deoxycytidine/deoxythymidine (MT1621) / UCB - LARVOL DELTA

Author response to Commentary on "Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders". (PubMed, Neurotherapeutics) - No abstract available

Journal

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=47 | Completed | Sponsor: UCB BIOSCIENCES, Inc. | Active, not recruiting ➔ Completed

Trial completion • Metabolic Disorders

Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders. (PubMed, Neurotherapeutics) - "Quality of life score improved at 3-month, 12-month, and 18-month timepoints (p < 0.05). In summary, our data suggest deoxycytidine/deoxythymidine is safe and effective for POLG-related disorders; however, further study is needed to clarify the therapeutic mechanism(s) so that the treatment can be refined and optimized."

Journal • CNS Disorders • Epilepsy • Metabolic Disorders • GDF15

Transforming the natural course of infantile onset thymidine kinase 2 deficiency through early nucleoside replacement therapy. (PubMed, J Neuromuscul Dis) - "Early nucleoside therapy halts disease progression and restores motor function in infantile-onset TK2 deficiency, the most severe form of the disease."

Journal • Metabolic Disorders • Myositis

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=40 | Not yet recruiting | Sponsor: Modis Therapeutics, Inc.

New P2 trial • Metabolic Disorders

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=40 | Enrolling by invitation | Sponsor: Modis Therapeutics, Inc. | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • Metabolic Disorders

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=47 | Active, not recruiting | Sponsor: UCB BIOSCIENCES, Inc. | Trial completion date: Jun 2025 ➔ Feb 2026 | Trial primary completion date: Jun 2025 ➔ Feb 2026

Trial completion date • Trial primary completion date • Metabolic Disorders

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=47 | Active, not recruiting | Sponsor: UCB BIOSCIENCES, Inc. | Trial completion date: Jun 2026 ➔ Jun 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Metabolic Disorders

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=47 | Active, not recruiting | Sponsor: Modis Therapeutics, Inc. | Trial completion date: Jan 2022 ➔ Jun 2026 | Trial primary completion date: Jan 2022 ➔ Jun 2024 | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • Metabolic Disorders

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=49 | Enrolling by invitation | Sponsor: Modis Therapeutics, Inc. | Active, not recruiting ➔ Enrolling by invitation

Enrollment open • Metabolic Disorders

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=47 | Active, not recruiting | Sponsor: Modis Therapeutics, Inc. | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Metabolic Disorders

An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency (clinicaltrials.gov) - P2 | N=47 | Active, not recruiting | Sponsor: UCB BIOSCIENCES, Inc. | Trial completion date: Feb 2026 ➔ Jun 2026 | Trial primary completion date: Feb 2026 ➔ Jun 2026

Trial completion date • Trial primary completion date • Metabolic Disorders

Effect of Renal Impairment on the Pharmacokinetics and Safety of Doxecitine and Doxribtimine: A Single-Dose Phase 1 Study. (PubMed, Clin Pharmacol Drug Dev) - "In conclusion, renal impairment was associated with increased dC and dT exposure following a single dose of doxecitine and doxribtimine. No safety issues were identified."

Journal • P1 data • PK/PD data • Metabolic Disorders • Renal Disease

Deoxynucleoside therapy for thymidine kinase 2-deficient myopathy: clinical case (SSIEM 2023) - "When the girl was 6.5 years old, experimental pathogenic therapy was started (deoxythymidine, deoxycytidine 400 mg/kg/day), and respiratory support was adjusted (non-invasive ventilation during sleep)...Conclusion Mitochondrial diseases are a group of poorly understood conditions with a diverse clinical presentation, lack of widely available specific laboratory markers, and a progressive course. Clinical studies with a large number of participants are currently underway addressing the safety and efficiency of the pathogenic and gene therapy possibilities."

Clinical • Fatigue • Gene Therapies • Metabolic Disorders • Myositis

MHRA grants Promising Innovative Medicine designation to UCB’s DoxTM for TK2d (PharmaTimes) - "UCB has announced that its developmental treatment DoxTM, a combination of doxecitine and doxribtimine, has been granted Promising Innovative Medicine (PIM) designation by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. TK2d is a rare genetic disorder caused by a mutation in the TK2 gene."

