Swiss Summary of the Risk Management Plan (RMP)

for

Galafold® (Migalastat)

Version: 4.0 Date: 30 July 2021 Based on EU RMP for migalastat (v6.0) Marketing authorisation holder: Amicus Therapeutics Switzerland GmbH

The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimise them. The RMP summary of Galafold® is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the “Arzneimittelinformation / Information sur le médicament” approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorisation. Please note that the reference document which is valid and relevant for the effective and safe use of Galafold in Switzerland is the “Arzneimittelinformation / Information sur le médicament” (see www.swissmedic.ch) approved and authorised by Swissmedic. Amicus Therapeutics Switzerland GmbH is fully responsible for the accuracy and correctness of the content of the published summary RMP of Galafold.

Registered address: Bahnhofstrasse. 100, 4. Etage, 8001 Zürich, Switzerland Company Registration No: 5541527 VV-PVG-000240 - V1.0 Galafold® Swiss RMP Summary v4.0

1. Overview of disease epidemiology

Galafold is used for long-term treatment of in adults and adolescents aged 16 years and older, who have certain genetic mutations (changes). In the European Union, Galafold use in patients aged 12 years and older was also approved on 27 July 2021. Fabry disease is caused by the lack of or a faulty enzyme called alpha-galactosidase A (α–Gal A). Depending upon the kind of mutation in GLA, the gene that produces α–Gal A, the enzyme does not work properly or is completely absent, resulting in a range of disease severity and age of onset. This enzyme defect leads to abnormal deposits of a fatty substance known as globotriaosylceramide (GL-3) in kidneys, heart, and other organs, leading to the symptoms of Fabry disease and eventually to premature death. Galafold works by stabilising the enzyme that the body produces naturally, so that it can work better to reduce the amount of GL-3 that has accumulated in cells and tissues. Fabry disease has an estimated rate of occurrence of 1:117,000 up to 1:40,000 and affects men and women. Since the gene providing the code for α–Gal A is located on the X-chromosome, women can have one mutated and one normal version of the gene, and consequently may be asymptomatic, or present with mild, moderate or severe forms of Fabry disease. More than 1,100 different disease- causing mutations have been identified so far and approximately 30-50% of patients with Fabry disease have so-called amenable mutations, which are mutations responding to treatment with Galafold. The median age for onset of symptoms is 11.0 years-old for men and 20.0 years-old for women. The median age at diagnosis is 30.0 years-old in men and 37.0 years-old in women, and the average age of death is 44.9 years in men and 57.8 years in women. Most patients with Fabry disease are Caucasian (white), but cases have been described in many ethnic groups, including those with Asian, Hispanic, African, and Middle-Eastern ancestry. Before the approval of Galafold, enzyme replacement therapy (ERT) consisting of intravenous infusion of synthetic enzyme was the only treatment available to patients with Fabry disease.

2. Summary of treatment benefits

Galafold contains the active ingredient migalastat and is taken in the form of a capsule by mouth every other day. Two phase 3 pivotal studies were conducted to demonstrate the efficacy and safety of migalastat for the treatment of Fabry disease in patients with amenable mutations. The first study (AT1001-011) was a 3-year study comparing migalastat to (a dummy treatment) in 67 patients who were ERT-naïve or did not receive ERT at least 6 months prior to the study. The second study (AT1001-012) was an 18-months study comparing migalastat and ERT in 60 ERT-experienced patients. The following key benefits of treatment with migalastat were demonstrated in these two studies:

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Stabilised kidney function (measured by glomerular filtration rate (GFR)) for up to 3 years. Effects on kidney function were comparable to those observed with ERT and significantly better than in untreated patients with Fabry disease. Improvement in heart function (measured by left ventricular mass index reduction) after 18 months in ERT-experienced patients compared to no improvement in patients with ERT. Improvement in heart function in ERT-naive patients continued for up to 3 years. Lower occurrence of undesirable effects in the kidney, heart, and blood vessels of the brain after 18 months, in 29% of patients in the migalastat group compared to 44% in the ERT group. Improvements in gastrointestinal symptoms (measured by Gastrointestinal Symptom Rating Scale scores), related to diarrhoea, reflux, and indigestion, and a trend for improvement in constipation. Increased activity of the α-Gal A enzyme and reduced levels of the disease-causing molecules processed by the α-Gal A enzyme (i.e., GL-3 in kidneys and lyso-Gb3 in blood plasma).

