A Pilot Study of Safety and Efficacy of the Oral IL-12/23 Inhibitor, STA-5326 Mesylate, for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency

This study will determine whether an experimental medicine, STA-5326 mesylate, is safe to use in patients with common variable immunodeficiency (CVID) who have inflammation of the gut. It will also determine if patients who take this drug show improvement in their symptoms, decrease in inflammatory chemicals in the gut, changes in their immune cells, and improvement in how their gut is functioning to absorb food.
Patients between 18 and 75 years of age with CVID and chronic diarrhea or involuntary weight loss of more than 5 percent of their past body weight over the past 12 months may be eligible for this study. Candidates are screened with a review of their medical records, a medical history and physical examination, blood, urine and stool tests, chest x-rays and skin test for exposure to tuberculosis, and a hydrogen breath test. For the latter, breath samples are collected before and every 20 minutes (for 2 hours) after the subject drinks a sugar solution. This test determines the digestive effects of bacteria in the upper intestine. Samples are collected by having the subject blow into a balloon.
Participants undergo the following tests and procedures:
Immune System and Gastrointestinal Evaluation
* 48-hour stool fat collection (measures the amount of undigested fat in the stool): Subjects keep a diary of what they eat for a 48-hour period. At the beginning of the 48 hours they take two dye capsules and then take another two capsules 48 hours later. They collect a stool sample when they pass the second set of capsules in their bowel movement. An additional 24-hour stool collection is tested for loss of protein in the stool.
* D-xylose absorption test (measures the ability of the gut to absorb nutrients): Subjects drink a solution of d-xylose (a sugar substitute). Blood samples are collected before and 1 hour after drinking the solution.
* Upper endoscopy: A thin flexible lighted tube is advanced through the mouth to evaluate the esophagus, stomach and beginning of the small intestine.
* Lower endoscopy: A thin flexible lighted tube is advanced through the rectum to evaluate the colon.
Treatment Period (Study days 1 to 57)
* Physical examination - study days 1, 8, 15, 29, 43 and 57
* Blood samples to test the levels of STA-5326 in the blood. On study days 1 and 57, samples are collected before the medication dose and 1, 2, 4, 6 and 8 hours after the dose; on day 29, one sample is collected before the medication dose.
* Blood samples for routine safety testing - study days 1, 8, 15, 29, 43 and 57
* Medication history - study days 1, 8, 15, 29, 43 and 57
* Interview about pain, discomfort, and well being - study days 1, 8, 15, 29, 43 and 57
* Pregnancy test for women who can become pregnant - study days 15, 43, and 57
* D-xylose absorption test - study days 29 and 57
* Electrocardiogram - study days 29 and 57
* Urine test - study days 29 and 57
* Blood test for research on immune cells - study day 57
* Repeat endoscopies and studies of gut function (24- and 48-hour stool collections)
Follow-up period (Day 85 and day 113)
-Physical examination, blood tests, medication history, questions about pain, discomfort and well being

Start Date02 Dec 2005

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

NCT00088062

/ CompletedPhase 1/2

A Phase I/IIa Trial of STA-5326 in Crohn's Disease Patients With CDAI Scores of 220-450

The purpose of this study is to determine the safety and tolerability of STA-5326 given once daily or twice daily to Crohn's Disease patients with moderate disease.

Start Date01 Feb 2004

Sponsor / Collaborator

Synta Pharmaceuticals Corp.

100 Clinical Results associated with Apilimod

100 Translational Medicine associated with Apilimod

100 Patents (Medical) associated with Apilimod

110

Literatures (Medical) associated with Apilimod

01 May 2026·EXPERIMENTAL EYE RESEARCH

PIKfyve is an essential component of the endolysosomal pathway within photoreceptors and the retinal pigment epithelium

Article

Author: Anjum, Ifrah ; Benson, Matthew D ; Hocking, Jennifer C ; MacDonald, Ian M ; Lingrell, Susanne ; Dworkind, Chavy ; Attia, Karen

