An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (Continuation)

A Phase 2 Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With Thymidine Kinase 2 Deficiency (TK2)

This is a Phase 2 prospective open-label treatment study of the safety and efficacy of doxecitine and doxribtimine in study participants with thymidine kinase 2 (TK2) deficiency who participated in the retrospective study MT-1621-101 [NCT03701568] or who were receiving nucleos(t)ide treatment and were approved by the Sponsor.

Study Overview

• Status: Active, not recruiting
• Conditions: Thymidine Kinase 2 Deficiency
• Intervention / Treatment: Drug: doxecitine and doxribtimine

Detailed Description

This is a Phase 2 prospective, open-label treatment study of the safety and efficacy of MT1621 in TK2 deficient subjects who participated in the retrospective Study MT-1621-101. Subjects who are being treated with dC/dT and did not participate in MT-1621-101 may also be allowed to enroll with Sponsor approval. For all subjects, it is important to ensure that collection of clinical and functional measurements prior to treatment with dC/dT are sufficient to serve as baseline assessments for purposes of evaluating safety and efficacy.

In MT-1621-102, all subjects will be treated with MT1621 at one of 3 protocol-specified dose levels: 260 mg/kg/day (130 mg/kg/day dC and 130 mg/kg/day dT), 520 mg/kg/day (260 mg/kg/day dC and 260 mg/kg/day dT), or 800 mg/kg/day (400 mg/kg/day dC and 400 mg/kg/day dT), divided in three equal doses (tid). On enrollment into the study, subjects already taking their medication at one of these dose levels will either transition from chemical-grade dC/dT or dCMP/dTMP to the same dose of MT1621, or continue use of MT1621 at their current dose. Subjects who were previously taking chemical-grade dC/dT, dCMP/dTMP, or MT1621 at a dose other than one of these dose levels will be transitioned to a protocol-specified dose of MT1621, whichever is closest to the subjects' previous dose of chemical-grade dC/dT, chemical-grade dCMP/dTMP, or MT1621. The dose may be reduced for tolerability reasons.

Safety and efficacy will be assessed upon enrollment, at 1 month, every 3 months through 18 months, every 6 months through 36 months, then annually thereafter, and at end of study participation. For subjects who did not participate in Study MT-1621-101, specific assessments for each subject will be determined by the Sponsor in discussion with the Investigator based on data collected as baseline assessments for purposes of evaluating safety and efficacy. MT1621 should be administered with food.

