Summary Basis of Decision for Galafold

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Galafold is located below.
Recent Activity for Galafold

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Galafold

Updated: 2023-08-10

The following table describes post-authorization activity for Galafold, a product which contains the medicinal ingredient migalastat (supplied as migalastat hydrochloride). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Numbers (DINs):

  • DIN 02468042 - 123 mg, migalastat, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NDS # 276328 2023-06-22 Issued NOC 2023-07-28 Submission filed to transfer ownership of the drug product from Amicus Therapeutics UK Ltd. to Amicus Therapeutics Canada Inc. An NOC was issued.
SNDS # 262810 2022-03-28 Issued NOC 2023-03-23 Submission filed as a Level I – Supplement to expand the indication, to provide long-term safety and efficacy data, and to update the list of mutations amenable and non-amenable to treatment. The indication was expanded to patients 12 years and older, with a weight specification (≥45 kg). The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; Adverse Reactions; Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued. A Regulatory Decision Summary was published.
SNDS # 247824 2021-01-08 Issued NOC 2021-12-16 Submission filed as a Level I – Supplement to update the PM with new efficacy information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration, Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 215579 2018-04-19 Issued NOC 2019-03-28 Submission filed as a Level I – Supplement to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions, Dosage and Administration, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
Drug product (DIN 02468042) market notification Not applicable Date of first sale:
2018-01-15		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 196956 2016-07-15 Issued NOC
2017-09-05		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Galafold

Date SBD issued: 2017-12-13

The following information relates to the New Drug Submission for Galafold.

Migalastat
123 mg migalastat (supplied as migalastat hydrochloride), capsule, oral

Drug Identification Number (DIN):

  • 02468042

Amicus Therapeutics UK Ltd.

New Drug Submission Control Number: 196956

 

On September 5, 2017, Health Canada issued a Notice of Compliance to Amicus Therapeutics UK Ltd. for the drug product Galafold.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Galafold is favourable for long-term treatment of adults with a confirmed diagnosis of Fabry disease (deficiency of α-galactosidase [α-Gal A]) and who have an α-Gal A mutation determined to be amenable by an in vitro assay.

1 What was approved?

Galafold was authorized for long-term treatment of adults with a confirmed diagnosis of Fabry disease (deficiency of α-galactosidase [α-Gal A]) and who have an α-Gal A mutation determined to be amenable by an in vitro assay. Galafold is classified as a various alimentary tract and metabolism product.

Treatment with Galafold should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of Fabry disease.

Clinical data supporting the effectiveness of Galafold for the treatment of Fabry disease patients with amenable mutations are limited. In clinical trials, individual response to Galafold treatment varied considerably among patients with amenable mutations. Patients should be assessed for treatment response or failure when initiating Galafold, and monitored periodically thereafter (every 6 months or more frequently) throughout the treatment.

Galafold is not indicated and should not be used in patients with non-amenable mutations. Efficacy was not demonstrated in these patients. Galafold may result in a net loss of α-Gal A activity in patients with non-amenable mutations, potentially worsening the disease condition.

Galafold should not be used concomitantly with enzyme replacement therapy.

Clinical studies of Galafold included a small number of patients aged 65 and over. Dosage adjustment is not expected in this population.

The safety and efficacy of Galafold in pediatric patients (<18 years of age) have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.

Galafold is contraindicated for use in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

Galafold was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Galafold (123 mg migalastat, as migalastat hydrochloride) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains black printing ink, gelatin, indigotine (FD&C Blue 2), magnesium stearate, pregelatinized maize starch, and titanium dioxide.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Galafold Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Galafold approved?

Health Canada considers that the benefit-harm-uncertainty profile of Galafold is favourable for the long-term treatment of adults with a confirmed diagnosis of Fabry disease (deficiency of α-galactosidase [α-Gal A]) and who have an α-Gal A mutation determined to be amenable by an in vitro assay.

