UCB drug becomes first FDA-approved drug to treat extremely rare and fatal mitochondrial disease
The energy that powers the body's cells comes from tiny cellular components called mitochondria. Just as a drained battery makes it difficult to operate an electronic device, mitochondrial disease impairs cellular function and causes progressive muscle weakness, impairing a patient's ability to move, swallow and even breathe. A specific mitochondrial depletion syndrome now has its first FDA-approved therapy, acquired by UCB as part of a $1.9 billion deal.
UCB's Kygevvi is approved to treat thymidine kinase 2 deficiency (TK2d) in adults and children aged 12 years or earlier who begin to develop symptoms of the disease. In addition to being the first approved TK2d therapy, Kygevvi is Brussels, Belgium-based UCB's first ultra-rare disease drug.
TK2d is caused by an inherited defect in the enzyme of the same name, which is essential for the production and repair of mitochondrial DNA. Although muscle weakness in the arms and legs is the most common symptom, the disease can also affect breathing. Respiratory failure is the most common cause of death in patients with TK2d. Prior to Kygevvi's approval, the only treatment for TK2d was supportive care to control disease symptoms. According to the FDA, there are an estimated 120 cases of TK2d in the medical literature, but the condition may be underdiagnosed.
Kygevvi consists of doxetine and doxiridine. Both are pyrimidine nucleosides, molecules necessary for the synthesis of mitochondrial DNA. UCB drugs are designed to integrate these molecules into skeletal muscle mitochondrial DNA. Kygevvi is formulated as an oral solution with a daily dose based on patient weight.
UCB added Kygevvi to its pipeline through its 2022 acquisition of rare disease drug developer Zogenix. The lead asset in the $1.9 billion deal is Fintepla. Fintepla is currently approved to treat two rare types of epilepsy and has become one of UCB's core neurology products. Prior to the acquisition, Zogenix planned to seek regulatory approval for Kygevvi based on results from a pivotal Phase 2 study that enrolled participants whose TK2d symptoms began when patients were 12 years of age or younger. UCB's submission to the FDA for the drug includes data from an open-label study as well as two retrospective chart review studies (a review of existing patient records) and an expanded access program.
The efficacy of Kygevvi was assessed by comparing overall survival in children and adults to an external control group of untreated patients. Results from 78 matched pairs showed three deaths in the Kygevvi group and 28 deaths in the external control group. At 10 years, average survival was 9.6 years in the study drug group and 5.7 years in the control group. The most common adverse reactions reported in clinical trials include diarrhea, abdominal pain, vomiting, and elevated liver enzyme levels, which may be a sign of drug toxicity. Kygevvi's label directs clinicians to take baseline liver measurements before starting treatment and to monitor these levels annually.
The origins of Kygevvi can be traced to the laboratory of Dr. Michio Hirano, professor of neurology and director of the Division of Neuromuscular Medicine at Columbia University Irving Medical Center. Hirano served as a consultant to UCB.
“I have been studying mitochondrial diseases for more than three decades and have seen firsthand the impact TK2d has on patients and their families,” Hirano said in UCB's Monday approval announcement. “We have been waiting for an approved treatment for years, and this approval marks an important milestone in how we support and manage this debilitating disease.”
UCB expects Kygevvi to be launched in the United States in the first quarter of next year. The drug is still under review by the European Medicines Agency. UCB plans to file regulatory applications in other markets.
The FDA's approval of Kygevvi comes with a rare pediatric disease priority review voucher. UCB may use the voucher to expedite regulatory review of another treatment in its pipeline for a rare pediatric disease, but the drugmaker could also choose to sell it to another company. Current coupon sales are approximately $150 million.
Photo: wir0man, Getty Images
