Regulatory Decision Summary for Cerdelga

Efficacy of Cerdelga was primarily supported by two randomised, controlled, pivotal trials; Engage and Encore.

Engage was a multi-centre, double-blind, randomized, placebo-controlled, 39-week (primary analysis period) study in patients (N = 40) who had not received substrate reduction therapy (SRT) or enzyme replacement therapy (ERT) for GD1 (that is [i.e.], treatment-naïve patients) with an uncontrolled, open-label extension providing data up to 78 weeks. The Engage results demonstrated a mean 27.6 % reduction in spleen volume from baseline to Week 39 in the Cerdelga group, compared to an increase of 2.1% in the placebo group, a difference of -30.0% (p <0.0001).

Encore was a multi-centre, randomized, open-label, active comparator (Cerezyme), 52-week (primary analysis period) non-inferiority study in GD1 patients (N = 160) who had already reached protocol-defined therapeutic goals with ERT. It followed with an uncontrolled, open-label extension period, up to 104 weeks. The Encore results found that Cerdelga was non-inferior to Cerezyme for the primary efficacy endpoint (stability in the composite endpoint including hemoglobin, platelet count, spleen and liver volume).

Safety was supported by the two pivotal studies, described above, as well as a Phase 2 study and a Phase 3b study; all performed in GD1 patients. The most commonly reported adverse reactions with Cerdelga (occurring in ≥5% of patients) were headache and dizziness. The most frequent serious adverse event (SAE) was syncope (5 patients [1%]). The most frequent serious cardiac events were myocardial infarction (3 [1%]), followed by one SAE each for acute myocardial infarction, atrioventricular (AV) block, AV block second degree, and ventricular tachycardia. The most common adverse events leading to discontinuation of Cerdelga and/or withdrawal from the studies were ventricular tachycardia (1%) and (acute) myocardial infarction (1%). Restrictions have been included in the product monograph to mitigate these risks.

Findings from a dedicated electrocardiogram (ECG) assessment study in healthy subjects showed that the active ingredient in Cerdelga can increase QRS duration and PR interval. At higher than therapeutic concentrations, it can also significantly increase the QTc interval. Based on these observations, warnings and precautions were included in the Canadian Product Monograph concerning drug-drug interactions and underlying risk factors that might increase the risk of experiencing a serious arrhythmia during treatment with Cerdelga. Concomitant use of Cerdelga with other drugs that are expected to markedly decrease its metabolism is contraindicated.

Eligibility for treatment with Cerdelga is dependent on CYP2D6 metabolizer status, as determined by genotype testing. Cerdelga is indicated for use in patients who are extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). New limitations of use have been added to the Indications and Clinical Use section restricting use in patients who are ultra-rapid metabolizers or patients with indeterminate metabolizer status.

In order to further reinforce the eligibility criteria of patients who can be prescribed Cerdelga and inform on the potential for drug-drug interactions, a medication guide will be distributed to the prescriber and a patient alert card to the patient.

Based on the data provided, the overall benefit-harm-uncertainty profile is favourable.

For more information on Health Canadas decision, please view the Summary Basis of Decision.