Fabry disease is a progressive X-linked lysosomal storage disorder with an estimated incidence of approximately 1:100,000. In Canada <500 people have Fabry disease. Mutations in the α-galactosidase A gene (GLA) result in a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) required for glycosphingolipid metabolism. Reduction in α-Gal A activity results in an accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Symptoms and signs of Fabry disease include pain, renal failure, cardiomyopathy, cerebrovascular events, gastrointestinal symptoms, and early mortality. Plasma lyso-Gb3 can be a useful biological marker for the diagnosis and treatment monitoring of Fabry disease.

Enzyme replacement therapy (ERT) is the currently approved therapy for Fabry disease and it consists of life-long biweekly intravenous infusions with 1 of 2 synthetic enzymes; agalsidase beta or agalsidase alfa. The ERT is associated with a number of limitations related to infusion reactions, antibody formation, and the burden to patients and their families of lifelong infusions.

Galafold has been shown to be efficacious in adults with Fabry disease who have an α-Gal A mutation. The market authorization was based on two completed Phase III pivotal studies and an ongoing open-label extension study. One completed study was an active comparator (ERT)-controlled study in ERT-experienced patients and the other was a placebo-controlled study in ERT-naïve patients. The endpoints assessed in both Phase III studies were clinically relevant in Fabry disease. Galafold was demonstrated to stabilize renal function, i.e., the glomerular filtration rate (GFR) for up to 30 months. Renal function was better in patients treated with Galafold than in untreated patients and comparable to that observed in patients with ERT. Long-term treatment with Galafold also led to significant reductions in Left Ventricular Mass Indices (LVMi) in ERT-naïve and ERT-experienced patients. A lower incidence of clinical composite events (renal, cardiac, cerebrovascular or deaths) was noted in patients treated with Galafold compared to ERT treatment. Treatment with Galafold was associated with reductions of disease substrates, GL-3 and plasma lyso-Gb3.

Galafold was shown to be generally safe and well-tolerated. The most common adverse drug reaction, occurring in >10% of patients, was headache. Adverse events were generally mild to moderate in severity and not related to treatment. Two patients experienced serious adverse events considered possibly related to Galafold treatment; proteinuria in one patient, and paraesthesia and fatigue in the other.

A number of uncertainties arose in the data. An important uncertainty stemmed from Galafold's mechanism of action with individual response to Galafold varying considerably among patients with different amenable mutations. In addition, Phase III clinical studies were conducted in patients with Fabry disease who had <17% of the mutations listed as "amenable" in the Product Monograph. As individual responsiveness of amenable mutations to Galafold is heterogeneous, it is unknown whether all patients with amenable mutations would respond adequately. In patients who do not have amenable mutations, who administer the wrong dosage, or who have severe renal impairment, Galafold has a theoretical potential to worsen the disease condition. As such, patients should be monitored for treatment-response periodically when they initiate Galafold treatment.

For a rare genetic disorder, limited clinical experience is expected. Approximately 16% of amenable mutations were represented in the Phase III studies. Too few patients who were elderly (≥65 years), pediatric (<18 years), or who had renal impairment were enrolled to properly assess the safety and efficacy in these populations. No data were available in patients ≥75 years of age, <16 years of age, and patients who had severe renal impairment or who had liver impairment. Galafold was not studied in combination with ERT. A drug interaction study showed that a single dose of Galafold increased exposure to agalsidase five-fold.

The effect of Galafold on human male fertility is unknown. The medicinal ingredient of Galafold, migalastat, impaired male fertility in rats at clinically relevant doses. These adverse effects were reversible following treatment cessation.

Safety concerns and uncertainties were addressed in the labelling and Risk Management Plan (RMP). An RMP for Galafold was submitted by Amicus Therapeutics UK Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Galafold was accepted.

Overall, Galafold has been shown to have a favourable benefit-harm-uncertainty profile based on the non-clinical and clinical studies. Appropriate warnings and precautions are in place in the Galafold Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Galafold?

