Intervention: Sodium Phenylbutyrate
Trial phase: Phase 1 | Phase 2
ATC code: A16AX03
SMILES: O=C([O-])CCCc1ccccc1.[Na+]
Sex: All
Age groups: Child
Healthy volunteers: No
Participants at risk: 5
Group description: Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first three subjects enrolled at 500 mg/kg/day for the duration of the study drug period. The next cohort's dosage was determined by the Modified Continual Re-assessment Method (MCRM) approach and approval of the Study Monitoring Committee (SMC). The MCRM calculation could indicate that additional subjects should be enrolled at the same dosage or a higher dosage. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Eligibility criteria:
Inclusion Criteria:

Subjects must meet all of the following inclusion criteria within 14 days prior to receiving the first dose of study drug.

Weakness and hypotonia consistent with a clinical diagnosis of spinal muscular atrophy (SMA) type I
Laboratory documentation of homozygous absence of SMN1 exon 7
Older than two months of age, but younger than 48 months of age, at the time of enrollment. If the subject is older than 24 months of age at the time of enrollment, the subject must require ventilatory support for at least 6 hours/day.
Written informed consent of parents/guardian
Weight greater than or equal to 7 kilograms
Laboratory results drawn within 14 days prior to start of study drug demonstrating: Hemoglobin within normal range at the clinical site; White Blood Cell Count ≥ 3000/mm³; Platelet Count ≥ 75,000/mm³; Lipase and Amylase ≤ 1.5 x upper limit of normal (ULN) in the absence of associated clinical symptoms; AST and ALT ≤2.5x ULN; Bilirubin ≤ 1.5x ULN in the absence of associated clinical symptoms; Sodium ≥ 130 and ≤ 150 mmol/L; Potassium ≥3.0 and ≤ 5.5 mmol/L; Chloride ≤ 110 mmol/L; Calcium ≥ 8.0 mg/dL; Bicarbonate ≥ 16 mmol/L; Glucose ≥ 55 and ≤ 160 mg/dL; BUN ≤ 39 mg/dL; Creatinine ≤ 1.5 x ULN
Subjects who are on ventilators may enroll in the protocol providing they have been on stable ventilator settings for at least the prior two weeks.
Subject is expected to survive for at least 6 months following study entry

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from participating in the study:

Evidence of renal dysfunction, blood dyscrasia, hepatic insufficiency, symptomatic pancreatitis, cardiac arrhythmia, congenital heart defect, known history of metabolic acidosis, hypertension, significant central nervous system impairment, or neurodegenerative or neuromuscular disease other than SMA.
Any adverse event ≥ Grade 3 at the time of screening based on the protocol toxicity grading table
Any acute co-morbid condition interfering with the well-being of the subject within 7 days of enrollment including bacterial infection, viral infectious process, food poisoning, temperature > 99.0ºF, need for acute treatment or observation due to any other reason, as judged by the investigator.
≥ Grade 2 vomiting;
≥ Grade 2 liver dysfunction/failure (clinical);
Any abnormality noted on EKG except for asymptomatic sinus arrhythmia
History of allergy/sensitivity to sodium phenylbutyrate
Use of sodium phenylbutyrate within 30 days of study entry
Serious illness requiring systemic treatment and/or hospitalization within 14 days prior to study entry (Subjects are not eligible following serious illness until therapy is complete and the subject is stable, or until the subject is on therapy and stable for at least 14 days.)
Poor respiratory status which is expected to require the initiation of BiPAP during the initial 29 days of drug administration.
Use of medications intended for the treatment of SMA including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, haloperidol, agents anticipated to increase or decrease muscle strength or agents with known or presumed histone deacetylase (HDAC) inhibition within 30 days prior to study entry.

Notes: Subjects who use a nebulizer or require an inhaler to receive albuterol will be allowed in the study; however oral use of albuterol is prohibited. Topical use of steroids will be allowed. Oral use of steroids is not allowed at entry, but these may be used as clinically indicated while on study. Event grading will be based on the toxicity-grading table in the protocol.