A Study of the Efficacy and Safety of MT1621 in Thymidine Kinase 2 (TK2) Deficiency

• ClinicalTrials.gov Identifier: NCT04581733
• Recruitment Status: Not yet recruiting
• First Posted: October 9, 2020
• Last Update Posted: December 19, 2020
• Sponsor: Modis Therapeutics, Inc.
• Collaborator: Zogenix, Inc.
• Information provided by (Responsible Party): Modis Therapeutics, Inc.

Study Description

Brief Summary:

This is a Phase 3, prospective, multicenter, open-label treatment study of the efficacy and safety of MT1621 in patients with thymidine kinase 2 deficiency (TK2d). In order to be eligible for this study, participants must have genetic confirmation of TK2d and must not have ever received MT1621 or nucleos(t)ides before entering the study.

Condition or disease	Intervention/treatment	Phase
Thymidine Kinase 2 Deficiency	Drug: MT1621	Phase 3

Detailed Description:

Thymidine kinase 2 (TK2) is a protein involved in the normal function of mitochondria. Thymidine kinase 2 deficiency (TK2d) is a form of mitochondrial DNA depletion syndrome and is a very rare inherited genetic disorder. TK2d leads to abnormally low amounts of DNA in mitochondria and because of the low amount of DNA, the mitochondria are not able to provide the energy that cells need to function properly, which causes severe muscle weakness that can progress until patients lose the ability to stand, walk, eat, and breathe independently. There are no FDA-approved medicines to treat TK2d.

MT1621 is a therapy that targets the underlying pathophysiology of TK2d by restoring mitochondrial DNA (mtDNA) replication fidelity. MT1621 consists of a combination of deoxynucleosides (the building blocks of mtDNA) given orally. Deoxynucleoside combination therapy improves nucleotide balance, increases mtDNA copy number, improves cell function, and prolongs life in preclinical models of TK2d.

This is a Phase 3, prospective, multicenter, open-label treatment study to assess the efficacy and safety of MT1621 in patients with TK2d. In order to be eligible for this study, participants must have the TK2d genetic mutation and must not have ever received MT1621 or nucleos(t)ides before entering the study.

Participants who meet entry criteria will be enrolled in one of the following two groups depending on their age at time of enrollment:

Group A: ≤12 years of age. Participants will receive MT1621 on Day 1 for up to 24 months and complete study visits every 3 months where they will undergo safety, motor milestone, and functional efficacy assessments.

Group B: >12 years of age. Participants will undergo up to a 9-month run-in phase where they will complete safety and efficacy assessments only to better characterize the natural course of late-onset TK2d. Once the run-in phase is complete or upon meeting the escape rules during the run-in phase (defined as an objective decline in motor or respiratory status per protocol), participants will receive MT1621 and complete safety, motor milestone, and functional efficacy assessments for up to 39 months.

Once all participants have completed the treatment phase as described above, they will complete a final follow-up contact 4 weeks after the last dose.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

All participants will receive MT1621 up to a maximum of 400 mg/kg/day

Eligible participants will enter 1 of 2 groups:

• Group A: approximately 10 participants aged ≤12.0 years will receive MT1621 on Day 1
• Group B: approximately 15 participants aged >12.0 years will receive MT1621 after completing an up to 9-month run-phase

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Single Arm Clinical Study to Evaluate the Efficacy and Safety of MT1621 in Subjects With Thymidine Kinase 2 (TK2) Deficiency
• Estimated Study Start Date: December 2020
• Estimated Primary Completion Date: March 2025
• Estimated Study Completion Date: April 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Participants ≤12.0 years (Group A); Group A: Male or female participants ≤12.0 year old. All participants will receive MT1621 starting on Day 1	Drug: MT1621; All patients will receive MT1621 up to a maximum of 400 mg/kg/day each dC and dT, as tolerated; Other Name: Deoxycytidine (dC) and deoxythymidine (dT)
Experimental: Participants >12.0 years (Group B); Group B: Male or female participants >12.0 years old (≤7 participants on ventilatory support) All participants will complete a 9-month run-in phase (MT1621 will not be administered). After the completion of the 9-month run-in phase, all participants will receive MT1621.	Drug: MT1621; All patients will receive MT1621 up to a maximum of 400 mg/kg/day each dC and dT, as tolerated; Other Name: Deoxycytidine (dC) and deoxythymidine (dT)

Outcome Measures

Primary Outcome Measures :

1. Time to Loss of Any Motor Milestone [ Time Frame: 24 months ]
   Risk of loss of any motor milestone (e.g., head control, rolling, standing, walking, jumping, hopping, running): Occurrence of loss of any motor milestone will be considered an event and the duration for event will be calculated as time from first MT1621 treatment date to the first date any of the motor milestones are lost. Patients who do not lose any milestone will be censored and their duration period will be the time from first MT1621 treatment date and the last contact date.

Secondary Outcome Measures :

1. Time to Acquisition of Any Motor Milestone [ Time Frame: 24 months ]
   Probability of acquisition of any motor milestone (e.g., head control, rolling, sitting, standing, walking, jumping, hopping, running): Occurrence of acquiring any motor milestone will be considered an event and the duration for event will be calculated as time from first MT1621 treatment date to the first date of acquiring any motor milestones. Patients who do not acquire any milestone will be censored and their duration period will be the time from first MT1621 treatment date and the last contact date.
2. Overall Survival [ Time Frame: 24 months ]
   Risk of death: Occurrence of death will be considered an event and the duration for event will be calculated as time from first MT1621 treatment date to death date. Patients who survived will be censored and their duration period will be the time from first MT1621 treatment date and the last contact date.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Diagnosis of TK2 deficiency based on confirmed disease-causing mutation(s) in the TK2 gene
• Absence of other confirmed genetic disease or polygenic disease that may confound evaluation of the efficacy of treatment for TK2 deficiency

Additional Inclusion Criteria, Evidence of a motor deficit:

• Group A: Significant loss or decline (regression) in previously achieved motor milestones or developmental delay in achieving motor milestones
• Group B: Unable to perform at least one of the motor milestones

Exclusion Criteria:

• History of liver disease, or liver function test results (alanine aminotransferase [ALT], aspartate transaminase [AST], or total bilirubin) ≥2× upper limit of normal at Screening without prior Sponsor approval
• EtCO2>45 mmHg if not on ventilatory support

Contacts and Locations

Contacts

Contact: Zogenix Clinical Trials Information Desk; 510-338-9968; MT1621ClinStudyInfo@zogenix.com

Sponsors and Collaborators

Modis Therapeutics, Inc.

Zogenix, Inc.

Investigators

• Study Director: Joanne Quan, MD; Modis Therapeutics, Inc.

More Information

• Responsible Party: Modis Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT04581733
• Other Study ID Numbers: MT-1621-104
• First Posted: October 9, 2020
• Last Update Posted: December 19, 2020
• Last Verified: December 2020

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.:

TK2d; TK2; 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