Translarna (ataluren) is an investigational treatment being developed by PTC Therapeutics. It is being studied for the treatment of some patients with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).
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. Both conditions are caused by a mutant (faulty) copy of the DMD gene, which encodes for a protein called dystrophin that is essential to protect muscles from damage.
The DMD 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 DMD gene encoding for a functional dystrophin 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.
How Translarna works
In these patients, nonsense mutation introduces a premature stop signal in the gene that causes the synthesis of the dystrophin protein in the cell to stop prematurely. This results in a truncated protein that cannot function normally and that is subsequently destroyed by the cell. Approximately 13 percent of DMD cases are caused by this type of mutation.
Translarna forces the cell to ignore this abnormal premature stop signal, enabling the production of the full-length, functional protein. Thus, Translarna works as a “protein restoration therapy”, which means that it aims to facilitate the production of a functional protein in patients who cannot produce it normally.
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 with DMD caused by nonsense mutation.
The results, published in the scientific journal Muscle and Nerve, were promising, as patients given 40 mg/kg oral doses of Translarna daily displayed a significant difference in their ability to walk compared to the placebo group after 48 weeks.
These results led the European Medicines Agency (EMA) to grant Translarna conditional approval and allowed PTC Therapeutics to market Translarna within the EU for ambulatory (able to walk) patients over 2 years of age. Translarna was the first treatment addressing the underlying genetic cause of DMD to be approved in the UK.
Further long-term observational studies are required to gain full approval for the treatment. Such a study (NCT02369731) is currently recruiting participants in Austria, France, Germany, Israel, and Sweden.
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 and the application needed further research. On October 24, 2017, the FDA gave its final decision stating that it is unable to approve the application due to the lack of substantial evidence of Translarna’s effectiveness and needs at least an additional adequate and well-controlled clinical trial to demonstrate the treatment’s effectiveness.
In October 2018, PTC Therapeutics announced that initial results from an international registry of patients, called STRIDE, taking Translarna showed slowing of the progression of the disease. The results showed that patients on Translarna were able to stay ambulatory up to 5 years longer than normal patient outcomes. The results were presented at the 23rd International Annual Congress of the World Muscle Society in Argentina.
In October 2019, it was announced that data from the STRIDE registry showed a trend toward slowing of decline of pulmonary (lung) function in DMD patients as well compared to patients receiving standard of care treatment.
PTC Therapeutics announced in April 2019 that Translarna has been approved in Brazil for the treatment of DMD in ambulatory patients 5 years and younger.
PTC Therapeutics applied for a label extension with the Committee for Medicinal Products for Human Use (CHMP) of the EMA for the use of Translarna in non-ambulatory patients as well. The CHMP gave a negative decision regarding the extension of the label, they did clarify the labeling to state that patients who start Translarna while ambulatory do not have to discontinue use once they can no longer walk. PTC Therapeutics intends to request a re-evaluation.
The most common adverse effects caused by Translarna are vomiting, diarrhea, nausea, headache, stomachache, and flatulence.
Last updated: Nov. 26, 2019
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