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

Perform a phase I/II study to evaluate effects of PBA in a cohort of 12 presymptomatic
infants. These infants are predicted to have either SMA 1 or 2 given genotype and family
history of an older sibling with the respective SMA type. Our goal is twofold: 1) to collect
additional safety and pharmacokinetic data in neonates and young infants administered this
compound, 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. Data obtained from this aim will guide future
trials designed to determine the efficacy of PBA or other butyrate analogs in attenuating
disease progression in SMA subjects identified in the presymptomatic period.

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.