Phosphoinositides (PIs) are a family of seven low abundance membrane lipids, each with distinct signaling functions. The phosphoinositide kinase PIKfyve generates phosphoinositide-3,5-bisphosphate (PI(3,5)P₂) and PI5P. Emerging evidence implicates PIKfyve in key cellular processes, including autophagy, phagocytosis, endosomal trafficking, lysosomal maintenance, and melanosome formation. Complete loss of PIKfyve function is embryonic lethal in model organisms. In humans, heterozygous mutations in PIKFYVE are associated with Fleck corneal dystrophy and congenital cataracts. In this study, we investigate the role of PIKfyve in photoreceptors and the adjacent retinal pigment epithelium (RPE), host to dynamic endolysosomal pathways required for enduring the high oxidative stress environment, transporting metabolites and phototransduction components, and the breakdown of outer segment discs. To assess PIKfyve function in the retina and RPE in our zebrafish model, we employed CRISPR/Cas9-mediated gene editing and pharmacological inhibition using the specific PIKfyve inhibitor apilimod. Loss of PIKfyve activity leads to RPE expansion characterized by the accumulation of LC3- and LAMP1-positive vacuoles, along with defects in phagosome degradation and minor changes to melanosome biogenesis. Photoreceptors deprived of PIKfyve function develop a single large vacuole in the inner segment, while the OS remains largely intact over the timespan analyzed. Electroretinography (ERG) recordings revealed complete visual impairment in pikfyve crispant larvae and significantly reduced visual function in larvae treated with apilimod post embryogenesis. These findings highlight the critical role of PIKfyve in the development and homeostasis of the RPE and retina.

01 Mar 2026·EUROPEAN JOURNAL OF PHARMACOLOGY

Chronic stress-induced depression-like behaviors through Th1-lymphocytes and microglia-mediated neuroinflammation in the mouse

Article

Author: Zhang, Cai ; Song, Cai ; Kunikullaya U, Kirthana ; Li, Xiaohong ; Charlier, Thierry D ; Liu, Baiping ; Steinbusch, HarryW M

Recent studies showed the activation of T helper (Th) 1 and microglia during depression. However, the changes in peripheral and central lymphocyte subtypes, and their relationship with microglia in the depression are still unclear. To answer these questions, this study investigated concurrent alterations in lymphocyte subsets (Th1/Th2), microglial activation, and related neuroinflammation and neuronal changes in a mouse model of depression induced by chronic unpredictable mild stress (CUMS). Furthermore, pharmacological inhibitors targeting Th1 (STA-5326), M1 microglia (minocycline), or p38 MAPK (SB203580) were utilized to assess the contribution of these factors to behavioral and molecular outcomes. CUMS induced significant anhedonia and anxiety-like behaviors. These symptoms were accompanied by a decrease in central CD4 T cells and peripheral CD4/CD8 ratio, alongside an increased Th1/Th2 ratio. Hippocampal levels of cortisol, interleukin (IL)-2, IL-12, and the IFN-γ/IL-4 ratio were elevated. CUMS also activated microglia, P38-MAPK pathway and increased neuronal apoptotic signaling (reduced Bcl-2/Bax ratio), and decreased both 5-HT/5-HIAA ratio and neuroplasticity (PSD-95, DCX) in the hippocampus and prefrontal cortex. Notably, the correlations between microglia (Iba-1) and Th1 cell (IL-12), as well as both of them correlations with p-p38 were found. All these parameters were normalized by the three treatments. Interestingly, STA-5326 showed greater efficacy in restoring anhedonia and meningeal CD4 T cell levels, while SB203580 was most effective in normalizing 5-HT neurotransmitter. In summary, inhibiting Th1 lymphocyte activity, M1-microglia or p-38-MAPK pathways improved depression-like behaviors, which were associated with the normalization of peripheral and central immune imbalances, attenuation of neuroinflammation, and protection of neuroplasticity.

