Intrathecal Therapy May Slow Fatal Niemann-Pick Disease

Nancy A. Melville

August 22, 2017

Treatment with intrathecal hydroxypropyl-β-cyclodextrin (HPBCD, VTS-270, Vtesse Inc) may reduce neuronal damage and slow neurologic disease progression in patients with Niemann-Pick type C disease, new research suggests.

The open-label, dose-escalation phase 1/2 study included 14 patients aged 2 to 25 years with nonsevere neurologic manifestations.

The rare condition is characterized by progressive neurodegeneration, typically leading to death within about 15 years from onset, and an inability to transport cholesterol and other lipids in cells, resulting in unwanted accumulation in areas such as the brain.

Niemann-Pick "is a devastating disease with no effective therapies. This is the first time that a drug has been shown to significantly slow clinically relevant disease progression," coinvestigator Forbes D. Porter, MD, Division of Translational Medicine at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, told Medscape Medical News.

While miglustat is approved in Europe for type C1 Niemann-Pick disease, its efficacy is limited and appears to be most effective in older patients with less aggressive disease, Dr Porter said. There are currently no approved treatments in the United States for Niemann-Pick disease.

The findings were published online August 10 in The Lancet.

Correction of Biochemical Defects?

The study participants were assigned to groups of three to receive lumbar intrathecal doses of HPBCD at 50 to 1200 mg per month. Three additional patients were treated every 2 weeks for 18 months. Doses were escalated based on tolerance or safety measures.

Two patients had treatment interrupted for one dose  because of ototoxicity in the first 12 months; from 12 to 18 months, one patient had a treatment interruption at 17 months due to hepatocellular carcinoma; one had dose interruption for two doses due to caregiver hardship; and one patient had treatment interrupted for one dose for mastoiditis.

Results showed significant increases in postdrug plasma 24 (S)-HC area under the curve (AUC) values, a biomarker indicating neuronal cholesterol homeostasis, compared with postsaline plasma levels after 900-mg (P = .006) and 1200-mg (P = .003) doses of the study drug.

Three patients treated with 600 or 900 mg of HPBCD showed two-fold increases in cerebral spinal fluid 24 (S)-HC concentrations (P = .003). No serious drug-related adverse events were reported.

Dr Porter noted that the improvements suggest a significant effect of the drug in storage of cholesterol in central nervous system neurons.

"This tells us that the drug is getting to the neurons and correcting the biochemical defect," he said.  

Using NPC Neurological Severity Scores, disease progression increased at a rate of 1.22 per year in the treatment group vs 2.92 in a comparison group of 21 patients.

Observed decreases in progression were strongest in the areas of cognition (P = .004) and speech (P = .04) and, to a lesser degree, ambulation (P = .06).

Hearing Loss

All patients experienced mid- to high-frequency hearing loss, a known and expected adverse event observed in preclinical studies. Such hearing impairments are common with Niemann-Pick disease, and seven of the participants had functional deficits in hearing at baseline. The authors note that the symptoms were managed with hearing aids.

"When managed with hearing aids, this did not have an appreciable effect on daily communication," they write.

Doses up to 1200 mg were generally well tolerated; however, transient postdose ataxia and fatigue could be dose-limiting side effects.

Dr Porter said future studies will need to focus on the effects of hearing loss, but the benefits of the treatment may outweigh the risk.

"Hearing loss was the biggest issue with this drug. Hearing loss is part of Niemann-Pick C1, but VTS-270 (HPBCD) causes hearing loss," he said.

"To date we can address this with hearing aids, and one has to balance this problem with the fact that Niemann-Pick type 1 is a lethal neurodegenerative disease."

Tie to Alzheimer's

The study gives rise to speculation on the mechanisms behind the potential HPBCD benefits in the treatment of Niemann-Pick disease, authors of an accompanying editorial note.

"The findings from [the] study raise many questions," write Robert P. Erickson, MD, University of Arizona School of Medicine, in Tucson, and Maria Teresa Fiorenza, MD, Sapienza University, Rome, Italy.

"First, is the benefit only from de-sequestering cholesterol in the cell, allowing more normal cholesterol metabolism, or removal of excess cholesterol? Second, are there particular cells for which the therapy is most important?"

They note that Niemann-Pick disease has been associated with Alzheimer's disease because of the key involvement of cholesterol metabolism and that a study involving mice did show some response to HPBCD.

"Both diseases share defects of autophagy and activation of microglia," the editorialists note.

"Correction of cholesterol storage in these cells may attenuate the microglial activation, which seems to be a major initiator of autophagic and other destructive pathways causing neurodegeneration in Niemann-Pick disease."

Another important concern with HPBCD is the drug's effect on the lungs. Pulmonary complications are a common contributor to mortality in patients with Niemann-Pick disease, particularly type 2. A further concern is whether HPBCD, laden with excess cholesterol, could add to cholesterol levels as it makes its way through the pulmonary capillary bed.

"This could be important as, in mouse models, systemic delivery of HPBCD did not decrease cholesterol storage in the lung, and might have made it worse," the authors write.

VTS-270 was previously granted breakthrough therapy designation from the US Food and Drug Administration. A multinational phase 3 trial of VTS270 is underway, with 54 patients enrolled at 21 sites.
Dr Erickson said the study should help answer some of the key questions regarding HPBCD for Niemann-Pick disease.

"I will be most interested in seeing if there is confirmation of the delay in progression of disease in a much larger cohort in a phase 3 trial," he told Medscape Medical News.

The study received funding from the National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson. Dr Porter is a member of the Vtesse Clinical NPC Advisory Committee and holds several patents relating to Niemann-Pick disease. The disclosures of the study's other authors can be viewed online. Dr Erickson and Dr Fiorenza have disclosed no relevant financial relationships.

Lancet. Published online August 10, 2017. Abstract, Editorial

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