Urea Cycle Disorders Prior Authorization Criteria Program Summary

Home , Glycerol phenylbutyrate, Sodium phenylbutyrate

OBJECTIVE The intent of the Urea Cycle Disorders Prior Authorization (PA) program is to appropriately select patients for treatment according to product labeling and/or clinical studies and/or clinical practice guidelines. The PA criteria consider these agents appropriate for use in patients who have been diagnosed with any of the following urea cycle disorders (UCD): carbamylphosphate synthetase I deficiency [CPSID], ornithine transcarbamylase deficiency [OTCD], argininosuccinic acid synthetase deficiency [ASSD], argininosuccinic acid lyase deficiency [ASLD], or arginase deficiency [ARGD]. The use of these agents in N-acetyl glutamate synthetase deficiency [NAGS] has not been evaluated. The agent may not be used in the acute setting. Patients must also not be able to manage the disease by a protein restricted diet or with essential amino acid supplementation alone. The patient may not have any FDA labeled contraindications to therapy with the requested agent and the dose must be within the FDA labeled dosing.

TARGET DRUGS aBuphenyl (sodium phenylbutyrate) Ravicti (glycerol phenylbutyrate) a-generic available

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Initial Evaluation Buphenyl OR Ravicti will be approved for use when ALL of the following are met: 1. ALL of the following: a. plasma ammonia level of 150 µmol/L (>260 µg/dl) or higher if a neonate or > 100 µmol/L (≥175 µg/dl) if an older child or adult AND b. The patient has a normal anion gap AND c. The patient has a normal blood glucose level AND 2. The patient has a diagnosis of ONE of the following urea cycle disorders: a. carbamylphosphate synthetase I deficiency [CPSID] b. ornithine transcarbamylase deficiency [OTCD] c. argininosuccinic acid synthetase deficiency [ASSD] d. argininosuccinic acid lyase deficiency [ASLD] e. arginase deficiency [ARGD] AND 3. The patient does not have acute hyperammonemia AND 4. The patient is unable to maintain a plasma ammonia level within the normal range with the use of a protein restricted diet and essential amino acid supplementation AND 5. The patient does not have any FDA labeled contraindication(s) to therapy with the requested agent AND 6. The dose is within the FDA labeled dosing

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Renewal Evaluation Buphenyl or Ravicti will be renewed when the following are met: 1. The patient has been previously approved through the Prime Therapeutics Prior Authorization process AND 2. The patient is unable to maintain a plasma ammonia level within the normal range with the use of a protein restricted diet and essential amino acid supplementation AND 3. The patient does not have any FDA labeled contraindication(s) to therapy with the requested agent AND 4. The dose is within the FDA labeled dosing

Length of Approval: 12 months

Agent Contraindication Buphenyl (sodium phenylbutyrate) acute hyperammonemia Ravicti (glycerol phenylbutyrate) -patients < 2 months of age -known hypersensitivity to phenylbutyrate

Agent(s) Dosing  Usual total daily dose in patients with UCD: 450-600 mg/kg/day in patients <20kg or 9.9-13.0 g/m2/day in larger patients in equally divided doses with each meal or feeding. Buphenyl  The powder is to be mixed with food for immediate use and is designed for oral use only (mouth, gastrostomy, or nasogastric tube).  The safety and efficacy of doses > 20 grams per day has not been evaluated.

Initial dose in phenylbutyrate naïve patients: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) to be given in 3 equally divided doses.  Switching from sodium phenylbutyrate: daily dosage of sodium phenylbutyrate (g) X 0.86. Ravicti  For patients with some enzyme activity who are not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m2/day.  Round total daily dose up to the nearest 0.5 mL. Maximum daily dosage is 17.5 mL.

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© Copyright Prime Therapeutics LLC. 10/2015 All Rights Reserved FDA APPROVED INDICATIONS AND DOSAGE1,4 Agent(s) Indication(s) Dosing  Adjunctive therapy in the chronic management of patients with urea cycle disorders (UCD) involving deficiencies of  Usual total daily dose in patients carbamylphosphate synthetase with UCD: 450-600 mg/kg/day in (CPS), ornithine patients <20kg or 9.9-13.0 transcarbamylase (OTC), or g/m2/day in larger patients in argininosuccinic acid synthetase equally divided doses with each (AS). meal or feeding. a Buphenyl (sodium  All patients with neonatal-onset  The powder is to be mixed with phenylbutyrate)^ deficiency (complete enzymatic food for immediate use and is deficiency, presenting within the designed for oral use only (mouth, first 28 days of life) gastrostomy, or nasogastric tube).  All patients with late-onset  The safety and efficacy of doses > disease (partial enzymatic 20 grams per day has not been deficiency, presenting after the evaluated. first month of life) who have a history of hyperammonemic encephalopathy.

