4.2.1. Efficacy

Previous studies evaluating the relationships between ammonia levels and clinical outcomes suggested that, although a “threshold” of blood ammonia level has not been established to indicate a definite change in health outcomes in patients with UCDs, higher initial ammonia concentrations (i.e., greater than 300 μmol/L) were found to be associated with higher risks of severe neurologic damage, cognitive impairment, HAC, or even death (APPENDIX 5). A more recent pooled analysis using data from four short-term and three long-term HPN-series studies indicated that a 10 μmol/L or 25 μmol/L increase in ammonia exposure increased the relative risk of a HAC by 50% and greater than 200%.²⁶ Results from HPN-100-006 suggest that GPB is noninferior to NaPBA in lowering blood ammonia levels. This was a crossover RCT without a washout period between treatment with GPB and NaPBA. There was a potential carry-over effect, which may have an impact on the study results. A previous study indicated that, in healthy volunteers, both GPB and NaPBA have short half-lives, and phenylacetic acid and phenylacetylglutamine reached steady state in two to three days after administration of multiple doses of GPB.^20,25 The clinical expert consulted for this review noted that, given the safety considerations, no washout period is common in UCD trials to avoid uncontrolled ammonia levels and related consequences; however, the carry-over effect would be minimal due to the short half-life of the drug, when the study end point was the end of the two-week treatment period. Occurrence of HAC was rare during the four-week treatment period. The 24-hour C_max values for blood ammonia in the GPB group were approximately 10 μmol/L lower compared with the NaPBA group. The between-group difference did not reach statistical significance. Insufficient power could partially explain the statistically insignificant change in this outcome between the two groups. According to the clinical expert, the 10 μmol/L difference in maximum blood ammonia level would not be considered a clinically meaningful change. In addition, the percentage of ammonia samples above the ULN was similar with GPB and NaPBA treatments. Clinical outcomes such as cognitive development and HRQoL were not assessed during the short treatment periods.

The effect of GPB on blood ammonia levels was also assessed in patients who were diagnosed with a UCD during their infancy and in those who were diagnosed with a UCD after infancy. The results from subgroup analysis implied that adults with early onset of a UCD (two years of age or younger) responded better to GPB treatment in ammonia control than adults with onset of a UCD at ages older than two, although the numbers of patients in the subgroups were very small and prevent drawing solid conclusions with respect to the effect of GPB in the subpopulation (APPENDIX 4).

Results from three short-term, non-randomized trials enrolling adults and children suggested that GPB had a similar effect in lowering the blood ammonia levels as NaPBA, after one week to 10 days of treatment. The risk of AEs was comparable between GPB and NaPBA, and the majority of reported AEs were of mild intensity. However, these small trials did not have sufficient power to detect clinically or statistically meaningful differences between GPB and the comparator. The results should be interpreted with caution (0). Post-hoc pooled analyses of short-term studies of GPB were conducted in order to increase the study power. The results suggested that GPB exhibited favourable pharmacokinetic and ammonia control relative to NaPBA in patients with a UCD.¹⁹ However, the results should be interpreted with caution due to the heterogeneity among the individual studies, such as study design and varied baseline patient characteristics. Results from three long-term, open-label, non-comparative studies indicated that the effects of GPB on blood ammonia and glutamine levels appeared to be maintained after 12 months of treatment in both children and adults. In addition, the number of HACs per patient was reduced compared with the values 12 months before screening. HRQoL improved in children, while it appeared to decrease in adults according to generic QoL assessment tools. Neuropsychological testing results were inconsistent across trials, age groups, and assessment tools. Considering the limitations of these long-term studies (open-label, lack of comparator, short duration, and small sample), the findings should be interpreted with caution (APPENDIX 7).

The clinical expert indicated that the duration of the included RCT and non-randomized trials was not long enough to appropriately assess clinical outcomes. Duration of at least eight weeks to six months would be required to evaluate the benefits and harms of study drug.

Treatment compliance was high in both treatment groups during the four-week periods.

4.2.2. Harms

No death occurred during the DB treatment period. Overall, patients treated with GPB were more likely to complain about AEs (61.4%) than those treated with NaPBA (51.1%). Symptoms of lower GI tract disorders were reported more frequently on GPB treatment, whereas symptoms of upper GI disorders were more likely to be reported during the NaPBA treatment. These events were generally mild. There was one case of hyperammonemia that led to treatment discontinuation with NaPBA. Compared with baseline (all patients received prior NaPBA treatment), there was a reduction in the number of patients still reporting any of the UCD treatment-specific symptoms (bad taste, body odour, etc.) after treatment with GPB. Because of the small number of study participants, it is challenging to make a definite conclusion on the safety of GPB.

As well, because of the relatively milder conditions of the patients recruited in HPN-100-006, AEs, and especially SAEs, would have been limited.

Longer-term safety was explored in extension studies (APPENDIX 7), which included patients from original pivotal study as well as new patients. The findings suggested that the overall frequency of AEs gradually increased. Almost all patients experienced AEs after one year of treatment with GPB. Infections and infestations, as well as GI disorders, were still the most frequently experienced AEs. Newly emerging AEs included nervous system disorders and general disorders as well as administration-site conditions.