Summary Basis of Decision for Cerdelga

 

Clinical Pharmacology

Gaucher disease type 1 (GD1) is caused by a deficiency of the lysosomal enzyme acid β-glucosidase. Acid β-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucosylceramide primarily in the lysosomal compartment of macrophages, giving rise to foam cells or Gaucher cells. Eliglustat (the medicinal ingredient in Cerdelga) is a specific inhibitor of glucosylceramide synthase and acts as a substrate reduction therapy for GD1.

The pharmacokinetics and pharmacodynamics of eliglustat were assessed in 13 clinical pharmacology studies in healthy adult subjects, as well as one Phase II study and three Phase III studies in adult patients with GD1.

Pharmacodynamics

An electrocardiographic evaluation of Cerdelga was conducted in a randomized, double-blind, placebo-and positive-controlled, crossover study conducted in 47 healthy subjects to provide information on cardiac safety. In this clinical trial, subjects received single 168 mg and 672 mg doses of Cerdelga, producing mean maximum plasma concentration (C_max) values of 16.7 ng/mL and 237 ng/mL, respectively, with upper range concentrations as high as 761 ng/mL. Of note, mean steady-state C_max values for Cerdelga in patients with Gaucher disease receiving the recommended therapeutic doses are predicted to be approximately 25 ng/mL in extensive metabolizers and approximately 75 ng/mL in intermediate and poor metabolizers on the basis of a population pharmacokinetic model.

Results of the clinical trial showed that with a single 168 mg dose of Cerdelga, there were statistically significant differences from placebo in baseline-adjusted mean QRS duration and PR interval, with maximum effects of 1.4 ms (90% Confidence Interval [CI]: 0.4, 2.3) for the QRS duration and 3.5 ms (90% CI: 1.2, 5.8) for the PR interval. At the Cerdelga 672 mg single dose, there were statistically significant differences from placebo in baseline-adjusted mean QTc interval, QRS duration, and PR interval, with maximum effects of 6.5 ms (90% CI: 3.6, 9.3) for the QTcF interval, 4.2 ms (90% CI: 3.1, 5.2) for the QRS duration, and 14.1 ms (90% CI: 11.7, 16.6) for the PR interval.

Based on the analysis of the pharmacokinetic/pharmacodynamic data, predictions of the magnitude of the cardiodynamic effects at concentrations in the therapeutic range have been provided in the Cerdelga Product Monograph along with guidance on dose adjustments.

Pharmacokinetics

Based on a population pharmacokinetic analysis (Pop-PK), results showed that the cytochrome P450 (CYP) 2D6 predicted phenotype based on genotype is the most important factor affecting pharmacokinetic variability. Poor metabolizers (PMs) individuals (approximately 5 to 10% of the population) are predicted to exhibit higher concentrations of eliglustat (the medicinal ingredient in Cerdelga) than intermediate metabolizers (IMs) or extensive metabolizers (EMs), therefore once daily dosing is recommended in PM patients. In addition, use of Cerdelga is contraindicated in patients who are ultra-rapid metabolizers (URMs) or indeterminate metabolizers.

The pop-PK analysis also revealed that mild renal impairment did not impact the pharmacokinetics of Cerdelga. However, Cerdelga has not been studied in patients with moderate to severe renal impairment or end-stage renal disease; therefore use of Cerdelga is not recommended in these patients. Cerdelga has also not been evaluated in patients with hepatic insufficiency.

A limited number of patients aged 65 years and over were enrolled in clinical trials. As greater rates of hepatic, renal, and cardiac function impairment are usually observed in elderly patients, these patients may be more sensitive to the effects of Cerdelga.

The safety and effectiveness of Cerdelga for use in pediatric patients have not been established.

Drug-Drug Interactions

Cerdelga is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Cerdelga is a substrate of P-glycoprotein (P-gp) and an inhibitor of P-gp and CYP2D6.

Drugs that inhibit CYP2D6 and CYP3A pathways may significantly increase the exposure and maximal concentrations to Cerdelga and result in prolongation of the PR, QTc, and/or QRS cardiac interval which could result in cardiac arrhythmias.

Based on the results of clinical trials and physiologic based pharmacokinetic modeling (PBPK)/pop-PK modeling, Cerdelga is contraindicated in patients who are IMs or EMs taking a strong or moderate CYP2D6 inhibitor (e.g. paroxetine, terbinafine) concomitantly with a strong or moderate CYP3A inhibitor (e.g. ketoconazole, fluconazole). Fold increases after co-administration were 4.2-17-fold increases for maximum plasma concentration (C_max) and 5.0-24 for plasma drug concentration time curve 0-12 hours (AUC_0-12) compared to Cerdelga administered alone in IM and EM subjects. Co-administration of Cerdelga with strong CYP3A inhibitors is contraindicated in IMs and PMs. Fold increases after co-administration were 4.3 - 4.4 for C_max (IM and PM), 5.4 for AUC_0-12 (IM), and 6.2 for AUC_0-24 (PM), compared to Cerdelga administered alone.

