CLINICAL STUDIES

Title
Author(s)
Summary
Brueggemann, A., Bicvic, A., Goeldlin, M., Kalla, R., Kerkeni, H., Mantokoudis, G., Abegg, M., Kolnikova, M., Mohaupt, M., Bremova-Ertl, T.

N-acetyl-leucine improved ataxia and ocular stability in 6 patients with Ataxia-Telangiectasia after 1-month treatment.

MARTAKIS, K., CLAASSEN, J., GASCON BAYARRI, J., GOLDSCHAGG,N., HAHN, A., HASSAN, A., HENNIG, A., JONES, S. , LAU, H., PERLMAN, S., SHARMA, R., SCHNEIDER, S. A., BREMOVA-ERTL. T

The IB1001-202 clinical trial with N-acetyl-L-leucine (IB1001) met its primary and secondary endpoints and demonstrated a statistically significant and clear clinically meaningful improvement in symptoms, functioning, and quality of life for pediatric and adult patients with GM2 Gangliosidosis (Tay-Sachs and Sandhoff). IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk-benefit profile for the treatment of GM2 Gangliosidosis. medRxiv

Bremova, T., Claassen, J., Foltan, T., Gascon Bayarri, J., Gissen, P., Hahn, A., Hassan, A., Hennig, A., Jones, S. , Kolnikova, M., Martakis, K., Ramaswami, U, Sharma, R., Schneider, S. A.

The IB1001-201 clinical trial with N-acetyl-L-leucine (IB1001) met its primary and secondary endpoints and demonstrated a statistically significant and clear clinically meaningful improvement in symptoms, functioning, and quality of life for pediatric and adult patients with NPC. IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk-benefit profile for the treatment of NPC.  Journal of Neurology.

Bremova-Ertl, T., Platt, F., Strupp, M.

Observational case-series: symptomatic and disease-modifying treatment effect with Acetyl-Leucine in a Juvenile Sandhoff patient.

Kaya, E., Smith, D., Smith, C., Morris, L., Bremova-Ertl, T., Cortina-Borja, M., Fineran, P., Morten, K., Poulton, J., Boland, B., Spencer, J., Strupp, M., Platt, F.M.

Acetyl-leucine improved symptoms of ataxia in particular in mice models and patients with the lysosomal storage disorders (LSD), Niemann-Pick disease type C  and GM2 Gangliosidosis. When N-acetyl-DL-leucine and N-acetyl-L-leucine were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas ADL did not. These data are consistent with ALL being the neuroprotective enantiomer. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in LSDs, supporting its therapeutic potential for lysosomal disorders.

Fields, T., Patterson, M., Bremova, T., Belcher, G., Billington, I., Churchill, G. C.., 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, F.M., Tsang, L., Verburg, C., Factor, M., Strupp, M.

The development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease; ‘GM2’), and Ataxia Telangiectasia (A-T).

BREMOVA T, MALINOVÁ V, AMRAOUI Y, MENGEL E, REINKE J, KOLNÍKOVÁ M, STRUPP M.

Demonstrates that Acetyl-DL-Leucine treatment is associated with improvements in ataxia and quality of life in patients with Niemann-Pick Disease Type C. Neurology 85, 1368-1375 (2015).

Strupp, M., Bayer, O., Feil, K., Straube, A.

A paper demonstrating the significant benefit of N-Acetyl-DL-Leucine for the prophylactic treatment of migraine, as well as migraine with aura. Journal of Neurology. 

Fields, T. Schoser, B., Oertel, W., Strupp, M.

Acetyl-leucine significantly improves restless legs syndrome – a case report.

Cortina-Borja,M., te Vruchte,D., Mengel,E., Amraoui,Y., Imrie, J. ,Jones,S., Dali,C., Fineran,P., Kirkegaard,T., Runz,H., Lachmann,R., Bremova-Ertl,T., Strupp,M., Platt,F.

Demonstrates the annual severity increment score (ASIS) has prognostic value in assessing the progression of Niemann-Pick type C, and that long-term treatment with N-Acetyl-DL-leucine is associated with a reduction in ASIS scores. Orphanet Journal of Rare Diseases 13, 1-16 (2018).

NON-CLINICAL STUDIES

Title
Author(s)
Summary
Churchill, C., Strupp, M., Factor, C., Bremova-Ertl, T., Factor, M., Patterson, M., Platt, F.M., Galione, A.

Small changes to molecules can have profound effects on their pharmacological activity as exemplified by the addition of the two‐carbon acetyl group to make drugs more effective by enhancing their pharmacokinetic or pharmacodynamic properties. Here we show that acetylation of leucine switches its uptake into cells from the l‐type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of N‐acetyl‐l‐leucine. MCT1‐mediated uptake of a N‐acetyl‐l‐leucine as a prodrug of leucine bypasses LAT1, the rate‐limiting step in activation of leucine‐mediated signalling and metabolic process inside cells such as mTOR. Nature Scientific Reports.

Churchill, C., Strupp, M., Bremova-Ertl, T., Factor, M., Patterson, M., Platt, F., Galione, A.

N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not.

Kaya, E., Smith, D., Smith, C., Morris, L., Bremova-Ertl, T., Cortina-Borja, M., Fineran, P., Morten, K., Poulton, J., Boland, B., Spencer, J., Strupp, M., Platt, F.M.

Acetyl-leucine improved symptoms of ataxia in particular in mice models and patients with the lysosomal storage disorders (LSD), Niemann-Pick disease type C  and GM2 Gangliosidosis. When N-acetyl-DL-leucine and N-acetyl-L-leucine were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas ADL did not. These data are consistent with ALL being the neuroprotective enantiomer. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in LSDs, supporting its therapeutic potential for lysosomal disorders.

Kaya, E., Smith, D.A, Smith, C., Boland, B. Strupp, M., Platt, F.M.

In Vivo studies with Acetyl-leucine significantly slowed disease progression and improved motor function in the GM2 gangliosidoses Sandhoff mouse model (Hexb-/-), supportive of the symptomatic and disease-modifying potential of treatment for patients with GM2 Gangliosidosis (Tay-Sachs and Sandhoff disease).

te Vrutche, D., Galione, A., Strupp, M., Mann, M.

N-Acetyl-DL-Leucine and N-Acetyl-L-Leucine reduced the relative lysosomal volume in NPC1-/- Chinese Hamster Ovary cells in a dose-dependent manner. N-Acetyl-L-Leucine was most effective at reducing relative lysosomal volumes in fibroblasts derived from NPC patients with severe disease (***p <0.001), followed by N-Acetyl-DL-Leucine (**p <0.01). Treatment with N-Acetyl-D-Leucine did not achieve statistical significance.

Hegdekar, N., Lipinski, M.M, Sarkar, C.

Scientific Reports, 2021. https://rdcu.be/cjEGa

Treatment with N-acetyl-L-leucine is expected to be beneficial in restricting neuronal death and hence improving neurological function after Traumatic Brain Injury (TBI) and is a promising, novel, neuroprotective drug candidate for the treatment of TBI.

Kalla, R., Teufel, J., Feil, K., Strupp, M.

Journal of Neurology 263 (2016).

Feil K, Bremova T, Muth C, Schniepp R, Teufel J, Strupp M.

Cerebellum.15(1):38-42. (2016).