Doxecitin and Doxribthymine in Adult Subjects With Thymidine Kinase 2 (TK2) Deficiency

This is an Open Label, single-arm, single-center clinical study to evaluate the efficacy and safety of dT+dC in adults with TK2 deficiency (TK2d). TK2 deficiency is one of several mitochondrial autosomal recessive disorders that are collectively referred to as mitochondrial DNA depletion and multiple deletions syndromes (MDDS), in fact, TK2d is an ultra-rare disease, presenting as progressive proximal muscle weakness in all patients; however, clinical presentations are heterogeneous in nature and manifest with variable levels of severity and functional impairment across patients.

The study seeks to enroll patients under follow-up in the Neuromuscular Unit of '12 de Octubre' Hospital. All participants will be required to attend a screening visit at which their eligibility for the study will be determined. After signing the informed consent and verifying that they met all inclusion and exclusion criteria, participants will receive a daily dose of dT+dC in 3 equal divided doses administered orally at an approximate interval of 6 (±2) hours. dT+dC is to be initially dosed (commencing on Day 1) at 130 mg/kg/day of each nucleoside (130 mg/kg/day dC and 130 mg/kg/day dT), divided into 3 equal daily doses of approximately 43 mg/kg/dose. If the tolerability profile is acceptable after 2 weeks (approximately Day 15), the dose is to be increased to 260 mg/kg/day of each nucleoside (approximately 86 mg/kg/dose three-times daily, (TID). If the tolerability profile remains acceptable after an additional 2 weeks of dosing (approximately Day 29) the dose is to be further increased to 400 mg/kg/day (approximately 133 mg/kg/dose TID). The maximum dose is 400 mg/kg/day. The tolerability profile of the treatment will be evaluated based on whether the patient has diarrhea.

The total number of participants for the safety and efficacy analysis will be 10 to 15 participants with progressive myopathy with respiratory involvement.

The estimated duration of the study for individual participants will be 24 months. Although, based on previous experience in treating these patients, the investigators expect to see results within the first 6 to 12 months of treatment.

It is hypothesized that dT+dC oral administration is safe, well tolerated and clinically beneficial in adults with TK2 deficiency.

Inclusion criteria

• Signed informed consent by the subject.
• Subject must be greater than 18 years of age at time of consent.
• Genetic diagnosis of TK2 deficiency
• Subject should have evidence of a moderate to severe disease, with motor and or respiratory involvement, shown by one of the following:

• North Star Ambulatory Assessment Scale (NSAA) less than 30
• 6-minute walking test less than 450 meters
• Force Vital Capacity in the sitting position less than 70 percent or a drop in the decubitus position greater than 10 percent or need for mechanical ventilation.
• Disabling symptoms and evidence of motor and/or respiratory function progressive decline.
• Female subjects must have no intention to become pregnant during the study. Female subjects who are of childbearing potential (that is, following menarche until at least 1 year post-menopausal if not anatomically and physiologically incapable of becoming pregnant) must agree and commit to the use of highly effective methods of birth control for the duration of the study and for 30 days after the end of the study, and be willing to have additional pregnancy tests conducted during the study. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (that is, less than 1 percent per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method.
• Male subjects with partners of childbearing potential must agree to use effective contraception methods during the study and for at least 90 days after the last dose of the study medication. Acceptable methods include the use of condoms combined with spermicidal foam/gel/film/cream/suppository.
• Willingness to comply with the study protocol, including but not limited to, all study procedures, study visits, and study drug compliance.

Exclusion criteria

• History of liver disease, or liver function test results (alanine aminotransferase [ALT], aspartate transaminase [AST], or total bilirubin) greater than or equal2 times (2X) the upper limit of normal. Patients with transaminases greater than 2 times (2X) can participate with the approval and monitoring of a doctor specializing in liver toxicity.
• Participation in a previous trial of any investigational agent for primary mitochondrial disease within 1 year prior to informed consent, or use of any other investigational therapy within 30 days (or 3 half-lives, whichever is longer) prior to informed consent, or participation in other clinical studies, within 30 days prior to informed consent, which in the opinion of the study Sponsor, may potentially confound results from this study.
• Pregnant (females 10.0 years old or older will have a pregnancy test at screening), or breastfeeding