Initial dose in phenylbutyrate naïve patients: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) to be given in 3 equally Chronic management of adult and divided doses. pediatric patients ≥2 years of age  Switching from sodium with urea cycle disorders that cannot phenylbutyrate: daily dosage of be managed by dietary protein sodium phenylbutyrate (g) X 0.86. Ravicti (glycerol restriction and/or amino acid supplementation alone. Ravicti must  For patients with some enzyme phenylbutyrate)^^ be used with dietary protein activity who are not adequately restriction and/or dietary controlled with dietary restriction, the recommended starting dose is supplements (e.g. essential amino 2 acids, arginine, citrulline, protein-free 4.5 mL/m /day. calorie supplements).  Round total daily dose up to the nearest 0.5 mL. Maximum daily dosage is 17.5 mL.

^ Must be combined with dietary protein restriction, and, in some cases, essential amino acid supplementation. ^^ Limitations of use: not indicated for the treatment of acute hyperammonemia; efficacy in N-acetylglutamate synthase (NAGS) deficiency has not been established; contraindicated in patients <2 months of age. a-generic is available

CLINICAL RATIONALE2,3 Urea cycle disorders (UCD) are rare genetically inherited metabolic deficiencies that result from defects in the metabolism of waste nitrogen from the breakdown of protein and nitrogen- containing molecules. UCD is caused by deficiency in the enzymes of the urea cycle: carbamylphosphate synthetase I [CPS1], ornithine transcarbamylase [OTC], argininosuccinic acid synthetase [ASS1], argininosuccinic acid lyase [ASL], arginase [ARG], and N-acetyl glutamate synthetase [NAGS]. Severe deficiency in any of the first four enzymes results in the accumulation of ammonia during the first few days of life. In severe disease, infants rapidly develop cerebral edema and signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma whereas milder disease and the associated accumulation of ammonia may be triggered by illness or stress.

Diagnosis is based upon clinical suspicion and biochemical and genetic testing. A normal anion gap and plasma glucose in the presence of a plasma ammonia concentration of 150 µmol/L (>260 µg/dl) or higher in neonates and > 100 µmol/L (175 µg/dl) in older children and adults is indicative of UCD.3 Molecular genetic testing is available for all urea cycle defects.

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© Copyright Prime Therapeutics LLC. 10/2015 All Rights Reserved Treatment for acute severe hyperammonemia include dialysis and hemofiltration to reduce plasma ammonia and intravenous administration of arginine hydrochloride and nitrogen scavenger drugs such as sodium phenylacetate combined with sodium benzoate and sodium phenylbutyrate to allow for alternative pathway excretion of excess nitrogen. Dietary restriction of protein for 12 to 24 hours to reduce the amount of nitrogen in the diet with calories given as carbohydrates and fat is an essential part of disease management. Patients may also need stabilization with IV fluids and vasopressors.

Long term management to prevent hyperammonemia include: dietary restriction of protein, use of specialized formulas, and oral nitrogen-scavenging agents. According to guidelines, not all patients who recover from a hyperammonemic episode require chronic nitrogen scavengers but they should be considered.3

EFFICACY1,4 Buphenyl (sodium phenylbutyrate) Clinical study data is not available for this agent. Prescribing information provides the following:

Previously, neonatal-onset disease was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogs. However, with hemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate, and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in newborns diagnosed after birth but within the first month of life is almost 80%. Most deaths have occurred during an episode of acute hyperammonemic encephalopathy. Patients with neonatal-onset disease have a high incidence of mental retardation. Those who had IQ tests administered had an incidence of mental retardation as follows: ornithine transcarbamylase deficiency, 100% (14/14 patients tested); argininosuccinic acid synthetase deficiency, 88% (15/17 patients tested); and carbamylphosphate synthetase deficiency, 57% (4/7 patients tested). Retardation was severe in the majority of the retarded patients. In patients diagnosed during gestation and treated prior to any episode of hyperammonemic encephalopathy, survival is 100%, but even in these patients, most subsequently demonstrate cognitive impairment or other neurologic deficits. In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recover from hyperammonemic encephalopathy and are then treated chronically with sodium phenylbutyrate and dietary protein restriction, the survival rate is 98%. The two deaths in this group of patients occurred during episodes of hyperammonemic encephalopathy. However, compliance with the therapeutic regimen has not been adequately documented to allow evaluation of the potential for BUPHENYL and dietary protein restriction to prevent mental deterioration and recurrence of hyperammonemic encephalopathy if carefully adhered to. The majority of these patients tested (30/46 or 65%) have IQ’s in the average to low average/borderline mentally retarded range. Reversal of pre-existing neurologic impairment is not likely to occur with treatment and neurologic deterioration may continue in some patients. Even on therapy, acute hyperammonemic encephalopathy recurred in the majority of patients for whom the drug is indicated.

Ravicti (glycerol phenylbutyrate) Study 1 was an active-controlled, 4 week, crossover, non-inferiority study in 45 patients with a diagnosis of UCD involving deficiencies of CPS, OTC, or ASS who had been on sodium phenylbutyrate prior to enrollment. Patients could not have any clinical evidence of hyperammonemia at enrollment. The primary endpoint was the 24-hour AUC for venous ammonia on days 14 and 28 (expected for drug to be at steady state on those days). Statistical non-inferiority would be established if the upper limit of the 2-sided 95% CI for the ratio of geometric means (Ravicti/sodium phenylbutyrate) for the endpoint was ≤1.25. Patients were

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© Copyright Prime Therapeutics LLC. 10/2015 All Rights Reserved randomized 1:1 to either sodium phenylbutyrate for 2 week then to Ravicti for 2 weeks or to the reverse. Patients were required to adhere to a low-protein diet and received amino acid supplements throughout the study. The majority of patients had adult-onset disease (33%) and had OTC deficiency (89%). Doses of Ravicti were calculated to provide the same amount of PBS as sodium phenylbutyrate. See table below for results.

