Regulatory Decision Summary for Carbaglu

The sponsor provided new data to support efficacy and safety of Carbaglu for the proposed indications of treatment of hyperammonemia due to Methylmalonic Acidemia (MMA) and due to Propionic Acidemia (PA). These include a randomized, placebo-controlled Trial (2894), additional propensity matching score (PMS) analyses of previously submitted retrospective observational data, and an assessment of cardiac safety. The indication for treatment of hyperammonemia in patients with isovaleric acidemia (IVA) was removed by the sponsor due to extremely limited data.

Trial 2894 evaluated the efficacy and safety of Carbaglu in the acute treatment of hyperammonemia in PA and MMA (N = 24 pediatric and adult patients; 94 episodes of hyperammonemia) using a dosage of 150 mg/kg/day divided into 2 equal doses for up to 7 days. The primary efficacy endpoint found no difference between treatment arms with an estimated relative benefit of Carbaglu/placebo for elapsed time from first dose to earlier of achieving ammonia level ≤50 µmol/L or hospital discharge of 1.34 (95% CI 0.86, 2.08, p = 0.19). Due to difficulty with enrolment, changes to the eligibility criteria allowed for inclusion of patients presenting with lower baseline ammonia levels. A post hoc subgroup analysis was conducted for episodes with higher baseline ammonia levels (using a cutpoint based on the median baseline ammonia level of 120 µmol/L) and showed a statistically significant difference in favour of Carbaglu (4.13 [95% Confidence Interval [CI] 1.94, 8.79], p<0.001 [46 episodes]). These results were considered meaningful, taking into account the greater context of difficulties with studying ultra-rare and life-threatening diseases for which there are no approved treatments. Recognizing the importance of reducing ammonia levels as quickly as possible in a metabolic crisis to avert serious consequences including death, the results showed a clinically meaningful advantage of Carbaglu over placebo with an observed reduction in time from baseline to reach a non-toxic ammonia level of 29 hours for Carbaglu, compared to 52 hours for Placebo. The secondary efficacy endpoints did not support the statistically significant results of the primary efficacy subgroup analysis but reflected a positive trend favouring Carbaglu in the subgroup of episodes with higher baseline ammonia levels.

The additional analyses from the retrospective observational dataset in pediatric and adult patients provided descriptive findings which supported a faster decrease in ammonia percent change from baseline in Carbaglu treated episodes, compared to treatment with ammonia scavengers alone. A descriptive analysis on the dose response relationship also suggested a dose related reduction of the ammonia levels as a function of the administered dose of Carbaglu. The findings of the retrospective observational dataset provided descriptive support as well as additional data studying Carbaglu doses 100 to 250 mg/kg/day (in 2 to 4 divided doses).

Trial 2894 showed slightly increased adverse events (AEs) for Carbaglu-exposed patients during hyperammonemic episodes, relative to placebo for neutropenia, anemia, electrolyte imbalance, vomiting, decreased appetite, and encephalopathy. Serious Adverse Events (SAEs) that were more common in Carbaglu exposures, compared to placebo included encephalopathy, vomiting, enterocolitis infection, seizure and apnea and there was one death (apnea and encephalopathy) after Carbaglu exposure. While the current Product Monograph was updated to include all safety results which occurred more frequently in Carbaglu-exposed episodes, no new warnings and precautions were added given the observed AEs are well-known to be associated with the underlying disease process and metabolic decompensation in the patient population.

The uncertainties surrounding efficacy and safety in patients with less pronounced ammonia levels or for chronic use, have been addressed in the Product Monograph. Notably, the proposed indications were revised to specify Carbaglu is for acute use only as an adjunctive treatment to standard of care therapies. The Product Monograph also states that it must be used in coordination with medical professionals experienced in metabolic disorders and recommends a maximum duration of use of up to 7 days. Additionally, close monitoring of ammonia levels to assess patient response to treatment is required with specific warnings about the dangers of uncontrolled hyperammonemia. While the approved recommended dosing reflects that studied systematically in Trial 2894, there are uncertainties based on how the drug is dosed internationally (100-250 mg/kg/day) and in clinical practice (Baumgartner et al 2014). To address these uncertainties, and recognizing the potential need for individualized dosing, taking into account the disease context, the approved Product Monograph was revised to indicate that a dose range of 100 to 250 mg/kg divided into 2-4 doses, has been studied and may be considered on an individual patient basis, as guided by severity of hyperammonemia, tolerability and response to available treatments.

The potential effects of Carbaglu on the QTc interval were re-examined with the use of concentration-response modelling provided in the R/NON. The model did not predict any clinically relevant QTc interval at concentrations of Carbaglu up to 7.5 mg/kg IV dose (which is approximately 4.7 times the orally administered clinical exposure of 250 mg/kg/day). Due to uncertainties with respect to other ECG parameters (PR interval, QRS interval and HR), monitoring of cardiac parameters is recommended in the Product Monograph.

The benefits of Carbaglu in reducing hyperammonemia associated with metabolic decompensation in PA and MMA pediatric and adult patients are considered to outweigh the risks under the recommended conditions of use. Given the rare nature of these conditions, it is unlikely that other robust data will become available to further characterize the effectiveness of Carbaglu, however, the revised Product Monograph reflects the uncertainties including revised indications and dosing and administration instructions. The Product Monograph was also updated to include new information pertaining to post-market safety, including new information on overdosage. The Marketed Health Products Directorate is updating the Risk Management Plan with additional characterization of off-label use.

In conclusion, the benefits of Carbaglu for acute hyperammonemia due to propionic acidemia and acute hyperammonemia due to methylmalonic acidemia outweigh the risks, when used as directed in the Product Monograph.