Design of a Phase 3 Prospective Clinical Study for the Treatment of Thymidine Kinase 2 Deficiency

Topic:

Clinical Trials

Poster Number: 56

Author(s):

Michio Hirano MD, FAAN, Qais Abu Ali MD, Cristina Dominguez-González MD, PhD, Andres Berardo MD, PhD, Richard Haas MB, BChir, Chamindra Konersman MD, Robert McFarland BA, MBBS, PhD, Gwyn D'Souza PhD, Shaheen Lakhan MD, PhD, Joanne Quan MD, Bruce Thompson PhD, Bruce H. Cohen MD, FAAN

Institutions:

1. Columbia University Irving Medical Center, 2. Modis Therapeutics (a Wholly Owned Subsidiary of Zogenix, Inc.), 3. Hospital Universitario 12 de Octubre, 4. Columbia University Irving Medical Center, 5. University of California San Diego, 6. University of California San Diego, 7. Newcastle University, 8. GDS ClinicalZest Ltd, 9. Modis Therapeutics (a Wholly Owned Subsidiary of Zogenix, Inc.), 10. Modis Therapeutics (a Wholly Owned Subsidiary of Zogenix, Inc.), 11. Theta Hat Statistical Consultants, 12. Akron Children's Hospital

Background: Thymidine kinase 2 deficiency (TK2d) is an ultra-rare, often lethal autosomal recessive mitochondrial disease in which primary mutations in the nuclear DNA-encoded TK2 gene cause depletion and/or deletions of mitochondrial DNA. TK2d presents as a myopathy with variable age of onset, causing weakness of limb, bulbar, and respiratory muscles. Preclinical studies in TK2-deficient mice and clinical compassionate use studies in patients with TK2d have demonstrated that oral administration of deoxynucleosides (deoxycytidine/deoxythymidine; dC/dT) is safe and efficacious.

Objectives: Here, we present the design of a global, multicenter, prospective, phase 3, single-arm clinical trial to evaluate and confirm the efficacy and safety of substrate enhancement therapy with pharmaceutical grade dC/dT (MT1621) for TK2d.

Results: The trial will recruit ~25 subjects with genetically confirmed TK2d. Subjects will be divided into 2 age groups: Group A (n=~10 patients, aged ≤12.0 years) and Group B (n=~15 patients, aged >12.0 years). Group A will be treated up to 24 months with MT1621. Before treatment, Group B will undergo up to a 9-month run-in phase to assess TK2d natural history, followed by MT1621 treatment up to 39 months. The primary endpoint will be loss of a motor milestone that was present at baseline (before MT1621) as assessed after 24 months of MT1621 treatment. Secondary endpoints will include survival and time to acquisition of a motor milestone that was absent at baseline. Change from pretreatment baseline will be assessed for additional motor assessments, respiratory function, and feeding tube status. Safety assessments and pharmacokinetics will be conducted in parallel.

Conclusions: This new prospective good clinical practice study characterizes the efficacy and safety of the investigational therapy MT1621 in subjects with TK2d. This study also provides a unique opportunity to collect prospective natural history information in adolescents and adults.

Funding: Modis Therapeutics, a wholly owned subsidiary of Zogenix.