Therapeutics

AIT-101

Tools

Back to the Top

Overview

Name: AIT-101
Synonyms: Apilimod, apilimod dimesylate, STA-5326, LAM-002A
Chemical Name: N-[(E)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2)
Company: OrphAI Therapeutics

Background

AIT-101 is a proprietary oral formulation of apilimod, an inhibitor of the phosphatidylinositol phosphate kinase PIKfyve. This lipid kinase phosphorylates signaling molecules in early endosomes that control endosomal function and fusion with lysosomes. Inhibitors of PIKfyve promote trafficking and clearance of aggregation-prone proteins via autophagy.

Apilimod was originally developed for autoimmune diseases, because it blocked inflammatory cytokine production evoked by Toll-like receptor activation (Wada et al., 2007). The compound progressed to Phase 2 clinical trials for Crohn’s disease and rheumatoid arthritis, where doses of 50-200 mg daily were safe but lacked efficacy (Sands et al., 2010; Krausz et al., 2012). Side effects were mild to moderate headache, fatigue, dizziness, and nausea. After these studies, apilimod’s target was identified as PIKfyve (Cai et al., 2013). Apilimod inhibits PIKfyve with an IC50 of 14 nM, and shows no activity toward other lipid or protein kinases.

The interest in repurposing apilimod for ALS arose when PIKfyve inhibitors were identified in a drug screen to extend the survival of iPSC-derived motor neurons from C9ORF72 ALS patients (Shi et al., 2018). In these cells, apilimod protected against neurotoxicity, and promoted clearance of toxic C9ORF72-encoded dipeptides by autophagy. In mouse models, apilimod blocked neurodegeneration and lowered levels of dipeptide protein aggregates in hippocampal neurons. It similarly rescued motor deficits in a zebrafish model of dipeptide toxicity (de Calbiac et al., 2024). Apilimod increased the exocytosis of toxic aggregates of the RNA binding protein TDP-43 in C9ORF72 cells and animal models of ALS, and also in cells from sporadic cases, or cases caused by mutations in TDP-43 or FUS. In ALS mouse models, intracranial delivery of apilimod reduced pathology and extended survival (Hung et al., 2023).

Apilimod has also been reported to reduce lysosomal trafficking and seeding of tau and synuclein aggregates (Soares et al., 2021; See et al., 2021).

Findings

In December 2021, AI Therapeutics began a Phase 2 biomarker study evaluating AIT-101’s safety, tolerability, and activity in 14 patients with C9ORF72-associated ALS. The trial compares 12 weeks of 250 mg daily AIT-101 or placebo, divided in two doses of five capsules each, added to standard care. After the placebo-controlled period, participants were to be offered 12-week and 36-week open-label extensions, for a maximum of 60 weeks on drug. Primary outcomes are adverse events and dropouts at 12 weeks, as well as plasma and CSF pharmacokinetics. Other outcomes include changes in plasma and CSF levels of C9 repeat expansion proteins, ALS disease biomarkers, and clinical measures of ALS symptoms.

On April 5, 2023, the company claimed announced positive results of the placebo-controlled study (press release). Participants taking AIT-101 for 12 weeks were claimed to have a 73 percent reduction in C9 poly(GP) proteins, and increased expression of a target engagement biomarker, sGPNMB. The drug was safe, and entered the brain. Results were published after peer review (Babu et al., 2024). Patients who completed the 12-week treatment were offered the drug under a compassionate use extension protocol.

Under the name LAM-002A, AIT-101 completed Phase 2 for SARS-COV2 infection in April 2021, and was also evaluated for lymphoma (Harb et al., 2017; see Phase 2 results on clinicaltrials.gov). Neither indication is listed on the company pipeline.

In 2023, AI Therapeutics changed its name to OrphAI Therapeutics. AIT-101 has orphan drug status in the U.S. and Europe. According to the company website, further development of AIT-101 is on hold pending additional funding.

For details on these trials, see clinicaltrials.gov.

