GALAFOLD 123mg capsules medication leaflet

Galafold 123 mg hard capsules

Each capsule contains migalastat hydrochloride equivalent to 123 mg migalastat.

For the full list of excipients, see section 6.1.

Hard capsule.

Size 2 hard capsule (6.4x18.0 mm) with an opaque blue cap and opaque white body with “A1001”printed in black, containing white to pale brown powder.

Galafold is indicated for long-term treatment of adults and adolescents aged 12 years and older with aconfirmed diagnosis of Fabry disease (α-galactosidase A deficiency) and who have an amenablemutation (see the tables in section 5.1).

Treatment with Galafold should be initiated and supervised by specialist physicians experienced in thediagnosis and treatment of Fabry disease. Galafold is not intended for concomitant use with enzymereplacement therapy (see section 4.4).

The recommended dosage regimen is 123 mg migalastat (1 capsule) taken once every other day at thesame time of the day.

Galafold should not be taken on 2 consecutive days. If a dose is missed entirely for the day, the patientshould take the missed dose of Galafold only if it is within 12 hours of the normal time the dose istaken. If more than 12 hours has passed the patient should resume taking Galafold at the next planneddosing day and time according to the every other day dosing schedule.

No dosage adjustment is required based on age (see section 5.2).

Galafold is not recommended for use in patients with Fabry disease who have estimated GFR less than30 mL/min/1.73 m2 (see section 5.2).

No dosage adjustment of Galafold is required in patients with hepatic impairment (see section 5.2).

Adolescents aged ≥ 12 to < 18 years and weighing ≥ 45 kg123 mg migalastat (1 capsule) taken once every other day at the same time of the day (see section 5.2).

Children <12 years

The safety and efficacy of Galafold in children aged less than 12 years have not yet been established.

No data are available.

For oral use.

Galafold exposure is decreased by approximately 40% when taken with food and 60% when takenwith coffee (see section 4.5 and 5.2). Food and caffeine should not be consumed at least 2 hoursbefore and 2 hours after taking Galafold to give a minimum 4 hours fast (see section 4.5).

Water (plain, flavored, sweetened), fruit juices without pulp, and caffeine-free carbonated beveragescan be consumed during the 4-hour fasting period.

Galafold should be taken every other day at the same time of day to ensure optimal benefits to thepatient.

Capsules must be swallowed whole. The capsules must not be cut, crushed, or chewed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

It is advised to periodically monitor renal function, echocardiographic parameters and biochemicalmarkers (every 6 months) in patients initiated on or switched to migalastat. In case of meaningfulclinical deterioration, further clinical evaluation or discontinuation of treatment with Galafold shouldbe considered.

Galafold is not indicated for use in patients with non-amenable mutations (see section 5.1).

No reduction in proteinuria was observed in patients treated with Galafold.

Galafold is not recommended for use in patients with severe renal insufficiency, defined as estimated

GFR less than 30 mL/min/1.73m2 (see section 5.2).

Limited data suggest that co-administration of a single dose of migalastat and a standard enzymereplacement therapy infusion results in an increased exposure to agalsidase of up to 5-fold. This studyalso indicated that agalsidase has no effect on the pharmacokinetics of migalastat. Galafold is notintended for concomitant use with enzyme replacement therapy.

Paediatric population123 mg migalastat capsules are not for children (≥ 12 years) weighing less than 45 kg, (seesection 5.2).

Based upon in vitro data, migalastat is not an inducer of CYP1A2, 2B6, or 3A4. Furthermore,migalastat is not an inhibitor or a substrate of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or3A4/5. Migalastat is not a substrate for MDR1 or BCRP, nor is it an inhibitor of BCRP, MDR1, or

BSEP human efflux transporters. In addition, migalastat is not a substrate for MATE1, MATE2-K,

OAT1, OAT3, or OCT2, nor is it an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2,

MATE1, or MATE2-K human uptake transporters.

Effect of other drugs on migalastat

Co-administration of migalastat with caffeine decreases migalastat systemic exposure (AUC and Cmax)which may reduce Galafold efficacy (see section 5.2). Avoid co-administration of Galafold withcaffeine at least 2 hours before and 2 hours after taking Galafold (see section 4.2).

Galafold is not recommended in women of childbearing potential not using contraception.

There are limited data from the use of Galafold in pregnant women. In rabbits, developmental toxicitywas observed only at maternally toxic doses (see section 5.3). Galafold is not recommended duringpregnancy.