Cerdelga is not recommended for EMs and IMs taking a strong CYP2D6 inhibitor (e.g. paroxetine), or PMs taking moderate (e.g. fluconazole) or weak (e.g. ranitidine) CYP3A inhibitors.

Dosage of Cerdelga is reduced to 84 mg once daily for EMs and IMs taking moderate CYP2D6 inhibitors (e.g. terbinafine), EMs and IMs taking moderate CYP3A inhibitors and EMs taking a strong CYP3A inhibitor (e.g. ketoconazole).

Concomitant administration of Cerdelga with strong CYP3A inducers (e.g., rifampin) substantially decreases the exposure and therapeutic effectiveness of Cerdelga; therefore concomitant administration is not recommended in EMs, IMs and PMs.

Cerdelga increases exposures and maximal concentrations of co-administered CYP2D6 (metoprolol) and P-gp substrates (digoxin). Lower doses of these may be required.

Conclusion

In conclusion, the pop-PK analysis showed eligibility for treatment with Cerdelga is dependent on CYP2D6 metabolizer status, as determined by genotype testing. Cerdelga is contraindicated in patients who are IMs or EMs, taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. Co-administration of Cerdelga with strong CYP3A inhibitors is also contraindicated in IMs and PMs. Cerdelga is not recommended for EMs and IMs taking a strong CYP2D6 inhibitor or PMs taking moderate or weak CYP3A inhibitors. New limitations of use have been added to the Indications and Clinical Use section in the Cerdelga Product Monograph restricting use of Cerdelga in patients who are ultra-rapid metabolizers or patients with indeterminate metabolizer status. Product Monograph restrictions have also been included to decrease risk of increased exposure due to drug-drug interactions which could result in prolongation of the PR interval, QRS duration, and/or QTc interval leading to cardiac arrhythmias.

Overall, the clinical pharmacological data support the use of Cerdelga for the recommended indication. The identified safety concerns above have been adequately captured in the Cerdelga Product Monograph to address these issues.

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

Clinical Efficacy

The clinical efficacy of Cerdelga was primarily supported by two randomised, controlled, pivotal trials, Engage and Encore.

The Engage trial was a Phase III, randomized, double-blind, placebo-controlled, multi-centre, 39-week (primary analysis period) clinical study conducted in 40 patients who had not received previous enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) therapy for GD1 (i.e., treatment-naïve patients) with an uncontrolled, open-label extension providing data up to 78 weeks. The aim of the study was to confirm the efficacy and safety of Cerdelga after 39 weeks of treatment in patients with GD1. The primary endpoint consisted of the percent change in spleen volume from baseline to Week 39 when comparing Cerdelga to a placebo.

The study design comprised a screening period (Days -45 to -1), a randomized, placebo-controlled, double-blind primary analysis period (Day 1 to Week 39), an open-label long-term treatment period (post-Week 39 through study completion), and a follow-up phone call approximately 30 to 37 days after the last dose of study medication.

Patients who met all eligibility criteria based on screening assessments were randomized to receive treatment with Cerdelga or placebo during the 39-week primary analysis period. Randomization was stratified according to baseline spleen volume (≤20 or >20 multiples of normal [MN]), and within each stratum patients were then randomized in a 1:1 ratio to each treatment group. All patients randomized to Cerdelga received a single 50 mg dose on Day 1 and repeat doses of 50 mg twice daily (BID) from Day 2 to Week 4; thereafter, patients received a dose of either 50 or 100 mg BID through Week 39, depending on each patient's trough plasma concentration of Cerdelga at Week 2.

Following completion of the Week 39 assessments, patients then entered a long-term treatment period. In this period, all patients received Cerdelga at an initial dose of 50 mg BID from post-Week 39 (Day 1 of the long-term treatment period) through Week 43. Thereafter, patients received a dose of 50 or 100 mg BID through Week 47 and a dose of 50, 100, or 150 mg BID from post-Week 47 through study completion, depending on their trough plasma concentration of Cerdelga at Week 41 and Week 45, respectively. The long-term treatment period extends to 130 weeks which currently remains ongoing. Data for up to Week 78 were provided in this New Drug Submission.

