PTC Therapeutics, Inc.: vatiquinone

1. After a detailed review of your application, we have concluded that the data do not demonstrate substantial evidence of effectiveness (SEE) for vatiquinone in the treatment of Friedreich's Ataxia (FA).

You proposed to meet the evidentiary standard based on a single adequate and well-controlled study with confirmatory evidence.

The single controlled trial supporting this application, PTC742-NEU003-FA (MOVE-FA), is not capable of serving as a single adequate and wellcontrolled study, with or without confirmatory evidence (CE), to provide SEE.

Change from baseline in mFARs is an outcome measure that is considered by FDA to be an acceptable primary endpoint to assess clinically meaningful change in how a patient with FA functions.

You have proposed that the nominally significant results of the prespecified exploratory analyses of the Upright Stability Subscale (USS) of the mFARS provide evidence of effectiveness of vatiquinone in FA.

The clinical meaningfulness of the treatment difference is uncertain.

At baseline, the placebo group had more subjects with younger age of onset (94% of subjects in placebo group versus 87% of subjects in vatiquinone group had disease onset before 14 years old).

Overall, the nominally significant findings on the USS are not sufficiently statistically robust or persuasive to overcome the limitations of the clearly negative findings on the prespecified analyses of the primary and secondary endpoints.

The overall persuasiveness of the findings on the USS, a nominally significant exploratory endpoint, in the setting of negative results on an acceptable clinically meaningful primary endpoint and key secondary endpoints are not sufficient to establish the effectiveness of vatiquinone for the treatment of FA.

Should you choose to resubmit the NDA in future, we encourage you to submit relevant biomarker data in patients with FA acquired as per FDA's regulatory standards to serve as confirmatory evidence of effectiveness.