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

• ClinicalTrials.gov Identifier: NCT03845712
• Recruitment Status: Active, not recruiting
• First Posted: February 19, 2019
• Last Update Posted: October 4, 2022
• Sponsor: Modis Therapeutics, Inc.
• Collaborator: Zogenix, Inc.
• Information provided by (Responsible Party): Modis Therapeutics, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Thymidine Kinase 2 (TK2)	Drug: MT1621	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: This is a Phase 2 prospective, open-label treatment study of the safety and efficacy of MT1621 in TK2 deficient patients.
• Masking: None (Open Label)
• Masking Description: Not applicable - this is an open label study.
• Primary Purpose: Treatment
• Official Title: A Phase 2 Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With Thymidine Kinase 2 Deficiency (TK2)
• Actual Study Start Date: July 5, 2019
• Estimated Primary Completion Date: June 24, 2024
• Estimated Study Completion Date: June 24, 2026

Arms and Interventions

Arm

Intervention/treatment

Experimental: MT1621, dC/dT; This is an open label study with all participants in a single arm. Patients will take MT1621 up to a maximum of 800 mg/kg/day (400 mg/kg/day dC and 400 mg/kg/day dT). MT1621 is deoxycytidine (dC) and deoxythymidine (dT) powders for solution for reconstitution in water or apple juice. Study drug will be supplied as powder in packets containing 0.5 or 2.0 g or 4.0 g of dC or dT, and is typically dosed three times/day. MT1621 should be administered with food.

Drug: MT1621; deoxythymidine/deoxythymidine substrate enhancement therapy; Other Name: dC/dT (deoxythymidine/deoxythymidine)

Outcome Measures

Primary Outcome Measures :

1. Safety as adverse events (AEs): number of participants who experience adverse events [ Time Frame: Approximately 3 years ]
   Safety as determined by the number of participants who experience adverse events (AE), type of AE, severity of AE.
2. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
   Number of Participants Who Experience a Clinically Significant Change from Baseline in Clinical Laboratory Tests.
3. Safety as determined by electrocardiograms (ECGs) [ Time Frame: Approximately 3 years ]
   Number of Participants Who Experience a Clinically Significant Change from Baseline ECG.

Secondary Outcome Measures :

1. Efficacy - Motor Function Assessments [ Time Frame: Approximately 3 years ]
   Patient or physician reported achievement (capable) or loss (not capable) of gross motor milestones.
2. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
   Pulmonary Function Tests (PFTs).
3. Efficacy - Growth/Nutrition [ Time Frame: Approximately 3 years ]
   Growth in patients over time compared to normals using the WHO reference standards and expressed as Z scores.
4. Efficacy - Growth/Nutrition [ Time Frame: Approximately 3 years ]
   Requirement for supplemental feeding/feeding tube within 1 patient over time and time to change of status of use of supplemental feeding/feeding tube (tube inserted for feeding use vs tube removed).
5. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
   PK of dC/dT (Cmax - peak plasma concentration).
6. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
   PK of dC/dT (Tmax - time to maximum plasma concentration).
7. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
   PK of dC/dT (AUC - area under the plasma concentration time curve).
8. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
   PK of dC/dT (t 1/2 - time to half life of drug or period of time required for plasma concentration or amount in the body to be reduced by exactly one-half).
9. Biomarkers (plasma from blood) [ Time Frame: Approximately 3 years ]
   Biomarkers which may be related to TK2 disease and/or drug treatment (eg, number of participants with normal vs abnormal creatine kinase measured in u/l compared to normal ranges).
10. Biomarkers (plasma from blood) [ Time Frame: Approximately 3 years ]
    Biomarkers which may be related to TK2 disease and/or drug treatment (eg, number of participants with normal vs abnormal lactate levels measured in mmol/l compared to normal ranges).
11. Quality of life through patient questionnaire - Individualized Neuromuscular Quality of Life (INQoL) [ Time Frame: Approximately 3 years ]
    INQOL Questionnaire with 15 questions in 3 sections about muscle weakness, pain, fatigue, locking of muscles, droopy eyelids, vision, swallowing, daily activity, independence, relationships, feelings, appearance, and treatment where patients aged 12 years and older rate how they feel and their muscles function to accomplish daily activities on a scale of 0 to 7, where lower values are generally associated with a better outcome.
12. Characterization of health care utilization [ Time Frame: Approximately 3 years ]
13. Efficacy Assessment: Clinical Global Impression of Improvement (CGI-I) and Patient Global Impression of Improvement (PGI-I) [ Time Frame: Approximately 3 years ]
    Clinical Global Impression of Improvement (CGI-I) completed by Investigator and Patient Global Impression of Improvement (PGI-I) completed by the patient/caregiver.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed informed consent by the parent(s) or legally authorized representative (LAR) and/or assent by the patient (when applicable).
2. Confirmed genetic mutation in the TK2 gene.
3. Absence of other genetic disease or polygenic disease.
4. Current treatment with nucleos(t)ides for TK2 deficiency. Patients who were not previously enrolled in MT 1621 101 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.
5. Female patients 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 patients 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.
6. Male patients 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.
7. Willingness to maintain current treatment regimen and current exercise regimen for the duration of the clinical study.
8. Willingness to comply with the study protocol, including but not limited to, all study procedures, study visits, and study drug compliance.

Exclusion Criteria:

1. History of liver disease, or liver function test results (ALT, AST, or total bilirubin) ≥2× upper limit of normal without prior Sponsor approval.
2. Other significant medical condition that, in the opinion of the Investigator or Study Sponsor, may confound interpretation of the clinical course of TK2 deficiency.

Contacts and Locations

Locations

United States, New York

New York Presbyterian Hospital-Columbia University Medical Center

New York, New York, United States, 10032

Israel

Rambam Hospital

Haifa, Israel, 3109601

Wolfson Medical Center

H̱olon, Israel, 5822012

Spain

Hospital Vall d'Hebron

Barcelona, Spain, 08035

Sant Joan de Deu Hospital

Barcelona, Spain, 08950

Hospital 12 de Octubre

Madrid, Spain, 28041

Hospital Universitario Virgen del Rocio

Seville, Spain, 41013

Sponsors and Collaborators

Modis Therapeutics, Inc.

Zogenix, Inc.

Investigators

• Study Director: Susan VanMeter, MD; Modis Therapeutics

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Modis Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03845712
• Other Study ID Numbers: MT-1621-102
• First Posted: February 19, 2019
• Last Update Posted: October 4, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Modis Therapeutics, Inc.:

Thymidine Kinase 2 Deficiency; TK2d; mitochondrial disorder; mitochondrial disease; Mitochondria; deoxythymidine/deoxythymidine substrate enhancement therapy; dC/dT; deoxythymidine/deoxythymidine; primary mitochondrial myopathy; mitochondrial depletion syndrome; Muscle weakness; Muscle atrophy; Loss of mobility