ACER-001 for Urea Cycle Disorders (UCDs)

Urea Cycle Disorders (UCD)

The urea cycle is a component of protein metabolism that takes place primarily in a person’s liver. When the body breaks down protein, ammonia is produced, which is toxic. Enzymes in the urea cycle are responsible for the process of converting ammonia into urea, which is then excreted harmlessly from the person’s body.

Urea cycle disorders (UCD) are genetic disorders caused by mutations in genes that code for enzymes in the urea cycle, resulting in a deficiency of those enzymes. Deficiency of any one of these enzymes required for ammonia detoxification constitutes a UCD:¹

• N-acetylglutamate synthase (NAGS)
• Carbamoyl phosphate synthase (CPS)
• Ornithine transcarbamylase (OTC)
• Argininosuccinate synthase (AS)
• Argininosuccinate lyase (AL)
• Arginase (ARG)

When one of these enzymes is deficient, the urea cycle is interrupted, resulting in hyperammonemia (elevated ammonia in the blood), encephalopathy (changes in alertness related to brain dysfunction), and respiratory alkalosis (an imbalance of oxygen and carbon dioxide in the breathing cycle).

Ammonia is a highly toxic substance that can reach the brain through the blood. It can cause reversible or irreversible brain damage, coma and/or death.¹ Other signs and symptoms may also be present based on the specific enzyme deficiency, such as AL deficiency, which may result in hypertension and deficiency of nitric oxide (NO) production.² Arginase deficiency is a bit different from the others, not usually presenting with hyperammonemia and its accompanying symptoms but rather mimicking cerebral palsy.

Urea cycle disorders are the most common serious liver-based inborn errors of metabolism, occurring in approximately one in every 30,000 to 46,000 live births. In individuals with a UCD involving a severe deficiency, infants may appear normal at birth but quickly develop symptoms of lethargy (abnormal sleepiness), which can progress to coma.  Vomiting may be an early symptom, along with instability in temperature, respiratory distress, and rapid breathing.^1,3 A less severe deficiency may produce symptoms such as poor appetite (fussy eater) and unconscious avoidance of protein, which may at first go unnoticed. Older children or even adults may not be diagnosed immediately, despite experiencing agitation, vomiting, and sometimes appearing intoxicated in the absence of alcohol consumption.  Initial symptoms may be brought on by an acute illness which produces more severe symptoms and may eventually lead to a correct diagnosis; in other cases children or adults present with these unusual symptoms multiple times before an accurate diagnosis is reached.¹ Affected individuals may also have an enlarged liver and abnormal liver function tests.³

Diagnosis

Early clinical suspicion and diagnosis is especially important for people with severe UCD to avoid the neurological damage of prolonged episodes of hyperammonemia. Newborn screening is available for some but not all forms of UCD and may be helpful in prevention of early prolonged hyperammonemia. Prenatal diagnostic testing is possible in many countries, though it would not normally be mentioned in a pregnancy unless there was a previously diagnosed family member.  When prenatal genetic testing is contemplated, genetic counselling should be offered (available from clinical geneticists/metabolic disease specialists and genetic counselors working with them).³

Diagnosis of a UCD is based on clinical suspicion with confirmation by biochemical and molecular testing. A person with an abnormally high plasma ammonia concentration of unknown cause strongly suggests the presence of a UCD. The person would then be evaluated for UCD enzyme deficiencies.  Biochemical testing including such tests as urine organic acids and blood amino acids is useful in these cases. Molecular genetic testing to identify the mutation and/or measurement of enzyme activity allows for a definitive diagnosis of a UCD.¹

Management

Treatment for a severe episode of hyperammonemia may include dialysis, hemofiltration, and/or ammonia scavenging medications that allow alternative methods of excretion of the excessive ammonia to help prevent the serious neurological impact of hyperammonemia.³ For people with severe UCD, liver transplantation is an option which some consider a cure for UCD. However, liver transplantation carries its own risks and accompanying health issues including risk of surgery, rejection of the transplanted liver, and the lifelong need to take medications to suppress the immune system.⁴ Liver transplantation in children also carries its own set of considerations, including the currently unknown impact of life-long immunosuppressant drugs on a child’s growth, development, and psychological well being.⁵ However, for a child with classic MSUD, these risks may be outweighed by considerations for the neurological health of the child.⁶

Ongoing medical therapy for UCDs includes strict dietary restrictions of protein often along with a special medical food containing essential amino acids to maintain a safe level of ammonia in the blood.^3,7 Replacement of amino acids from the urea cycle such as arginine and citrulline (for some UCDs), and supplementation of vitamins and minerals that may be lacking due to protein restrictions is often employed.¹

Acer is advancing ACER-001, a taste-masked formulation of NaPB as a treatment option for patients with UCDs.

