AIT-101 is a proprietary, oral disintegrating formulation of a potent and highly selective PIKfyve kinase inhibitor. The active drug substance in AIT-101 is an experimental therapy that has been evaluated and demonstrated to be safe in almost 1,000 human subjects, including healthy volunteers and patients1,2,3,4.

AIT-101 and PIKfyve

AIT-101 is a potent inhibitor of PIKfyve kinase, an endosomal lipid protein kinase. It is one of the most highly selective and potent kinase inhibitors known5.  

Inhibition of PIKfyve kinase by AIT-101 leads to the activation of the transcription factor TFEB, which is a master regulator of lysosomal biogenesis. Activated TFEB relocates from the cytoplasm to the nucleus and leads to increased lysosomal and autophagosomal activity responsible for clearing misfolded proteins from cells.

Several neurodegenerative diseases, including ALS, Alzheimer’s, Huntington’s, Parkinson’s and frontotemporal dementia, are characterized by the accumulation of protein aggregates6 and have been shown to have a depletion of nuclear TFEB in neural tissues7. The induction of TFEB activity in relevant animal models has been shown to reverse the pathological and functional consequences of these toxic aggregates8, 9.

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis is a rare, life-threatening neurodegenerative disease that results in the progressive degeneration of motor neurons leading to muscle weakness, paralysis and ultimately death. Approximately 30,000 individuals suffer from ALS in the United States10, with an average life expectancy of 3-5 years despite treatment with standard of care. Currently there are only 4 approved drugs for ALS: Relyvrio, riluzole, edaravone, and QALSODYTM (for SOD1 ALS), and there is a significant need for further treatment options to slow disease progression and improve survival11.

OrphAI Therapeutics has been granted orphan status in the US and EU for the treatment of ALS with AIT-101.

AIT-101 and ALS

The potential of AIT-101 to treat ALS has been shown in recent publications and internal OrphAI Therapeutics studies12,13.

Preclinically, AIT-101 improves the survival of motor neurons from ALS patients. Animal models show that orally dosed AIT-101 crosses the blood brain barrier (BBB) and intrathecal delivery has been shown to induce TFEB-driven clearance of abnormal protein aggregates in neural tissue.  These protein aggregates are known to lead to motor neuron degeneration.

OrphAI Therapeutics has initiated a clinical trial of LAM-002A, the current formulation in the AIT-101 program, in ALS patients with a C9orf72 mutation (C9ALS) to evaluate safety, tolerability, blood brain barrier (BBB) penetration, and impact on target and disease biomarkers as well as functional parameters.  The C9ALS subpopulation was chosen for this initial trial because of the ability to directly measure the reduction of the accumulated C9 repeat expansion proteins, in addition to other ALS disease biomarkers. Future studies of AIT-101 will consider inclusion of a broader ALS population.

For more information on OrphAI Therapeutics’ trial of AIT-101/LAM-002A in ALS, click here to visit ( Identifier: NCT05163886).

AIT-101 References

1 Sands BE, Jacobson EW, Sylwestrowicz T, Younes Z, Dryden G, Fedorak R, Greenbloom S. Randomized, double-blind, placebo-controlled trial of the oralinterleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn disease. Inflamm Bowel Dis. 2010 Jul;16(7):1209-18. PMID:19918967.
2Krausz 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, aninterleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis. Arthritis Rheum. 2012 Jun;64(6):1750-5. PMID: 22170479
3 WadaY, Cardinale I, Khatcherian A, Chu J, Kantor AB, Gottlieb AB, Tatsuta N, Jacobson E, Barsoum J, Krueger JG. Apilimod inhibits the production of IL-12 andIL-23 and reduces dendritic cell infiltration in psoriasis. PLoS One. 2012;7(4):e35069. PMID: 22493730.
4 Diefenbach CSM, Cohen JB, Harb WA, Ansell SM, Nastoupil LJ, Abramson JS, Lakhani NJ, Schreeder MT, Sher T, Patel-Donnelly D, Aboulafia DM, Fuchs CA, Nix D, Landrette S, Graham PS, King LB, Young PR, Miller LL,  Lichenstein H, and Rutherford SC. Results of a completed phase I study of LAM-002 (apilimod dimesylate), a first-in-classphosphatidylinositol-3-phosphate 5 kinase (PIKfyve) inhibitor, administered as monotherapy or with rituximab or atezolizumab to patients with previously treated follicular lymphoma or other B-cell cancers. Journal of Clinical Oncology 2020 38:15_suppl, 8017-8017 
5 GayleS, 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. PMID: 28104689
6 SchmidtMF, Gan ZY, Komander D, Dewson G.Ubiquitin signaling in neurodegeneration: mechanisms and therapeutic opportunities. Cell Death & Differentiation. 2021 Jan: 28, 570-590.
7 WangH, Wang R, Xu S, Lakshmana MK. Transcription factor EB is selectively reducedin the nuclear fractions of alzheimer's andamyotrophic lateral sclerosis brains. Neurosci J.2016;2016:4732837. PMID: 27433468.
8 Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, Xu Y, Swartzlander DB, Palmieri M, di Ronza A, Lee VM, Sardiello M, Ballabio A, Zheng H. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB.EMBO Mol Med. 2014 Sep;6(9):1142-60. doi: 10.15252/emmm.201303671. PMID:25069841.
9 Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björklund A. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci U S A. 2013 May7;110(19):E1817-26. doi:10.1073/pnas.1305623110. Epub 2013 Apr 22. PMID: 23610405;.
10 Johns Hopkins:
11 National Institutes of Health:
12 Staats KA, Seah C, Sahimi A, Wang Y, Koutsodendris N, Lin S, Kim D, Chang WH, Gray KA, ShiY, Li Y, Chateau M, Vangoor VR, Senthilkumar K, Pasterkamp R, Cannon P, Zlokovic BV, Ichida, JK. Small molecule inhibition of PIKFYVE kinase rescues gain-and loss-of-function C9ORF72 ALS/FTD disease processes in vivo. bioRxiv.2019 Jun 28. Available at:
13 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. PMID: 29400714.