3. Unknowns relating to treatment benefits

The population studied in the migalastat clinical trials was broadly representative of the general population and included older patients, patients of different races, and patients with other conditions typically associated with Fabry disease. There is relatively little experience in pregnant patients or those with severe kidney function impairment; and no experience in breastfeeding mothers and the elderly older than the age of 74 years. There is no evidence that migalastat is unsafe in these populations but there are little to no data available in these populations. Children below the age of 16 years have not been included in the initial clinical registration program. However, a study in children aged 12 to <18 years old with Fabry disease is currently ongoing; as of 31-Jan-2020, 9 adolescent subjects aged 12 to <16 years enrolled in the study had completed 1 month of migalastat treatment. Another study in adolescent subjects >12 years old is also ongoing, and a study in children from 2 to <12 years of age is planned. In addition, an ongoing registry study is planning to include children aged 12 to <16 years due to the approval for use in patients 12 years and older in the EU.

4. Summary of safety concerns

There are no important identified risks for migalastat. Important potential risks and missing information are presented in Table 1 and Table 2, respectively.

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4.1 Important potential risks

Table 1: Important Potential Risks

Risk What is known Lack of efficacy in Migalastat has not been shown to be effective in patients with non-amenable case of use in patients mutations in the α-Gal A gene. Therefore, the use of migalastat in such patients is with non-amenable considered a potential risk. mutations Male infertility When migalastat was given to male rats at doses of ≥2.5 mg/kg/day, there were (reversible) observations of infertility. This finding was rapidly and completely reversible when treatment with migalastat was stopped. Furthermore, no changes were observed in the reproductive organs of male monkeys when migalastat was administered at doses up to 500 mg/kg/day for 39 weeks.

4.2 Missing information

Table 2: Missing Information

Risk What is known There is limited or no Migalastat has been shown to be generally safe and well-tolerated in patients information on use of aged 16 to 74. migalastat in pregnant or Migalastat is not recommended during pregnancy. However, during the breast-feeding women; development programme (up to 25 May 2020), 3 female subjects became older patients; patients pregnant and the partners of 3 male subjects became pregnant. Healthy babies with severe kidney were born in all cases; no congenital abnormalities were reported. Additionally, function impairment; up to 25 May 2020, there have been 3 spontaneous reports of pregnancy in patients taking female patients treated with migalastat; 2 resulted in healthy babies and no migalastat for more than abnormalities were reported (the 3rd pregnancy case was ongoing at last report). 1 year, and paediatric It is not known whether migalastat is excreted in human milk. However, patients aged 12 to <16 migalastat has been detected in the milk of lactating rats. Accordingly, a risk of years. migalastat exposure to the breast-feeding infant cannot be excluded. Data from the development programme have shown that migalastat is safe and well-tolerated across treatment periods of >1 year and up to 12.8 years. However, this is based on limited information (128 patients with long-term use). There is limited data in the paediatric population aged 12 to <16 years. As of 31-Jan-2020, 9 adolescent subjects aged 12 to <16 years weighing ≥45 kg and enrolled in an ongoing paediatric study had completed 1 month of migalastat treatment at the same dosage regimen as adults. There are no data on the use of migalastat in elderly patients over the age of 74 years. Migalastat has not been evaluated in patients with severe kidney function impairment (eGFR <30 mL/min/1.73 m2) due to the potential for drug accumulation.

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5. Summary of risk minimisation measures

All medicines have an Information for Professionals (“Arzneimittelinformation”) which provides physicians, pharmacists, and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet (“Patienteninformation”). The measures listed in these documents are known as ‘routine risk minimisation measures’. The current Information for Professionals and the Patient Information for Galafold can be found on www.swissmedicinfo.ch. There are no routine pharmacovigilance activities beyond adverse reactions reporting and signal detection. Additional pharmacovigilance activities consist of the two ongoing studies as described in section 6.

6. Planned post-authorisation development plan

There are four safety and efficacy studies, three completed and one still ongoing. A patient registry is also ongoing.

