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Modified Amino Acid Improves Cerebellar Ataxia in Niemann-Pick Type C, A Case Series Shows

ARTICLE IN BRIEF

A new study reported that in 12 patients with Niemann-Pick disease type C, a modified amino acid produced improvements in cerebellar ataxia.

WASHINGTON — A modified amino acid can quickly and dramatically improve cerebellar ataxia in some patients with Niemann-Pick disease type C, according to the results of a case series that were presented here at the 2015 AAN Annual Meeting in April.

In an observational study of 12 patients, the researchers found that the amino acid, acetyl-DL-leucine, produced significant improvements in median scores on the Scale for the Assessment and Rating of Ataxia (SARA; p<0.005), the Spinocerebellar Ataxia Functional Index (SCAFI; p<0.05), and the modified Disability Rating Scale (mDRS; p<0.005) — all of which measure functional disability associated with the condition.

Scores on these scales rose to previous levels once the drug treatment ended after a month, said Michael Strupp, MD, a professor of neurology at the University of Munich, who collaborated with Tatiana Bremova, MD, on the study.

An international group of researchers will be enrolling the first patients in a randomized controlled trial of the drug this summer, Dr. Strupp said.

A rare disorder, Niemann-Pick type C (NPC) occurs mainly in children and is associated with an inability to process cholesterol and other lipids within the cell, causing lipids to build up in the liver, spleen, and brain. NPC also involves a deficiency in the enzyme acid sphingomyelinase, which can lead to cell death when the sphingomyelin lipid isn't metabolized properly.

Most patients with NPC die by age 40, and sometimes as early as age 10.

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DR. MICHAEL STRUPP: “I think this is quite promising. These effects are often acute. If you stop the drug, you see the deterioration within a few days. So from my point of view, its quite convincing. But we have to be careful: The findings of our observational studies have to be evaluated in a randomized controlled trial, which starts this summer.”

NPC is diagnosed primarily by a vertical supranuclear palsy, primarily affecting downward then upward saccades, and, finally, also horizontal saccades.

“As neurologists, we're in a good position to diagnose Niemann-Pick type C when we properly examine eye movements,” Dr. Strupp said. Diagnosis is important because once diagnosed, the patients can be treated with miglustat, the only therapy that has been approved for the disease, he said.

Although exercise can help, there are no effective pharmacological treatments for managing symptoms, Dr. Strupp said. A consensus paper published last year in Cerebellum, for which Dr. Strupp was a contributing author, noted that there were no effective treatments, though the authors recommended aminopyridines for episodic ataxia type 2 and cerebellar downbeat nystagmus.

Acetyl-DL-leucine is inexpensive and has been used in France since the 1950s to treat vertigo and dizziness, Dr. Strupp noted.

In a paper published in 2013 in the Journal of Neurology, Dr. Strupp's group reported that the drug was effective for cerebellar ataxia in two case series. In one, significant differences were seen after one week in SARA scores (p<0.0001) and SCAFI scores (p=0.0176).

STUDY METHODOLOGY

In the current study, patients were treated with 3g per day of acetyl-DL-leucine for one week, then 5g per day for three weeks.

Patients had a median SARA score of 10.8 at baseline. The score fell to 7.0 while on the medication. After a month, the medication was stopped, and the SARA scores rose to 10.5. (SARA scores range from 0, indicating no ataxia, to 40, indicating the most severe ataxia.)

On the SCAFI, in which researchers also time how long it takes for patients to put nine pegs into holes, it took more than 100 seconds at a baseline using the non-dominant hand and about 70 seconds during treatment. The test took well over 100 seconds again once treatment was ended.

Figure

INDIVIDUAL (A) AND VALUE CHANGES (B) on the Scale for the Assessment and Rating of Ataxia (SARA) in 12 patients with Niemann-Pick type C. Measurements were performed at baseline, after one month on medication with acetyl-DL-leucine (5g a day), and after one month of wash-out. SARA significantly changed from the baseline (median [±SD, IQR] of 10.8 [11.2, 8-24.6] to 7.0 [10.7, 5.6-19.6] [difference 3.8 points] on medication and 10.5 [11.5, 7.1-23.9] after wash-out [difference 3.5 points]; p = 0.000412; post hoc p = 0.003 between baseline and on-medication, and on-medication and wash-out p = 0.005). The length of the boxes (B) indicates the interquartile space (P25-P75); the horizontal line into the box represents the median (P50), and the whiskers indicate the adjacent values. The circle indicates the outlier.

“I think this is quite promising,” Dr. Strupp said. “These effects are often acute. If you stop the drug, you see the deterioration within a few days. So from my point of view, it's quite convincing. But we have to be careful: The findings of our observational studies have to be evaluated in a randomized controlled trial, which starts this summer.”

At the Annual Meeting, Dr. Strupp showed videos taken at baseline and mid-treatment, which demonstrated improvements in dysarthrophonia and hand-arm coordination while doing the nine-hole peg test.

Significant improvements were also seen on the mDRS during the treatment period compared with baseline, only to rise back to baseline levels when treatment was stopped. On FDG-PET scans, Dr. Strupp said responders to the drug showed increased metabolic activity in the midbrain and on the pontine level.

A possible mechanism of action is that the drug binds to protein kinase C-epsilon in the cerebellum, meaning it can thereby modulate the activity of many ion channels, although no more is known at this time, Dr. Strupp said. The next step in evaluating the mechanism is electrophysiological evaluation, Dr. Strupp said.

EXPERT COMMENTARY

Daniel Ory, MD, director of the Washington University Metabolomics Facility in Seattle, who has studied Niemann-Pick type C, said many questions remain to be answered before the drug can be properly assessed.

“The results presented in the abstract are intriguing, but it is hard to fully assess the work because there are a lot of unknowns,” he said. “It is unclear to me, for example, what the hypothesis is, and the rationale for pursuing this therapy. I am unaware whether this therapy has been tested in preclinical models.”

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DR. DANIEL ORY: “The results presented in the abstract are intriguing, but it is hard to fully assess the work because there are a lot of unknowns. It is unclear to me, for example, what the hypothesis is, and the rationale for pursuing this therapy. I am unaware whether this therapy has been tested in preclinical models.”

Niemann-Pick disease has multiple animal models in which candidate drugs have been tested and proven “instrumental in predicting clinical treatment,” he noted.

Because the data so far has been uncontrolled, “a rigorous placebo-controlled trial is needed in order to draw valid conclusions,” Dr. Ory said.

“Without understanding the mechanism of action and the effect of the drug in animal models, it is nearly impossible to say whether this compound has the potential to provide additional benefit beyond miglustat or cyclodextrin monotherapy,” Dr. Ory said. “In the case of miglustat and cyclodextrin, for example, the available data would suggest that miglustat may not provide any benefit on top of cyclodextrin.”

LINK UP FOR MORE INFORMATION:

•. AAN Annual Meeting Abstract: Acetyl-DL-leucine for treatment Niemann-Pick type C: A case series: http://bit.ly/NiemanPick
    •. Ilg W, Bastian AJ, Boesch S, et al. Consensus paper: management of degenerative cerebellar disorders http://link.springer.com/article/10.1007%2Fs12311-013-0531-6. Cerebellum 20142;13(2):248–268.
    •. Strupp M, Teufel J, Habs M, et al. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: A case series http://link.springer.com/article/10.1007%2Fs00415-013-7016-x. J Neurol 2013;260(10):2556–2561.