Well, the development was just accidental. So in 2012, I got the idea that this small molecule acetyl-L-leucine, which had been shown in animal studies to be effective on acute vertigo, acts via the cerebellum. And therefore I thought, why not use a molecule which acts via the cerebellum in cerebellar diseases? So then we did a first case series in patients with different types of ataxias, and we saw a clinically meaningful benefit...
Well, the development was just accidental. So in 2012, I got the idea that this small molecule acetyl-L-leucine, which had been shown in animal studies to be effective on acute vertigo, acts via the cerebellum. And therefore I thought, why not use a molecule which acts via the cerebellum in cerebellar diseases? So then we did a first case series in patients with different types of ataxias, and we saw a clinically meaningful benefit. That was the beginning of the story. Later on, we switched to other diseases with the leading symptom of ataxia, and we started with lysosomal diseases, namely so-called Niemann-Pick type C and gangliosidosis type 2, Tay-Sachs disease. First we did a Phase II study and later on a Phase III study. The latter on NPC was published in the New England Journal of Medicine in 2024, and based on these studies we got approval by the FDA and the EMA for the treatment of Niemann-Pick type C.
Further on, we broadened our spectrum of diseases which can be potentially treated by this small molecule, and this was also based on preclinical animal studies at the Department of Pharmacology and Biochemistry in Oxford by Frances Platt and Antony Galione. They used the appropriate animal models of NPC and GM2. From these studies we learned that one basic mechanism of this molecule is to improve glucose metabolism. That means per glucose molecule, more ATP is produced, which brings cells into a better state. Other mechanisms of action are normalization of excitability of neurons and also primary improvement of lysosomal function, namely via the so-called transcription factor TFEB, which was shown by Antony Galione. So in other words, this molecule has multiple mechanisms of action. Later on we performed a phase three trial in ataxia-telangiectasia. This is a disease which is based on an impaired function of a DNA repair gene. At first I was a little bit skeptical. Would we see a benefit in a disease with a totally different mechanism? Luckily, the clinical effect was even stronger than in Niemann-Pick type C. The paper was published in The Lancet Neurology at the end of June. Of course, we will try to get approval by the FDA and later on the EMA for this small molecule also in ataxia-telangiectasia.
Another thing, of course, in any treatment is safety, and it has been shown that this small molecule, a modified amino acid, has an excellent safety profile. This was expected. What is so special about this molecule and the acetyl group? Well, due to the acetyl group, leucine is transported via so-called monocarboxylate transporters with a very high capacity. This was also measured by some studies in animals. In other words, if you take leucine, it does not show up in the brain in relevant concentrations. Due to the acetyl group, it appears in very high concentrations inside the cells. So this is very special about this small molecule. Leucine alone does not work. The acetyl group is important. Another detail is that we have an L form and a D form. Originally, the racemate with the D and the L form was used. These days we use the L form only because the L form is the bioactive component. This is also due to the fact that we do have transporters for the L form and not for the D form. L amino acids are physiological. D amino acids are counterproductive, they even inhibit the transporter.
What are now the perspectives? The next trial, and the trial protocol is ready, will be a trial on so-called CACNA1A neurodevelopmental disease. This is a new ICD-10 term since October last year, and it covers a lot of different phenotypes. Most familiar to neurologists is episodic ataxia type 2 and familial hemiplegic migraine, but there is also a neurodevelopmental disease which leads to severe persistent dizziness, imbalance, and ataxia. This is going to be the next target, the next clinical trial, and we expect to recruit the first patients in Q3-Q4 2026. We have also demonstrated that this molecule has a neuroprotective effect, and the paper was published in Neurology, showing in the extension phase of the Phase III trial that we can delay the progression of the disease in patients with Niemann-Pick type C. In other words, after 24 months of treatment, the patients with NPC are in a better state than before beginning the treatment. The difference between the treatment group and a natural history group was 120%. So to make that clear, the molecule has a symptomatic effect which you see after about 6 to 12 weeks, and in addition, on top of that, it has a neuroprotective effect which delays the progression of the disease. This brings me to another paper which we published in Nature Communications. We had patients with so-called prodromal Parkinson’s disease. They had a so-called REM sleep behavior disorder. If you suffer from REM sleep behavior disorder, the risk that you are going to develop manifest Parkinson’s disease with motor symptoms within the next 10 years is about 85%. We had access to a cohort of these individuals with REM sleep behavior disorder, and we also performed a DaTscan to measure the function of dopaminergic transmission. After 24 months of treatment with acetyl-L-leucine, there was an improvement of dopamine transporter function, which is very exceptional.
So this molecule has a symptomatic effect and a disease-modifying effect, which we demonstrated in NPC, which we demonstrated in GM2, but also in prodromal Parkinson’s disease. This molecule, beginning as a small baby, has now grown up, is in its late puberty, and we expect many more positive findings in the near future.
This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.