Submission Milestones: Galafold

Submission Milestone Date
Pre-submission meeting: 2016-03-07
Submission filed: 2016-07-15
Screening  
Screening Deficiency Notice issued: 2016-09-06
Response filed: 2016-09-26
Screening Acceptance Letter issued: 2016-11-08
Review  
Biopharmaceutics Evaluation complete: 2017-07-05
Review of Risk Management Plan complete: 2017-07-27
Quality Evaluation complete: 2017-08-23
Clinical Evaluation complete: 2017-08-30
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-08-31
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2017-09-05

The Canadian regulatory decision on the non-clinical and clinical review of Galafold was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken placefor Galafold?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Galafold is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of the enzyme α-galactosidase A (α-Gal A), and the subsequent deposition of glycosylsphingolipids in tissues throughout the body, in particular, the kidney, heart, and brain. Fabry disease is due to mutations within the α-galactosidase A (GLA) gene. More than 800 different mutations in the GLA gene have been reported in Fabry disease patients. Of these, more than 60% are missense mutations that result in a single amino acid substitution. Many of the mutated proteins are fully or partially catalytically competent but are structurally unstable, resulting in reduced levels in the lysosomes for breaking down globotriaosylceramide (GL-3) and other lipid substrates. Protein instability varies significantly among different mutant forms of α-Gal A proteins.

The medicinal ingredient of Galafold, migalastat, is a specific potent reversible competitive inhibitor of human α-Gal A and also a specific structural stabilizer for the wild-type and many mutant forms of α-Gal A. Certain missense mutations are amenable to treatment with migalastat. Binding stabilizes specific mutant forms (the corresponding genotypes are referred to as "amenable" mutations), increases α-Gal A activity and reduces cellular levels of accumulated substrates, GL-3 and plasma globotriaosylsphingosine (lyso-Gb3). Approximately 30 to 50% of patients with Fabry disease have amenable mutations; the majority of mutations classified as amenable are associated with the classic phenotype of the disease.

In patients with non-amenable mutations in Phase II and Phase III clinical studies, Galafold 123 mg (equivalent to 150 mg migalastat hydrochloride [HCl]) every other day (QOD) resulted in a significant increase from baseline in the levels of plasma lyso-Gb3 and urine GL-3 in all the male patients and 80% of the female patients. Galafold-induced increases in GL-3 or lyso-Gb3 indicates inhibition of α-Gal A.

A thorough QT study demonstrated that migalastat hydrochloride at a therapeutic dose (150 mg) or supratherapeutic dose (1,250 mg) had no effect on QTc interval.

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

Clinical Efficacy

The clinical efficacy of Galafold was primarily evaluated in two Phase III pivotal studies Study AT1001-012 and Study AT1001-011, as well as an open-label extension study. The Phase III clinical studies were conducted in patients with Fabry disease having 43 (<17%) of the amenable mutations listed in the Galafold Product Monograph.

Study AT1001-012

Study AT1001-012, referred to as the enzyme replacement therapy (ERT)-experienced study, was an 18-month randomized open-label active comparator study that evaluated the efficacy and safety of Galafold (123 mg migalastat equivalent to 150 mg migalastat hydrochloride [HCl]) compared to ERT (agalsidase beta or agalsidase alfa). The study had male and female patients (84% Caucasian) with Fabry disease who were receiving ERT prior to study entry and who had amenable mutations (based on a Good Laboratory Practice [GLP] validated in vitro assay, number of patients [n] = 52). At baseline, 53% of patients had neurologic disorders, 72% had cardiac disorders, and 75% of patients had renal disorders. Patients were randomized in a ratio of 1.5:1 to switch to Galafold (150 mg migalastat HCl, every other day [QOD]) or continue with ERT. After 18 months of treatment, patients in the ERT group switched to Galafold (150 mg migalastat HCl, QOD) and patients in the Galafold group continued on the same treatment for a 12-month extension period.

The primary efficacy parameters were the annualized rates of change in both the estimated glomerular filtration rate using the CKD-EPI creatinine equation (eGFRCKD-EPI) and measured glomerular filtration rate by iohexol clearance (mGFRiohexol). Demographics were comparable in both treatment groups. Medical history and prior and concomitant medication were comparable between the groups. The mean eGFRCKD-EPI at baseline for the Galafold group was 89.6±22.2 mL/min/1.73 m2, and 95.8±19.2 mL/min/1.73 m2 in the ERT group. The mean mGFRiohexol at baseline was 82.4±18.1 mL/min/1.73 m2 for the Galafold group and 83.6±23.9 mL/min/1.73 m2 for the ERT group. All patients had proteinuria at baseline based on the urine protein: creatinine ratio (Galafold group 19.9±21.5 mg/mmol; ERT group 12.8±16.3 mg/mmol). Thus, these patients were considered as having mild renal impairment with proteinuria.