Results from the primary analysis of the Engage trial demonstrated superior efficacy in the percentage reduction in spleen volume from baseline to Week 39 (primary endpoint) compared to placebo. Over the 39-week period, the least squares mean percentage decrease in spleen volume was -27.6% for the Cerdelga treatment group, compared to an increase of +2.1% for the placebo group, resulting in a statistically significant treatment difference of -30.0% (p<0.0001).

All secondary efficacy endpoints (absolute change in hemoglobin levels, percentage change in liver volume, and percentage change in platelet counts) also showed statistically significant results favouring Cerdelga over placebo.

In contrast to the Engage trial, the purpose of the Encore trial was to assess efficacy and safety in 159 patients who had been treated with enzyme replacement therapy (ERT) while comparing Cerdelga to Cerezyme (ERT). The Encore trial was a multi-centre, randomized, open-label, active comparator (Cerezyme), 52-week (primary analysis period) non-inferiority study in GD1 patients who had already reached protocol-defined therapeutic goals with ERT. Uncontrolled, open-label extension data were provided up to 104 weeks. The primary endpoint was defined as the percent of patients who remained stable for 52 weeks which was evaluated through use of a composite endpoint which included hemoglobin, platelet count, spleen and liver volumes. Stable hematological parameters were defined as hemoglobin level not decreasing >1.5 g/dL from baseline and platelet count not decreasing >25% from baseline. Stable organ volumes consisted of spleen volume (in MN) not increasing >25% from baseline, if applicable, and liver volume (in MN) not increasing >20% from baseline.

The Encore trial design comprised a screening period (Days -45 to -1), a randomized, placebo-controlled, double-blind primary analysis period (Day 1 to Week 52), an open-label long-term treatment period (post-Week 52 through at least Week 104), and a safety follow-up period (30 to 37 days after the patient's last dose of study medication for patients who had discontinued study).

Patients who met all eligibility criteria based on screening assessments were randomized to receive treatment with Cerdelga or Cerezyme during the 52-week primary analysis period. The randomization was stratified based on the patient's every 2 weeks (q2w) equivalent ERT dose (<35 U/kg/q2w or ≥35 U/kg/q2w) prior to any unanticipated treatment interruption, dose reduction, or regimen change. Within each stratum, patients were randomized in a 2:1 ratio to receive Cerdelga or Cerezyme, respectively for 52 weeks. All patients randomized to Cerdelga received a dose of 50 mg BID from Day 1 to Week 4; thereafter, patients received a dose of either 50 or 100 mg BID through Week 8, depending on their trough plasma concentration of Cerdelga at Week 2. Post-Week 8, patients randomized to Cerdelga received a dose of either 50, 100 or 150 mg BID through Week 52, depending on their trough plasma concentration of Cerdelga at Week 6.

Results from the primary analysis collected at 52 weeks for both the Cerdelga and Cerezyme treatment groups showed the percentage of patients who remained stable in the composite efficacy endpoint was 84.8% in the Cerdelga treatment group and 93.6% in the Cerezyme treatment group. The mean difference in the percentage of patients remaining stable in the two treatment groups was -8.8% with a CI: -17.6, 4.2. Given the lower bound of the 95% CI: -17.6% was noted to be in the pre-specified non-inferiority margin of -25%, the criteria for concluding non-inferiority of Cerdelga to Cerezyme was met.

The results of the secondary efficacy endpoints in Encore generally supported the primary efficacy results (including mean change from baseline in spleen volume, platelet count, liver volume and a composite endpoint including binary parameters for hemoglobin, platelet count, spleen and liver volumes).

While efficacy was supported by clinical data provided from both the Encore and Engage trials, there were differences in dose determination and regimen employed in these trials compared to that proposed for marketing. Specifically, these clinical trials were designed to allow for dose determination based on plasma drug concentrations, rather than CYP2D6 metabolizer status. The trials also permitted dose up-titration (up to 150 mg BID) during the extension period for Engage and during both primary and extension periods for Encore, exceeding the highest dose proposed for marketing (i.e., 100 mg BID). Finally, for PMs, Cerdelga 50 mg BID was evaluated in both trials instead of the proposed 100 mg once daily regimen. As such, appropriate rationale and data (including pharmacometric modelling) were provided by the sponsor to support the proposed marketed conditions of use.

Indication

The New Drug Submission for Cerdelga was filed by the sponsor with the following indication:

• Cerdelga is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs) or extensive metabolizers (EMs).

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Cerdelga is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs) or extensive metabolizers (EMs), as determined by CYP2D6 genotype testing.
  
  Limitations of Use
  Cerdelga should not be used in patients genotyped as:
  • CYP2D6 ultra-rapid metabolizers (URMs) as these patients may not achieve adequate concentrations of Cerdelga to achieve a therapeutic effect.
  • CYP2D6 indeterminate metabolizers as a specific dosage cannot be recommended for these patients.

