IL-12 inhibitors(Interleukin-12 inhibitors), IL-23 inhibitors(Interleukin-23 inhibitors), PIKFYVE inhibitors(phosphoinositide kinase, FYVE-type zinc finger containing inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseOther Diseases+ [3]

Active Indication

Amyotrophic Lateral SclerosisB-Cell Malignant NeoplasmB-Cell Lymphoma+ [1]

Inactive Indication

COVID-19Crohn DiseaseRheumatoid Arthritis

Originator Organization

Lam Research Corp.

Active Organization

OrphAI Therapeutics, Inc.

Horizon Oncology Research LLC

Inactive Organization

Synta Pharmaceuticals Corp.

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (US), Orphan Drug (EU)

Structure

Molecular FormulaC25H34N6O8S2

InChIKeyGAJWNIKZLYZYSY-UHFFFAOYSA-N

CAS Registry870087-36-8

Clinical Trials associated with Apilimod Dimesylate

NCT05163886 / Active, not recruitingPhase 2

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).

Start Date23 Dec 2021

Sponsor / Collaborator

OrphAI Therapeutics, Inc.

NCT04446377 / CompletedPhase 2

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.

Start Date15 Jul 2020

Sponsor / Collaborator

Yale University

NCT02594384 / CompletedPhase 1

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.

Start Date01 Oct 2015

Sponsor / Collaborator

OrphAI Therapeutics, Inc.

100 Clinical Results associated with Apilimod Dimesylate

100 Translational Medicine associated with Apilimod Dimesylate

100 Patents (Medical) associated with Apilimod Dimesylate

Literatures (Medical) associated with Apilimod Dimesylate

03 Sep 2024·Brain : a journal of neurology

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

Article

Author: Swenson, Andrea ; Sampognaro, Paul J ; 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.

10 Jan 2024·Antimicrobial agents and chemotherapy

Pan-antiviral effects of a PIKfyve inhibitor on respiratory virus infection in human nasal epithelium and mice

Article

Author: Knowles, Ian ; Ombredane, Hugo ; Ito, Kazuhiro ; Baker, Jonathan ; Daly, Leah ; Rapeport, Garth

ABSTRACT:

Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of phosphatidylinositol (3, 5)biphosphate (PtdIns (3, 5)P2) and has been implicated in virus trafficking via the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study, we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virus in vitro and in vivo . PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in an MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, while improving the cell integrity of human nasal air-liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2 mg/mL), when intranasally treated, exhibited a significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated antiviral effects in RSV A2-infected human nasal epithelium in vitro and mouse in vivo , with an equivalent effect to that of ribavirin. AM also showed antiviral effects against human rhinovirus and seasonal coronavirus in vitro . Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for a pan-viral approach against respiratory viruses.

20 Jul 2023·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.

Author: 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.

News (Medical) associated with Apilimod Dimesylate

21 Feb 2024

·www.pharmaceutical-technology.com

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

ImmunotherapyCell TherapyDrug ApprovalGene TherapyClinical Study

02 Oct 2023

·www.biospace.com

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

Phase 2Clinical Result

05 Apr 2023

·www.fiercebiotech.com

AI Therapeutics' narrowed ambitions for ALS drug pay off as phase 2/3 beckons

AI Therapeutics reported that its lead asset knocked down concerning protein aggregates in ALS patients. AI Therapeutics has cast a wide net around AIT-101 with indications including follicular lymphoma and COVID-19. But those ambitions have come and gone. Now, the company is pointing to new phase 2a data in 15 patients with a form of amyotrophic lateral sclerosis (ALS), saying the results show promise. AI announced Wednesday that AIT-101—formerly LAM-002A— hit the primary endpoints of safety, tolerability and successful drug deliverability and that critical biomarkers are trending in the right direction. Specifically, the company found a 73% reduction in poly(gp) levels, a toxic protein aggregate considered to be a viable biomarker for ALS therapies. “This study provides early clinical evidence of AIT-101’s ability to clear the toxic protein aggregates that may contribute to the adverse pathology of ALS and provides a strong rationale for further clinical studies,” said Murat Gunel, M.D., professor of genetics and neuroscience at Yale University as well as a member of AI’s scientific advisory board, in the release. The company plans to launch a phase 2/3 trial of AIT-101 in a broader ALS population in 2024, CEO Brigette Roberts, M.D., told Fierce Biotech. AIT-101 works by clearing toxic protein aggregates in motor neurons. It's a familiar strategy, with much of the work in Alzheimer's aimed at knocking down amyloid-beta plaques, worrisome protein buildups associated with dementia. The name of the asset’s formal compound is apilimod, a PIKfyve kinase inhibitor that’s previously been touted as having potential therapeutic benefits against certain cancers and COVID-19, indications that AI Therapeutics has tried to target in the past. Yale and AI Therapeutics sprang into action in July 2020 after research pointed to apilimod as one of the most likely existing drug candidates to have a therapeutic benefit for COVID-19. The two launched a phase 2 trial testing the drug in patients with confirmed infection but the results were never reported. Since the COVID trial launched, the company has recalibrated, electing to focus apilimod on neurodegenerative diseases. The biotech is also developing an inhaled version of sirolimus, the compound behind Pfizer’s lung disease drug Rapamune, and oncology med AIT-102.

Phase 2Clinical Result

100 Deals associated with Apilimod Dimesylate

External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Amyotrophic Lateral Sclerosis	Phase 2	US	OrphAI Therapeutics, Inc.	23 Dec 2021
COVID-19	Phase 2	US	-	15 Jul 2020
Rheumatoid Arthritis	Phase 2	NL	Synta Pharmaceuticals Corp.	01 Dec 2005
Crohn Disease	Phase 2	US	Synta Pharmaceuticals Corp.	01 Aug 2005
Crohn Disease	Phase 2	CA	Synta Pharmaceuticals Corp.	01 Aug 2005
B-Cell Malignant Neoplasm	Phase 1	US	OrphAI Therapeutics, Inc.	07 Dec 2017
B-Cell Malignant Neoplasm	Phase 1	US	Horizon Oncology Research LLC	07 Dec 2017
B-Cell Lymphoma	Phase 1	US	OrphAI Therapeutics, Inc.	01 Oct 2015
Lymphoid Leukemia	Phase 1	US	OrphAI Therapeutics, Inc.	01 Oct 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04446377 (CTgov)	Phase 2	COVID-19	142	Apilimod Dimesylate Capsule (LAM-002A)	ivyleruayh(qrtwablwmq) = gxiebkoeer qcuhfdnpvp (awachwncbt, vxswjxbdkj - sfzmicwdek) View more	-	08 Aug 2023
				Placebo (Placebo)	ivyleruayh(qrtwablwmq) = yflluzxevf qcuhfdnpvp (awachwncbt, vgtlvzgbxv - obwrtomiai) View more
NCT00642629 (Pubmed)	Phase 2	Rheumatoid Arthritis	29	Apilimod mesylate 100 mg/day	gohhuyzmzc(ltjsfqodph) = mvncbscbvc xlbwctnnfg (lymcmbjbci )	Negative	01 Jun 2012
				Placebo	gohhuyzmzc(ltjsfqodph) = tcahsruyjb xlbwctnnfg (lymcmbjbci )

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