FDA approval makes Zevra drug the first therapy for rare and fatal metabolic disease

A drug from Zevra Therapeutics is now the first FDA-approved therapy for an extremely rare, inherited metabolic disorder whose effects on the central nervous system can be fatal in the patient's teenage years.

The drug, acrimoclomol, is used to treat Niemann-Pick disease type C (NPC). Friday's approval decision comes three years after the FDA rejected the small molecule and nearly two months after an agency advisory committee discussed additional clinical data and then voted in favor of the drug. Celebration, Florida-based Zevra will market the new drug under the brand name Miplyffa.

NPC is a lysosomal storage disease, a condition in which defects in enzymes critical to cellular metabolism lead to a buildup of toxic substances in cells. In NPC, the disease is caused by changes in the NPC1 or NPC2 genes that affect the transport of cholesterol and other fats within a cell. As a result, cells no longer function properly, leading to organ damage.

Symptoms of NPC include progressive deterioration of mobility, as well as impairments in cognition, speech and swallowing. According to the FDA, patients affected by NPC only survive for about 13 years. Zevra says that of the estimated 1,800 patients in the U.S. and Europe who suffer from NPC, about 300 have been diagnosed with the disease in the U.S.

Miplyffa is a small molecule that is taken as a capsule three times a day; the exact dose is based on the patient's weight. The exact way Miplyffa works in treating NPC is unknown, but Zevra has stated that the drug is designed to combat the symptoms of NPC by slowing the progression of the disease, rather than serving as a purely symptomatic treatment.

While NPC can affect organs throughout the body, Zevra's FDA approval of the drug specifically covers treatment of the neurological effects of the disease. The drug was studied in a Phase 2/3 trial involving 50 NPC patients between the ages of 2 and 19. During the 12-month study, patients were randomly assigned to receive either Miplyffa or a placebo.

Miplyffa's effectiveness was demonstrated using a rating scale used to assess the severity of NPC symptoms, such as walking, speaking, swallowing and fine motor skills. The higher the score, the more severe the disease symptoms. Patient ratings in the study showed that Miplyffa resulted in a slower disease progression compared with a placebo. Zevra's application also included long-term data from a four-year open-label extension study. These results suggest improved outcomes compared with historical controls.

Of the 50 patients enrolled in the study, 39 also received miglustat as background treatment during the study. Miglustat, brand name Zavesca, is a drug made by Johnson & Johnson that is approved in the United States for another lysosomal storage disease, Gaucher disease. This now generic drug is also approved to treat NPC in Europe, Canada, Australia, New Zealand, and certain countries in Asia and South America. Miplyffa's label states that the drug should be given in combination with miglustat.

The most common side effects reported in the studies include upper respiratory tract infections, diarrhea, and weight loss. The drug's label includes warnings about hypersensitivity reactions, including hives and swelling under the skin.

In a note to investors on Friday, analysts at William Blair noted two aspects of the drug's labeling. The requirement that the drug be used in combination with miglustat is surprising, as that therapy is not currently approved for NPC, nor was that a requirement of the pivotal trial. However, they added that this requirement should not shrink the addressable market, as most NPC patients are already treated with miglustat. The second surprise is the labeling, which specifically states that the drug treats neurological symptoms of NPC, rather than just treating NPC.

“Due to the neurodegenerative nature of the disease, we do not expect this to impact market opportunities. However, it could become a sticking point for some stakeholders, such as payers, as they see it as a negotiating tool to limit or restrict coverage,” said analysts at William Blair.

Miplyffa was previously developed by Danish biotech company Orphazyme, whose New Drug Application was rejected by the FDA in 2021. That application was based on a single Phase 2/3 study. The regulator requested further clinical data to confirm safety and efficacy. Zevra acquired the worldwide rights to the drug in 2022, paying Orphazyme $12.8 million for it. Zevra then conducted additional clinical trials to support a resubmission.

In late June, Zevra (which changed its name from KemPharm last year) reported cash on hand of $39.2 million. After the advisory committee vote in early August, Zevra raised $64.5 million through a stock offering, part of which it said would be used to support pre-commercial activities for the NPC drug. In its most recent quarterly report, Zevra said its capital was sufficient to sustain the company's operations through the first quarter of 2027. Zevra said the FDA approval of Miplyffa comes with a priority review voucher for rare pediatric diseases. While companies can use these vouchers to expedite review of a future drug candidate, biotechs typically sell them to big pharma at prices in excess of $100 million.

Zevra expects Miplyffa to be available in the U.S. in the next eight to 12 weeks. The company has scheduled a conference call for Sept. 23 at 8 a.m. Eastern Time to discuss the drug's approval.

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