Orphazyme A/S: arimoclomol

Please refer to your new drug application (NDA) dated July 17, 2020, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for arimoclomol capsules.

We acknowledge receipt of your major amendment dated December 22, 2020, which extended the goal date by three months.

In situations such as this one, we must incorporate regulatory flexibility, while still ensuring there is substantial evidence of effectiveness.

Based upon our review of your submitted data, we are unable to conclude that there is substantial evidence of effectiveness.

We also question the appropriateness of the underlying missing at random assumption based on derived estimated means of the missing hypothetical scores conditional on the observed rajectories using your Mixed Model Repeated Measures (MMRM) analysis.

In a meeting dated July 20, 2017, we reiterated that our earlier advice communicated on September 2, 2016 and January 19, 2017 had not been fully incorporated, and indicated that establishing the validity and standardization of all five domains was needed, especially performance tests for swallowing, cognition, and speech.

We have several concerns with the swallow domain (which together with speech and fine motor skills accounts for the numerical difference in the 5DNPCCSS endpoint between arimoclomol and placebo).

However, the placebo arm had less opportunity to show improvement because 44% of placebo-treated patients had a non-zero score at baseline, with only 38% having high enough baseline scores to allow for a two-point improvement compared to 65% of arimoclomol-treated patients with a non-zero score at baseline.

The confirmatory evidence of effectiveness for arimoclomol appears weak and contradictory, as summarized below:

One of the non-GLP studies showed improved ataxia at the low dose but not at the high dose of arimoclomol.

The second non-GLP study showed improved survival with an unexpected increase in brain glycosphingolipid with arimoclomol.

Although the Lyso-SM-509 data may suggest a possible pharmacologic effect of arimoclomol in NPC patients, the data were not consistent across the 6 and 12 month timepoints and none of the other pharmacodynamic biomarker data showed statistically significant differences between arimoclomol and placebo.

Therefore, the submitted biomarker data are not considered adequate to serve as confirmatory evidence.

Provide substantial evidence of effectiveness for arimoclomol for the treatment of NPC.

4. We recommend that you bolster the confirmatory evidence of effectiveness to help establish that there is a true drug effect.

This application may need discussion at an advisory committee meeting during the next review cycle.