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MT1621 (nucleoside therapy)

What is MT1621?

MT1621 is an investigational treatment, also known as nucleoside therapy or deoxynucleoside ‘substrate enhancement therapy’ (SET), for a mitochondrial DNA depletion syndrome called TK2 deficiency (TK2d). It is being developed by a global pharmaceutical company called Zogenix (who acquired Modis Therapeutics in August 2019).

How does it work?

MT1621 is thought to work by providing some of the chemical ‘building blocks’, or deoxynucleosides, needed to make and repair mitochondrial DNA (mtDNA). This mtDNA provides the instructions for the machinery that converts energy in mitochondria and is crucial for the normal function of the cell. There are four building blocks needed to make and repair mtDNA, two of which (cytidine and thymidine) are depleted in patients with TK2d. MT1621 is a combination of the two deoxynucleosides found at reduced levels in patients with the condition.

What is it supposed to do?

In TK2 deficiency, there is a ‘traffic jam’ in making mtDNA. MT1621‘bypasses’ this traffic jam by making use of an ‘alternative route’ that avoids the traffic jam.  The correct building blocks are then delivered to the appropriate place and the process of making (or repairing) mtDNA can be restored. This could lead to improved mitochondrial function, which could reduce some of the clinical symptoms associated with TK2 deficiency.

Is it a cure?

Unfortunately not. MT1621 cannot fix the underlying genetic defect that causes this form of mitochondrial disease but it does, at least partially, correct the problem caused by the genetic defect.

What types of mitochondrial disease could it treat?

MT1621 is currently being investigated as a treatment for a mitochondrial DNA depletion syndrome called TK2 deficiency that is caused by genetic errors (mutations) in the thymidine kinase 2 (TK2) gene.

There are other mitochondrial DNA depletion syndromes caused by genetic mutations in a number of different genes, including POLG1 and RRM2B. It is unclear at this stage whether MT1621 could benefit all patients with a mitochondrial DNA depletion syndrome and further preclinical studies are required.

Have there been any trials of MT1621?

Based on preclinical research, MT1621 has been used for a small number of patients in both Europe and America on compassionate grounds. All of the patients who received MT1621 had a mitochondrial DNA depletion syndrome caused by mutations in the TK2 gene.

A retrospective study of 38 patients with TK2d previously treated with MT1621 was completed in May 2019. This involved collecting patient information from the onset of symptoms to understand the disease course and evaluate MT1621.  For more information click here

What is the latest update on this trial?

Those who took part in the previous study were invited to continue using MT1621 in a phase 2, prospective, open-label treatment study to assess the safety and efficacy of MT1621 in patients with TK2d. Patients being treated with MT1621 who did not participate in the previous study can also enroll following approval by the Sponsor. The study aims to recruit up to 40 people with TK2 deficiency and results are expected around December 2021. For more information click here.

Other news

MT1621 has been granted Orphan Drug designation by both the U.S Food and Drug Administration (FDA) and European Medicines Agency (EMA). This aims to advance both the evaluation and development of drugs that have the potential to treat rare diseases and should make it easier for MT1621 to gain marketing approval.

In addition, Modis Therapeutics announced in November 2018 that the EMA had granted PRIME (PRIority MEdicines) designation to MT1621. This was followed by an announcement in February 2019 that the FDA had granted Breakthrough Therapy designation to MT1621. Both of these are designed to speed up the development, review and approval process for drugs that are intended to treat a serious or life-threatening condition so that they may reach patients as early as possible.

For more information click here.

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