It is not known whether Galafold is secreted in human milk. However, migalastat has been shown tobe expressed in the milk of lactating rats. Accordingly, a risk of migalastat exposure to thebreast-feeding infant cannot be excluded. A decision must be made whether to discontinuebreast-feeding or to discontinue Galafold, taking into account the benefit of breast-feeding for thechild relative to the benefit of therapy for the mother.

The effects of Galafold on fertility in humans have not been studied. Transient and fully reversibleinfertility in male rats was associated with migalastat treatment at all doses assessed. Completereversibility was seen after 4 weeks off-dose. Similar findings have been noted pre-clinicallyfollowing treatment with other iminosugars (see section 5.3). Migalastat did not affect fertility infemale rats.

Galafold has no or negligible influence on the ability to drive and use machines.

The most common adverse reaction was headache, which was experienced by approximately 10% ofpatients who received Galafold.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimatedfrom the available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing frequency within each System Organ Class.

Table 1: Adverse reactions with Galafold

System organ class Frequency Adverse reaction(preferred term)

Psychiatric disorders Common Depression

Nervous system disorders Very common Headache

Common Paraesthesia, dizziness, hypoaesthesia

Ear and labyrinth disorders Common Vertigo

Cardiac disorders Common Palpitations

Respiratory, thoracic, and Common Dyspnoea, epistaxismediastinal disorders

Gastrointestinal disorders Common Diarrhoea, nausea, abdominal pain,constipation, dry mouth, defaecationurgency, dyspepsia

Skin and subcutaneous tissue Common Rash, pruritusdisorders Uncommon Angioedema*

Musculoskeletal and connective Common Muscle spasms, myalgia, torticollis,tissue disorders Pain in extremity

Renal and urinary disorders Common Proteinuria

General disorders and Common Fatigue, painadministration site conditions

Investigations Common Blood creatine phosphokinaseincreased, weight increased

* Reported from post-marketing data

Adolescent population

The safety assessment in 21 adolescents (12 to <18 years of age and weighing ≥ 45 kg) is based on1-year safety data from the open label AT1001-020 study in which subjects received the same dosageregimen as adults (see section 5.2). No age-specific differences in adverse reactions were observedbetween adolescent and adult subjects. The frequency, type and severity of adverse reactions inadolescents are expected to be the same as in adults based on these data.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, general medical care is recommended. Headache and dizziness were the mostcommon adverse reactions reported at doses of Galafold of up to 1250 mg and 2000 mg, respectively.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC code: A16AX14

Fabry disease is a progressive X-linked lysosomal storage disorder which affects males and females.

Fabry disease-causing mutations in the GLA gene result in a deficiency of the lysosomal enzyme-galactosidase A (α-Gal A) that is required for glycosphingolipid substrate (e.g., GL-3, lyso-Gb3)metabolism. Reduced α-Gal A activity is, therefore, associated with the progressive accumulation ofsubstrate in vulnerable organs and tissues, which leads to the morbidity and mortality associated with

Fabry disease.

Certain GLA mutations can result in the production of abnormally folded and unstable mutant forms ofα-Gal A. Migalastat is a pharmacological chaperone that is designed to selectively and reversibly bindwith high affinity to the active sites of certain mutant forms of α-Gal A, the genotypes of which arereferred to as amenable mutations. Migalastat binding stabilises these mutant forms of α-Gal A in theendoplasmic reticulum and facilitates their proper trafficking to lysosomes. Once in lysosomesdissociation of migalastat restores α-Gal A activity, leading to the catabolism of GL-3 and relatedsubstrates.

The GLA mutations amenable to treatment with Galafold are listed in Table 2 below. The GLAmutations are also accessible by health care providers at www.galafoldamenabilitytable.com.

The nucleotide changes listed represent potential DNA sequence changes that result in the amino acidmutation. The amino acid mutation (protein sequence change) is most relevant when determiningamenability. If a double mutation is present on the same chromosome (males and females), that patientis amenable if the double mutation is present in one entry in Table 2 (e.g., D55V/Q57L). If a doublemutation is present on different chromosomes (only in females) that patient is amenable if either oneof the individual mutations is present in Table 2.