30 Jan 2026·CIRCULATION RESEARCH

1-Phosphatidylinositol 3-Phosphate 5-Kinase Inhibition by Apilimod Promotes an Adipocyte-Like Vascular Smooth Muscle Cell Phenotype and Prevents Arterial Calcification

Article

Author: Ramirez-Torres, Maria Alejandra ; Falgayrac, Guillaume ; Rauner, Martina ; Rauch, Alexander ; Matic, Ljubica ; Thiel, Jessica ; Barsoum, Mirna ; Hedin, Ulf ; Goettsch, Claudia ; Sun, Jiangming ; van der Vorst, Emiel P.C. ; Gombert, Alexander ; Hense, Nicolas ; Marx, Nikolaus ; Gorgels, Andrea ; Edsfeldt, Andreas ; Goncalves, Isabel ; Preisinger, Christian ; Mir, Bilal ; Noels, Heidi ; Terliesner, Mara ; Hayat, Sikander

BACKGROUND::

Cardiovascular calcification is a significant predictor and contributor to cardiovascular diseases. Vascular smooth muscle cell (SMC)–derived extracellular vesicles (EVs) play a crucial role in microcalcification formation. EVs can originate from the endosomal system, and PIKFYVE (1-phosphatidylinositol 3-phosphate 5-kinase), a lipid kinase, plays a key role in endomembrane maturation. We hypothesize that PIKFYVE inhibition will modulate EV cargo and, thereby, arterial calcification.

METHODS::

Human coronary artery SMCs were cultured in osteogenic media to induce calcification. PIKFYVE inhibition was achieved using the pharmacological inhibitor apilimod and siRNA. We characterized the SMC phenotype and EVs through proteomics, transcriptomics, and kinomics. Ldlr -deficient mice fed a high-fat, high-cholesterol diet received apilimod for 5 weeks.

RESULTS::

Calcified human arteries and SMCs exhibited increased PIKFYVE protein expression compared with controls. In calcifying SMCs, phosphatidylinositol 3-phosphate levels were reduced but restored by apilimod. Apilimod prevented matrix mineralization and collagen deposition in calcifying SMCs, accompanied by reduced procollagen 1A1 secretion. Apilimod inhibited TNAP (tissue-nonspecific alkaline phosphatase) at mRNA, protein, and activity levels. EVs released from apilimod-treated calcifying SMCs exhibited lower mineral cargo, reduced aggregation potential, and diminished TNAP cargo. Phenotypic omics analyses revealed that apilimod induced a shift toward an adipocyte-like SMC phenotype, marked by upregulation of adipogenic TFs (transcription factors), fatty acid metabolism genes, and increased fatty acid uptake. Reactivation of YAP (Yes-associated protein)-TEAD (transcriptional enhancer factor) signaling partially reversed these phenotypic changes. In vivo, apilimod reduced vascular calcification and plaque TNAP activity but increased plaque lipid accumulation.

CONCLUSIONS::

Pharmacological inhibition of PIKFYVE disrupts YAP-TEAD signaling, thereby reducing arterial calcification by limiting the calcification potential of EVs and suppressing osteogenic SMC programming, but also induces an adipocyte-like SMC phenotype with lipid accumulation. These findings emphasize the need to consider SMC phenotypic plasticity and potential adverse effects when developing therapeutic strategies for arterial calcification.

News (Medical) associated with Apilimod

16 Feb 2024

·www.globenewswire.com

OrphAI Therapeutics receives Orphan Drug Designation for AIT-101 as a treatment for amyotrophic lateral sclerosis in the European Union

