apilimod (STA-5326) / Madrigal Pharma - LARVOL DELTA

Biologic drugs for induction and maintenance of remission in Crohn's disease: a network meta-analysis. (PubMed, Cochrane Database Syst Rev) - "This review has supported evidence generation, but head-to-head comparative trials for key interventional subclasses or specific agents may be needed, as guided by key stakeholders; for example, on the use of biosimilar versions of medications out of patent. The role of concomitant purine analogues is a key confounding factor and future studies may not only want to investigate specifically the role of combinations, but also consider stratifying populations or purposefully excluding participants based on this key class of therapy to avoid such heterogeneity. Given the majority of evidence focusses on the outcomes of clinical remission and relapse, future studies may want to further consider other outcomes of clear interest to clinicians and patients, particularly endoscopic remission. Finally, long-term safety data are limited throughout the networks. Whilst future studies with longer follow-ups could provide increased data, it may be that study designs outside of..."

Clinical • Journal • Retrospective data • Review • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • IL7R

PIKfyve-specific Pt(II)-based targeted drug conjugate in treatment of ovarian cancer through multi-mode actions. (PubMed, J Inorg Biochem) - "In vivo tests showed that AP-604 at a high dose achieved stronger tumor suppression than Cisplatin, Apilimod, and their combination without inducing significant histopathological damage. These findings proved that AP-604 has potential as a promising drug candidate with enhanced efficacy and favorable safety profiles in treatment of ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • BCL2

Naked antisense oligonucleotides remain endolysosomally sequestered despite induced membrane damage. (PubMed, bioRxiv) - "In apilimod-expanded organelles, ASOs concentrated at limiting membranes and intraluminal foci with constrained motion, consistent with association with membrane and luminal structures. Although G3BP1/2 has been proposed to plug damaged endocytic membranes, we detected no recruitment of G3BP1 to endosomes or lysosomes; loss of G3BP1 and G3BP2 increased functional delivery modestly. We therefore propose that productive escape occurs earlier in endocytosis, most likely in early or recycling endosomes, where ASOs would still be unbound within the lumen and where membrane fusion and fission could generate perforations permitting release."

Journal • G3BP1 • G3BP2 • MALAT1

Endolysosomal trafficking regulator SH-BC-893 inhibits coronavirus entry in vitro and in vivo. (PubMed, Sci Rep) - "SH-BC-893 alters endolysosomal trafficking similar to PIKfyve inhibitors and, like hydroxychloroquine, reduces cathepsin L activity...Thus, poor in vivo outcomes when using apilimod or chloroquine as anti-virals likely reflect pharmacologic limitations of these compounds rather than a flawed therapeutic strategy...Because it targets host rather than viral proteins, SH-BC-893 might also block infection by many other viruses that enter via endosomal pathways: orthomyxoviruses (influenza), filoviruses (Ebola, Marburg), flaviviruses (Dengue, Zika, and West Nile), alphaviruses (Chikungunya) rhabdoviruses (rabies), and bunyaviruses (Hantaan or Sin Nombre). In sum, further evaluation of SH-BC-893 and/or optimized analogs as potential pan-antiviral agents is merited."

Journal • Preclinical • Chikungunya • Dengue Fever • Ebola Virus Disease • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity. (PubMed, Cell Death Dis) - "These results demonstrate that PIKfyve is essential for maintaining photoreceptor and RPE integrity by supporting lysosomal function, protein turnover, and metabolic stability, and suggest that enhancing PIKfyve activity may offer therapeutic potential for retinal degenerative diseases. This study is timely, as pharmacological inhibition of PIKfyve with apilimod-currently under clinical investigation for autoimmune, neurodegenerative, and infectious diseases-raises significant safety concerns, including lysosomal swelling, vacuolization, and impaired protein degradation, which could ultimately compromise retinal homeostasis and vision."

Journal • CNS Disorders • Immunology • Infectious Disease • Ophthalmology • Targeted Protein Degradation

How endosomal PIKfyve inhibition prevents viral membrane fusion and entry. (PubMed, Proc Natl Acad Sci U S A) - "Acute PIKfyve inhibition with apilimod or brief hypotonic treatment produced endosomal swelling and impaired infection by interrupting a late endosomal entry step...These data support a simple biophysical mechanism: endo-lysosomal swelling, likely increasing endosomal membrane tension, creates an energy barrier to fusion and genome release. Inducing such swelling may offer a general strategy to inhibit viruses that depend on late endosomal entry."

Journal • Ebola Virus Disease • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Apilimod in Oncology: From Non-Malignant Origins to Emerging Anti-Cancer Potential. (PubMed, Eur J Pharmacol) - "In particular, the translatability of preclinical observations to clinical benefit, the identification of predictive biomarkers, and the management of potential adverse effects require further investigation. Finally, we discuss emerging therapeutic strategies, including combination approaches with RAS pathway inhibitors, while highlighting the key challenges that must be addressed to fully exploit the therapeutic potential of Apilimod."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

PIKfyve mediates the maturation of mycobacteria-containing vesicles. (PubMed, Front Cell Infect Microbiol) - "Here, we studied the role of PIKfyve in Mycobacterium marinum (Mm) infection of zebrafish larvae using two chemical inhibitors of the enzymatic activity of PIKfyve, YM201636 and Apilimod...We found that in the infected macrophages, PIKfyve facilitates autophagy pathway activation and (auto)phagosome maturation, and protects against cell death, thus boosting the host immune response against mycobacterial infection. This study links PIKfyve to the autolysosomal defense against a mycobacterial pathogen."