Ravicti was non-inferior to sodium phenylbutyrate with respect to 24-hour AUC for ammonia levels.

In a series of 1-2 week open-label crossover studies in children aged 6-17, pooled into a 12 month open-label extension study, Ravicti demonstrated a lower mean ammonia exposure compared to sodium phenylbutyrate (mean [SD] AUC0–24: 627 [302] vs. 872 [516]μmol/L; p = 0.008). This exposure results in significantly fewer abnormal ammonium lab values (15% on GPB vs. 35% on NaPBA; p = 0.02). Compared with the 12 months preceding enrollment, a smaller percentage of patients taking Ravicti (24.5% vs. 42.9%) experienced hyperammonemia crises (17 vs. 38).5 Management of hyperammonemia crisis requires hospitalization and often dialysis. Peak ammonia levels in an acute state strongly correlate with neurodevelopmental outcomes.6

In a phase III randomized double-blind, double-dummy, active-controlled crossover study followed by a long-term study, 44 patients were treated and showed noninferiority between Ravicti and sodium phenylbutyrate. Mean ammonia exposure was significantly lower for Ravicti in the pooled study (AUC0-24 mean (SD) 866 (661) vs 977 (865) μmol h/L, p < 0.05) as well as plasma glutamine with a mean (SD) of 740.7 (262.8) vs. 792.7 (247.3) μmol/L (p = 0.006). Executive function measured by the BRIEF questionnaire (Behavior Rating Inventory of Executive Function) in adults remained stable over time while executive function in pediatric patients was significantly improved, reported as change in the score of each BRIEF category, Behavioral Regulation Index 53.7 (9.8) versus 60.4 (14.0) (p = 0.028); Metacognition Index 57.5 (9.8) versus 67.5 (13.7) (p < 0.001); and Global Executive Scale 56.5 (9.7) versus 66.2 (14.0) (p < 0.001). The improvement in executive function while taking GPB suggests that UCD patients exhibit neuropsychological abnormalities that may be reversible with effective treatment, demonstrating an improvement in outcomes with Ravicti. The study reported no change in intellectual ability (Wechsler Abbreviated Scale of Intelligence) or mood (Child Behavior Checklist).7

SAFETY1,4 Buphenyl (sodium phenylbutyrate) The most common adverse events obtained from patient-visit reports from 206 patients include amenorrhea, decreased appetite, body odor, bad taste or taste aversion, metabolic abnormalities, anemia, and increased liver transaminases.

Ravicti (glycerol phenylbutyrate)

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© Copyright Prime Therapeutics LLC. 10/2015 All Rights Reserved The use of glycerol phenylbutyrate is contraindicated in patients <2 months of age as these patients may have immature pancreatic exocrine function, which could impair hydrolysis of this agent. Pivotal studies in patients ≥2 months and < 2 years of age only had 4 patients which provided insufficient data to establish a safe and effective dose in this age group. The most common adverse events in ≥10% of patients include diarrhea, flatulence, and headache. The active moiety of phenylbutyrate is phenylacetate and may be toxic. The dosage is reduced for symptoms of neurotoxicity; pancreatic insufficiency or intestinal malabsorption reduce the absorption of this agent.

Agent Contraindication Buphenyl (sodium phenylbutyrate) acute hyperammonemia Ravicti (glycerol phenylbutyrate) -patients < 2 months of age -known hypersensitivity to phenylbutyrate

REFERENCES 1. Ravicti prescribing information. Hyperion Therapeutics, Inc. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=73bc6b83-2513-11e1-bfc2- 0800200c9a66. Accessed 8/10/15. 2. Lanpher BC, Gropman A, Chapman KA et al. Urea Cycle Disorders Overview. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1217/. Accessed 7/24/14. 3. Urea Cycle Disorders Consortium. Urea Cycle Disorders Treatment guidelines. Available at: http://rarediseasesnetwork.epi.usf.edu/ucdc/physicians/guidelines- main.htm. Accessed 7/24/14. 4. Buphenyl prescribing information. Hyperion Therapeutics, Inc. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa638c13-3048-42b2-8a8b- 79dae040ea35. Accessed 7/10/15. 5. Berry SA, Lichter-Konecki U, Diaz GA, et al. Glycerol phenylbutyrate treatment in children with urea cycle disorders: Pooled analysis of short and long-term ammonia control and outcomes. Molecular Genetics and Metabolism, 2014. (112): 17-24. 6. Haberle J, Boddaert N, Burlina A et al. Suggested Guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis, 2012. 7:32. 7. Diaz GA, Krivitzky LS, Mohktarani M et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology, 2013. 57: 2171-2179.

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