Translarna Improved Activity Measures in Phase 3 Trial, But Results Lack Significance

PTC Therapeutics shared additional data from a Phase 3 trial of Translarna (ataluren), showing that the treatment slightly slowed disease progression in ambulatory boys with Duchenne muscular dystrophy.

The data was presented at the recent American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting in Phoenix, Arizona.

But although several parameters favored Translarna, the differences from placebo-treated patients were not statistically significant.

The presented data was an analysis of the ACT DMD Phase 3 trial, (NCT01826487), which assessed Translarna’s effectiveness and safety in 228 Duchenne patients with so-called nonsense mutations in their dystrophin gene.

Nonsense mutations introduce a stop signal — read by the protein-making machinery — in a gene. This mutation leads to the production of a truncated, and nonfunctional, form of dystrophin. Translarna works by bypassing the stop sign to produce a functional dystrophin protein.

Researchers assessed how well study participants moved using the North Star Ambulatory Assessment (NSAA), which is a tool developed specifically to measure disease progression in Duchenne patients who are still able to walk.

The NSAA scores a variety of activities, ranging from standing up from a chair to jumping. Each activity can be given a score of 0, 1, or 2, with low numbers representing a poorer function.

The presentation, “Results of North Star Ambulatory Assessments in the Phase 3 Ataluren Confirmatory Trial in Patients With Nonsense Mutation Duchenne Muscular Dystrophy,” showed that over the 48 weeks of the trial, Translarna-treated patients had an average score reduction of 7.0. Those who received placebo worsened by 8.5 points — making a difference of 1.5 points between the groups.

Researchers also reported that fewer patients in the Translarna group shifted from a score of 1 or 2, which signified they were able to perform the activity, to 0 or an inability to perform. This was seen across all 17 functions tested, researchers said.

Looking at individual function tests, Translarna-treated patients consistently performed better, with differences ranging between 1 percent for lifting head, to 12 percent for rising from a chair.

The U.S. Food and Drug Administration (FDA) is reviewing the marketing application for Translarna, and is expected to reach a conclusion by Oct. 24, 2017. But the outcome of the review is far from clear.

In 2016, the FDA rejected a new drug application (NDA) for Translarna because of an incomplete application. In March 2017, PTC applied again. The FDA has called PTC to a meeting, scheduled Sept. 28, to discuss the application.

But the NDA builds on data from a trial — ACT DMD — that failed to show a statistical difference in its primary outcome measure of the 6-minute walk test (6-MWT). The test, which assesses exercise tolerance, showed that Translarna-treated boys performed on average 15 meters more than their placebo-treated peers at the end of the study.

While this difference was too subtle to be considered statistically significant, U.S. regulators still agreed to review the data. The willingness to accept the application might be tied to Translarna’s better efficiency in a subgroup of patients who could walk 300–400 meters in the 6-MWT when the trial began. In this group, Translarna-treated boys performed on average 47 meters more than those receiving a placebo — a difference considered statistically significant.

Meanwhile, however, PTC needs to perform another trial to provide more data. This long-term study (NCT03179631) is ongoing.

European regulators adopted a different approach to the drug. Translarna is conditionally approved for Duchenne patients, five years or older. While the approval was renewed in January, its continuing approval is dependent on data from the long-term trial, which is expected to complete in 2021.