Therapeutics

AQNEURSA

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Overview

Name: AQNEURSA
Synonyms: N-acetyl-L-leucine, NALL, IB1001, levacetylleucine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Niemann-Pick Diseases, Ataxia, Lysosomal Storage Diseases, Nervous System
U.S. FDA Status: Niemann-Pick Diseases (Approved), Ataxia (Phase 3), Lysosomal Storage Diseases, Nervous System (Phase 2)
Company: IntraBio
Approved for: Neurological symptoms of Niemann-Pick Disease Type C

Background

N-acetyl-L-leucine is a modified derivative and prodrug of the naturally occurring essential amino acid leucine. In September 2024, the FDA approved this formulation of the pure L-leucine isomer to treat neurologic symptoms of the lysosomal storage disease Niemann-Pick type C in adults and children. NALL is currently in clinical trials for ataxia telangiectasia.

N-acetylation of L-leucine allows the amino acid to more easily enter cells (Churchill et al., 2021). The racemic mixture N-acetyl-DL-leucine has been used in France since the 1950s for the treatment of acute vertigo and dizziness, despite a lack of randomized clinical trials supporting its effectiveness (Vanderkam et al., 2019). Anecdotal reports and case studies reporting improvements in movement, cognition, and quality of life in patients with Niemann-Pick type C (NPC) or cerebellar ataxias of varying etiologies spurred interest in repurposing this drug (Bremova et al., 2015; Strupp et al., 2013). Other case series reported no benefit in cerebellar ataxia patients (Pelz et al., 2015), or in people with multiple systems atrophy (Scigliuolo et al., 2017). 

Additional anecdotes describe improved mobility, cognition, and mood in mentally healthy elderly people, that disappear when the drug is discontinued (Platt and Strupp, 2016; Kolb, 2023). Symptomatic improvements and possible neuroprotection have also been reported in two people with REM sleep disorder, a prodrome of Parkinson’s disease (Oertel et al., 2024; Balint and Bhatia, 2024), and in people with the movement disorder restless leg syndrome (Fields et al., 2021).

The mechanism of NALL in these conditions is unknown. Earlier preclinical work indicated that N-acetyl-DL-leucine was able to normalize activity in vestibular neurons responsible for balance. This gave rise to a theory that similarly normalizing cerebellar neuron activity could improve ataxia symptoms. In a mouse model of NPC, the L-enantiomer NALL, but not the D-version, significantly delayed the onset of gait abnormalities and motor dysfunction, slowed disease progression, reduced microgliosis, and survival (Kaya et al., 2020). In a similar study of a mouse model of a lysosomal storage disease called Sandhoff’s, N-acetyl-dl-leucine improved motor function and slightly increased lifespan (Kaya et al., 2020). In these models, NALL normalized glucose and glutamate metabolism, increased autophagy, increased levels of superoxide dismutase, and improved mitochondrial energy metabolism.

NALL was investigated in other neurodegenerative conditions. In a mouse model of Parkinsonism, it alleviated motor deficits and was associated with neuroprotection and diminished neuroinflammation (Xu et al., 2023). NALL prevented cortical cell death and neuroinflammation, and improved functional recovery, in a mouse model of traumatic brain injury (Hegdekar et al., 2021).

Findings

NALL was approved to treat NPC based on a Phase 3 trial involving 53 children and adults. Twelve weeks of treatment improved total scores on the Scale for the Assessment and Rating of Ataxia (SARA), which includes gait, sitting, stance, and speech symptoms (Bremova-Ertl et al., 2024; and commentary by Tifft, 2024). The most common side effects were abdominal pain, difficulty swallowing, upper respiratory tract infections, and vomiting. The approved dose is 4 g daily for adults, and the drug is formulated as granules to be suspended in water, orange juice, or almond milk. In tests of phagocytic function of peripheral blood macrophages as a biomarker for microglial activity in NPD, NALL treatment was found to decrease this activity in six patients tested (Dinkel et al., 2024).

Prior to the pivotal Phase 3, IntraBio had completed Phase 2 studies for NPC and the related lysosomal storage diseases Tay-Sachs and Sandhoff. In both trials, NALL improved symptoms, functioning, and quality of life for children and adults, and was well-tolerated with no serious side effects (Bremova-Ertl et al., 2022; Martakis et al., 2023).

In 2016-2017, ALCAT tested 5 g daily acetyl-DL-leucine in 80 people with cerebellar ataxia of varying etiologies. This investigator-initiated trial showed no difference between drug and placebo on the SARA (Feil et al., 2021).

