Summary Basis of Decision for Pheburane

 

Clinical Pharmacology

Urea cycle disorders (UCDs) are a group of inborn errors of metabolism caused by partial or complete inactivation of one of the enzymes of the urea cycle, the biochemical pathway which allows humans to eliminate waste nitrogen. Defects in this pathway cause excessive levels of waste nitrogen to accumulate in the blood in the form of ammonia, which is neurotoxic. These disorders are characterized by life-threatening episodes of hyperammonemia and neurological damage.

Sodium phenylbutyrate, the medicinal ingredient in Pheburane, is a pro-drug that is rapidly metabolized to phenylacetate. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine, which is then excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore provides an alternate vehicle for waste nitrogen excretion.

To support the efficacy and safety of Pheburane, results from comparative bioavailability Study LUC-1001, an open-label two-period crossover study conducted under fasting conditions in 13 healthy volunteers comparing two formulations of sodium phenylbutyrate, were provided. The purpose was to establish that the product used in studies reported in the literature was representative of the proposed Pheburane. The data demonstrated that a single 5 g oral dose of sodium phenylbutyrate from the sponsor's Pheburane (483 mg/g granules) met the requirements for comparative bioavailability with the European reference product (940 mg/g granules).

No formal drug-drug interaction studies were performed in support of approval of sodium phenylbutyrate. However, caution is required with administration of other drugs which have the potential to affect the nitrogen lowering effects of phenylbutyrate and/or elevate plasma ammonia levels (pharmacodynamic interactions).

For further details, please refer to the Pheburane Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of sodium phenylbutyrate in the treatment of urea cycle disorders (UCDs) was evaluated in an open label, single arm, multicentre Phase III study of patients with deficiencies of carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinate synthetase (ASS). The study was performed without a control group on ethical grounds, due to the seriousness of the disorders being treated and the lack of an effective treatment to serve as comparator. Efficacy results were evaluable for 183 patients enrolled across the United States and Canada over a period of more than 10 years. Health Canada's review of Pheburane is based on data from this study available from three published study reports, in addition to a foreign review from the European Medicines Agency (EMA).

Efficacy criteria included survival, incidence of hyperammonemic episodes, cognitive development, growth, and plasma ammonia and glutamine levels.

The final patient cohort examined in the European Medicines Agency (EMA) review included 208 patients. Of the 183 evaluable patients, there were 122 (67%) patients diagnosed with ornithine transcarbamylase (OTC) deficiency, 39 (21%) with argininosuccinate synthetase (ASS) deficiency, and 22 (12%) with carbamyl phosphate synthetase (CPS) deficiency. Patients were classified according to time of diagnosis as follows: rescue: 72 (39%), prospective: 14 (8%), late-onset: 29 (16%), and OTC females: 68 (37%). Assessment of the overall efficacy of sodium phenylbutyrate is challenging since patients represented a heterogeneous group, with different enzyme deficiencies characterized by various ages of onset and severity. Patients initially recruited in the earliest phase of the study (pre-1987) may have been stabilized on other nitrogen scavengers according to earlier versions of the treatment protocol (sodium benzoate or sodium benzoate combined with phenylacetate), before being switched to phenylbutyrate. Since the program consisted of a single arm study, efficacy can only be assessed compared to historical controls.

The sponsor submitted three pivotal scientific publications documenting evidence of safety and efficacy, which formed part of the original evidence used to support authorization of sodium phenylbutyrate in Europe and the United States, along with the Scientific Discussion from the 1999 EMA review of the original sodium phenylbutyrate marketing authorization application.

In the case of neonatal onset patients treated at or shortly after birth, acute treatment included hemodialysis combined with intravenous administration of sodium benzoate and phenylacetate, to achieve rapid reduction in plasma ammonium levels. Once plasma ammonium levels returned to normal, dialysis was discontinued and patients were switched to oral therapy with sodium phenylbutyrate, 450-600 mg/kg/day. Patients also received a target protein intake of 1.25-2 g/kg/day, along with amino acid supplementation.

In the first patient cohort, 4 of 16 rescue patients died over their first 15 months (survival rate of 75%). Previously, neonatal onset urea cycle disorders were almost always fatal. Four of 6 prospectively diagnosed patients who were treated at birth discontinued treatment within the first two and a half years of life. Three of 13 late onset patients ceased treatment after an unknown time. Female patients with OTC deficiency displayed the most favourable prognosis, with no deaths in 26 patients.

Based on the last available survival data, 82 patients had been treated with sodium phenylbutyrate only, whereas 101 of the patients had already been treated according to previous protocols (sodium benzoate and/or phenylacetate). The overall survival rate was approximately 80%. Of the reported deaths, 18 patients died during an acute hyperammonemic episode, sometimes after phenylbutyrate therapy was discontinued.

