Urea Cycle Disorders (UCDs)

Urea cycle disorders (UCDs) are rare genetic conditions characterized by deficiencies of enzymes necessary for urea synthesis, resulting in hyperammonemia and central nervous system damage. Severe neonatal-onset UCDs typically present in the first month of life with seizures, coma, and cerebral edema. Partial enzyme deficiencies associated with late-onset UCDs may manifest later, often triggered by stressors. If untreated, UCDs can be fatal due to hyperammonemic encephalopathy.¹Early diagnosis and urgent treatment of UCDs is critical to improve outcomes.

Key therapies include hemodialysis, sodium phenylbutyrate, sodium phenylacetate, sodium benzoate, protein restriction, and amino acid supplementation. Hemodialysis most rapidly removes ammonia but drug therapy can be tried first. Overall survival is around 80% for neonatal-onset UCDs with treatment initiation before repeated hyperammonemic episodes. However, most survivors have later cognitive or neurologic deficits. In late-onset UCDs, survival exceeds 90% with treatment, but neurologic impairment may continue progressing.

Many patients require lifelong sodium phenylbutyrate to help manage chronic hyperammonemia. Glycerol phenylbutyrate is an alternative that provides additional waste nitrogen excretion but does not treat acute hyperammonemia. Increased exposure to its metabolite phenylacetate may risk neurotoxicity. Recurrent hyperammonemic episodes should be urgently treated as medical emergencies with all ammonia-lowering therapies.

Definitions

Acute Hyperammonemia

refers to sudden onset of severely elevated blood ammonia levels that can quickly cause brain damage or death if left untreated.

Amino Acid Supplementation

refers to medical supplementation with essential amino acids.

Ammonia

refers to a compound made in the body during protein metabolism and normally converted to urea by the liver.

Dietary Protein Restriction

refers to limiting protein intake in the diet as a therapeutic strategy to reduce ammonia production.

Hyperammonemia

refers to abnormally high levels of ammonia in the blood.

Late-onset

refers to onset of the disorder after the first 28 days of life, often partially deficient enzymes.

Neonatal-onset

refers to onset of the disorder within the first 28 days of life.

Orphan Drug

refers to an FDA designation for drugs treating rare diseases affecting less than 200,000 people in the US.²

Urea Cycle Disorder (UCD)

refers to a group of rare genetic conditions characterized by deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia, resulting in toxic accumulation of ammonia.

Medical Necessity Criteria for Initial Authorization

The Plan considers Urea Cycle Disorder (UCD) Treatment Agents medically necessary when ALL of the following criteria are met:

1. Prescribed by or in consultation with a specialist experienced in the treatment of urea cycle disorders (e.g., geneticist, metabolic disorders); AND
2. Confirmed diagnosis of a urea cycle disorder, defined by ALL of the following:
   • Elevated plasma ammonia levels per age; and
   • Normal anion gap; and
   • Normal blood glucose level; and
   • Supportive amino acid profile, urine organic acids, enzymatic testing, or genetic testing;
   AND
3. Dietary protein restriction and/or amino acid supplementation alone cannot adequately manage the disorder; AND
4. Agent is prescribed as adjunctive therapy to dietary restriction; AND
5. Agent will not be used to treat acute hyperammonemia; AND
6. Member is unable to use, or has tried and failed generic sodium phenylbutyrate OR Pheburane, unless request is for:

Sodium Phenylbutyrate [generic Buphenyl]
b. Pheburane
c. Brand Buphenyl

d.is established on requested agent with documented positive response; AND

For (Brand) Buphenyl requests, in addition to meeting the criteria herein, is also subject to Oscar Clinical Guideline: Brand Medically Necessary Drugs (PG186).

7. Agent is being prescribed at a dose and frequency that is within FDA approved labeling OR is supported by compendia or evidence-based published dosing guidelines for the requested indication.
   • For neonates, the requested agent is FDA approved for use in neonates and the prescribed dose is within FDA labeled dosing for neonates
   • For Olpruva, and the member meets BOTH of the following:
     1. weighing 20 kg or greater; and
     2. with a body surface area (BSA) of 1.2 m² or greater
   • For members requiring doses or frequencies exceeding FDA labeled dosing, the prescribed regimen is supported by compendia or evidence-based published dosing guidelines for the requested indication
   • For members with partial UCD deficiencies, the prescribing physician has provided information indicating the requested agent is appropriate for the member's type of UCD. Information must include:
     1. Specific UCD mutation or enzyme deficiency
     2. Rationale for using the requested medication for the member's type of partial UCD (e.g. expected clearance of toxic metabolites, reduced risk of hyperammonemia)
     3. Any available lab results, ammonia levels, or prior response to the requested medication supporting its use in the member's type of partial UCD
   If the above prior authorization criteria are met, the requested product will be authorized for 6- months.