Feb. 15, 2024 -- OrphAI Therapeutics Inc. (“OrphAI”), a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today that it has received Orphan Drug Designation (ODD) in the European Union (EU) for the treatment of amyotrophic lateral sclerosis (ALS). AIT-101 previously received ODD from the U.S. FDA in June 2023 for the treatment of ALS. “OrphAI Therapeutics now has orphan designation for AIT-101 both in the US and the EU for the treatment of ALS, an important step toward bringing the drug to patients suffering from this neurodegenerative disorder,” said Dr. Brigette Roberts, CEO and Director of OrphAI. “AIT-101 has demonstrated compelling activity in its ability to clear toxic aggregates, which are a hallmark of ALS and other neurodegenerative diseases. We look forward to moving AIT-101 into the next stage of clinical development." AIT-101 is a first-in-class, potent and highly selective inhibitor of the lipid kinase PIKfyve. Inhibition of PIKfyve leads to activation of the transcription factor TFEB which drives the increased clearance of toxic protein aggregates via the lysosomal autophagy pathway. AIT-101 has now been demonstrated to reduce aggregates in human subjects, to improve the survival of motor neurons in in vitro models of familial and sporadic ALS, and to ameliorate functional deficits in a mutant TDP-43 animal model of ALS. AIT-101 is the most clinically advanced PIKfyve inhibitor in development. 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 Group 1 and 3 pulmonary hypertension and bronchiolitis obliterans syndrome (BOS); and AIT-102, a proprietary analogue of mithramycin, in preclinical development, for the treatment of SWI/SNF mutated or dysregulated tumors. The content above comes from the network. if any infringement, please contact us to modify.

Orphan DrugClinical Result

24 Jan 2024

·www.globenewswire.com

OrphAI Therapeutics Announces Appointment of Jay Fine to Board of Directors

Seasoned leader in drug discovery and developmentGUILFORD, Conn., Jan. 24, 2024 (GLOBE NEWSWIRE) -- OrphAI Therapeutics Inc. (“OrphAI”), a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today the appointment of Jay S. Fine, Ph.D. to its Board of Directors. Dr. Fine has a strong track record of drug discovery and development leadership in respiratory diseases, oncology, immunology and fibrotic disease indications. His leadership has contributed to the progression of over 30 new molecular entities into clinical development, leading to the commercial launch of multiple products including Skyrizi™ for Plaque Psoriasis, Psoriatic Arthritis and Crohn’s Disease and Spevigo™ for Generalized Pustular Psoriasis. He has chaired various governance and steering committees at several global pharmaceutical companies. Dr. Fine currently serves as President of Research and Development at EvolveImmune Therapeutics, a development-stage company focused on advancing differentiated immunotherapeutic approaches for the treatment of cancer. Previously, he served as Senior Vice President and Global Therapeutic Area Head for Immunology and Respiratory Diseases Research at Boehringer Ingelheim and as the Discovery Research Site Head at their Ridgefield, CT location. Dr. Fine also served as Head of Translational Biology at Roche Pharmaceuticals, was a Director in the Inflammation department at Schering-Plough and worked in the Biologic Response Modifiers Program at the National Cancer Institute. He holds a B.S. degree from Cornell University and a Ph.D. from the University of Rochester School of Medicine. Dr. Fine has authored over 75 scientific publications and patents and has been the recipient of numerous honors and awards during his career. “Jay Fine represents an extraordinary resource both for the Board as well as for the OrphAI management team, given his years of experience and success in the operational leadership of drug discovery and development. I am personally excited to work with him in this capacity,” said Dr. Brigette Roberts, CEO and Director of OrphAI. “I am very pleased to join the OrphAI Therapeutics’ Board of Directors,” said Dr. Fine. “The company has established an exciting product pipeline which holds tremendous potential to meaningfully improve the lives of patients with rare diseases. I look forward to working closely with the OrphAI team and its board to accelerate the progress of its promising pipeline.” “We are excited to welcome Jay Fine to our Board of Directors,” said David Scheer, Chairman of the Board of Directors at OrphAI. “Jay’s extensive leadership experience and drug development insights will be especially valuable to OrphAI and our Board as we collectively embark on this next stage of the company’s growth.” 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

Phase 2Executive Change

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

100 Deals associated with Apilimod

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Indication	Highest Phase	Country/Location	Organization	Date
Amyotrophic Lateral Sclerosis	Phase 2	United States	OrphAI Therapeutics, Inc.	27 Jul 2022
Crohn Disease	Phase 2	United States	Synta Pharmaceuticals Corp.	01 Feb 2004
Uveitis	Preclinical	United States	Synta Pharmaceuticals Corp.	01 May 2008

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