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.7C>G c.C7G L3Vc.8T>C c.T8C L3Pc.[11G>T; 620A>C] c.G11T/A620C R4M/Y207Sc.13A>G c.A13G N5Dc.15C>G c.C15G N5Kc.16C>A c.C16A P6Tc.16C>T c.C16T P6Sc.17C>A c.C17A P6Qc.17C>G c.C17G P6Rc.17C>T c.C17T P6Lc.19G>A c.G19A E7Kc.20A>T c.A20T E7Vc.21A>T c.A21T E7Dc.22C>A c.C22A L8Ic.23T>A c.T23A L8Qc.23T>C c.T23C L8Pc.25C>T c.C25T H9Yc.26A>G c.A26G H9Rc.26A>T c.A26T H9Lc.27T>A c.T27A H9Qc.28C>A c.C28A L10Mc.28C>G c.C28G L10Vc.29T>A c.T29A L10Qc.29T>C c.T29C L10Pc.29T>G c.T29G L10Rc.31G>A c.G31A G11Sc.31G>C c.G31C G11Rc.31G>T c.G31T G11Cc.32G>A c.G32A G11Dc.32G>T c.G32T G11Vc.34T>A c.T34A C12Sc.34T>C c.T34C C12Rc.34T>G c.T34G C12Gc.35G>A c.G35A C12Yc.37G>A c.G37A A13Tc.37G>C c.G37C A13Pc.38C>A c.C38A A13Ec.38C>G c.C38G A13Gc.40C>G c.C40G L14Vc.40C>T c.C40T L14Fc.41T>A c.T41A L14Hc.43G>A c.G43A A15Tc.44C>G c.C44G A15Gc.49C>A c.C49A R17Sc.49C>G c.C49G R17Gc.49C>T c.C49T R17Cc.50G>A c.G50A R17Hc.50G>C c.G50C R17Pc.52T>A c.T52A F18Ic.53T>G c.T53G F18C

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.54C>G c.C54G F18Lc.58G>C c.G58C A20Pc.59C>A c.C59A A20Dc.59C>G c.C59G A20Gc.62T>A c.T62A L21Hc.64G>A c.G64A V22Ic.64G>C c.G64C V22Lc.64G>T c.G64T V22Fc.65T>C c.T65C V22Ac.65T>G c.T65G V22Gc.67T>A c.T67A S23Tc.67T>C c.T67C S23Pc.[70T>A; 1255A>G] c.T70A/A1255G W24R/N419Dc.70T>C or c.70T>A c.T70C or c.T70A W24Rc.70T>G c.T70G W24Gc.71G>C c.G71C W24Sc.72G>C or c.72G>T c.G72C or c.G72T W24Cc.73G>C c.G73C D25Hc.77T>A c.T77A I26Nc.79C>A c.C79A P27Tc.79C>G c.C79G P27Ac.79C>T c.C79T P27Sc.80C>T c.C80T P27Lc.82G>C c.G82C G28Rc.82G>T c.G82T G28Wc.83G>A c.G83A G28Ec.85G>C c.G85C A29Pc.86C>A c.C86A A29Dc.86C>G c.C86G A29Gc.86C>T c.C86T A29Vc.88A>G c.A88G R30Gc.94C>A c.C94A L32Mc.94C>G c.C94G L32Vc.95T>A c.T95A L32Qc.95T>C c.T95C L32Pc.95T>G c.T95G L32Rc.97G>C c.G97C D33Hc.97G>T c.G97T D33Yc.98A>C c.A98C D33Ac.98A>G c.A98G D33Gc.98A>T c.A98T D33Vc.99C>G c.C99G D33Ec.100A>C c.A100C N34Hc.100A>G c.A100G N34Dc.101A>C c.A101C N34Tc.101A>G c.A101G N34Sc.102T>G or c.102T>A c.T102G or c.T102A N34Kc.103G>C or c.103G>A c.G103C or c.G103A G35Rc.104G>A c.G104A G35Ec.104G>C c.G104C G35A

