Rare disease clinical research network's urea cycle consortium delivers a successful clinical trial to improve alternate pathway therapy


  • Pramod K. Mistry M.B., B.S., Ph.D., F.R.C.P.

    Corresponding author
    1. Department of Pediatrics Section of Pediatric Gastroenterology and Hepatology Yale School of Medicine New Haven, CT
    • Department of Pediatrics, Section of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, 333 Cedar Street, LMP 4093, New Haven, CT 06562
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  • See Article on Page 2171.


AL, argininosuccinate lyase; AS, argininosuccinic acid synthetase; AUC, area under the curve; CPS, carbamyl phosphate synthetase; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; GPB, glycerol phenylbutyrate; NaPBA, Na phenylbutyrate; OTC, ornithine transcarbamylase; PAA, phenylacetic acid; PAGN, phenylacetyiglutamine; PBA, pyrenebutyric acid; UCDs, urea cycle disorders.

Five enzyme-catalyzed reactions that constitute the urea cycle function primarily to prevent the accumulation of toxic nitrogenous entities by incorporating them into urea. Inherited defects in four of these five enzymes (carbamyl phosphate synthetase [CPS], ornithine transcarbamylase [OTC], argininosuccinic acid synthetase [AS], and argininosuccinate lyase [AL]) (Fig. 1) lead to protein intolerance and massive accumulation of ammonia, with most catastrophic presentations in full-term infants in the first week of life.1 There is wide genotypic and phenotypic heterogeneity such that milder forms of these diseases may present in childhood or in adults manifesting as dietary protein aversion and encephalopathy that may be misdiagnosed for years. Treatment entails restriction of dietary protein intake and pharmacological activation of alternate pathways of waste nitrogen synthesis and excretion. Despite these therapeutic strategies, there remains significant unmet need, and even in apparently well-controlled patients, there is suboptimal control of ammonia, subclinical neurocognitive dysfunction, and impaired quality of life.2

Figure 1.

Urea cycle and alternate pathway activation. Deficiencies of these enzymes lead to hyperammonemia and protein intolerance. More than 80% of patients enrolled in the clinical trial reported on by Diaz et al. had OTC deficiency.

It is instructive to trace the evolution of therapies for urea cycle disorders (UCDs). It illustrates daring efforts to circumvent formidable hurdles facing investigators attempting to develop therapies for rare orphan diseases that generally exhibit extreme genotype and phenotype heterogeneity.3 The history is rich with triumphs that have been uniformly propelled by powerful advocacy of individual treating physicians in collaboration with patient support groups. Pioneering efforts by Saul Brusilow and Mark Batshaw at Johns Hopkins spanning more than a quarter of a century have dramatically improved prospects for patients and families affected by UCDs.4 Following on from observations in animal studies of nitrogen metabolism, these investigators developed a scientific rationale for the first-generation alternate pathway therapy in the form of oral Na benzoate and Na phenylacetate combined with dietary protein restriction. This alone was sufficient to have approval of this regimen; what a far cry from current exacting requirements for demonstrating efficacy for therapies for rare diseases. However, this treatment resulted in incapacitating body odor, prompting Brusilow to conceive of a prodrug in the form of Na Phenylbutyric Acid (NaPBA), which was efficiently cleaved to phenylacetate and, subsequently, to phenyacetylglutamine (Fig. 1). Early studies indicated good bioavailability and it was clearly more tolerable. However, the drug could not be approved by the U.S. Food and Drug Administration (FDA) because of the lack of any efficacy and safety data, nor was there any federal support to carry out these studies. It was philanthropy and patient advocacy that advanced the field beyond the gridlock. An ad-hoc dispensary was set up at Johns Hopkins to ensure the supply of the drug to families affected by UCDs. Again, without a clinical trial, but based on real-world experience and advocacy of patient groups, the FDA approved the use of NaPBA in 1996. This development made possible the formulation and distribution of combination intravenous therapy of phenylacetate and benzoate (Ammonul), which was eventually approved by the FDA in 2005. This approval was based on experience of this treatment in consecutive young patients with severe, potentially life-threatening hyperammonemia with striking improvement of outcomes.5 Hence, Na PBA became the standard of care for maintenance therapy of UCDs in the absence of rigorous randomized, controlled clinical trials. Nevertheless, despite the improvement represented by NaPBA, it still required daily ingestion of as many as 40 large capsules every day and resulted in bad taste and gastrointestinal (GI) disturbance, even when administered by a gastrostomy tube. Hence, another modification proposed by Brusilow, glycerol phenylbutyrate (GPB), became the focus of therapeutic development. GPB is attractive because it is a liquid triglyceride prodrug of PBA, a nearly tasteless, odorless oil devoid of sodium. GPB is hydrolyzed by human pancreatic triglyceride lipase and other lipases releasing PBA that is absorbed from the intestine and converted to the active moiety, phenylacetic acid (PAA) via β oxidation (Fig. 1).6 PAA is conjugated with glutamine in the liver and the kidney by way of N acyl-coenzyme A/L-glutamine N-acyltransferase to form phenylacetylglutamine (PAGN). Like urea, PAGN incorporates two waste nitrogens and is excreted in the urine.

The article by Diaz et al. in this issue of HEPATOLOGY is a remarkable illustration that it is possible to conduct randomized, controlled trials even in ultraorphan diseases.7 However, its success depended critically on academic-industry synergy represented by the Rare Disease Clinical Research Network's Urea Cycle Consortium,8 a pharmaceutical company (Hyperion Therapeutics, Inc., South San Francisco, CA), and the patient support organization, the National Urea Cycle Disorders Foundation. The study involved 91 patients from fewer than 500 known patients with UCDs in the United States, treated with Na PBA by investigators in the Urea Cycle Consortium.

The 4-week, multicenter, randomized, double-blind, cross-over phase III study was designed to evaluate the noninferiority of GPB to NaPBA in 46 adults with UCDs, some 80% of whom suffered from OTC deficiency. The primary efficacy measure was daily ammonia exposure, measured by 24-hour AUC (area under the curve) at the end of each treatment period. Subjects were administered NaPBA or GPB at equimolar doses of PBA. Twenty-four-hour ammonia AUC for the two treatments were similar, with a slight trend toward lower ammonia in the GPB group. One hyperammonemic crisis occurred on NaPBA, but none on GPB. Interestingly, GI symptoms were similar in both groups, despite better tolerability of GPB. In a pooled analysis of 65 adult and pediatric patients on 12 months of open-label GPB treatment, ammonia control was normal, and in the pediatric patients, there was significant improvement of executive function, including behavioral regulation, goal setting, planning, and self-monitoring. These results significantly improve therapy of ultra-rare UCDs, but also have important implications for far more common forms of encephalopathy secondary to cirrhosis. It is estimated that 1 million patients in the United States suffer from cirrhosis, and > 10% suffer from chronic encephalopathy. Early results indicate safety and tolerability of GPB in patients with cirrhosis.9 Moreover, GPB contains no sodium, compared to almost 2.4 g of sodium in a standard adult dose of NaPBA. Thus, this remarkable clinical trial in ultraorphan UCDs may eventually expand treatment options for more frequently encountered patients with cirrhosis suffering from chronic encephalopathy.