European Commission Approves First Treatment for Rare Mitochondrial Disease TK2d

The European Commission has granted marketing authorization under exceptional circumstances for KYGEVVI (doxecitine and doxribtimine) as the first and only approved treatment for thymidine kinase 2 deficiency (TK2d) in the European Union. The therapy is indicated for pediatric and adult patients with genetically confirmed TK2d with an age of symptom onset on or before 12 years, marking a historic milestone for the ultra-rare disease community.

In the main retrospective study supporting approval, the drug was shown to reduce the risk of death by 95% when compared to a historical cohort of untreated patients. The analysis also showed that 84% of KYGEVVI-treated patients regained one or more motor functions, such as sitting upright unassisted, with 22% of recipients able to come off respiratory support.

Supporting data for EC approval came from pooled data from two studies of treatment with KYGEVVI in patients with genetically confirmed TK2d with age of symptom onset ≤12 years. These studies investigated the impact of treatment on functional outcomes as well as survival. Use of KYGEVVI led to improvements in motor function, as well as a reduction in use of ventilatory and feeding support.

Prior to treatment start, 18 out of 39 participants had initiated ventilatory support and no participants discontinued ventilatory support. After initiation of treatment, 5 out of 21 participants started ventilatory support while 5 out of 23 discontinued ventilatory support. Regarding feeding support, prior to treatment start, 12 out of 39 participants had a feeding tube. After initiation of treatment, 4 out of 28 participants started feeding support, with 2 of these participants subsequently discontinuing feeding support after initiation of treatment.

In the studies, KYGEVVI was well tolerated with the most commonly reported adverse reactions of diarrhea (86%), vomiting (28%), and abdominal pain (including abdominal pain upper) (26%). The most common side effects were gastrointestinal disorders.

TK2d is an ultra-rare, progressive, and life-threatening mitochondrial myopathy caused by pathogenic variants of the thymidine kinase 2 gene. It leads to mitochondrial DNA depletion, resulting in severe and progressive muscle weakness that can be fatal within three years of symptom onset. Many affected individuals lose mobility, require respiratory support, and need assistance with basic functions such as eating. Those experiencing initial symptoms on or before the age of 12 years face a high risk of premature death.

The number of patients with the disease is hard to estimate, as symptoms can be confused with other neuromuscular disorders like spinal muscular atrophy or general myopathy, but one recent study suggested there were around 500 patients in the top four EU economies and the UK, with a similar number in the US, where UCB's drug was approved last November. It is estimated that the worldwide prevalence of TK2d is 1.64 cases per 1,000,000 people.

The primary mechanism of action of KYGEVVI is the incorporation of pyrimidine nucleosides deoxycytidine and deoxythymidine into skeletal muscle mitochondrial DNA to restore mitochondrial DNA copy number and improve skeletal muscle function in patients with TK2d. It is a combination of pyrimidine nucleosides designed to integrate into skeletal muscle mitochondrial DNA and compensate for reduced activity of the TK2 enzyme.

The EMA's PRIority MEdicines (PRIME) scheme, which gives enhanced support to medicines that address unmet medical needs, supported the development of KYGEVVI. Authorization under exceptional circumstances may be granted in cases where the rarity of the disease, or the difficulty of studying it, make the collection of full information about the treatment impossible.