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Arimoclomol Appears to Slow Progression of Niemann-Pick Type C Disease

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

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

“This difference was maintained in the subsequent 24-month open-label extension study," Dr. Patterson told Neurology Today At the Meetings. He noted that while treatment with arimoclomol slowed the disease trajectory, it does not cure the disorder.

Dr. Patterson and colleagues enrolled 50 children who had been diagnosed with Niemann-Pick Type C into the multicenter, international study, and randomly assigned them to receive arimoclomol or placebo.  Disease progression was monitored using the 5-domain Niemann-Pick Type C clinical severity scale, which has been validated in a cohort of these patients, he said.

Eventually 34 children were given arimoclomol, and 16 children were on placebo. In the extension trial, 26 children from the arimoclomol group and 15 children from the placebo group were administered arimoclomol. All participants received routine clinical care in addition to their investigative therapy.

At two years during the open-label extension, Niemann-Pick Type C clinical severity scale scores—the primary endpoint—increased 3.5 points, whereas the estimated natural history of the 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 were switched to arimoclomol, their disease progression also flattened.

“The US Food and Drug Administration had requested additional subgroup analyses in advance of the study," he said. “This included analysis of patients 4 years and older, and those taking miglustat. The positive differences between the placebo and intervention groups were maintained and were larger in magnitude in these subgroups, than in the overall study group."

The treatment with arimoclomol was well tolerated," Dr. Patterson added. “There were no unexpected serious adverse effects in the course of the study.  In fact, the frequency of serious adverse effects was substantially greater in the control group than in the intervention group. Of note, 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 two genes. About 95 percent of cases are the result of mutations in the NPC1 gene; the remainder are associated with mutations in the NPC2 gene.

“The disease can present at any age from fetal life—when it causes enlargement of the liver and spleen and accumulation of fluid in the abdomen—to the newborn period, when it presents with the same symptoms plus jaundice, with a poor prognosis for survival, to childhood and even adult life, when it presents as a progressive neurodegenerative disease," he said.

“The features include progressive cerebellar ataxia, dysarthria and dysphagia, and eventually, cognitive slowing and overt dementia," Dr. Patterson said. “There is a characteristic eye movement disorder, vertical supranuclear gaze palsy, which is an important clinical clue to the diagnosis. Many children and adults experience seizures, which are often difficult to control, as well as gelastic cataplexy, and sleep disturbances, particularly sleep inversion."

“In addition to this, spasticity and dystonia frequently occur," Dr. Patterson said. “Without effective intervention, the disease is relentlessly progressive, disabling, and shortens the life span."

He noted that arimoclomol enhances the expression of heat shock protein. “Pre-clinical studies have demonstrated that heat shock proteins co-localize with areas of relative sparing of Purkinje cells in the cerebellum in mouse models of this disease; treatment of cellular and animal models of Niemann-Pick Type C disease and other lysosomal diseases with recombinant human heat shock protein has been shown to ameliorate the disease," Dr. Patterson said.

“Because delivery of recombinant human heat shock protein to the nervous system clinically is challenging, if not impossible, enhancing the expression of endogenous heat shock protein with arimoclomol, a small molecule that is able to access the central nervous system, is an attractive alternative," he said.

Current treatment of Niemann-Pick Type C disease often included miglustat, which inhibits glucosylceramide synthase, and reduces the accumulation of glycosphingolipids in Niemann-Pick Type C disease, Dr. Patterson said. “Miglustat has been approved in more than 40 countries since 2009, and there is evidence that this drug slows disease progression and extends the life span 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 the current study found that it could be safely combined with arimoclomol, and that patients taking both drugs had the best outcome."

“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 extended study we see that these patients' conditions appear to plateau rather than have an upswing. This is impressive," he said.

Because the study is small, Dr. Kothare said that further research is necessary, “not to prove efficacy, but for safety. We will need a large multicenter, international study to make sure that arimoclomol is safe for long-term use and that no unexpected adverse events arise."

He also suggested that researchers carefully determine if some of the seizures observed among the patients are not misdiagnoses. “Narcolepsy-like phenomena occur with Niemann-Pick Type 3 disease," Dr. Kothare said. “These sudden drop events may be evidence of cataplexy, which can be treated with other drugs."

Drs. Patterson and Kothare disclosed no relationships with industry.​

Link Up for More Information:

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

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