FDA Approves Zevra Drug as First Therapy for Rare Fatal Metabolic Disease

Zevra Therapeutics has recently achieved a significant milestone with the FDA's approval of its drug, acrimoclomol, marketed under the brand name Miplyffa. This approval marks the first-ever FDA-approved treatment for Niemann-Pick disease type C (NPC), an ultra-rare, inherited metabolic disorder. NPC typically impacts the central nervous system severely, leading to fatal outcomes by the teenage years of the affected individuals.

NPC is categorized as a lysosomal storage disorder, where enzyme defects necessary for cellular metabolism cause toxic substance accumulation in cells. This disorder arises from mutations in either the NPC1 or NPC2 genes, impeding cholesterol and other fat transport within cells, thereby causing cellular malfunction and organ damage. As a result, individuals with NPC suffer from progressively worsening mobility, cognitive decline, speech difficulties, and swallowing impairments. The FDA states that patients with NPC typically have a life expectancy of around 13 years. In the U.S., approximately 300 out of an estimated 1,800 patients across the U.S. and Europe have been diagnosed with NPC.

Miplyffa, intended to address NPC, is administered as a capsule taken three times daily, with the dosage tailored according to the patient’s weight. Although the precise mechanism by which Miplyffa treats NPC is not fully understood, Zevra claims the drug aims to slow the disease's progression rather than merely alleviating symptoms. The FDA’s approval specifically targets the neurological symptoms of NPC, although the disease can affect various organs in the body.

The approval of Miplyffa is based on findings from a Phase 2/3 clinical trial involving 50 NPC patients aged between 2 and 19 years. Over 12 months, the trial participants were randomly assigned to receive either Miplyffa or a placebo. Efficacy was measured using a rating scale that assessed the severity of NPC symptoms, including walking ability, speech, swallowing, and fine motor skills. Higher scores indicated more severe symptoms. The trial results showed that patients treated with Miplyffa experienced a slower progression of the disease compared to those who received the placebo. Additionally, long-term data from a four-year open-label extension study suggested improved outcomes relative to historical controls.

While 39 of the 50 patients in the trial also received miglustat, a treatment for Gaucher disease and approved for NPC in several regions outside the U.S., the Miplyffa label specifies that it should be used alongside miglustat. Common side effects observed during the studies included upper respiratory tract infections, diarrhea, and weight loss. The label also contains a warning for hypersensitivity reactions.

Analysts at William Blair highlighted two notable aspects of the drug's label in their communication to investors. First, the requirement for Miplyffa to be used in combination with miglustat was unexpected, given that miglustat is not currently approved for NPC in the U.S. and was not a prerequisite in the pivotal study. However, they noted that since most NPC patients already use miglustat, this requirement is unlikely to impact the market significantly. Secondly, the label specifies that Miplyffa treats the neurological symptoms of NPC, which may be a point of negotiation for stakeholders like payers.

Originally developed by Danish biotech Orphazyme, Miplyffa faced an FDA rejection in 2021 due to insufficient clinical data. Zevra acquired global rights to the drug in 2022 for $12.8 million and subsequently conducted additional clinical research to bolster its resubmission to the FDA. Zevra, previously known as KemPharm, reported a cash reserve of $39.2 million as of June and raised an additional $64.5 million through a stock offering in August to support pre-commercial activities for Miplyffa. The company’s latest quarterly report indicates that its capital is sufficient to sustain operations until the first quarter of 2027.

The FDA’s approval of Miplyffa grants Zevra a rare pediatric disease priority review voucher, which the company can use to expedite the review of a future drug candidate or sell to other pharmaceutical companies for substantial sums. Zevra anticipates that Miplyffa will be available in the U.S. within the next eight to 12 weeks and has scheduled a conference call to discuss the drug’s approval.