat mesylate, in a formulation that is stable for over 3 months at room temperature. Administration of these drugs up to 6 hours post infection did not inhibit infection of the lungs but substantially reduced death of infected airway epithelial cells. The efficiency and simplicity of formulation of the drug combination suggests its suitability as prophylactic or therapeutic treatment against SARS-CoV-2 infection in households, point of care facilities, and under conditions where refrigeration would not be readily available.

2012-06-01·Arthritis and rheumatism

Brief Report: A phase IIa, randomized, double‐blind, placebo‐controlled trial of apilimod mesylate, an interleukin‐12/interleukin‐23 inhibitor, in patients with rheumatoid arthritis

Article

作者: Arno W. R. van Kuijk ; Kris A. Reedquist ; Maarten de Boer ; Michael O'Meara ; Beatrijs M. Lodde ; Paul P. Tak ; Sarah Krausz ; Joelle Lufkin ; Eric W. Jacobson ; Alian Bakker ; Danielle M. Gerlag ; Maria J. H. Boumans

Abstract:

Objective:

To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin‐12 (IL‐12)/IL‐23 inhibitor, in patients with rheumatoid arthritis (RA).

Methods:

We performed a phase IIa, randomized, double‐blind, placebo‐controlled proof‐of‐concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod‐treated to placebo‐treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis.

Results:

While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod‐treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL‐12 and IL‐23 expression.

Conclusion:

Our results do not support the notion that IL‐12/IL‐23 inhibition by apilimod is able to induce robust clinical improvement in RA.

项与 Apilimod Dimesylate 相关的新闻（医药）

2024-02-21

·Pharmaceutical Technology

WuXi ATU gains approval for Amtagvi manufacturing at US site

WuXi Advanced Therapies’ 55,000ft² commercial non-viral cell therapy manufacturing site in Philadelphia, US. Credit: WuXi AppTec. WuXi Advanced Therapies (WuXi ATU) has received approval from the US Food and Drug Administration (FDA) to begin the analytical examination and production of Iovance’s Amtagvi (lifileucel) at its facility in Philadelphia, US. WuXi ATU is WuXi AppTec ‘s wholly owned subsidiary. The move marks a significant milestone as Amtagvi is the first individualised T-cell therapy approved by the US regulator for adults with unresectable or metastatic melanoma. The tumour-derived autologous T-cell immunotherapy received accelerated approval for its biologics licence application from the FDA. It is intended for patients who received treatment with a programmed cell death 1-hindering antibody and in cases where the BRAF V600 mutation is positive and has a BRAF inhibitor with or without a mitogen-activated protein kinase inhibitor. See Also: Telehealth abortion is an “effective, safe” tool for equitable healthcare – US study Apilimod mesylate by OrphAI Therapeutics for Amyotrophic Lateral Sclerosis: Likelihood of Approval Amtagvi utilises the T-cells of the patient extracted from tumour tissue and manufactured for re-infusion as a single dose. WuXi ATU’s site in Philadelphia became the first US external manufacturing location authorised to support the commercial production and supply of an individualised T-cell therapy for solid tumours. It is the first contract testing, development and manufacturing organisation to receive such an endorsement. Iovance operates an FDA-approved Iovance Cell Therapy Center adjacent to WuXi ATU in the Navy Yard, Philadelphia. WuXi ATU CEO and WuXi AppTec vice-chairman Edward Hu stated: “We congratulate Iovance on this major milestone in their quest to address unmet patient needs in the treatment of advanced melanoma. “WuXi ATU has partnered with Iovance since 2015 and we are thrilled to help them through each step of the drug development pipeline – from research to clinical manufacturing to FDA approval. “We are proud of our track record of enabling healthcare innovators to advance medical discoveries and deliver groundbreaking treatments to patients globally.” Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva. Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. By Cytiva Thematic By downloading this case study, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

免疫疗法细胞疗法上市批准基因疗法临床研究

2023-10-02

·BioSpace

OrphAI Therapeutics Announces Oral Presentation and Posters at the 22nd Annual NEALS Conference

