A Phase 3b Single Arm Clinical Study to Evaluate the Efficacy and Safety of MT1621 in Nucleos(t)Ide Treatment Naïve Pediatric and Adolescent Subjects With Thymidine Kinase 2 (TK2) Deficiency

This is a Phase 3b, prospective, single-arm, multicenter, open-label treatment study of the efficacy and safety of MT1621 in pediatric and adolescent 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.

Start Date30 Sep 2022

Sponsor / Collaborator

Zogenix, Inc.

NCT03701568 / CompletedNot Applicable

A RETROspective Study of the Combination of Pyrimidine Nucleos(t)Ides in Patients With Thymidine Kinase 2 Deficiency (TK2)

This is a medical chart review study to collect information for patients who have been taking pyrimidine nucleosides for treatment of TK2 deficiency. Information from the time of onset of symptoms will be collected to describe the pre treatment course of TK2 deficiency.

Start Date19 Nov 2018

Sponsor / Collaborator

Zogenix, Inc.

100 Clinical Results associated with Deoxythymidine/Deoxycytidine

100 Translational Medicine associated with Deoxythymidine/Deoxycytidine

100 Patents (Medical) associated with Deoxythymidine/Deoxycytidine

Literatures (Medical) associated with Deoxythymidine/Deoxycytidine

01 Aug 2024·eClinicalMedicine

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

Article

Author: Eberhard, Ralf ; Cheung, Anthony C T ; Myers, Kenneth A ; Gagnon, Tommy ; Dassi, Christelle ; Pekeles, Heather ; Waters, Paula J ; Buhas, Daniela ; Berrahmoune, Saoussen

BackgroundDNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months-12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders.MethodsIn this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December, 2023.FindingsWe present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3 at baseline to 20.7 at 6 months (estimated difference 6.0; 95% CI 2.5-∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031 pg/ml to 729 pg/ml (estimated difference 200; 95% CI 12-∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved.InterpretationdC/dT is a promising treatment option for people with POLG-related disorders. 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.FundingThis 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.

01 May 2024·Mitochondrion

Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report

Article

Author: Hernández-Voth, Ana ; Martin-Jimenez, Paloma ; Martin, Miguel A ; Blázquez, Alberto ; Domínguez-González, Cristina ; Bermejo-Guerrero, Laura ; Serrano-Lorenzo, Pablo

OBJECTIVESThymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d.METHODSAn adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented.RESULTSAfter 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea.DISCUSSIONTreatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d.

01 Nov 2020·BMJ Open Respiratory Research

Deoxynucleoside therapy for respiratory involvement in adult patients with thymidine kinase 2-deficient myopathy

Article

Author: Dominguez-Gonzalez, Cristina ; Sayas Catalan, Javier ; Castaño Mendez, Alba ; Villena Garrido, Victoria ; Hernandez-Voth, Ana ; Martin, Miguel Angel ; De Fuenmayor Fernandez de la Hoz, Carlos ; Corral Blanco, Marta

BackgroundRecessive mutations in the thymidine kinase 2 (TK2)gene cause a rare mitochondrial myopathy, frequently with severe respiratory involvement. Deoxynucleoside therapy is currently under investigation.Research questionWhat is the impact of nucleosides in respiratory function in patients with TK2-deficient myopathy?Study design and methodsRetrospective observational study of patients treated with deoxycytidine and deoxythymidine. Evaluations were performed every 3 to 4 months after treatment during approximately 30 months. Forced vital capacity (FVC), maximuminspiratory and expiratory pressures (MIP/MEP), sniff nasal inspiratory pressure (SNIP), cough peak flow (CPF), arterial blood gas and nocturnal pulse oximeter (SpO2) were collected.ResultsWe studied six patients, five of which were women, with a median age at onset of symptoms was 35.8 (range 5 to 60) years old. Patients presented a restrictive ventilatory pattern (median FVC of 50 (26 to 71)%) and severe neuromuscular respiratory weakness (MIP 38 (12 to 47)% and SNIP 14 (8 to 19) cmH2O). Four patients required ventilatory support before starting the treatment. FVC improved by 6%, proportion of sleep time with SpO2 <90% diminished from 14% to 0%, CPF increased by 23%, MEP increased by 73%, production and management of bronchial secretions improved and respiratory infections diminished.InterpretationEarly detection of respiratory involvement requires an active search, even in asymptomatic patients. The nucleosides therapy may improve respiratory function, and stabilise the loss of respiratory capacity.

100 Deals associated with Deoxythymidine/Deoxycytidine

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Indication	Highest Phase	Country/Location	Organization	Date
Thymidine kinase 2 deficiency	NDA/BLA	BE	UCB SA	30 Jan 2022

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