The FDA approves a treatment co-created at Vall d’Hebron for a rare muscle disease

The U.S. Food and Drug Administration (FDA) has announced the approval of KYGEVVI®, the first therapy for adult and paediatric patients with thymidine kinase 2 deficiency (TK2d). The treatment was created and developed with the participation of the team led by Dr. Ramon Martí, head of the Neuromuscular and Mitochondrial Pathology group at the Vall d’Hebron Research Institute (VHIR), and is currently produced by the biopharmaceutical company UCB.

TK2d is an ultra-rare genetic mitochondrial disease characterised by severe and progressive muscle weakness that may lead to loss of motor abilities and affect vital functions such as swallowing or breathing. Although there is considerable variability among patients, it is often a fatal condition, and those who develop symptoms before or around the age of two are at high risk of premature death, usually within three years after symptom onset. The estimated global prevalence of TK2d is 1.64 cases per million people.

Patients with this condition lack a key protein required for mitochondrial DNA synthesis — thymidine kinase 2 (TK2). As a result, mitochondria, which provide energy to cells, fail to function properly, triggering the disease, for which there was previously no treatment.

In this context, the team led by Dr. Ramon Martí at VHIR and Dr. Michio Hirano at Columbia University (USA) developed an oral therapy based on two nucleosides (thymidine and deoxycytidine) that compensate for the lack of TK2. The involvement of Modis Therapeutics, a company founded specifically to develop this therapy, was key in the drug’s progress. Modis Therapeutics was acquired by Zogenix in 2019, which was later acquired by UCB in 2022.

A therapy that significantly improves patient survival

The therapy was first administered at Vall d’Hebron under a compassionate use programme. Given the positive results observed, a clinical trial was later launched with patients from national and international centres, including Vall d’Hebron, through the participation of the team led by Dr. Francina Munell from the Paediatric Neurology Group at VHIR.

The approval of KYGEVVI® is based on safety and efficacy data from a phase 2 clinical study, two documented retrospective reviews, and an expanded compassionate use programme. These studies involved a total of 82 patients whose TK2d symptom onset was at or before 12 years of age.

Efficacy was assessed by comparing overall survival of treated paediatric and adult patients with that of an untreated control group matched by age at symptom onset (≤2 years or >2 to ≤12 years). A total of 78 matched pairs were identified. The results showed that survival time after treatment initiation improved substantially: the overall risk of death after starting therapy was reduced by approximately 86%. “This treatment has proven to work very well and rapidly, and it can save the lives of patients severely affected by the disease”, said Dr. Martí.

Among the 78 treated patients included in the survival analysis, the median age at symptom onset was 1.5 years (range: 0.01–12 years). The median treatment duration was 4 years (range: 1 day–12 years). The most frequent adverse reactions were non-serious and included diarrhoea, abdominal pain, vomiting, and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

“We are very proud that, from a preclinical research group like ours, we have contributed to bringing a treatment for such a severe disease to patients. It is undoubtedly great news that motivates us to continue researching new therapies for other similar conditions”, concluded Dr. Martí.

The European Medicines Agency (EMA) is currently reviewing this therapy for approval in Europe.