6.1 List of studies in post-authorisation development plan

Table 3: Completed, ongoing and Planned Studies for Post-Authorisation Pharmacovigilance Development Plan

Study/activity type, Objectives Safety concerns addressed Status Date for title (planned, submission started) of interim or final reports to the EMA (planned or actual) AT1001-012 (30 Long-term extension No specific safety concern; Completed Final study months): A Phase 3 of 18-month study this study provided report long-term extension additional long-term safety submitted 06 study to a Phase 3 data. July 2016 pivotal study to compare the efficacy and safety of migalastat and enzyme replacement therapy in subjects with Fabry disease previously treated with ERT

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Study/activity type, Objectives Safety concerns addressed Status Date for title (planned, submission started) of interim or final reports to the EMA (planned or actual) AT1001-041: A Long-term safety and No specific safety concern; Completed Final study Phase 3 open label efficacy of migalastat this study provided report extension study to treatment additional long-term safety submitted 21 assess the safety and data. April 2017 efficacy of 150 mg migalastat HCl QOD in subjects with Fabry disease who have completed Studies AT1001- 011, AT1001-012 or FAB-CL-205 AT1001-042: An To assess the long- Long-term treatment Completed Final study open-label extension term safety and (>1 year) report study to evaluate the explore the long -term submitted 17 long-term safety and efficacy/ December efficacy of pharmacodynamics of 2020 migalastat migalastat in the hydrochloride treatment of subjects monotherapy in with Fabry disease subjects with Fabry who completed Disease treatment in a previous study of migalastat

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Study/activity type, Objectives Safety concerns addressed Status Date for title (planned, submission started) of interim or final reports to the EMA (planned or actual) AT1001-030: A To evaluate the effects Lack of efficacy in case of Ongoing Planned Q2 prospective, of migalastat patients with non-amenable 2027 observational treatment on long mutations registry of patients term safety, Male infertility (reversible) with Fabry disease effectiveness, and Use in pregnant or breast- health-related quality feeding women of life in Fabry disease patients as Use in patients with severe determined by the kidney function impairment 2 occurrence of all (GFR <30 mL/min/1.73 m ) serious adverse events Use in older patients >74 (SAEs) over the 5- years year period. Long-term treatment (>1 year) Use in the paediatric population aged 12 to <16 years AT1001-020: An To characterize the Use in the paediatric Ongoing Planned Q3 open-label study of of population aged 12 to <16 2021 the safety, PK, PD, migalastat in years and efficacy of 12- adolescents with month treatment Fabry disease and with migalastat in validate extrapolation paediatric subjects of migalastat plasma (aged 12 to <18 exposure in adults to years) with Fabry adolescents weighing disease and ≥45 kg and to amenable GLA evaluate the safety of variants migalastat treatment in paediatric patients with Fabry disease who have amenable mutations.

6.2 Studies which are a condition of the marketing authorisation None of the above studies are a condition of the marketing authorisation.

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7. Summary of changes to the risk management plan over time

The EU RMP has been updated several times over the last 12 months: • Version 3.2 was submitted (Version 6.0) as part of the closing sequence of the Galafold renewal application in view of re-assessing the overall benefit-risk balance of migalastat. No changes to the important risks or missing information were included in this EU RMP update. • Versions 5.0 and 5.1 were submitted as part of a completed type II variation procedure to submit the final study report from Study AT1001-042. No changes to the important risks or missing information were included in these EU RMP updates. The status of Study AT1001- 042, which is part of the Pharmacovigilance Plan to better characterize missing information of long-term treatment (> 1 year) with migalastat, was updated from ongoing to completed. • Versions 4.0, 4.1 and 6.0 were submitted as part of a completed type II variation procedure to expand the indication of Galafold to include treatment of adolescents aged 12 to <16 years old with Fabry disease. Version 6.0 incorporates revisions from Version 4.1 atop Version 5.1 as well as additional adjustments to address the Rapporteur’s Request for Supplementary Information. Relevant information from the interim results from Study AT1001-020 was added. Based on limited clinical trial data in this population, ‘Use in paediatric population aged 12 to <16 years’ was added as a new topic of missing information. The Pharmacovigilance Plan was modified to address this missing information. To further characterize the use of Galafold in this population, ongoing Study AT1001-020 was added as additional pharmacovigilance activity, and the existing pharmacovigilance activity (patient registry AT1001-030, in place to address other safety concerns) was extended to patients under 16 years of age (protocol amendment in development). Routine communication was added as a risk minimisation measure to address this new safety concern. The Swiss RMP Summary Version 4.0 reflects the updates in EU RMP Version 6.0.

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