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Patients with Niemann-Pick disease type C who received N-acetyl-L-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, showed reduced neurologic signs and symptoms after 3 months, a phase III found.

After 12 weeks of treatment, the mean change from baseline in scores on the Scale for the Assessment and Rating of Ataxia (SARA) was -1.97 points after receiving NALL and -0.60 points after receiving placebo (least-squares mean difference -1.28 points, 95% CI -1.91 to -0.65, P<0.001), reported Tatiana Bremova-Ertl, PhD, of the University Hospital Bern in Switzerland, and colleagues in the .

SARA scores range from 0-40, with lower scores indicating better neurologic status. At baseline, SARA scores were 15.88 before receiving the first NALL dose and 15.68 before receiving placebo.

"In this trial, patients with Niemann-Pick type C had a significant reduction in neurologic signs and symptoms during the period they were receiving NALL, as compared with the period they were receiving placebo," Bremova-Ertl and co-authors wrote.

"The deterioration in neurologic status when the patients were receiving placebo, after having crossed over from NALL treatment, suggests that treatment with NALL has an effect on symptoms," they added. "However, such deterioration does not establish whether there was a fundamental biologic effect on the disease."

Niemann-Pick disease type C is a rare, progressive, . Many cases are detected during childhood.

Neurologic symptoms often are treated with miglustat (Zavesca), a substrate reduction therapy currently not approved in the U.S. for Niemann-Pick disease type C. In animal models, treatment with NALL showed a potential neuroprotective effect, delaying functional decline and prolonging survival. A found that in humans, 6 weeks of treatment with NALL led to reduced symptoms and improved functioning and quality of life.

In the phase III trial, 85% of participants had been treated with miglustat and continued it throughout the trial.

"If neuroinflammation is attenuated by treatment with NALL, clinical improvement may be seen in many and perhaps all neurodegenerative lysosomal storage disorders," observed Cynthia Tifft, MD, PhD, of the National Human Genome Research Institute in Bethesda, Maryland, in an . "As shown in the current study, synergy with other therapies for lysosomal storage disorders would be anticipated."

The pivotal trial included two consecutive 12-week treatment periods. Participants were randomly assigned to one of the two periods: one began with NALL for 84-91 days and ended with a placebo for the same amount of time, and the other began with placebo and ended with NALL. Patients weighing 35 kg or more received 4 g per day orally of NALL or matching placebo. Patients ages 4-12 years who weighed less received weight-based doses from 2 g to 4 g per day.

Participants were ages 4 years and older and came from 13 trial sites in Europe, the U.K., and the U.S. A total of 60 participants were enrolled in the study, with half assigned to each sequence. Less than half of the study population (45%) were female and 90% were white; 62% were 18 years or older.

The primary outcome was based on the SARA scale which assessed gait, stance, sitting, and speech disturbance, as well as the finger-chase test, the nose-to-finger test, the fast-alternating-hand movements test, and the heel-along-shin slide test. A modified version (mSARA) without sitting and stance domains was used for U.S. patients, with scores ranging from 0-30. Scores were taken at the end of the baseline period, the crossover period after the first 12 weeks, and at the end of the second 12 weeks.

Secondary outcomes generally supported the findings in the primary analysis. The incidence of adverse events was similar with NALL and placebo and no adverse events led to early discontinuation. No treatment-related serious adverse events occurred.

The study had several limitations including its short treatment period and its focus on symptomatic endpoints, which meant people younger than 4 years, asymptomatic participants, and those unable to complete functional assessments were excluded. In addition, SARA has been validated for use in patients with variants of spinocerebellar ataxia but not in people with Niemann-Pick disease type C, the researchers acknowledged.

Data from the trial's ongoing extension phase may provide more information about NALL's potential effects on disease progression and adverse events, they added.

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