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.104G>T c.G104T G35Vc.106T>A c.T106A L36Mc.106T>G c.T106G L36Vc.107T>C c.T107C L36Sc.107T>G c.T107G L36Wc.108G>C or c.108G>T c.G108C or c.G108T L36Fc.109G>A c.G109A A37Tc.109G>T c.G109T A37Sc.110C>A c.C110A A37Ec.110C>G c.C110G A37Gc.110C>T c.C110T A37Vc.112A>G c.A112G R38Gc.112A>T c.A112T R38Wc.113G>T c.G113T R38Mc.114G>C c.G114C R38Sc.115A>G c.A115G T39Ac.115A>T c.A115T T39Sc.116C>A c.C116A T39Kc.116C>G c.C116G T39Rc.116C>T c.C116T T39Mc.121A>G c.A121G T41Ac.122C>A c.C122A T41Nc.122C>G c.C122G T41Sc.122C>T c.C122T T41Ic.124A>C or c.124A>T c.A124C or c.A124T M42Lc.124A>G c.A124G M42Vc.125T>A c.T125A M42Kc.125T>C c.T125C M42Tc.125T>G c.T125G M42Rc.126G>A or c.126G>C or c.G126A or c.G126C or c.G126T M42Ic.126G>Tc.128G>C c.G128C G43Ac.133C>A c.C133A L45Mc.133C>G c.C133G L45Vc.136C>A c.C136A H46Nc.136C>G c.C136G H46Dc.137A>C c.A137C H46Pc.138C>G c.C138G H46Qc.142G>C c.G142C E48Qc.143A>C c.A143C E48Ac.149T>A c.T149A F50Yc.151A>G c.A151G M51Vc.152T>A c.T152A M51Kc.152T>C c.T152C M51Tc.152T>G c.T152G M51Rc.153G>A or c.153G>T or c.G153A or c.G153T or c.G153C M51Ic.153G>Cc.157A>C c.A157C N53Hc.[157A>C; 158A>T] c.A157C/A158T N53Lc.157A>G c.A157G N53D

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.157A>T c.A157T N53Yc.158A>C c.A158C N53Tc.158A>G c.A158G N53Sc.158A>T c.A158T N53Ic.159C>G or c.159C>A c.C159G or c.C159A N53Kc.160C>G c.C160G L54Vc.160C>T c.C160T L54Fc.161T>A c.T161A L54Hc.161T>C c.T161C L54Pc.161T>G c.T161G L54Rc.163G>C c.G163C D55Hc.163G>T c.G163T D55Yc.164A>C c.A164C D55Ac.164A>G c.A164G D55Gc.164A>T c.A164T D55Vc.[164A>T; 170A>T] c.A164T/A170T D55V/Q57Lc.165C>G c.C165G D55Ec.167G>A c.G167A C56Yc.167G>T c.G167T C56Fc.168C>G c.C168G C56Wc.170A>G c.A170G Q57Rc.170A>T c.A170T Q57Lc.172G>A c.G172A E58Kc.175G>A c.G175A E59Kc.175G>C c.G175C E59Qc.176A>C c.A176C E59Ac.176A>G c.A176G E59Gc.176A>T c.A176T E59Vc.177G>C c.G177C E59Dc.178C>A c.C178A P60Tc.178C>G c.C178G P60Ac.178C>T c.C178T P60Sc.179C>A c.C179A P60Qc.179C>G c.C179G P60Rc.179C>T c.C179T P60Lc.182A>T c.A182T D61Vc.183T>A c.T183A D61Ec.184_185insTAG c.184_185insTAG S62delinsLAc.184T>C c.T184C S62Pc.184T>G c.T184G S62Ac.185C>A c.C185A S62Yc.185C>G c.C185G S62Cc.185C>T c.C185T S62Fc.190A>C c.A190C I64Lc.190A>G c.A190G I64Vc.193A>G c.A193G S65Gc.193A>T c.A193T S65Cc.195T>A c.T195A S65Rc.196G>A c.G196A E66Kc.197A>G c.A197G E66G