Medical Necessity Criteria for Reauthorization

Reauthorization for 12-months will be granted if the member has recent (within the last 3 months) clinical chart documentation demonstrating ALL of the following criteria:

1. The member previously met Initial Authorization criteria; AND
2. Prescribed by or in consultation with a specialist experienced in the treatment of urea cycle disorders (e.g. geneticist, metabolic disorders); AND
3. The member has achieved or maintained disease stability or improvement as indicated by normalized or controlled plasma ammonia levels; AND
4. Agent will NOT be used to treat acute hyperammonemia; AND
5. The member requires ongoing therapy in conjunction with dietary management.

Experimental or Investigational / Not Medically Necessary

Urea Cycle Disorder (UCD) Treatment Agents for any other indication or use is considered not medically necessary by the Plan, as it is deemed to be experimental, investigational, or unproven.

Non-covered Indications

Non-covered indications include, but are not limited to, the following:⁴

• Absence of positive response to therapy
• Alzheimer's Disease (AD)
• Amyotrophic Lateral Sclerosis (ALS)
• Cirrhosis of the Liver / Hepatic Encephalopathy (HE)
• Cystic Fibrosis (CF)
• Huntington's Disease (HD)
• Lack of confirmed urea cycle enzyme deficiency diagnosis
• Parkinson's Disease (PD)
• Spinal Muscular Atrophy (SMA)
• Therapeutic Agent Toxicity
• Use for acute hyperammonemia

Appendix

Table 1: Common ICD-10-CM Codes for Urea Cycle Disorder (UCD) Treatment Agents

Code
Description

• Disorder of urea cycle metabolism, unspecified
• Argininemia
• Arginosuccinic aciduria
• Citrullinemia
• Other disorders of urea cycle metabolism
• E72.4
  Disorders of ornithine metabolism

Table 2: Main Enzymatic Deficiencies Causing Urea Cycle Disorders

Disorder
Also Known As
MIM Number

• Carbamyl phosphate synthetase | (CPSI) deficiency
  237300
• Ornithine transcarbamylase (OTC) deficiency
  311250
• Argininosuccinate synthetase (ASS) deficiency
  Classic citrullinemia, Type I citrullinemia (CTLN1)
  215700
• Argininosuccinate lyase (ASL) deficiency
  Argininosuccinic aciduria
  207900
• N-acetyl glutamate synthetase (NAGS) deficiency
  237310
• Arginase deficiency
  Argininemia
  207800

The table summarizes the main enzymatic deficiencies that can lead to urea cycle disorders. For complete gene, molecular, and chromosomal location information on these disorders, please refer to the Online Mendelian Inheritance in Man® (OMIM®) database.

References

1. Buphenyl (sodium phenylbutyrate) tablets, powder [prescribing information]. Deerfield, IL: Horizon Therapeutics USA Inc; March 2023.
2. Olpruva (sodium phenylbutyrate) [prescribing information]. Newton, MA: Acer Therapeutics Inc;December 2022.
3. Pheburane (sodium phenylbutyrate) [prescribing information]. Bryn Mawr, PA: Medunik USA Inc; June 2022.
4. Ravicti (glycerol phenylbutyrate) [prescribing information]. Lake Forest, IL: Horizon Therapeutics USA Inc; September 2021.
5. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007;30(6):865–79.
6. Batshaw ML, Berry GT. Use of citrulline as a diagnostic marker in the prospective treatment of urea cycle disorders. J Pediatr 1991;118(6):914–7.
7. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001;138(1 Suppl):S30–9.
8. Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr 2001;138(1 Suppl):S6–10.
9. Häberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr 2011; 170:21.
10. Lilliu F. Treatment of organic acidurias and urea cycle disorders. J Matern Fetal Neonatal Med 2010; 23 Suppl 3:73.
11. Daniotti M, la Marca G, Fiorini P, Filippi L. New developments in the treatment of hyperammonemia: emerging use of carglumic acid. Int J Gen Med 2011; 4:21.
12. Burrage LC, Jain M, Gandolfo L, et al. Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Mol Genet Metab 2014; 113:131.
13. Berry SA, Longo N, Diaz GA, et al. Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2 months to 2 years. Mol Genet Metab 2017; 122:46.
14. Smith W, Diaz GA, Lichter-Konecki U, et al.

15. Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. J Pediatr 2013; 162:1228.
16. Batshaw ML, Tuchman M, Summar M, et al. A longitudinal study of urea cycle disorders. Mol Genet Metab 2014; 113:127.

Clinical Guideline Revision / History Information

Original Date: 12/14/2023
Reviewed/Revised:7