The results demonstrated that Galafold and ERT have comparable effects on renal function over the 18-month treatment period in patients with amenable mutations. The co-primary endpoints were met with the pre-specified criteria of the >50% overlap of 95% confidence interval (CI) and the difference between the least square (LS) means within 2.2 mL/min/1.73 m2 per year for both eGFRCKD-EPI and mGFRiohexol.

The annualized rate of change in eGFRCKD-EPI was comparable between treatment groups and met both pre-specified measures of comparability; 100% of the width of the Galafold group 95% CI (-2.3, 1.5 mL/min/1.73 m2) was encompassed by the lower bound of the ERT group 95% CI (-3.6, 1.6 mL/min/1.73 m2), and the difference between the LS means of the treatment groups was <2.2 mL/min/1.73 m2 (Galafold, -0.4 mL/min/1.73 m2; ERT, -1.0 mL/min/1.73 m2). The annualized rate of change in mGFRiohexol was comparable between treatment groups and met both pre-specified measures of comparability; 100% of the width of the Galafold group 95% CI (-7.7, -1.1 mL/min/1.73 m2) was encompassed by the lower bound of the ERT group 95% CI (-7.8, 1.3 mL/min/1.73 m2), and the difference between the LS means of the treatment groups was <2.2 mL/min/1.73 m2 (Galafold, -4.4 mL/min/1.73 m2; ERT, -3.2 mL/min/1.73 m2).

All secondary efficacy parameters related to GFR; the annualized rate of change using the modification of diet in renal disease (MDRD) in eGFRMDRD and the change from baseline in eGFRCKD-EPI, eGFRMDRD, and mGFRiohexol, were consistent with the primary efficacy parameters. At Month 18, more reductions in 24-hour urine protein were noted in the ERT group compared to the Galafold group. Of note, the ERT group had higher baseline values compared to the Galafold group.

The composite clinical outcome (percentage of subjects with a renal, cardiac, or cerebrovascular event or death during the 18-month treatment period) was 29% in the Galafold group and 44% in the ERT group.

The levels of plasma lyso-Gb3 remained low and stable in patients with amenable mutations in both treatment groups during the 18-month treatment period. In 2 male patients with non-amenable mutations, plasma lyso-Gb3 levels increased from baseline after switching from ERT to Galafold.

The left ventricular mass index (LVMi) as assessed by an echocardiogram (ECHO) showed decreases from baseline to Month 18 for patients in the Galafold group (mean change, -6.6 g/m2), and less decreases from baseline for patients in the ERT group (mean change, -2.0 g/m2). More reductions were noted in patients with left ventricular hypertrophy (LVH) at baseline (mean change, -8.4 g/m2, n = 13). Males in the Galafold group had an increase in white blood cell α-Gal A activity from baseline to Month 18.

Data at Month 30 showed durability of the response to long-term Galafold treatment for both primary endpoints; eGFRCKD-EPI and mGFRiohexol. The data demonstrated reductions in LVMi after long-term Galafold treatment, with larger reductions in patients with LVH at baseline. Galafold was also able to maintain low levels of plasma lyso-Gb3 over 30 months.

Study AT1001-011

Study AT1001-011, referred to as the ERT-naïve study, was a 6-month randomized double-blind placebo-controlled study with an 18-month open-label period. The study evaluated the efficacy and safety of Galafold in male and female patients (97% Caucasian) with Fabry disease who were naïve to ERT or who had previously been on ERT and had stopped for at least 6 months prior to study entry and who have amenable mutations (based on a preliminary in vitro assay, n = 67). Patients were randomized in a ratio of 1:1 to receive either Galafold QOD or placebo for 6 months (Stage 1), followed by Stage 2 in which patients in the Galafold group continued to receive Galafold QOD (the G-G group) and patients in the placebo group switched to Galafold QOD (the P-G group) for 6 months, followed by an open-label extension phase in which all patients continued to receive Galafold treatment for 12 months.

