DMD is an inherited progressive muscle wasting condition, where the patient’s muscles gradually weaken over time. BMD is a milder version of the disease. The condition is caused by inheriting a mutant (faulty) copy of the dystrophin gene, which is essential to protect muscles from damage. The dystrophin gene is located on the X chromosome. Because males have only one X chromosome, if they inherit a faulty copy of the gene from their mother, they develop the disease. Females are usually not affected because they inherit a second copy of the X chromosome from their father, which contributes a healthy version of the dystrophin gene encoding for a functional protein. Symptoms of DMD can begin as early as age 3. As the disease progresses the patient will find activities such as walking increasingly more difficult, eventually losing the ability to walk altogether.
Translarna can only treat people with DMD caused by a particular type of defect in the dystrophin gene called a nonsense mutation, which results in no functional dystrophin gene being produced by the body. Approximately 13 percent of DMD cases are caused by this type of mutation.
How Translarna works
Translarna is a “protein restoration therapy,” which means it aims to facilitate the production of a functional protein in patients who cannot produce it normally.
In DMD patients who have a nonsense mutation in the dystrophin gene, the mutation introduces a premature stop signal in the gene. This causes the synthesis of the dystrophin protein in the cell to stop prematurely, resulting in a truncated protein that cannot function normally and that is destroyed by the cell.
Translarna forces the cell to ignore this abnormal premature stop signal, enabling the production of the full-length, functional protein.
Translarna in clinical trials
A key clinical study for Translarna was a Phase 2b randomized, double-blind, placebo-controlled study (NCT00592553) to assess the safety, dosage, and efficacy of the treatment in boys (5 years or older) from 11 countries. The results, published in the scientific journal Muscle and Nerve, were promising, as patients given 40mg/kg of Translarna daily displayed a significant difference in their ability to walk compared to the placebo group after 48 weeks.
These results led to the European Medicines Agency (EMA) giving Translarna conditional approval, allowing PTC Therapeutics to market the drug within the EU. However, participants are currently being recruited for further long-term observational studies (NCT02369731) required to gain full approval. Approval may also be withdrawn if certain conditions are not met. Translarna was the first drug addressing the underlying genetic cause of DMD to be approved in the UK.
The U.S Food and Drug Administration (FDA) accepted a New Drug Application (NDA) for Translarna on March 6, 2017. However, on September 28, 2017, the FDA’s Peripheral and Central Nervous Systems Drugs Advisory Committee concluded that the evidence to support the effectiveness of Translarna as a DMD treatment was inconclusive. The committee’s opinion is that further research is needed to support the application, and this will be considered in the FDA’s final decision for marketing approval. The FDA have set an action date of October 24, 2017, to complete its review of the Translarna application.
Translarna is provided as granules, to be taken orally with liquid or semi-solid food three times daily at 10mg/kg (in the morning and midday) and 20mg/kg (in the evening).
The most common adverse effects caused by the drug are vomiting, diarrhea, nausea, headache, stomach ache, and flatulence.
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