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.197A>T c.A197T E66Vc.198G>C c.G198C E66Dc.199A>C c.A199C K67Qc.199A>G c.A199G K67Ec.200A>C c.A200C K67Tc.200A>T c.A200T K67Mc.201G>C c.G201C K67Nc.202C>A c.C202A L68Ic.205T>A c.T205A F69Ic.206T>A c.T206A F69Yc.207C>A or c.207C>G c.C207A or c.C207G F69Lc.208A>T c.A208T M70Lc.209T>A c.T209A M70Kc.209T>G c.T209G M70Rc.210G>C c.G210C M70Ic.211G>C c.G211C E71Qc.212A>C c.A212C E71Ac.212A>G c.A212G E71Gc.212A>T c.A212T E71Vc.213G>C c.G213C E71Dc.214A>G c.A214G M72Vc.214A>T c.A214T M72Lc.215T>C c.T215C M72Tc.216G>A or c.216G>T or c.G216A or c.G216T or c.G216C M72Ic.216G>Cc.217G>A c.G217A A73Tc.217G>T c.G217T A73Sc.218C>T c.C218T A73Vc.[218C>T; 525C>G] c.C218T/C525G A73V/D175Ec.220G>A c.G220A E74Kc.221A>G c.A221G E74Gc.221A>T c.A221T E74Vc.222G>C c.G222C E74Dc.223C>T c.C223T L75Fc.224T>C c.T224C L75Pc.226A>G c.A226G M76Vc.227T>C c.T227C M76Tc.229G>A c.G229A V77Ic.229G>C c.G229C V77Lc.232T>C c.T232C S78Pc.233C>T c.C233T S78Lc.235G>A c.G235A E79Kc.235G>C c.G235C E79Qc.236A>C c.A236C E79Ac.236A>G c.A236G E79Gc.236A>T c.A236T E79Vc.237A>T c.A237T E79Dc.238G>A c.G238A G80Sc.238G>T c.G238T G80Cc.239G>A c.G239A G80D

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.239G>C c.G239C G80Ac.239G>T c.G239T G80Vc.242G>T c.G242T W81Lc.244A>G c.A244G K82Ec.245A>C c.A245C K82Tc.245A>G c.A245G K82Rc.245A>T c.A245T K82Mc.246G>C c.G246C K82Nc.247G>A c.G247A D83Nc.248A>C c.A248C D83Ac.248A>G c.A248G D83Gc.248A>T c.A248T D83Vc.249T>A c.T249A D83Ec.250G>A c.G250A A84Tc.250G>C c.G250C A84Pc.250G>T c.G250T A84Sc.251C>A c.C251A A84Ec.251C>G c.C251G A84Gc.251C>T c.C251T A84Vc.253G>A c.G253A G85Sc.[253G>A; 254G>A] c.G253A/G254A G85Nc.[253G>A; 254G>T; 255T>G] c.G253A/G254T/T255G G85Mc.253G>C c.G253C G85Rc.253G>T c.G253T G85Cc.254G>A c.G254A G85Dc.254G>C c.G254C G85Ac.257A>T c.A257T Y86Fc.260A>G c.A260G E87Gc.261G>C or c.261G>T c.G261C or c.G261T E87Dc.262T>A c.T262A Y88Nc.262T>C c.T262C Y88Hc.263A>C c.A263C Y88Sc.263A>G c.A263G Y88Cc.265C>G c.C265G L89Vc.265C>T c.C265T L89Fc.271A>C c.A271C I91Lc.271A>T c.A271T I91Fc.272T>C c.T272C I91Tc.272T>G c.T272G I91Sc.273T>G c.T273G I91Mc.286A>G c.A286G M96Vc.286A>T c.A286T M96Lc.287T>C c.T287C M96Tc.288G>A or c.288G>T or c.G288A or c.G288T or c.G288C M96Ic.288G>Cc.289G>A c.G289A A97Tc.289G>C c.G289C A97Pc.289G>T c.G289T A97Sc.290C>A c.C290A A97Dc.290C>T c.C290T A97V

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.293C>A c.C293A P98Hc.293C>G c.C293G P98Rc.293C>T c.C293T P98Lc.295C>G c.C295G Q99Ec.296A>C c.A296C Q99Pc.296A>G c.A296G Q99Rc.296A>T c.A296T Q99Lc.301G>C c.G301C D101Hc.302A>C c.A302C D101Ac.302A>G c.A302G D101Gc.302A>T c.A302T D101Vc.303T>A c.T303A D101Ec.304T>A c.T304A S102Tc.304T>C c.T304C S102Pc.304T>G c.T304G S102Ac.305C>T c.C305T S102Lc.310G>A c.G310A G104Sc.311G>A c.G311A G104Dc.311G>C c.G311C G104Ac.311G>T c.G311T G104Vc.313A>G c.A313G R105Gc.314G>A c.G314A R105Kc.314G>C c.G314C R105Tc.314G>T c.G314T R105Ic.316C>A c.C316A L106Ic.316C>G c.C316G L106Vc.316C>T c.C316T L106Fc.317T>A c.T317A L106Hc.317T>C c.T317C L106Pc.319C>A c.C319A Q107Kc.319C>G c.C319G Q107Ec.320A>G c.A320G Q107Rc.321G>C c.G321C Q107Hc.322G>A c.G322A A108Tc.323C>A c.C323A A108Ec.323C>T c.C323T A108Vc.325G>A c.G325A D109Nc.325G>C c.G325C D109Hc.325G>T c.G325T D109Yc.326A>C c.A326C D109Ac.326A>G c.A326G D109Gc.327C>G c.C327G D109Ec.328C>A c.C328A P110Tc.334C>G c.C334G R112Gc.335G>A c.G335A R112Hc.335G>T c.G335T R112Lc.337T>A c.T337A F113Ic.337T>C or c.339T>A or c.T337C or c.T339A or c.T339G F113Lc.339T>Gc.337T>G c.T337G F113V