The primary endpoint, the proportion of patients with a reduction of ≥50% from baseline to Month 6 in the average number of interstitial capillaries (IC) GL-3 inclusions, was not met. However, the mean difference for the secondary endpoint of change in percentage of kidney IC with zero GL-3 inclusions was higher in Galafold treatment (7.3%) compared to placebo (1.3%, p = 0.042). The post-hoc analysis at Month 6 in patients determined to have amenable mutations based on a GLP-validated in vitro assay, demonstrated a statistically significantly greater reduction in mean IC GL-3 inclusions for Galafold (-0.25 ±0.10; -39%, n = 25) compared to placebo (+0.07±0.13; +14%, n = 20) (p = 0.008).

At Month 12 (Stage 2), the reduction in the mean number of GL-3 inclusions per IC remained stable in the G-G group with no further reduction. For patients who switched from placebo to Galafold (the P-G group), a statistically significant reduction in the mean number of GL-3 inclusions per IC was demonstrated at Month 12 (-0.33 ± 0.15; -58%, n = 17) (p = 0.014). Qualitative reductions in GL-3 levels were observed in multiple renal cell types: podocytes, mesangial cells, and glomerular endothelial cells, over 12 months of treatment with Galafold.

At Month 6, a statistically significant decrease in plasma lyso-Gb3 was demonstrated in patients with amenable mutations in the Galafold group compared to the placebo group. From Month 6 to Month 12, patients with amenable mutation in the G-G group maintained their reduced levels of plasma lyso-Gb3, and those in the P-G group demonstrated a statistically significant decrease in plasma lyso-Gb3 during Stage 2 compared to Stage 1.

In patients with amenable mutations, no clinically significant differences in renal function were observed during the initial 6-month placebo-controlled period. In the open-label period, renal function remained stable for up to 24 months of Galafold treatment in patients with amenable mutations. After 18/24 months of Galafold treatment, the mean annualized rate of change in eGFRCKD-EPI was -0.30 mL/min/1.73 m2 (95% CI: -1.65, 1.04; n = 41).

In patients with amenable mutations, no clinically significant differences in LVMi or other ECHO parameters were observed during the initial 6-month placebo-controlled period. At Month 24, the mean change from baseline in LVMi was -7.7 g/m2 (95% CI: -15.4, -0.01; n = 27). Larger reductions were seen in those patients who had LVH at baseline, in whom the mean change from baseline to Months 18/24 in LVMi was -18.6 g/m2 (95% CI: -38.2, 1.0; n = 8). Further reductions in LVMi were demonstrated in patients with amenable mutations who continued on Galafold treatment in the long-term extension study.

Overall Analysis of Efficacy

Galafold was demonstrated to stabilize renal function (GFR) up to 30 months. The effect on renal function was comparable to that observed with ERT and better than that reported in untreated patients with Fabry disease. Treatment with Galafold led to a significant reduction in LVMi after 18 months of Galafold treatment in patients who switched from ERT compared to a smaller reduction in patients who remained on ERT. The reduction in LVMi was maintained after 30 months of Galafold treatment, with larger reductions in patients with LVH at baseline. Similar reductions in LVMi were noted in ERT-naïve patients for up to 24 months of treatment. After 18 months of treatment, a lower incidence of clinical composite events (renal, cardiac, or cerebrovascular) was noted with Galafold treatment (29%) compared to the ERT treatment (44%). Treatment with Galafold was associated with increased endogenous α-Gal A activity and reductions of disease substrates, kidney IC GL-3 and plasma lyso-Gb3.

The reduction in plasma lyso-Gb3 in patients with amenable mutations was considerably variable among patients with different types of amenable α-Gal A mutations and also among patients having the same amenable mutation. Variable reductions in plasma lyso-Gb3 were also seen for males vs. female patients.

