MT1621 Substrate Enhancement Therapy Successful in Rare TK2 Deficiency Syndrome


The impact MT1621 had on survival probably for those treated in comparison to the natural history of the often-fatal disorder was highly significant, with all patients remaining alive as of October.

Dr Michio Hirano

Michio Hirano, MD, chief, Division of Neuromuscular Medicine, Columbia University

Michio Hirano, MD

New phase 2 data suggest that TK2-related mitochondrial DNA depletion syndrome (TK2d) may be positively impacted by treatment with MT1621, a deoxynucleoside substrate enhancement therapy (SET), an investigational therapy developed by Modis Therapeutics, a Zogenix subsidiary.1

Presented at the 24th International Annual Congress of the World Muscle Society, in Copenhagen, Denmark, the impact on survival probably for those treated in comparison to the natural history of the often-fatal disorder was highly significant (P <.0006). In addition to the survival benefit, the vast majority of treated patients (94.7%) had either improved (68%) or stabilized (26%) responses in major functional domains.2

As of October 2019, all 38 adult and pediatric patients with TK2 deficiency in the study are still alive. Overall, the study treatment was considered well-tolerated.

“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, Division of Neuromuscular Medicine, Columbia University, said in a statement. “This is a landmark study demonstrating that nucleoside therapy provided meaningful clinical benefit to patients across the spectrum of TK2 deficiency.”

There are currently no treatments or cures available for TK2d. No reliable estimates on the prevalence of TK2-related mitochondrial DNA maintenance defect are known, with a total of only slightly more than 100 affected individuals reported to date.3

This study, dubbed RETRO, is a global retrospective evaluation of MT1621 SET, which consists of a fixed combination of a pair of pyrimidine nucleosides (dC/dT), administered to participants for an average of 77 weeks (range, 92 days to 7 years). The study consists of 8 clinical sites in the US, Spain, and Israel. Study participants were assessed across motor, respiratory, and feeding domains and compared to pre-treatment status to assess whether responses improved, remained stable, or worsened.

In a parallel effort, Zogenix built out a global dataset of TK2d natural history from case reports and available literature, which ultimately consisted of 68 patients and represented the range of disease severity, age, and disease onset comparisons for treated patients.

In the treated cohort, 40% (n = 15) had disease onset at ≤2 years, 37% (n = 14) had onset between age 2 and 12 years, and 24% (n = 9) had onset after age 12. At baseline, 42% (n = 16) of the entire cohort was ambulatory, 50% (n = 19) required ventilator support, and 21% (n = 8) required a feeding tube.

A low percentage of subjects in the overall cohort (5%; n = 2) worsened, with both patients in the late-onset (after age 12 years) group. For the early onset group, 73% (n = 11) improved while 27% (n = 4) remained stable. In the mid-onset and late-onset groups, respectively, 79% (n = 11) and 44% (n = 4) improved while 21% (n = 3) and 33% (n = 3) remained stable.

Among the clinical responders, a subgroup displayed particularly profound responses. In some cases, these patients regained previously lost motor milestones. Relative to ambulation, 3 patients who had lost the ability to walk before to treatment regained ambulation, while 1 patient who had never walked gained ambulation.

Additionally, a single patient receiving 24 hours/day of invasive mechanical ventilation pretreatment was able discontinued all respiratory support, and of the 8 patients were on feeding tubes at baseline, 3 had their feeding tubes removed.

“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 study author Joanne Quan, MD, chief medical officer, Modis Therapeutics. “We look forward to continuing the development of MT1621, with the goal of bringing it to patients as quickly as possible.”

With regard to safety, 95% (n = 36) of patients reported at least 1 adverse event (AE), with the majority (199 of 292) deemed unrelated to treatment or were rated Grade 1 (186 of 292). The most common AEs were diarrhea (63%; n = 24), increased blood creatine phosphokinase (18%; n = 7), increased alanine aminotransferase (16%; n = 6), pyrexia (16%; n = 6), and increased aspartate aminotransferase (13%; n = 5).

Serious AEs occurred in 37% (n = 14) of patients, though only 2 patients reported 3 total events considered treatment-related (kidney stone, kidney stone removal, and diarrhea). There were 2 discontinuations due to AEs, by patients who experienced increased gamma-glutamyl transferase and increased liver enzymes, though both elevations were reversible.


1. Zogenix Presents Positive Clinical Study Results for Investigational Treatment for TK2 Deficiency [press release]. Emeryville, CA: Zogenix; Published October 7, 2019. Accessed October 9, 2019.

2. Quan J, Domínguez-González C, Paradas C, et al. A RETROspective Study of Combination Pyrimidine Nucleoside Therapy in Patients with Thymidine Kinase 2 (TK2) Deficiency. Presented at: World Muscle Society Annual Meeting; October 1-5, 2019; Copenhagen, Denmark.

3. Wang J, El-Hattab AW, Wong L-JC. TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form. Gene Reviews. Updated July 26, 2018. Accessed October 9, 2019.

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