A Zevra Therapeutics drug is now the first FDA-approved therapy for an ultra-rare, inherited metabolic disorder whose effects on the central nervous system can become fatal by the time a patient is a teenager.
The drug, acrimoclomol, treats Niemann-Pick disease type C (NPC). The Friday regulatory decision comes three years after the FDA rejected the small molecule and nearly two months after an advisory committee to the agency 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 disorder, a type of disease in which defects to enzymes crucial to cellular metabolism lead to a buildup of toxic substances in cells. In NPC, the disease stems from changes to either the NPC1 or NPC2 genes, which affect the transport of cholesterol and other fats within a cell. Consequently, cells to not function properly, leading to organ damage.
NPC symptoms include progressively worsening mobility as well as impairment of cognition, speech, and swallowing. According to the FDA, patients affected by NPC only live for about 13 years. Zevra says that of the estimated 1,800 patients in the U.S. and Europe have NPC, about 300 have been diagnosed with the disease in the U.S.
Miplyffa is a small molecule formulated as a capsule taken three times a day; the specific dose is determined by a patient's weight. While the exact way Miplyffa works to treat NPC is unknown, Zevra has said the drug is designed to address the symptoms of NPC by slowing the disease's progression rather than serving as a solely symptomatic treatment.
While NPC can affect organs throughout the body, FDA approval of Zevra's drug specifically covers treatment of neurological effects of the disease. The drug was evaluated in a Phase 2/3 study that enrolled 50 NPC patients between the ages of 2 and 19. The 12-month study randomly assigned patients to receive Miplyffa or a placebo.
Efficacy of Miplyffa was shown according to a rating scale used to assess the severity of NPC symptoms such as walking ability, speech, swallowing, and fine motor skills. The higher the score, the more severe the disease symptoms. Patient scores in the study showed that Miplyffa led to slower disease progression compared to a placebo. Zevra's application also included long-term data from a four-year open label extension study. These results suggest improved outcomes compared to historical controls.
Of the 50 patients enrolled in the trial, 39 also received miglustat as a background treatment during the study. Miglustat, brand name Zavesca, is a Johnson & Johnson drug approved in the U.S. for a different lysosomal storage disorder, Gaucher disease. This now generic drug is also approved for treating NPC in Europe, Canada, Australia, New Zealand, and certain countries in Asia and South America. The Miplyffa label says the drug should be administered in combination with miglustat.
The most common side effects reported in the studies include upper respiratory tract infection, diarrhea and weight loss. The drug's label includes a warning for hypersensitivity reactions, including hives and swelling under the skin.
In a note sent to investors Friday, William Blair analysts took note of two aspects of the drug's label. The requirement that the drug be used in in combination with miglustat is a surprise, given that this therapy is not currently approved for NPC and it was not a requirement of the pivotal study. But they added that since most NPC patients are already treated with miglustat, this requirement should not reduce the addressable market. The second surprise is the label specifically stating the drug treats neurological symptoms of NPC as opposed to just treating NPC.
"Given the neurodegenerative nature of the disease, we would not expect this to impact the market opportunity, though it could potentially be a sticking point for some stakeholders, such as payers who may see it as a bargaining chip to limit or restrict coverage," the William Blair analysts said.
Miplyffa was previously developed by Danish biotech Orphazyme, whose new drug application was turned down by the FDA in 2021. That submission was based on the single Phase 2/3 study. The regulator asked for more clinical data showing safety and efficacy. Zevra acquired global rights to the drug in 2022, paying Orphazyme $12.8 million. Zevra then conducted additional clinical research to support a resubmission.
As of the end of June, Zevra (which last year changed its name from KemPharm) reported its cash position was $39.2 million. Following 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 is sufficient to support company operations into the first quarter of 2027. Zevra said the FDA approval of Miplyffa comes with a rare pediatric disease priority review voucher. While companies can use these vouchers to speed up the review of a future drug candidate, biotechs typically sell them to big pharma companies for prices that can top $100 million.
Zevra expects Miplyffa will become available in the U.S. in the next eight to 12 weeks. The company has scheduled an 8 a.m. Eastern, Sept. 23 conference call to discuss the drug's approval.