Indication

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

  • Galafold (migalastat) is indicated for long-term treatment of adult and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency) and who have an amenable mutation.

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

  • Galafold (migalastat) is indicated for long-term treatment of adults with a confirmed diagnosis of Fabry disease [deficiency of α-galactosidase (α-Gal A)] and who have an α-Gal A mutation determined to be amenable by an in vitro assay.
  • Treatment with Galafold should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of Fabry disease.
  • Clinical data supporting the effectiveness of Galafold for the treatment of Fabry disease patients with amenable mutations are limited. In clinical trials, individual response to Galafold treatment varied considerably among patients with amenable mutations. Patients should be assessed for treatment response or failure when initiating Galafold, and monitored periodically thereafter (every 6 months or more frequently) throughout the treatment.
  • Important Limitations of Use: Galafold is not indicated and should not be used in patients with non-amenable mutations. Efficacy was not demonstrated in these patients. Galafold may result in a net loss of α-Gal A activity in patients with non-amenable mutations, potentially worsening the disease condition. Galafold should not be used concomitantly with enzyme replacement therapy.

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

 

Clinical Safety

The Galafold (migalastat) clinical programme for Fabry disease comprised 20 studies in patients/healthy volunteers from ten Phase I, six Phase II, and four Phase III studies. Two of the four Phase III studies were completed (the ERT-naïve study in 67 patients treated for up to 24 months and the ERT-experienced study in 57 patients treated for up to 30 months, described in the Clinical Efficacy section) and two non-comparative long-term extension studies, of which one was discontinued.

Study AT1001-011

In the ERT-naïve study, during Stage 1 (the 6-month, placebo-controlled, double-blind phase), the overall frequency of treatment-emergent adverse events (AEs) was generally similar for Galafold and placebo; 31 (91%) in the Galafold group and 30 (91%) in the placebo group. The most frequently reported AEs (≥10%) in the Galafold group were headache, nasopharyngitis, nausea, fatigue, pyrexia, and paresthesia. AEs with a higher frequency (≥10% difference) in the Galafold group compared to the placebo group were headache and nasopharyngitis. The overall percentage of patients who experienced adverse drug reactions (ADRs), defined as definitely, probably, or possibly related to study drug, was 44% in the Galafold group and 27% in the placebo group. Common ADRs reported in ≥3% of patients in the Galafold group and not reported in the placebo group included diarrhea, nausea, defecation urgency, inflammation, weight increased, blood pressure increased, torticollis, myalgia, paraesthesia, dizziness, hyperaesthesia, hypoaesthesia, depression and rash.

During Stage 2 (all patients treated with Galafold for 6 months), a lower percentage of patients (79%) reported AEs compared to those in Stage 1 (91%). The percentage of patients who reported ADRs was 27% in the Placebo-Galafold (P-G) group and 12% in the Galafold-Galafold (G-G) group.

During Stage 3 (all patients on Galafold for 12 months), a total of 48 (84%) patients experienced at least 1 AE. Twelve (21%) patients reported ADRs. The most frequently reported (≥5%) AE was proteinuria which was experienced by 5 (9%) patients.

Two serious adverse events (SAEs) led to study discontinuation. Both of them occurred during Stage 2 and both were assessed as unlikely to be related to Galafold treatment. The frequency of SAEs increased from 6% in Stage 1 to 19% in the open-label extension periods (Stages 2 and 3); however, post-hoc analyses and additional safety data showed that the AE frequency was not increased over time.

Study AT1001-012

In the ERT-experienced study, the number of subjects who experienced at least 1 AE during the study was comparable between treatment groups (94% in the Galafold group and 95% in the ERT group). The most frequently reported AEs (≥10%) in the Galafold group were nasopharyngitis, headache, dizziness, influenza, abdominal pain, diarrhea, nausea, upper respiratory tract infection, urinary tract infection, and back pain. Upper respiratory tract infection and back pain were reported more in the Galafold group compared to the ERT group and occurred in ≥10% of patients in either treatment group. More ADRs were reported for Galafold compared to ERT over 18 months (39% vs. 14%, respectively). None of the patients discontinued treatment due to AEs. Serious adverse events (SAEs) were reported less in the Galafold group as compared to the ERT group (19% vs. 33%, respectively).

