Satisma: New drug formulation development program of sodium phenylbutyrate in SMA patients.

Fred Marin
GMP-Orphan SAS, France

Friday 22nd June 2012

The applicant presented a program to evaluate the non-selective HDAC inhibitor sodium phenylbutyrate (NaPB), a compound registered for treatment of urea cycle disorders, in SMA. NaPB is an unpleasant drug (taste and odor) so compliance is poor and a real problem with children. GMP-Orphan proposes a paediatric formulation for treatment of SMA. The FDA and EMA have both awarded Orphan Drug Designation to GMP-Orphan. The proposed preclinical plan is a 28 or 90-day safety/ PK bio-comparison of oral and new formulations of NaPB that will be conducted in juvenile minipigs, according to a design consistent with regulatory guidelines. The clinical target population proposed for the subsequent clinical trial is a sub-group of SMA. This study would dose for a limited period of time with an option to extend on the basis of clinical benefit based on a primary endpoint of a biomarker's level and a secondary endpoint of improved survival.  NaPB is known to modify that biomarker's level in patient fibroblasts and human lymphocytes from individuals who have been treated with oral NaPB. The committee felt this was an ambitious plan and identified several challenges, most notably: a) feasibility of identifying the target population; b) the proposed safety package may not support the planned clinical work so early Regulatory interactions were strongly advised; c) preclinical work has not supported changes in brain biomarker level; therefore its use as a primary endpoint in patients may be questionable, although gene copy number is known to correlate positively with survival. A number of recommendations concerned with patient population selection and clinical trial design were made to address these challenges.

12 Apr 2017