The energy that powers cells of the human body comes from tiny cellular components called mitochondria. Just as a draining battery makes it difficult to operate an electronic device, mitochondrial disorders impair cellular function and cause progressively worsening muscle weakness that diminishes a patient’s ability to move, swallow, and even breathe. One particular mitochondrial depletion syndrome now has its first FDA-approved therapy, a drug acquired by UCB as part of a $1.9 billion deal.
UCB’s Kygevvi is approved for treating thymidine kinase 2 deficiency (TK2d) in adults and children whose disease symptoms started at age 12 or earlier. In addition to becoming the first approved therapy for TK2d, Kygevvi is also the first ultra-rare disease drug for Brussels, Belgium-based UCB.
TK2d develops from an inherited deficiency of the disease’s namesake enzyme, which is key to the production and repair of mitochondrial DNA. While arm and leg muscle weakness is the most common symptom, the disease also affects breathing. Respiratory failure is the most common cause of death for TK2d patients. Prior to Kygevvi’s approval, the only treatment for TK2d was supportive care to manage disease symptoms. According to the FDA, an estimated 120 TK2d cases have been described in medical literature but the condition may be underdiagnosed.
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Kygevvi is comprised of doxecitine and doxribtimine. Both are pyrimidine nucleosides, molecules essential for the synthesis of mitochondrial DNA. The UCB drug is intended to incorporate those molecules into skeletal muscle mitochondrial DNA. Kygevvi is formulated as an oral solution whose daily dose is determined by patient weight.
UCB added Kygevvi to its pipeline through the 2022 acquisition of rare disease drug developer Zogenix. The main asset in the $1.9 billion deal was Fintepla. Currently approved for treating two rare types of epilepsy, Fintepla has become one of UCB’s core neurology products. Before the acquisition, Zogenix was planning to seek regulatory approval of Kygevvi based on the results of a pivotal Phase 2 study that enrolled participants whose TK2d symptoms started when the patients were age 12 or younger. UCB’s FDA submission for the drug included that open-label study as well as data from two retrospective chart review studies (reviews of existing patient records) and an expanded access program.
Efficacy of Kygevvi was assessed by comparing pediatric and adult overall survival 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, the average survival in the study drug group was 9.6 years versus 5.7 years in the control group. The most common adverse reactions reported in clinical testing included diarrhea, abdominal pain, vomiting, and increased levels of liver enzymes, which can be a sign of drug toxicity. Kygevvi’s label directs clinicians to take baseline liver measures prior to starting treatment and monitoring these levels annually.
Kygevvi traces its origins to the lab of Dr. Michio Hirano, professor of neurology and chief of the division of neuromuscular medicine at Columbia University Irving Medical Center. Hirano has served as an advisor to UCB.
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“I’ve been studying mitochondrial diseases for more than three decades and have witnessed firsthand the impact TK2d has on patients and their families,” Hirano said in UCB’s approval announcement on Monday. “We have been waiting for an approved treatment for many years, and this approval marks a significant milestone in how we can support and manage this debilitating condition.”
UCB expects Kygevvi will launch in the U.S. in the first quarter of next year. The European Medicines Agency is still reviewing the drug. UCB plans regulatory submissions in other markets.
FDA approval of Kygevvi comes with a rare pediatric disease priority review voucher. UCB may use this voucher to speed up regulatory review of another therapy in its pipeline addressing a rare pediatric disease, but the drugmaker also has the option to sell it to another company. The going rate of voucher sales is around $150 million.
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