Overall Analysis of Safety

The most frequently reported adverse events (≥10%) in patients treated with Galafold were nasopharyngitis, headache, dizziness, influenza, abdominal pain, diarrhea, nausea, upper respiratory tract infection, urinary tract infection, and back pain. There were few discontinuations due to SAEs (seven cases in Phase II and III studies), and most were related to underlying Fabry disease comorbidities. In the clinical program, four patients had adverse events that lead to discontinuation that were considered related to Galafold (vomiting, hypertension, proteinuria, vomiting and diarrhea).

Two deaths were reported to date during the clinical program. Both occurred during the Phase III long-term extension study AT1001-041 and both were assessed as unrelated to Galafold treatment. In Phase III studies, 2 subjects experienced SAEs that were assessed as related to Galafold: proteinuria in one subject, and fatigue and paraesthesia in another subject. No treatment-related SAEs were reported in early phase trials.

In the Phase I, II and III studies, no changes or trends of clinical significance were observed for any vital sign parameters or physical examination findings. No dose-related trends were observed and there were no differences between Galafold and comparator treatments (placebo or ERT) with regard to safety parameters. There were no trends of clinical significance for any of the electrocardiogram (ECG) parameters. None of the ECG changes were assessed as ADRs. A QT study demonstrated that Galafold at a therapeutic dose (150 mg) or supratherapeutic dose (1,250 mg) had no effect on QTc interval.

Limited data and analyses prevented drawing any definite conclusions regarding patient subgroups. From the limited safety information in the ERT-experienced study, women experienced more AEs compared to men (both in frequency and as distinct AEs). Overall, very few patients over the age of 65 and no patients over the age of 75 were included in the safety database. The number of non-Caucasian Fabry disease patients was too small to draw conclusions regarding race. Safety analyses suggested that the frequency and severity of AEs were not related to renal function; however, the number of patients with renal impairment was also limited.

Although the effect of Galafold on male fertility was not studied in humans, no infertility was reported in the clinical trials.

In conclusion, the collective safety data provided in this drug submission (based on the AE profile, laboratory evaluations, physical examinations, vital signs, and ECGs), demonstrated that Galafold (150 mg migalastat HCl QOD) was generally safe and well-tolerated in the treatment of patients with Fabry disease. The Galafold safety profile has been characterized in a limited number of patients with a relatively short-term exposure considering the chronic nature of Fabry disease. Although this is considered acceptable for approval, the safety profile of Galafold will be further characterized post-approval.

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

7.2 Non-Clinical Basis for Decision

The non-clinical pharmacology and toxicology studies support the use of migalastat, the medicinal ingredient of Galafold, for the specified indication.

Migalastat has low acute and chronic toxicity potential, and is non-mutagenic, non-genotoxic, and non-carcinogenic.

Migalastat may impair male fertility in humans at clinically relevant doses. Based on non-clinical studies in rats, adverse effects on male fertility were reversible following treatment cessation. There were no macroscopic and no histological changes in the male reproductive system or changes in sperm parameters that could account for the reduction in fertility. The mechanism of fertility impairment is unknown.

In the embryo-fetal development study in rabbits, a dose-related increase in embryo-fetal death, a reduction in mean fetal weights, retarded ossification and slightly increased incidences of other minor skeletal abnormalities were observed at migalastat doses which were maternally toxic. Based on exposure margins to humans, these effects were observed at plasma exposures that far exceeded the exposure expected in humans. In lactating rats, migalastat was excreted into milk. These risks are considered acceptable given the unmet medical need for the treatment of Fabry disease.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Galafold Product Monograph. Appropriate warnings and precautionary measures are in place in the Galafold Product Monograph to address the identified safety concerns.

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

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Galafold has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the drug product is stored at room temperature (15oC to 30oC) and kept in the original package to protect from moisture.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

The excipients used in the drug product formulation are not of animal or human origin.

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