Dose-Escalation Safety Study of HPN-100 to Treat Urea Cycle Disorders

Inclusion Criteria:

• Male and female patients at least 18 years old

• Signed written informed consent by patient or patient's representative

• Diagnosis of urea cycle enzyme deficiency confirmed via enzymatic or genetic testing

• Currently treated with Buphenyl® TID for a minimum of 2 weeks prior to Visit 1

• Able to perform study activities (including the ability to collect all urine in theclinic, i.e., no patients in diapers)

• Negative pregnancy test for all females of childbearing potential. All females ofchildbearing potential must agree to use an acceptable method of contraceptionthroughout the study

Exclusion Criteria:

• Use of any investigational drug within 30 days of Buphenyl® Visit 1

• Active infection (viral or bacterial) or any other condition that may increaseammonia levels

• Laboratory values outside the normal range that are determined to be clinicallysignificant by the investigator

• Any clinical or laboratory abnormality of Grade 3 or greater severity according tothe Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditionsnot covered by the CTCAE, a severe or life-threatening toxicity); except that Grade 3 elevations in liver enzymes are allowed in an otherwise clinically stable patient

• Use of any medication known to significantly affect renal clearance (e.g.,probenecid) or to increase protein catabolism (e.g., corticosteroids), or othermedication (e.g., valproate) known to increase ammonia levels, within the 24 hoursprior to Visit 1

• Preexisting QTc interval prolongation (> 450 msec for males or > 460 msec forfemales)

• Other severe chronic medical conditions

• Known hypersensitivity to PAA, PBA, or benzoate

• Creatinine levels equal to or greater than 1.5 × ULN

• Liver transplant