Miplyffa (arimoclomol)

The first FDA-approved NPC drug and 1 of 2, with levacetylleucine (Aqneursa) approved 4 days later. Miplyffa is approved only in combination with miglustat, while Aqneursa's label does not require miglustat. The 2 have not been compared head-to-head.

In Niemann-Pick disease type C (NPC), faulty NPC1 or NPC2 proteins leave cholesterol and other fats trapped inside lysosomes, the cell's recycling compartments, which slowly damages nerve cells. The label states that how arimoclomol works in NPC is unknown. Zevra reports that in lab studies it increases the activity of TFEB and TFE3, switches that turn on a network of lysosome genes, and that it reduced trapped cholesterol in lysosomes of cells from people with NPC, though the meaning of these findings for patients is not fully understood. It is taken with miglustat, an older drug that lowers production of certain fats, and the label says there was not enough data to show whether it works without miglustat. In the trial it slowed worsening; it does not reverse damage that has already happened.

Miplyffa has no boxed warning and no contraindications. In the main trial, among patients also taking miglustat, the most common side effects on Miplyffa against placebo were upper respiratory infections (31% against 15%), diarrhea (23% against 23%), weight loss (15% against 0%), and decreased appetite, tremor, hives, headache, lower respiratory infections and seizures (each 12% on Miplyffa against 0% to 8% on placebo). The groups were small (26 and 13 patients), so these figures are rough. Allergic-type reactions, hives and angioedema (swelling under the skin), occurred in 3 patients within the first 2 months, and 2 of them stopped the drug. Based on animal studies it may harm an unborn baby and may reduce fertility. It raises blood creatinine by 10% to 20% without harming the kidneys, because it blocks a transporter that clears creatinine, so kidney function should be checked with tests that do not rely on creatinine^[1].

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Approved for the neurological symptoms of NPC in adults and children 2 years and older, used together with miglustat. Safety and effectiveness under age 2 are not established. The pivotal trial enrolled ages 2 to 19 with a genetically confirmed diagnosis. Dosing is less frequent when eGFR is 15 to under 50 mL/min, and it has not been studied with eGFR under 15.

Source: Miplyffa financial support (AmplifyAssist)

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Approval rested on a 12-month, randomized, double-blind, placebo-controlled Phase 2/3 trial (NCT02612129) of 50 patients aged 2 to 19 with genetically confirmed NPC, randomized 2 to 1 to arimoclomol or placebo 3 times a day. Effectiveness was judged in the 39 patients who were also taking miglustat, using a 4-part NPC severity scale (R4DNPCCSS) that scores walking, speech, swallowing and fine motor skills, where higher scores mean more severe disease. Over 12 months, scores improved slightly, by 0.2 points, on Miplyffa and worsened by 1.9 points on placebo, a difference of 2.2 points in favor of Miplyffa (95% CI 0.6 to 3.8)^[1]. Of the 50 patients, 41 continued into an open-label extension, and 17 had taken Miplyffa for more than 5 years^[1]. The trial was published in the Journal of Inherited Metabolic Disease in 2021^[7].

The FDA first received the application for arimoclomol on July 17, 2020 and declined to approve it in a complete response letter on June 17, 2021^[2]. KemPharm, which renamed itself Zevra Therapeutics in 2023, bought substantially all of the assets of the Danish company Orphazyme, including arimoclomol, in May 2022^[6]. Zevra resubmitted in December 2023, and Miplyffa was the first application discussed by the FDA's new Genetic Metabolic Diseases Advisory Committee, in August 2024^[2][3]. The FDA approved it on September 20, 2024 as the first NPC treatment and gave Zevra a rare pediatric disease priority review voucher^[2][5]. Levacetylleucine (Aqneursa) followed 4 days later, on September 24, 2024^[4]. Zevra submitted an application to the European Medicines Agency in July 2025, which it says is under review^[6].

NPC has 2 FDA-approved drugs, both approved in September 2024 for the neurological symptoms: arimoclomol (Miplyffa), taken with miglustat, and levacetylleucine (Aqneursa). Miglustat is approved for NPC in Europe, but in the US it has no NPC approval of its own, so US patients take it for NPC off-label or as the required partner drug for Miplyffa.