GUILFORD, Conn., Oct. 02, 2023 (GLOBE NEWSWIRE) -- OrphAI Therapeutics Inc., a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today data presentations at the 22nd Annual NEALS (Northeast ALS Consortium) meeting being held October 4 - 6, 2023 in Clearwater Florida. Oral Presentation: October 5, 2023, 11:10 a.m. ET Title: Results of the Phase 2a clinical trial of LAM-002A (apilimod dimesylate) in C9orf72 ALS Presenters: Dr. Suma Babu, Sean M. Healey Center for ALS at MGHl; Peter Young, Ph.D. Chief Scientific Officer, OrphAI Therapeutics. Location: Opal Ballroom Poster Presentations: Title: AIT-101 Improves Functional Deficits in a Human TDP-43 Animal Model of ALS Presenter: Peter Young, Ph.D., Chief Scientific Officer, OrphAI Therapeutics Location and Time: Poster Session 1, Abstract:4, October 4, 2023, 5:15p – 7:15p ET Title: Results of a double blind, placebo-controlled clinical trial of AIT-101 (LAM-002A) in C9ORF72 ALS- A biomarker driven Phase 2a clinical trial targeting PIKfyve inhibition Presenter: Dr. Suma Babu, Sean M. Healey Center for ALS at MGH Location and Time: Poster Session 2, Abstract:136, October 5, 2023, 4:30p - 6:30p ET About OrphAI Therapeutics OrphAI Therapeutics’ mission is to transform the lives of patients with rare diseases. The company is currently developing three investigational therapies across multiple orphan indications: AIT-101, a first-in-class PIKfyve inhibitor, which recently completed a Phase 2a clinical trial in amyotrophic lateral sclerosis (ALS); LAM-001, a proprietary inhaled form of rapamycin, currently in Phase 2 for bronchiolitis obliterans syndrome (BOS) and pulmonary arterial hypertension (PAH); and AIT-102, a proprietary analogue of mithramycin, in preclinical development for the treatment of SWI/SNF mutated or dysregulated tumors. To learn more, please visit: OrphAI-Therapeutics.com MEDIA CONTACT: info@orphai-therapeutics.com

临床2期临床结果

2023-04-07

·SYNAPSE

渐冻人症在研疗法AIT-101获积极数据，减少毒性蛋白聚集体达73%

4月6日，AI Therapeutics公司宣布，其在研疗法AIT-101（LAM-002A）在治疗携带C9ORF72基因突变的肌萎缩侧索硬化（ALS）患者的Ⅱa期临床试验中获得积极结果。数据表明，服用AIT-101的受试者在12周内表现出药物与靶结合的生物标志物表达增加，毒性蛋白聚集体减少73%。肌萎缩侧索硬化（ALS）也叫运动神经元病（MND）。我国通常将肌萎缩侧索硬化和运动神经元病混用。它是上运动神经元和下运动神经元损伤之后，导致包括球部（延髓支配的部分肌肉）、四肢、躯干、胸部腹部的肌肉逐渐无力和萎缩。2018年5月11日，国家卫生健康委员会等5部门联合制定了《第一批罕见病目录》，肌萎缩侧索硬化被收录其中。肌萎缩侧索硬化的病因至今不明。目前ALS的主要治疗方法为神经保护和支持治疗，而国际承认、且唯一通过美国食品药物监督局（FDA）批准治疗肌萎缩侧索硬化的药物为力如太（Rilutek）。 AIT-101是一类新型的高度选择性的脂质激酶PIKfyve抑制剂。AIT-101和其活性代谢产物可以穿越血脑屏障，对中枢神经系统的神经元产生作用。AIT-101通过抑制PIKfyve表达，导致转录因子TFEB的激活，TFEB通过自噬溶酶体途径促进有毒蛋白聚集物的清除。已有数据证明AIT-101可以减少人类受试者的有毒蛋白聚集物，在家族性和散发性ALS体外模型中提高运动神经元的存活。本次试验为一项为期24周的、随机、安慰剂对照的Ⅱa期研究。5例C9ORF72 ALS受试者以2：1的比例被分配至AIT-101组或安慰剂组，随后进行12周的开放性扩展研究。本实验的主要、次要和探索性终点包括安全性、耐受性、脑脊液中药物和活性代谢物的水平、AIT-101对靶点结合生物标志物的影响、毒性蛋白聚集体和神经退行性病变的影响。实验结果表明，服用AIT-101的受试者在12周内，其体内药物与靶结合的生物标志物表达增加，毒性蛋白聚集体减少73%。该研究还达到了其主要终点，即安全性和耐受性，以及确认药物和三种活性代谢物被递送至大脑。除本次公布的Ⅱa期临床数据外，AI Therapeutics还首次宣布，AIT-101已在ALS的TDP-43动物模型中证明了有效性，并改善TDP-43突变ALS动物模型的功能缺陷。这一最新数据与AIT-101对家族性和散发性ALS患者的运动神经元的体外研究显示的活性，表明该药物可以广泛适用于多种形式的ALS。耶鲁大学神经外科系主任、遗传学和神经科学教授、AI Therapeutics公司科学顾问委员会主席Murat Gunel博士评论：“这项研究提供了AIT-101能够清除可能导致ALS不良病理的毒性蛋白聚集体的早期临床证据，并为进一步的临床研究提供了强有力的理论基础。” 哈佛医学院病理学副教授兼本次试验的首席研究员Suma Babu评论：“这项试验的积极结果令人鼓舞，有助于AIT-101在ALS中的进一步发展。AIT-101属于一种新的实验疗法，直接靶向清除运动神经元中的有毒蛋白质聚集体，而运动神经元中的有毒蛋白质聚集体是ALS的一个标志。这个数据可能对所有的ALS患者都有广泛的影响，而不仅仅是C9ORF72 ALS患者。” 参考资料： https://www.ai-therapeutics.com/news/ai-therapeutics-announces-positive-results-from-phase-2a-biomarker-driven-trial-of-ait-101-in-patients-with-c9orf72-amyotrophic-lateral-sclerosis-als