Furthermore, given that no safe and effective dose was able to be determined for patients who are ultra-rapid metabolizers or patients with indeterminate metabolizer status, new limitations for use were added in the Indications and Clinical Use sections of the Cerdelga Product Monograph, thereby restricting use of Cerdelga in these patients.

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

Clinical Safety

The safety profile of Cerdelga was primarily evaluated from the pooled safety data from two Phase III trials (Engage and Encore) previously described in the Clinical Efficacy section. Supportive data were derived from one Phase II trial and one Phase IIIb trial.

The Phase II trial (GZGD00304) was a single-arm, open-label, multicentre trial designed to evaluate the efficacy, safety and pharmacokinetics of Cerdelga in 26 GD1 patients. Nineteen patients completed four years of treatment. Cerdelga showed improvements from baseline in organ volume and hematological parameters over the 4-year treatment period.

The Phase IIIb Edge trial (GZGD03109) was a randomized, double-blind, multicentre trial designed to evaluate the efficacy, safety, and pharmacokinetics of once daily versus twice daily dosing of Cerdelga in 170 patients with GD1 who had demonstrated clinical stability on a twice daily dose of Cerdelga. The Edge trial data included only data from the open-label lead-in period (between 6 and 18 months in length).

Based on these four trials, the pooled safety data for Cerdelga consisted of 393 patients with GD1 who received at least one treatment with Cerdelga. Mean duration of exposure to Cerdelga was 1.4 years with 349 patients (89%) having received Cerdelga for at least six months, and 204 patients (52%) having received Cerdelga for at least one year.

Overall, 334/393 (85%) of Cerdelga-treated patients experienced one or more treatment-emergent adverse events (TEAEs) while receiving Cerdelga. The most common adverse reactions with the use of Cerdelga (occurring in ≥5% of patients) were headache and dizziness. The most frequent serious adverse event (SAE) was syncope (5 [1%]). The most frequent SAE in reference to cardiac disorders were myocardial infarction (2[1%]), followed by one SAE each for acute myocardial infarction (MI), atrioventricular (AV) block, AV block second degree, and ventricular tachycardia (non-sustained). The SAEs considered by the investigators to be possibly/probably or definitely related to use of Cerdelga were syncope, ventricular tachycardia (non-sustained), AV block and AV block second degree. 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%).

Treatment-emergent adverse events classified as 'cardiac disorders' were reported for 41/393 (10%) of patients. Palpitations were reported for 20 patients (5%) and syncope was reported for 8 patients (2%), with two additional patients experiencing syncope including late breaking safety data (as of January 2015; as presented in the Response to the NOD). While unscheduled electrocardiograms (ECGs), obtained as part of post-event diagnostic testing, did not reveal any cardiac arrhythmias as the potential cause for these syncopal events, there was insufficient information in all cases to completely rule out a potential contributing cardiac origin. Serious adverse events under 'cardiac disorders' showed myocardial infarction (MI) as being the most frequent [2(1%)], followed by one SAE each for acute MI, AV block, AV block second degree, and ventricular tachycardia. Within the results from the ECGs and Holter monitoring, there were three additional patients who were noted to have second degree AV block that were not reported as TEAEs and two who were reported to have ventricular tachycardia not reported as TEAEs.

With eligibility for treatment with Cerdelga being dependent on CYP2D6 metabolizer status (as determined by genotype testing) Cerdelga is indicated for use in patients who are EMs, IMs and PMs. As such, new limitations of use have been added to the Indications and Clinical Use section in the Cerdelga Product Monograph restricting use of Cerdelga in patients who are ultra-rapid metabolizers or patients with indeterminate metabolizer status.

Product Monograph restrictions have been included to decrease risk of increased exposure due to drug interactions which could result in prolongation of the PR interval, QRS duration, and/or QTc interval leading to cardiac arrhythmias. Specifically, Cerdelga is contraindicated in patients who are IMs or EMs, taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. Co-administration of Cerdelga with strong CYP3A inhibitors is also contraindicated in IMs and PMs. With certain other drugs and conditions, Cerdelga is not recommended or dosage is adjusted (reduced to once daily).

Based on all of the data provided, the overall benefit-harm-uncertainty profile is favourable. Cerdelga has demonstrated efficacy for both GD1 treatment naïve patients and GD1 patients switching from ERT. The primary safety concern is the potential for cardiac arrhythmias. This risk is addressed in the Contraindications, Warnings and Precautions, Drug Interactions, and Dosage and Administration sections of the Cerdelga Product Monograph. Further, in order to 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.

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