In January 2020, IntraBio began a Phase 2 trial for the symptomatic treatment of ataxia telangiectasia (Fields et al., 2021). This rare genetic disorder of DNA repair includes prominent symptoms of ataxia. The trial assesses six weeks of up to 4 grams daily NALL in 39 children and adults, with a primary endpoint of clinician impression of change in severity. Secondary outcomes include ataxia scales, and clinician, parent, or patient clinical global impressions, and quality of life. The trial, at five locations in the U.S., Germany, Spain, and the United Kingdom, is expected to finish in March, 2025. At that time, the company plans to begin a new, pivotal Phase 3 study in 60 children and adults, who will be treated for 12 weeks with 2-4 g daily against a primary outcome of the SARA. That trial is planned to run to the end of 2027.

Previously, an independent trial of children with ataxia telangiectasia found no benefit of 1-4 grams NALL per day on ataxia symptoms, although constipation and nausea improved (Beyraghi-Tousi et al., 2024).

NALL has multiple Orphan Drug Designations for rare inherited lysosomal storage disorders, spinocerebellar ataxia, ataxia telangiectasia, multiple systems atrophy, and others. Investigators in Switzerland and Germany are awaiting approval to conduct clinical trials in PD and AD (Jan 2025 news).

For details on NALL trials, see clinicaltrials.gov.