For historical comparison, in a study reported from France (1972-2000), in a population of 217 urea cycle disorder patients with a similar distribution of enzyme deficiencies, the survival rate for neonatal onset cases was 16%, inferior to that reported in the United States study, and the reported mortality rate was 29% (28/96) for late-presenting cases. Based on historical data from a separate study inclusive of female heterozygous patients with undiagnosed OTC deficiency, 11 of 61 patients (18%) experienced episodes of encephalopathy of whom 9 (82%) died during or subsequent to those episodes. Results from a long-term study inclusive of symptomatic OTC deficiency females receiving phenylbutyrate therapy and related compounds with at least one hyperammonemic episode, observed that 29 of 32 patients survived at least five years. These data are consistent with a beneficial effect of phenylbutyrate on mortality.

Plasma ammonia levels were monitored for 85 patients during clinically stable periods (excluding hyperammonemic episodes). Based on 281 measurements, 40 patients (47%) had no values exceeding the upper limit of normal (ULN). A total of 6% of the measurements were >2× ULN. Of 148 evaluable patients maintained on phenylbutyrate and followed for up to 9 years, 114 (77%) experienced at least one episode of hyperammonemia requiring hospitalization.

At study enrolment patients treated with phenylbutyrate had below average heights and weights, with the most marked decreases seen in neonatal rescue patients. Height and weight-for-age z scores remained relatively stable over time, however, indicating at least that phenylbutyrate did not adversely affect the children's expected growth trajectories.

The overall effect of phenylbutyrate on cognitive development is difficult to estimate. Only some of the patients underwent repeat evaluations, the reliability of estimates obtained during the first months of life is questionable, and different cognitive tests were used to assess the same patient. However, results from the long-term treatment of the subgroup of girls with OTC deficiency suggest stabilization of cognitive functioning with treatment.

For more information, refer to the Pheburane Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Pheburane was established primarily through linkage of the Pheburane formulation to that of the European reference product by the demonstration of comparative bioavailability.

Characterization of the safety of sodium phenylbutyrate in the pivotal Phase III study, described in the Clinical Efficacy section, was largely dependent on spontaneous reporting. The capture of adverse events (AEs) was therefore likely limited, and the frequencies of AEs most likely underestimated. Out of 183 patients, 56% reported at least one AE. Of these, 36% were central nervous system-related, including hyperactivity, speech disorder, seizures, and mental retardation; however it is very difficult to distinguish these AEs from the common neurological manifestations of the underlying urea cycle disorders.

Other frequently reportedAEs were amenorrhoea/irregular menstrual cycles (23% of menstruating women), decreased appetite (4% of patients), body odour (likely due to the metabolite, phenylacetate; 3%) and bad taste/taste aversion (3%). Less common AEs included abdominal pain, gastritis, nausea/vomiting, constipation, rectal bleeding, peptic ulcer disease, pancreatitis, aplastic anaemia, ecchymoses, arrhythmia, oedema, renal tubular acidosis, depression, rash, headache, syncope and weight gain.

Neurotoxicity has been observed when phenylacetate, the active metabolite of phenylbutyrate, was administered intravenously to cancer patients. Symptoms, chiefly somnolence and dizziness, were seen at plasma phenylacetate concentrations >3.5 mmol/L, and were rapidly reversible on discontinuation. The significance of these findings for urea cycle disorder patients receiving phenylbutyrate orally is unclear. Warnings regarding possible risk of neurotoxicity are included in the Pheburane Product Monograph, with recommendations for monitoring of phenylacetate levels, as necessary.

In light of its developmental toxicity in rodent studies, Pheburane is contraindicated during pregnancy and lactation.

Laboratory abnormalities included acidosis (14%), hypoalbuminemia (11%), anemia (9%), alkalosis (7%), hyperchloremia (7%), hypophosphatemia (6%), increased alkaline phosphatase (6 %) and increased liver transaminases (4%). Monitoring of laboratory parameters, including plasma ammonium, glutamine, phenylacetate and phenylglutamine levels, is recommended.

The limitations of the literature-based review, and of the clinical database accepted for review, are considered justified in light of the special circumstances of this submission: Pheburane represents a drug to treat a rare, serious and life-threatening condition, for which no treatment is marketed in Canada; the original safety and efficacy database is unavailable; sodium phenylbutyrate, the active pharmaceutical ingredient, has been authorized and in use in the United States and Europe for more than 15 years and is considered standard of care; and consequently, it is not anticipated that further data will become available to augment the existing evidence of efficacy. It is noted that, since 2000, Canadian urea cycle patients have had access to sodium phenylbutyrate via the Special Access Programme, and in clinical practice these patients are followed closely by specialists with knowledge and experience in the treatment of urea cycle disorders.

For more information, refer to the Pheburane Product Monograph, approved by Health Canada and available through the Drug Product Database.