临床结果

100 项与 Apilimod Dimesylate 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肌萎缩侧索硬化	临床2期	美国	OrphAI Therapeutics, Inc.	2021-12-23
新型冠状病毒感染	临床2期	美国	-	2020-07-15
类风湿关节炎	临床2期	荷兰	Synta Pharmaceuticals Corp.	2005-12-01
克罗恩病	临床2期	美国	Synta Pharmaceuticals Corp.	2005-08-01
克罗恩病	临床2期	加拿大	Synta Pharmaceuticals Corp.	2005-08-01
B细胞恶性肿瘤	临床1期	美国	OrphAI Therapeutics, Inc.	2017-12-07
B细胞恶性肿瘤	临床1期	美国	Horizon Oncology Research LLC	2017-12-07
B细胞淋巴瘤	临床1期	美国	OrphAI Therapeutics, Inc.	2015-10-01
淋巴细胞白血病	临床1期	美国	OrphAI Therapeutics, Inc.	2015-10-01

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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


NCT04446377 (CTgov)	临床2期	新型冠状病毒感染	142	Apilimod Dimesylate Capsule (LAM-002A)	積鹽遞餘鬱範構積蓋範(壓鬱網窪選選齋淵構積) = 廠膚餘夢鹽醖網簾選夢遞鬱淵願衊鏇獵獵衊餘 (鬱鹹憲積鑰願夢艱艱鹽, 網膚膚鏇糧觸齋廠憲餘 ~ 廠鑰淵遞繭糧築顧艱鹽) 更多	-	2023-08-08
				Placebo (Placebo)	積鹽遞餘鬱範構積蓋範(壓鬱網窪選選齋淵構積) = 夢顧窪遞壓鬱願蓋襯窪遞鬱淵願衊鏇獵獵衊餘 (鬱鹹憲積鑰願夢艱艱鹽, 餘膚遞壓範積醖憲觸製 ~ 選顧觸願糧鹽製糧鑰獵) 更多
NCT00642629 (Pubmed)	临床2期	类风湿关节炎	29	Apilimod mesylate 100 mg/day	(遞選壓齋鑰壓艱繭顧製) = 鹽齋廠構構繭鏇糧夢鏇鬱簾繭範餘鹽鹽範壓廠 (膚憲壓鏇壓願築壓鏇構 )	不佳	2012-06-01
				Placebo	(遞選壓齋鑰壓艱繭顧製) = 鏇選鏇襯醖醖觸製簾鹹鬱簾繭範餘鹽鹽範壓廠 (膚憲壓鏇壓願築壓鏇構 )