Last Updated: 23 Jan 2025

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References

News Citations

  1. Microglia Drive Neurodegeneration in Niemann-Pick Type C

Paper Citations

  1. Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. PubMed.
  2. Tifft CJ. N-Acetyl-l-Leucine and Neurodegenerative Disease. N Engl J Med. 2024 Feb 1;390(5):467-470. PubMed.
  3. Dinkel L, Hummel S, Zenatti V, Malara M, Tillmann Y, Colombo A, Monasor LS, Suh JH, Logan T, Roth S, Paeger L, Hoffelner P, Bludau O, Schmidt A, Müller SA, Schifferer M, Nuscher B, Njavro JR, Prestel M, Bartos LM, Wind-Mark K, Slemann L, Hoermann L, Kunte ST, Gnörich J, Lindner S, Simons M, Herms J, Paquet D, Lichtenthaler SF, Bartenstein P, Franzmeier N, Liesz A, Grosche A, Bremova-Ertl T, Catarino C, Beblo S, Bergner C, Schneider SA, Strupp M, Di Paolo G, Brendel M, Tahirovic S. Myeloid cell-specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease. Sci Transl Med. 2024 Dec 4;16(776):eadl4616. Epub 2024 Dec 4 PubMed.
  4. Bremova-Ertl T, Claassen J, Foltan T, Gascon-Bayarri J, Gissen P, Hahn A, Hassan A, Hennig A, Jones SA, Kolnikova M, Martakis K, Raethjen J, Ramaswami U, Sharma R, Schneider SA. Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C. J Neurol. 2022 Mar;269(3):1651-1662. Epub 2021 Aug 13 PubMed.
  5. Martakis K, Claassen J, Gascon-Bayari J, Goldschagg N, Hahn A, Hassan A, Hennig A, Jones S, Kay R, Lau H, Perlman S, Sharma R, Schneider S, Bremova-Ertl T. Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses. Neurology. 2023 Mar 7;100(10):e1072-e1083. Epub 2022 Dec 1 PubMed.
  6. Feil K, Adrion C, Boesch S, Doss S, Giordano I, Hengel H, Jacobi H, Klockgether T, Klopstock T, Nachbauer W, Schöls L, Steiner KM, Stendel C, Timmann D, Naumann I, Mansmann U, Strupp M, ALCAT Study Group. Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial. JAMA Netw Open. 2021 Dec 1;4(12):e2135841. PubMed.
  7. Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, Davis W, Evans W, Flint S, Galione A, Granzer U, Greenfield J, Karl R, Kay R, Lewi D, Mathieson T, Meyer T, Pangonis D, Platt FM, Tsang L, Verburg C, Factor M, Strupp M. A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Trials. 2021 Jan 22;22(1):84. PubMed.
  8. Beyraghi-Tousi M, Sahebkar A, Houra M, Sarvghadi P, Jamialahmadi T, Bagheri R, Tavallaie S, Gumpricht E, Saberi-Karimian M. Efficacy and safety of N-acetyl-L-leucine in patients with ataxia telangiectasia: A randomized, double-blind, placebo-controlled, crossover clinical trial. Eur J Paediatr Neurol. 2024 May;50:57-63. Epub 2024 Apr 22 PubMed.
  9. Churchill GC, Strupp M, Factor C, Bremova-Ertl T, Factor M, Patterson MC, Platt FM, Galione A. Acetylation turns leucine into a drug by membrane transporter switching. Sci Rep. 2021 Aug 4;11(1):15812. PubMed.
  10. Vanderkam P, Blanchard C, Naudet F, Pouchain D, Vaillant Roussel H, Perault-Pochat MC, Jaafari N, Boussageon R. Efficacy of acetylleucine in vertigo and dizziness: a systematic review of randomised controlled trials. Eur J Clin Pharmacol. 2019 May;75(5):603-607. Epub 2019 Jan 6 PubMed.
  11. Bremova T, Malinová V, Amraoui Y, Mengel E, Reinke J, Kolníková M, Strupp M. Acetyl-dl-leucine in Niemann-Pick type C: A case series. Neurology. 2015 Oct 20;85(16):1368-75. Epub 2015 Sep 23 PubMed.
  12. Strupp M, Teufel J, Habs M, Feuerecker R, Muth C, van de Warrenburg BP, Klopstock T, Feil K. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J Neurol. 2013 Oct;260(10):2556-61. Epub 2013 Jul 9 PubMed.
  13. Pelz JO, Fricke C, Saur D, Classen J. Failure to confirm benefit of acetyl-DL-leucine in degenerative cerebellar ataxia: a case series. J Neurol. 2015 May;262(5):1373-5. Epub 2015 Apr 11 PubMed.
  14. Scigliuolo GM, Sagnelli A, Brenna G, Pareyson D, Salsano E. Lack of benefit of acetyl-dl-leucine in patients with multiple system atrophy of the cerebellar type. J Neurol Sci. 2017 Aug 15;379:12-13. Epub 2017 May 11 PubMed.
  15. Platt F, Strupp M. An anecdotal report by an Oxford basic neuroscientist: effects of acetyl-DL-leucine on cognitive function and mobility in the elderly. J Neurol. 2016 Jun;263(6):1239-40. Epub 2016 Apr 28 PubMed.
  16. Kolb SA. Beneficial effect of N-acetyl-DL-leucine on cognitive function, emotional well-being and QoL in a mentally healthy elderly person. J Neurol. 2023 Apr;270(4):2317-2319. Epub 2022 Dec 17 PubMed.
  17. Oertel WH, Janzen A, Henrich MT, Geibl FF, Sittig E, Meles SK, Carli G, Leenders K, Booij J, Surmeier DJ, Timmermann L, Strupp M. Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern-case reports. Nat Commun. 2024 Sep 2;15(1):7619. PubMed.
  18. Balint B, Bhatia KP. Small Molecule, Big Hope-Can Acetyl-DL-Leucine Reverse Parkinson's Disease?. Mov Disord Clin Pract. 2024 Dec 27; Epub 2024 Dec 27 PubMed.
  19. Fields T, Schoser B, Oertel W, Strupp M. Acetyl-DL-leucine improves restless legs syndrome: a case report. J Neurol. 2021 Jul;268(7):2595-2596. Epub 2021 May 30 PubMed.
  20. Kaya E, Smith DA, Smith C, Morris L, Bremova-Ertl T, Cortina-Borja M, Fineran P, Morten KJ, Poulton J, Boland B, Spencer J, Strupp M, Platt FM. Acetyl-leucine slows disease progression in lysosomal storage disorders. Brain Commun. 2021;3(1):fcaa148. Epub 2020 Dec 20 PubMed.
  21. Kaya E, Smith DA, Smith C, Boland B, Strupp M, Platt FM. Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease. J Clin Med. 2020 Apr 8;9(4) PubMed.
  22. Xu Z, Lian C, Pan L, Lai W, Zhang F, Peng L, Zhou S, Zhao G, Yang X, Zhang G, Tan Z, Wang Y. N-acetyl-L-leucine protects MPTP-treated Parkinson's disease mouse models by suppressing Desulfobacterota via the gut-brain axis. Brain Res Bull. 2023 Oct 1;202:110729. Epub 2023 Aug 12 PubMed.
  23. Hegdekar N, Lipinski MM, Sarkar C. N-Acetyl-L-leucine improves functional recovery and attenuates cortical cell death and neuroinflammation after traumatic brain injury in mice. Sci Rep. 2021 Apr 29;11(1):9249. PubMed.

External Citations

  1. ALCAT
  2. clinicaltrials.gov

Further Reading

No Available Further Reading