A retrospective study of nucleoside therapy for treating the very rare mitochondrial disorder thymidine kinase 2 deficiency (TK2d) has shown positive results, including improved survival rates among children and adults with this genetic disorder, for which there are no approved therapies.
Those findings were presented in a poster titled “A RETROspective Study of Combination Pyrimidine Nucleoside Therapy in Patients with Thymidine Kinase 2 (TK2) Deficiency” at the 24thInternational Annual Congress of the World Muscle Society, in Copenhagen, Denmark.
Mitochondria are responsible for producing all the energy cells needed to function properly. To be functionally active, they need to produce certain proteins and to do so they depend on their own DNA.
TK2 works as an intermediate in the mitochondrial DNA (mtDNA) production process, without it the “building blocks” of DNA — nucleosides — are not generated. Low levels of TK2 compromise muscle function, including lung and eye muscles.
“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,” Michio Hirano, MD, chief of the Division of Neuromuscular Medicine at Columbia University, explained in a press release.
Evidence indicates that providing additional nucleosides can help bypass mtDNA maintenance problems, alleviating the manifestations of mitochondrial DNA depletion syndromes.
Zogenix‘ and Modis Therapeutics‘ candidate oral therapy, MT1621, targets the underlying disease mechanism of TK2 deficiency by restoring mtDNA production. The investigational treatment consists of a combination of deoxynucleosides (a type of nucleosides), meaning it can improve mtDNA’s “building blocks” numbers, mtDNA production, and improve cell function.
“The data from RETRO form the basis of Zogenix’s ongoing investigational MT1621 program and support the safety and efficacy of pyrimidine nucleoside substrate enhancement therapy (SET) for the treatment of Thymidine Kinase 2 deficiency (TK2d),” according to the press release.
In a retrospective, case-only, medical chart review Phase 2 study (NCT03701568), also known as RETRO and MT-1621-101, researchers have examined the effects of MT1621 in patients with TK2 deficiency — more specifically the therapy’s safety, effectiveness and tolerability. Investigators also looked into the patients’ motor, respiratory and feeding status pre- and post-treatment.
They analyzed the records of 38 pediatric and adult TK2 deficiency patients (21 males and 17 females; median age of disease onset 2.5 years). Patients were treated for a median of 71 weeks (range of 92 days to seven years).
Treatment effects were compared to 68 untreated patients included in previously published natural history studies and individual case reports. The control group reflected the range of disease severity, age, and age of disease onset, in comparison to the treatment sample.
The therapy was well-tolerated, safe and effective at improving or stabilizing TK2 deficiency. None of the treated patients died during treatment. Besides the survival benefit, most treated subjects (94.7%) had either improved (68%) or stabilized (26%) responses in major functional domains.
After treatment, three patients regained their walking abilities (one had never walked before); one patient discontinued his/her 24/7 respiratory support; three patients had their feeding tubes removed (of a total of eight subjects on feeding tubes at the beginning of the study).
Mild or moderate diarrhea was the most common therapy-related side effect, occurring in 24 of 38 patients (63%).
Serious adverse side effects, mostly related to the condition, were reported by 14 patients. Two of the patients experienced three events related to the study therapy alone (kidney stone, kidney stone removal, diarrhea).
“This is a landmark study demonstrating that nucleoside therapy provided meaningful clinical benefit to patients across the spectrum of TK2 deficiency,” noted Hirano, the study’s lead author.
“The results from this study demonstrate the potential of our investigational drug, MT1621, to improve outcomes in patients with TK2d [TK2 deficiency] and to significantly alter the course of disease,” said Joanne Quan, MD, 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,” Quan said.
The company is now enrolling (by invitation) patients in an open-label treatment study (NCT03845712) of the safety and effectiveness of MT1621 in TK2 deficient patients who participated in the RETRO study. With sponsor approval, participants on nucleoside therapy who did not participate in RETRO also can enroll.