MHRA approval • Genetic Disorders

Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial. (PubMed, J Neurol) - "These data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders."

Journal • P2 data • Genetic Disorders • Metabolic Disorders • GDF15 • RRM2B

Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures. (PubMed, Neurology) - "Our report highlights the importance of deep-phenotyping infantile TK2d before dC/dT supplementation to stratify disease severity further and suggests a limited tissue-specific brain efficacy."

Journal • CNS Disorders • Epilepsy • Metabolic Disorders • Myositis • Respiratory Diseases

Carbon fluxes rewiring in engineered E. coli via reverse tricarboxylic acid cycle pathway under chemolithotrophic condition. (PubMed, J Biol Eng) - "This study demonstrates a novel strategy to engineer E. coli for CO2 fixation using only one or two heterologous enzymes under chemolithotrophic conditions. These findings reveal the minimal genetic and nutritional requirements for CO2 assimilation and provide insights into metabolic flux partitioning in engineered strains. This research paves the way for sustainable applications in carbon fixation and biotechnological innovation."

Journal

Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial. (PubMed, EClinicalMedicine) - P2 | "Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders. This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé."

Combination therapy • Journal • P2 data • Ataxia • CNS Disorders • Epilepsy • Hepatology • Liver Failure • Metabolic Disorders • Movement Disorders • Myositis • Pain • GDF15

Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults. (PubMed, Clin Ther) - "Doxecitine and doxribtimine are orally bioavailable in the intended clinical dose range. The PK profile supports a formulation consisting of equal doses of doxecitine and doxribtimine, a 3-times-daily dosing regimen, and administration with food."

Journal • P1 data • PK/PD data • Metabolic Disorders

Safety and Efficacy of Deoxycytidine/Deoxythymidine Combination Therapy for POLG-Related Disorders: Clinical Trial (AES 2023) - "dC/dT therapy appears safe and possibly effective in the treatment of POLG-related disorders. Further research is necessary, including randomized controlled trials with long-term follow-up, in order to confirm efficacy and determine the impact on the long-term natural history of the disease."

Clinical • Combination therapy • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy • Hepatology • Liver Failure • Metabolic Disorders • Otorhinolaryngology • Pediatrics • GDF15

Deoxycytidine/Deoxythymidine Combination Therapy Safety and Efficacy in Treatment of POLG-Related Disorders: Results After 6 Months of Treatment (AAN 2023) - "dC/dT therapy appears safe and effective in treatment of POLG-related disorders involving mtDNA depletion."

Clinical • Combination therapy • Late-breaking abstract • Ataxia • CNS Disorders • Epilepsy • Hepatology • Liver Failure • Metabolic Disorders • Movement Disorders • Myositis • Nephrology • Otorhinolaryngology • Pain • Pancreatitis • Pediatrics • Renal Disease • GDF15

A Study of the Efficacy and Safety of MT1621 in Thymidine Kinase 2 (TK2) Deficiency (Treatment naïve) (clinicaltrials.gov) - P3b | N=0 | Withdrawn | Sponsor: Modis Therapeutics, Inc. | N=16 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Metabolic Disorders • Pediatrics

"$ZGNX Zogenix to Host Key Opinion Leader Webinar on Thymidine Kinase 2 Deficiency and MT-1621 https://t.co/5QyaOrYDdV" (,@stock_titan)

Metabolic Disorders

A Study of the Efficacy and Safety of MT1621 in Thymidine Kinase 2 (TK2) Deficiency (Treatment naïve) (clinicaltrials.gov) - P3b; N=16; Not yet recruiting; Sponsor: Modis Therapeutics, Inc.; Phase classification: P3 ➔ P3b; N=25 ➔ 16; Initiation date: Dec 2020 ➔ Sep 2021

Clinical • Enrollment change • Phase classification • Trial initiation date • Metabolic Disorders • Pediatrics