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Treatment with the investigative agent, arimoclomol, appeared to slow the progression of Niemann-Pick Type C, a degenerative disease, researchers reported at the Annual Meeting of the Child Neurology Society.

“We were able to show that at 12 months there was a statistically significant difference in disease progression between the placebo group and the intervention group, favoring arimoclomol,” said Marc C. Patterson, MD, FAAN, FRACP, professor of neurology, pediatrics and genetic medicine at the Mayo Clinic Children’s Center in Rochester, MN.

“This difference was maintained in the 24-month open-label extension study that followed,” said Dr. Patterson. Neurology today At the Meetings. He noted that while treatment with arimoclomol slowed the disease trajectory, it did not cure the disorder.

Dr. Patterson and his colleagues enrolled 50 children diagnosed with Niemann-Pick type C in the international multi-center study and randomly assigned them to receive arimoclomol or a placebo. Disease progression was monitored using the 5-domain Niemann-Pick Type C Clinical Severity Scale, which was validated in a cohort of these patients, he said.

Finally, 34 children received arimoclomol and 16 children received a placebo. In the extension trial, 26 children in the arimoclomol group and 15 children in the placebo group received arimoclomol. All participants received routine clinical care in addition to their investigative therapy.

At two years during the open-label extension, scores on the Niemann-Pick Type C Clinical Severity Scale – the primary endpoint – increased by 3.5 points, whereas the natural history estimated disease would have an expected increase of 5.19 points.

Dr Patterson said that once the patients who had been in the placebo arm of the trial switched to arimoclomol, their disease progression flattened as well.

“The United States Food and Drug Administration had requested additional subgroup analyzes prior to the study,” he said. “This included an analysis of patients 4 years and older and those taking miglustat. Were larger in these subgroups than in the study group as a whole.”

Treatment with arimoclomol was well tolerated, ”added Dr. Patterson. “There were no unexpected serious side effects during the study. In fact, the frequency of serious side effects was considerably higher in the control group than in the intervention group. It should be noted that the study was successfully executed despite the challenges of the COVID-19 pandemic. “

Dr Patterson explained that Niemann-Pick disease, type C, is an ultra-rare autosomal recessive lysosomal disorder caused by mutations in one of the two genes. About 95% of cases are the result of mutations in the NPC1 gene; the others are associated with mutations in the NPC2 gene.

“The disease can occur at any age, from fetal life – when it causes enlarged liver and spleen and fluid buildup in the abdomen – to the neonatal period, when it has the same symptoms. plus jaundice, with a poor survival prognosis, in childhood and even adulthood, when it presents as a progressive neurodegenerative disease, ”he said.

“Features include progressive cerebellar ataxia, dysarthria and dysphagia, and possibly cognitive slowdown and overt dementia,” said Dr. Patterson. “There is a characteristic disorder of eye movements, vertical supranuclear gaze palsy, which is an important clinical clue for diagnosis. Many children and adults suffer from seizures, which are often difficult to control, as well as gelastic cataplexy and sleep disturbances, in particular sleep inversion. “

“On top of that, spasticity and dystonia occur frequently,” Dr. Patterson said. “Without effective intervention, the disease is relentlessly progressive, crippling and shortens the lifespan.”

He noted that arimoclomol enhances the expression of heat shock protein. “Preclinical studies have demonstrated that heat shock proteins co-localize with areas of relative Purkinje cell sparing in the cerebellum in mouse models of this disease; Treating cell and animal models of Niemann-Pick disease type C and other lysosomal diseases with recombinant human heat shock protein has been shown to improve disease, ”said Dr. Patterson.

“Because the administration of recombinant human heat shock proteins to the nervous system is clinically difficult, if not impossible, enhancing the expression of the endogenous heat shock protein with arimoclomol, a small molecule capable of accessing the central nervous system, is an interesting alternative, “he said.

Current treatment for Niemann-Pick type C disease often included miglustat, which inhibits glucosylceramide synthase and reduces the buildup of glycosphingolipids in Niemann-Pick type C disease, Dr. Patterson said. “Miglustat has been approved in over 40 countries since 2009, and this drug is shown to slow disease progression and extend lifespan between five and 10 years,” he said..

Dr Patterson added: “Because miglustat has become the de facto standard of care, most patients in the arimoclomol study were already taking this drug – prescribed in Europe and off-label in the United States – and l ‘current study found that it could be safely combined with arimoclomol, and that patients taking both drugs had the best result. “

“This is an encouraging study,” said Sanjeev V. Kothare, MD, FAAN, division director of pediatric neurology at Cohen Children’s Medical Center and professor of neurology and pediatrics at Hofstra Zucker Medical School in New Hyde Park, NY. , who was not involved. with the study.

“Niemann-Pick type C disease is a relentless degenerative disease, and in this in-depth study, we see that the conditions of these patients seem to be leveling off rather than having a recovery. It’s impressive,” he said. he declares.

Because the study is small, Dr Kothare said more research is needed, “not to prove efficacy, but for safety. We will need a large, multi-center international study to ensure that arimoclomol is safe for long-term use and that no unexpected adverse events occur. “

He also suggested that researchers carefully determine whether some of the seizures seen in patients are misdiagnosis. “Narcolepsy-like phenomena occur with Niemann-Pick type 3 disease,” said Dr Kothare. “These sudden fall events can be a sign of cataplexy, which can be treated with other medications.”

Drs. Patterson and Kothare have not disclosed any connection with the industry.

Log in for more information:

CNS Abstract 69: Patterson C, Mengel E, Da Riol RM, et al. Persistent effect of arimoclomol in patients with Niemann-Pick type C disease: 24-month results of an open-label extension of a pivotal phase 2/3 study.

Patterson MC, Garver WS, Giugliani R, et al. Long-term survival results of patients with Niemann-Pick disease type C receiving miglustat treatment: a large retrospective observational study. I inherit from Metab Dis 2020; 43 (5): 1060-1069.


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