Last Updated: 18 Oct 2024

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. Babu S, Nicholson KA, Rothstein JD, Swenson A, Sampognaro PJ, Pant P, Macklin EA, Spruill S, Paganoni S, Gendron TF, Prudencio M, Petrucelli L, Nix D, Landrette S, Nkrumah E, Fandrick K, Edwards J, Young PR. Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial. Brain. 2024 Sep 3;147(9):2998-3008. PubMed.
  2. Harb, WA, Diefenbach, CS, Lakhani N, Rutherford SC, Schreeder MT, Ansell SM, Sher T, Aboulafia DM, Cohen JB, Nix D, Landrette S, Flanders K, Miller LL, Lichenstein H, Abramson JS. Phase 1 Clinical Safety, Pharmacokinetics (PK), and Activity of Apilimod Dimesylate (LAM-002A), a First-in-Class Inhibitor of Phosphatidylinositol-3-Phosphate 5-Kinase (PIKfyve), in Patients with Relapsed or Refractory B-Cell Malignancies. https://doi.org/10.1182/blood.V130.Suppl_1.4119.4119 Blood
  3. Wada Y, Lu R, Zhou D, Chu J, Przewloka T, Zhang S, Li L, Wu Y, Qin J, Balasubramanyam V, Barsoum J, Ono M. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. Blood. 2007 Feb 1;109(3):1156-64. Epub 2006 Oct 19 PubMed.
  4. Sands BE, Jacobson EW, Sylwestrowicz T, Younes Z, Dryden G, Fedorak R, Greenbloom S. Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease. Inflamm Bowel Dis. 2010 Jul;16(7):1209-18. PubMed.
  5. Krausz S, Boumans MJ, Gerlag DM, Lufkin J, van Kuijk AW, Bakker A, de Boer M, Lodde BM, Reedquist KA, Jacobson EW, O'Meara M, Tak PP. 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. Arthritis Rheum. 2012 Jun;64(6):1750-5. Epub 2011 Dec 14 PubMed.
  6. Cai X, Xu Y, Cheung AK, Tomlinson RC, Alcázar-Román A, Murphy L, Billich A, Zhang B, Feng Y, Klumpp M, Rondeau JM, Fazal AN, Wilson CJ, Myer V, Joberty G, Bouwmeester T, Labow MA, Finan PM, Porter JA, Ploegh HL, Baird D, De Camilli P, Tallarico JA, Huang Q. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chem Biol. 2013 Jul 25;20(7):912-21. PubMed.
  7. Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST, Hendricks E, Linares GR, Wang Y, Son EY, Wen X, Kisler K, Wilkinson B, Menendez L, Sugawara T, Woolwine P, Huang M, Cowan MJ, Ge B, Koutsodendris N, Sandor KP, Komberg J, Vangoor VR, Senthilkumar K, Hennes V, Seah C, Nelson AR, Cheng TY, Lee SJ, August PR, Chen JA, Wisniewski N, Hanson-Smith V, Belgard TG, Zhang A, Coba M, Grunseich C, Ward ME, van den Berg LH, Pasterkamp RJ, Trotti D, Zlokovic BV, Ichida JK. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018 Mar;24(3):313-325. Epub 2018 Feb 5 PubMed.
  8. de Calbiac H, Renault S, Haouy G, Jung V, Roger K, Zhou Q, Campanari ML, Chentout L, Demy DL, Marian A, Goudin N, Edbauer D, Guerrera C, Ciura S, Kabashi E. Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects. Autophagy. 2024 Oct;20(10):2164-2185. Epub 2024 Sep 24 PubMed.
  9. Hung ST, Linares GR, Chang WH, Eoh Y, Krishnan G, Mendonca S, Hong S, Shi Y, Santana M, Kueth C, Macklin-Isquierdo S, Perry S, Duhaime S, Maios C, Chang J, Perez J, Couto A, Lai J, Li Y, Alworth SV, Hendricks E, Wang Y, Zlokovic BV, Dickman DK, Parker JA, Zarnescu DC, Gao FB, Ichida JK. PIKFYVE inhibition mitigates disease in models of diverse forms of ALS. Cell. 2023 Feb 16;186(4):786-802.e28. Epub 2023 Feb 7 PubMed.
  10. Soares AC, Ferreira A, Mariën J, Delay C, Lee E, Trojanowski JQ, Moechars D, Annaert W, De Muynck L. PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding. J Biol Chem. 2021 Jan-Jun;296:100636. Epub 2021 Apr 6 PubMed.
  11. See SK, Chen M, Bax S, Tian R, Woerman A, Tse E, Johnson IE, Nowotny C, Muñoz EN, Sengstack J, Southworth DR, Gestwicki JE, Leonetti MD, Kampmann M. PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation. bioRxiv. January 22, 2021

External Citations

  1. press release
  2. clinicaltrials.gov
  3. company pipeline
  4. clinicaltrials.gov

Further Reading

Papers

  1. Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Mandelkern T, Zheng M, Xu T, Rothberg J, Lichenstein H. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30;129(13):1768-1778. Epub 2017 Jan 19 PubMed.