» For up-to-date information about EDSIVO™ (celiprolol) for vEDS, subscribe to receive email updates here.

1. Ah Mew N, Lanpher BC, Gropman A, Chapman KA, al. e. Urea cycle disorders overview. Gene Reviews. Seattle, Washington: University of Washington, Seattle; 1993.
2. Nagamani SC, Campeau PM, Shchelochkov OA, et al. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am j Hum Gen. 2012;90(5):836-846.
3. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases. 2012;7(32).
4. Yu L, Rayhill SC, Hsu EK, Landis CS. Liver Transplantation for Urea Cycle Disorders: Analysis of the United Network for Organ Sharing Database. Transplantation Proceedings 2015;47:2413-2418.
5. Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001;138:S6-10.
6. Squires RH, Ng V, Romero R, et al. Evaluation of the Pediatric Patient for Liver Transplantation: 2014 Practice Guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. 2014:362-398.
7. Sirrs SM, Faghfoury H, Yoshida EM, Geberhiwot T. Barriers to Transplantation in Adults with Inborn Errors of Metabolism. JIMD Rep. 2013;8:139-144.
8. Camp KM, Parisi MA, Acosta PB, et al. Phenylketonuria Scientific Review Conference: State of the science and future research needs. Mol Genet Metab. 2014;112(2):87-122.
9. Chin HL, Aw MM, Quak SH, et al. Two consecutive partial liver transplants in a patient with Classic Maple Syrup Urine Disease. mol Genet Metab Rep. 2015;4:49-52.
10. McDiarmid SV. Liver transplantation. The pediatric challenge. Clin Liver Dis. 2000;4(4):879-927.
11. Mazariegos GV, Holmes Morton D, Sindhi R, et al. Liver Transplantation for Classical Maple Syrup Urine Disease: Long-Term Follow-Up in 37 Patients and Comparative United Network for Organ Sharing Experience. J Pediatr. 2012;160(1):116-121.
12. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. 2001;2001(138):S60-S61.
13. Shchelochkov OA, Dickinson K, Scharschmidt BF, Lee B, Marino M, Le Mons C. Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives. Mol Genet Metab. 2016;8:43-47.

ACER-001 for UCDs

ACER-001 is a taste-masked, immediate-release formulation of sodium phenylbutyrate (NaPB) developed using a microencapsulation process. NaPB has been found to help control blood ammonia levels in conjunction with a restricted diet for people with a urea cycle disorder (UCD). However, adherence to treatment has been a challenge for people with UCD due to the foul taste of NaPB. ACER-001 is designed to support adherence to treatment with NaPB by eliminating the foul taste reported to be a barrier to adherence.⁹

For the treatment of UCD, NaPB is a prodrug that metabolizes quickly to become phenylacetate.  Phenylacetate then binds to glutamine via acetylation to become phenylacetylglutamine. Phenylacetylglutamine is similar to urea in that it contains two moles of nitrogen and is excreted by the kidneys. Through this process, NaPB is an alternate way to excrete excessive nitrogen created by ineffective processing of ammonia during the urea cycle.¹⁰

Clinical trials of ACER-001 will determine if the ACER-001 formulation has the same impact as NaPB on ammonia blood levels and is as safe as treatment with NaPB.

» For up-to-date information about EDSIVO™ (celiprolol) for vEDS, subscribe to receive email updates here.

1. Shchelochkov OA, Dickinson K, Scharschmidt BF, Lee B, Marino M, Le Mons C. Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives. Mol Genet Metab. 2016;8:43-47.
2. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-170.

Patient resources

The National Urea Cycle Disorders Foundation

The National Urea Cycle Disorders Foundation (NUCDF) is a national non-profit organization formed in 1988 by parents whose children were affected by UCD. NUCDF is dedicated to the identification, treatment and cure of urea cycle disorders by providing information and education for families and healthcare professionals impacted by UCDs.

The Foundation is operated and supported by the volunteer efforts of families with children suffering from UCDs and is a supportive network of families, friends, and medical professionals.

» Find out more at their website.

 The National Organization for Rare Disorders (NORD)

The National Organization for Rare Disorders (NORD), a 501(c)(3) organization, is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them. NORD, along with its more than 250 patient organization members, is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services.

NORD serves the rare disease community, including patients and their families, patient organizations, researchers, medical professionals, and companies developing orphan products. They also work closely with many government agencies, most notably the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). NORD programs are focused on improving the lives of individuals and families affected by rare diseases.

» Find out more at their website.

 The American College of Medical Genetics Clinic Services Search Engine

The American College of Medical Genetics (ACMG) maintains a list of genetics clinics with a comprehensive search engine for people in need of a genetics clinic. You can search based on location, specialty, and your own individual needs.

» Find the search engine at the ACMG website.