12:00 AM
Jun 02, 2014
 |  BioCentury  |  Regulation

History lesson

How PTC changed CHMP's mind on Translarna for DMD

CHMP's recommendation for conditional approval of Translarna ataluren to treat Duchenne muscular dystrophy just five months after rebuffing the compound suggests the agency is getting a clearer picture about how to interpret efficacy measures across the course of the disease.

In January's negative opinion, EMA's CHMP noted PTC Therapeutics Inc.'s main study of Translarna - a 174-patient Phase IIb trial (Study 007) - did not show a benefit on the primary endpoint of six-minute walk distance (6MWD). The committee also said other measures of effectiveness provided "only limited supportive evidence of the beneficial effects of Translarna."

PTC overcame the committee's concerns by submitting reanalyzed data from Study 007, including post hocsubgroup analyses, and additional data from studies that demonstrated the natural history of DMD, plus Translarna's MOA and dose-response relationship.

According to CEO Stuart Peltz, PTC had to first help CHMP understand the natural course of DMD as proper context for interpreting the efficacy analyses.

Defining the disease course let PTC zero in on two patient subpopulations that would most dramatically show treatment effects, and justify the most appropriate outcome measures for them.

Peltz said the key groups and outcomes for CHMP's reassessment were boys with a baseline 6MWD less than 350 meters, for whom 6MWD is a sensitive outcome, and boys aged 5-6, for whom muscle strength is a sensitive outcome.

Though some boys in the trial didn't fall into either of these two groups, CHMP backed conditional approval to treat the entire trial population: patients five years and older who are able to walk.

In announcing its decision, EMA said CHMP found "some evidence of efficacy" that outweighed the product's risks sufficiently to recommend conditional marketing authorization.

EMA also said Translarna's safety profile was "not of concern," and acknowledged the unmet medical need of DMD patients.

There are no approved therapies for DMD. Corticosteroids are often prescribed to reduce inflammation and maintain muscle mass and function, but they have serious side effects when used chronically.

If the EC grants conditional approval, it may be renewed yearly, with full approval contingent upon results of an ongoing Phase III trial of Translarna. The study is expected to complete in mid-2015. An EC decision is expected in three months.

Translarna is a small molecule that treats the 13% of DMD cases caused by nonsense mutations that insert a premature stop codon in the gene encoding dystrophin (DMD). Translarna induces the ribosome to read through premature stop codons and express the full dystrophin protein.


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