Study to Evaluate Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy

Prospective Phase I/II Study to Evaluate Effects of Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy

In this single-center trial, we will evaluate the effects of NaPB on presymptomatic Spinal Muscular Atrophy (SMA) type I (cohort 1)and presymptomatic SMA type II (cohort 2) infants. A variety of outcome measures will be performed at each study visit to follow the course of the disease. Total duration of the study for type I infants will be 18 months, for type II infants, 24 months.

Perform a phase I/II study to evaluate effects of sodium phenylbutyrate (NaPB) in a cohort of presymptomatic infants, predicted to develop either SMA type 1 or SMA type 2 given genotype and family history of an older sibling with the respective SMA type. Primary outcomes: 1) to collect additional safety and pharmacokinetic data in neonates and young infants administered NaPB within the dosing guidelines already in use for urea cycle disorder therapy, and 2) to determine possible benefit of early treatment intervention with regard to status of denervation and functional motor status at specific time points for which we have matched natural history data to perform a comparison between cohorts and between each cohort and participants from our natural history database matched for age, SMN2 dosage and gender.

Inclusion Criteria:

• Laboratory documentation of homozygous absence of SMN1 exon 7.
• Confirmation of no more than 3 SMN2 copies for cohort 1; no more than 4 copies for cohort 2.
• Family history of affected sibling with SMA type I for cohort 1 and SMA type II for cohort 2.
• Age ≤ 3 months, cohort 1; Age ≤ 6 months, cohort 2.
• Written informed consent of parents/guardian.
• Laboratory results demonstrating normal values for age.

Exclusion Criteria:

-Evidence of hepatic insufficiency, renal insufficiency, edema with sodium retention, known seizure disorder, urea cycle disorder, cardiac arrhythmia, congenital heart defect, hypertension, significant central nervous system (CNS) impairment, or neurodegenerative or neuromuscular disease other than SMA.

History of allergy/sensitivity to sodium phenylbutyrate (NaPB).

• Use of NaPB within 30 days of study entry.
• Serious illness requiring hospitalization ≤ 14 days prior to study entry.
• Use of medications intended for the treatment of SMA including riluzole, valproic acid, hydroxyurea, oral use of albuterol, NaPB, butyrate derivatives, creatine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, or agents anticipated to increase or decrease muscle strength or agents with presumed histone deacetylase (HDAC) inhibition within 30 days prior to study entry.
• Unwillingness to travel for study assessments.