Journal • Infectious Disease

Phosphoinositide kinase PIKfyve inhibitor apilimod blocks hepatitis E virus infection. (PubMed, eGastroenterology) - "Hepatitis E virus (HEV) is a leading cause of viral hepatitis, yet treatment remains limited to the off-label use of ribavirin, which can have significant side effects and is not suitable for all patients, highlighting the need for new antiviral strategies...Five compounds (apilimod, raloxifen, verapamil, chloroquine and tamoxifen) inhibited HEV infection in a dose-dependent manner...Overall, our data suggest that the endolysosomal protein PIKfyve plays a crucial role during the entry of HEV. Considering the reported safety profile of apilimod in previous human clinical trials, the pharmacological targeting of PIKfyve kinase activity might guide novel antiviral strategies against HEV."

Journal • Infectious Disease • Inflammation

Chronic stress-induced depression-like behaviors through Th1-lymphocytes and microglia-mediated neuroinflammation in the mouse. (PubMed, Eur J Pharmacol) - "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. 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."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Mood Disorders • Psychiatry • BCL2 • CD4 • CD8 • IFNG • IL12A • IL4

PIKfyve is an essential component of the endolysosomal pathway within photoreceptors and the retinal pigment epithelium. (PubMed, Exp Eye Res) - "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."

Journal • Cataract • Ophthalmology • LAMP1

1-Phosphatidylinositol 3-Phosphate 5-Kinase Inhibition by Apilimod Promotes an Adipocyte-Like Vascular Smooth Muscle Cell Phenotype and Prevents Arterial Calcification. (PubMed, Circ Res) - "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."

Journal • Cardiovascular

Lysosomal exocytosis by macrophages as a druggable mechanism for anti-inflammatory clearance of dead adipocytes in adipose tissue. (PubMed, Cell Death Dis) - "Notably, activation of lysosomal exocytosis with the mTOR inhibitor Rapamycin enhanced adipocyte clearance and significantly reduced inflammatory ATM abundance and TNF-α secretion...In contrast, inhibition of lysosomal exocytosis with PIKfyve inhibitor Apilimod or targeted inhibition of LAL using Lalistat-2 disrupted lysosomal function and promoted a pro-inflammatory ATM phenotype. Our findings highlight lysosomal exocytosis as a critical pathway for the resolution of dead adipocytes and the regulation of inflammation in adipose tissue. Pharmacological enhancement of this process may represent a promising therapeutic approach to attenuate inflammation in AT and its metabolic consequences, including insulin resistance and type 2 diabetes."

Journal • Diabetes • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • LAMP1 • LAMP2 • TNFA

How endosomal PIKfyve inhibition prevents viral membrane fusion and entry. (PubMed, bioRxiv) - "Acute PIKfyve inhibition with apilimod or brief hypotonic treatment produced endosomal swelling and impaired infection by interrupting a late endosomal entry step...These data support a simple biophysical mechanism: endo-lysosomal swelling, likely increasing endosomal membrane tension, creates an energy barrier to fusion and genome release. Inducing such swelling may offer a general strategy to inhibit viruses that depend on late endosomal entry."

Journal • Ebola Virus Disease • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Tau seeding in neurons enabled by transient endolysosomal perforations are confined within endolysosomes. (PubMed, bioRxiv) - "Pharmacologic inhibition of the endolysosomal lipid kinase PIKfyve with apilimod suppressed seeded tau aggregation and prevented neuronal toxicity. These data indicate that templated conversion proceeds within acidic, membrane-intact endolysosomes; tau seeding in neurons is enabled by transient, self-limited endolysosomal perforations yet remains confined to the endolysosomal lumen, and it requires PIKfyve- dependent PI(3,5)P₂."

Journal • Alzheimer's Disease • CNS Disorders

Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals. (PubMed, Cell Stem Cell) - "Harnessing these insights, we show that both Lyz2 knockout (KO) and pharmacological inhibition of lysosomal degradation confer rapid functional recovery in injured non-regenerative hearts. Thus, targeting a remote injury response in a non-CM cell type rapidly promotes post-MI recovery of non-regenerative hearts."

Journal • Cardiovascular • Myocardial Infarction • LYZ

A New Pikfyve Inhibitor Shows Subnanomolar Potency in Multiple Myeloma (IMS 2025) - "PIK085 also displayed an improved metabolic stability, with increased plasma concentrations following oral and IV administrations in mice when compared to PIK001 and apilimod.PIKfyve inhibitors displayed synergistic activity with relevant anti-MM therapeutics, including selinexor, venetoclax, and iberdomide. We present PIK085 as a promising preclinical candidate with subnanomolar potency in MM. Validation of PIKfyve inhibition as a single agent and in combination with other disease relevant therapeutics in in vivo models are n ongoing. Collectively, our work encourages further exploration of autophagy disruption in MM via PIKfyve inhibition, highlighting the potential of targeting plasma cell biology when investigating innovative treatment strategies."