The study will evaluate sparse PK sampling at steady state using sparse sampling methodology.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel
    • Tk0102 4038
  • Holon, Israel
    • Tk0102 4039
  • Nehariya, Israel
    • Tk0102 4037
• Spain
  • Barcelona, Spain
    • Tk0102 3102
  • Esplugues de Llobregat, Spain
    • Tk0102 3121
  • Madrid, Spain
    • Tk0102 3031
  • Seville, Spain
    • Tk0102 3101
• United States
  • New York
    • New York, New York, United States, 10032
      • Tk0102 1005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent by the parent(s) or legally authorized representative (LAR) and/or assent by the study participant (when applicable).
• Confirmed genetic mutation in the TK2 gene.
• Absence of other genetic disease or polygenic disease.
• Current treatment with nucleos(t)ides for TK2 deficiency. Study participants who were not previously enrolled in MT-1621-101 [NCT03701568] will require Sponsor approval to ensure that collection of clinical and functional measurements prior to treatment are sufficient to serve as baseline assessments for purposes of evaluating safety and efficacy.
• Female study participants must not be breastfeeding, have a negative pregnancy test at screening (females ≥10 years old), and have no intention to become pregnant during the course of the study. Female study participants who are of childbearing potential (ie, following menarche until ≥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. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (ie, <1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method. In certain countries (if permitted by law), women of childbearing potential may instead agree to abide by heterosexual sexual abstinence during the study and for 30 days after the end of the study.
• Male study participants with sexual partners should use condoms for the duration of the study and for 30 days after the last dose of study drug to prevent passing study drug to the partner in the ejaculate. Male participants should be advised not to donate sperm for 30 days after the last dose of study drug.
• Willingness to maintain current treatment regimen and current exercise regimen for the duration of the clinical study.
• 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 (ALT, AST, or total bilirubin) ≥2× upper limit of normal without prior Sponsor approval.
• Other significant medical condition that, in the opinion of the Investigator or Study Sponsor, may confound interpretation of the clinical course of TK2 deficiency.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: doxecitine and doxribtimine; This is an open label study with all participants in a single arm. Study participants will take doxecitine and doxribtimine up to a maximum of 800 mg/kg/day (400 mg/kg/day doxecitine and 400 mg/kg/day doxiribtimine).	Drug: doxecitine and doxribtimine; Doxecitine and doxribtimine is administered orally in 3 equal doses given approximately 6 to 8 hours apart. Doxecitine and doxribtimine is administered with food.; Other Names: MT1621; GMP grade dC/dT (deoxycytidine and deoxythymidine)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events (TEAEs)	An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication.	From first administration of study drug until end of safety follow-up (up to approximately 7 years)
Incidence of TEAEs leading to study drug withdrawal	An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication.	From first administration of study drug until end of safety follow-up (up to approximately 7 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Global Impression of Improvement (CGI-I) Response score	The CGI-I rating scale permits a global evaluation by the clinician of the study participant's improvement over time after study drug has been initiated. Improvement in a study participant's condition is rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse) as follows: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.	Assessed at end of study (approximately 7 years)
Mean minimum plasma concentration (Cmin) of deoxycytidine (dC) and deoxythymidine (dT) at steady state	Cmin = Minimum plasma concentration	Plasma samples will be collected at Months 1, 3, and 6
Mean maximum plasma concentration (Cmax) of dC and dT at steady state	Cmax = Maximum plasma concentration	Plasma samples will be collected at Months 1, 3, and 6
Mean area under the plasma concentration - time curve from time 0 to 24 hours (AUC0-24) of dC and dT at steady state	AUC0-24 = Area under the plasma concentration-time curve from 0 to 24 hours	Plasma samples will be collected at Months 1, 3, and 6

Collaborators and Investigators

• Sponsor: UCB BIOSCIENCES, Inc.
• Collaborators: Zogenix, Inc.
• Investigators: Study Director: UCB Cares, 001 844 599 2273

Publications and helpful links

General Publications

• Hernandez-Voth A, Sayas Catalan J, Corral Blanco M, Castano Mendez A, Martin MA, De Fuenmayor Fernandez de la Hoz C, Villena Garrido V, Dominguez-Gonzalez C. Deoxynucleoside therapy for respiratory involvement in adult patients with thymidine kinase 2-deficient myopathy. BMJ Open Respir Res. 2020 Nov;7(1):e000774. doi: 10.1136/bmjresp-2020-000774.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2019
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: February 6, 2019
• First Submitted That Met QC Criteria: February 15, 2019
• First Posted (Actual): February 19, 2019

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Mitochondria; Muscle atrophy; mitochondrial disorder; mitochondrial disease; Muscle weakness; TK2d; primary mitochondrial myopathy; mitochondrial depletion syndrome; Loss of mobility; Thymidine Kinase 2 Deficiency; deoxycytidine and deoxythymidine; doxecitine and doxribtimine; MT1621
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Manifestations; Pathologic Processes; Pathological Conditions, Anatomical; Metabolic Diseases; Atrophy; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Muscle Weakness; Muscular Atrophy; Mitochondrial Diseases; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Deoxyribonucleosides; Deoxycytidine; Thymidine
• Other Study ID Numbers: TK0102; 2018-004277-27 (EudraCT Number); U1111-1304-0423 (Other Identifier: World Health Organization (WHO)); 2023-510427-29 (Registry Identifier: EU Clinical Trials)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.
• IPD Sharing Time Frame: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
• IPD Sharing Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No