Rare Daily Staff

Zogenix and its wholly-owned subsidiary, Modis Therapeutics, reported positive top-line results from its pivotal retrospective phase 2 RETRO study of its experimental pyrimidine nucleoside substrate enhancement therapy for the treatment of thymidine kinase 2 deficiency, a rare and often fatal genetic disorder.

Thymidine kinase 2 deficiency (TK2d) is a genetic disorder that primarily affects infants and children that  results in mitochondrial dysfunction and leads to inadequate energy production in cells. TK2d presents as severe and progressive muscle weakness that profoundly impairs movement, breathing, eating, and other normal functions, and is often fatal. There are currently no approved therapies for this disease. 

RETRO is a global retrospective study of SET, a fixed combination treatment of two pyrimidine nucleosides, in 38 pediatric and adult patients with TK2 deficiency (median age of disease onset, 2.5 years) treated at eight clinical sites in three countries (United States, Spain, and Israel). Subjects received SET for a median of 77 weeks (range 92 days – 7 years). Each subject was scored across motor, respiratory, and feeding domains according to pre-defined response criteria and was compared to pre-treatment status to assess whether responses improved, remained stable, or worsened.

The data showed that Zogenix’s MT1521 substrate enhancement therapy (SET) had a significant impact on survival probability for treated patients compared to untreated natural history control subjects, with all treated patients remaining alive. Ninety five percent of treated patients experienced improvement (68 percent) or disease stabilization (26 percent). Among the clinical responders, profound responses, such as re-acquiring previously lost motor milestones, were measured in a subset of treated patients. The data were presented at the recent World Muscle Society congress in Copenhagen.


Among the responders to treatment: three patients who had lost the ability to walk prior to treatment regained ambulation; one patient who had never walked gained ambulation; one patient receiving 24 hours per day of invasive mechanical ventilation prior to treatment discontinued all respiratory support; and of eight patients who were on feeding tubes at study start, three had their feeding tubes removed.

Safety data from RETRO indicated that SET is generally safe and well-tolerated. Most reported adverse events were considered not related to study drug, with mild or moderate diarrhea being the most common treatment-related adverse event, occurring in 63 percent of patients.

Serious adverse events were reported in 14 subjects, most of which were related to TK2d.  Two patients experienced three events related to study drug alone (kidney stone, kidney stone removal, and diarrhea). Two adult-onset patients stopped treatment due to asymptomatic increases in aminotransferase liver enzymes (no increase in bilirubin levels), which resolved upon discontinuation of treatment.

“TK2d is an inherited mitochondrial DNA depletion disorder that causes severe muscle weakness that progresses until patients, typically children, lose the ability to stand, walk, eat, and breathe independently,” said Michio Hiranochief of the Division of Neuromuscular Medicine at Columbia University, New York. “This is a landmark study demonstrating that nucleoside therapy provided meaningful clinical benefit to patients across the spectrum of TK2 deficiency.”

Parallel to RETRO, Zogenix compiled a comprehensive, global TK2d natural history dataset from published studies and individual case reports to document untreated patients’ disease course. From this natural history dataset, 68 patients reflecting the range of disease severity, age, and age of disease onset, were selected as a control group for treated patients in the RETRO study.

“The results from this study demonstrate the potential of our investigational drug, MT1621, to improve outcomes in patients with TK2d and to significantly alter the course of disease,” said Joanne Quan, chief medical officer at Modis Therapeutics. “We look forward to continuing the development of MT1621, with the goal of bringing it to patients as quickly as possible.”

Zogenix acquired Modis Therapeutics and MT1621 in September 2019.

Photo: Joanne Quan, chief medical officer at Modis Therapeutics

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