Hematological Malignancies • Multiple Myeloma • SQSTM1

LUMINEV, SEMI HIGH -THROUGHPUT (96 -WELL) ANALYSIS OF EXTRACELLULAR VESICLES IN PLASMA SAMPLES. (ADPD 2025) - "Using tetraspanin levels as a readout, we noted suppression of EV in cells treated with GW6869 and elevation following Monensin, Bafilomycin -A, and Apilimod treatments... LuminEV is a sensitive, multiplexed assay for measuring EV surface proteins in cell culture media and plasma samples. The current results verify the specificity of the assay, provide a reference standard in healthy individuals, and suggest elevated EV secr etion in neurodegenerative patients."

CNS Disorders • CD63 • CD81 • CD9

Integrative analysis based on CRISPR screen identifies apilimod as a potential therapeutic agent for cisplatin-induced acute kidney injury treatment. (PubMed, Sci China Life Sci) - "Apilimod and elacridar emerged as the top two candidates of mitigating cisplatin-induced nephrotoxicity, with apilimod demonstrating superior efficacy in drug matrix experiments. Additionally, apilimod treatment did not compromise the antitumor effect of cisplatin in cancer cells or tumor-bearing mice. Overall, our study suggests that apilimod could be a promising therapeutic agent for the treatment of cisplatin-induced AKI and revealed its underlying molecular mechanism."

Journal • Acute Kidney Injury • Metabolic Disorders • Nephrology • Oncology • Renal Disease • TFEB

Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve is a Therapeutic Strategy for Pancreatic Cancer. (PubMed, Cancer Res) - "Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux and dependency, and concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK-MAPK pathway inhibitors can synergistically block PDAC growth...PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment...Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings indicate that concurrent inhibition of RAS and PIKfyve is a synergistic, cytotoxic combination that may represent a therapeutic strategy for PDAC."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve. (PubMed, J Med Chem) - "Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn's disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability."

Journal • Preclinical • Crohn's disease • Gastroenterology • Immunology • Infectious Disease • Inflammatory Arthritis • Inflammatory Bowel Disease • Novel Coronavirus Disease • Rheumatoid Arthritis • Rheumatology

Elucidation of metabolic resistance mechanisms to RAS inhibition (AACRPanCa 2024) - P1, P2 | "We previously determined that concurrent inhibition of autophagy, using the lysosomal inhibitor chloroquine (CQ), and of ERK, using a small molecule ERK inhibitor (ERKi), synergistically suppressed the growth of pancreatic ductal adenocarcinoma (PDAC) cell lines and patient xenograft-derived (PDX) organoids in vitro and PDX tumors in vivo. Our findings provided the rationale for our initiation of Phase I and Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with hydroxychloroquine (HCQ) in PDAC...PIKfyve inhibition with apilimod resulted in a potent reduction of autophagic flux and growth...We hypothesize that further dissection of the dynamic regulation of autophagy and macropinocytosis will improve current anti-nutrient scavenging treatment strategies. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for..."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Concurrent inhibition of the RAS ERK-MAPK pathway and PIKfyve as a therapeutic strategy for pancreatic cancer (AACRPanCa 2024) - P2 | "Furthermore, we demonstrated that concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK MAPK inhibitors synergistically blocked PDAC growth. These findings provided rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT4132505) or ERKi (LY3214996; NCT04386057) with HCQ in PDAC...We demonstrated that PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment...Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings implicate PIKfyve as an effective anti-autophagy target when paired with RAS or ERK-MAPK pathway inhibition in pre-clinical models of PDAC."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • LAMP1

Vertical inhibition of the autophagy pathway enhances sensitization to RAS MAPK pathway inhibition in pancreatic ductal adenocarcinoma (AACRPanCa 2024) - P1, P2 | "Based on these findings, combined ERK/MEK inhibition and hydroxychloroquine (HCQ) is currently under clinical evaluation (NCT03825289, NCT04386057)...Additionally, both ULK1 and VPS34 inhibitor treatment sensitized cells to PIKfyve inhibition with apilimod, a chemically and mechanistically distinct inhibitor of the termination phase of the autophagic pathway...Finally, vertical inhibition of the autophagic pathway via VPS34 inhibition and CQ sensitized PDAC cells to RAS inhibition to further reduce PDAC proliferation. Ongoing and future studies are aimed at elucidating the mechanism leading to decreased proliferation of combined anti-autophagy and RAS inhibitor therapies, as well as mechanistically understanding the effect of autophagy inhibition at multiple nodes on autophagic flux."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • PIK3C3

Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects. (PubMed, Autophagy) - "Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • CASP3 • CASP9 • SQSTM1