FDA greenlights first treatment for Niemann-Pick Disease Type C

The Food and Drug Administration (FDA) has approved Miplyffa (arimoclomol; Zevra Therapeutics, Celebration, FL) for use in combination with miglustat for the treatment of neurologic manifestations of Niemann-Pick disease type C (NPC) for adult and pediatric patients aged ≥2 years. Miplyffa is a capsule that is administered orally 3 times daily, and it is the first FDA-approved medication for NPC. In conjunction with the approval, Zevra Therapeutics announced that it has received a rare pediatric disease priority review voucher, enabling the company to receive a priority review for an additional product.

The FDA approval is based on the totality of data from Miplyffa’s New Drug Application, including positive data from a randomized, double-blind, placebo-controlled trial with a population of 50 participants with NPC who were aged 2 to 19 years. Participants were randomly assigned 2:1 to receive either Miplyffa at a weight-assigned dose or placebo 3 times daily. Thirty-nine (78%) participants received miglustat as a background treatment during the 12-month trial, and in these individuals, efficacy of Miplyffa was measured according to restored 4-domain NPC Clinical Severity Scale (R4DNPCCSS).

The 76% of participants in the treatment group who received Miplyffa in combination with miglustat experienced a 0.2-point decrease in R4DNPCCSS score from baseline through 12 months.

The 81% of participants in the placebo group who received miglustat alone experienced a 1.9-point decrease in R4DNPCCSS score from baseline through 12 months.

The trial results demonstrate that, compared with placebo, Miplyffa is associated with the halting of disease progression. Additionally, confirmatory evidence, such as data from a 48-month open label extension (OLE) study, suggest that people who receive Miplyffa experience improved disease outcomes compared with a natural history cohort. The most common adverse reactions associated with treatment are upper respiratory tract infection, diarrhea, and decreased weight. Miplyffa’s prescribing information includes precautions for hypersensitivity reactions, embryofetal toxicity, and increased creatinine without affecting glomecular function.

NPC is a rare lysosomal storage disease with a range of clinical manifestations, often presenting in children aged <10 years. The condition is associated with progressive neurologic disease, with symptoms including developmental delays, cognitive decline, tremor, epilepsy, and cerebellar ataxia, among others, with a terminal stage characterized by severe dementia, weakness, and loss of volitional movement. Miplyffa functions by increasing activation of transcription factor EB (TFEB) and transcription factor E3 (TFE3), upregulating the coordinated lysosomal expression and regulation (CLEAR) genes.

https://practicalneurology.com/news/fda-greenlights-first-treatment-for-niemann-pick-disease-type-c

Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Grønborg S, Harmatz P, Héron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsøe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, Í Dali C. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021 Nov;44(6):1463-1480. doi: 10.1002/jimd.12428. Epub 2021 Sep 7. PMID: 34418116; PMCID: PMC9293014.

Abstract

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Sitarska D, Tylki-Szymańska A, Ługowska A. Treatment trials in Niemann-Pick type C disease. Metab Brain Dis. 2021 Dec;36(8):2215-2221. doi: 10.1007/s11011-021-00842-0. Epub 2021 Oct 1. PMID: 34596813; PMCID: PMC8580890.

Abstract

Niemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood-brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.

From the above article:

For the development of an effective treatment, it is essential to know the molecular and biochemical bases of the disease. The pathomechanism of NPC is not yet fully understood. In human cells the cholesterol esters (CE) reach the interior of the lysosome by means of LDL. The lysosomal acid lipase cleaves free fatty acids (FFA) from the CE. FFAs cross the lysosome membrane into the cytoplasm. Free cholesterol (CH) is captured by the NPC2 protein and transported to the NPC1 protein localized in the lysosomal membrane. The NPC1 protein receives CH from NPC2 and transports it across the lysosomal membrane into the cytoplasm, where CH can then be reintroduced into the metabolic pathway. When NPC1 or NPC2 are not produced or the produced proteins are abnormal, it leads to lipid accumulation inside the lysosomes and the development of Niemann-Pick type C disease...

In summary, the treatment efforts applied in NPC were focused on i) decreasing the quantity of intra lysosomal free cholesterol, ii) reducing the synthesis of glucosylceramide by inhibiting the activity of its synthase, iii) restriction of inflammatory processes and immune system response, iv) strengthening the efflux of free cholesterol from the lysosomal compartment into cytosol, v) influencing the expression of genes needed to induce cell differentiation by inhibiting histone deacetylases (HDAC), vi) action of pharmacological chaperones to stimulate cellular protein repair pathway by activation of molecular chaperones such as heat shock proteins, vii) the development of gene therapy.