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.338T>A c.T338A F113Yc.341C>T c.C341T P114Lc.343C>A c.C343A H115Nc.343C>G c.C343G H115Dc.346G>C c.G346C G116Rc.350T>C c.T350C I117Tc.351T>G c.T351G I117Mc.352C>T c.C352T R118Cc.361G>A c.G361A A121Tc.362C>T c.C362T A121Vc.367T>A c.T367A Y123Nc.367T>G c.T367G Y123Dc.368A>C c.A368C Y123Sc.368A>G c.A368G Y123Cc.368A>T c.A368T Y123Fc.370G>A c.G370A V124Ic.371T>G c.T371G V124Gc.373C>A c.C373A H125Nc.373C>G c.C373G H125Dc.373C>T c.C373T H125Yc.374A>G c.A374G H125Rc.374A>T c.A374T H125Lc.376A>G c.A376G S126Gc.376A>T c.A376T S126Cc.377G>T c.G377T S126Ic.379A>G c.A379G K127Ec.383G>A c.G383A G128Ec.383G>C c.G383C G128Ac.385C>G c.C385G L129Vc.388A>C c.A388C K130Qc.389A>T c.A389T K130Mc.390G>C c.G390C K130Nc.391C>G c.C391G L131Vc.397A>C c.A397C I133Lc.397A>G c.A397G I133Vc.397A>T c.A397T I133Fc.398T>C c.T398C I133Tc.399T>G c.T399G I133Mc.[399T>G; 434T>C] c.T399G/T434C I133M/F145Sc.403G>A c.G403A A135Tc.403G>T c.G403T A135Sc.404C>A c.C404A A135Ec.404C>G c.C404G A135Gc.404C>T c.C404T A135Vc.406G>A c.G406A D136Nc.407A>C c.A407C D136Ac.407A>T c.A407T D136Vc.408T>A or c.408T>G c.T408A or c.T408G D136Ec.409G>A c.G409A V137Ic.409G>C c.G409C V137L

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.410T>A c.T410A V137Dc.410T>C c.T410C V137Ac.410T>G c.T410G V137Gc.413G>C c.G413C G138Ac.415A>C c.A415C N139Hc.415A>T c.A415T N139Yc.416A>G c.A416G N139Sc.416A>T c.A416T N139Ic.417T>A c.T417A N139Kc.418A>C c.A418C K140Qc.418A>G c.A418G K140Ec.419A>C c.A419C K140Tc.419A>G c.A419G K140Rc.419A>T c.A419T K140Ic.420A>T c.A420T K140Nc.421A>T c.A421T T141Sc.427G>A c.G427A A143Tc.428C>A c.C428A A143Ec.428C>G c.C428G A143Gc.428C>T c.C428T A143Vc.430G>A c.G430A G144Sc.430G>C c.G430C G144Rc.430G>T c.G430T G144Cc.431G>A c.G431A G144Dc.431G>C c.G431C G144Ac.431G>T c.G431T G144Vc.433T>G c.T433G F145Vc.434T>A c.T434A F145Yc.434T>C c.T434C F145Sc.434T>G c.T434G F145Cc.435C>G c.C435G F145Lc.436C>A c.C436A P146Tc.436C>G c.C436G P146Ac.436C>T c.C436T P146Sc.437C>A c.C437A P146Hc.437C>G c.C437G P146Rc.437C>T c.C437T P146Lc.440G>C c.G440C G147Ac.442A>G c.A442G S148Gc.442A>T c.A442T S148Cc.443G>C c.G443C S148Tc.446T>G c.T446G F149Cc.449G>A c.G449A G150Ec.449G>T c.G449T G150Vc.451T>G c.T451G Y151Dc.452A>C c.A452C Y151Sc.452A>G c.A452G Y151Cc.454T>A c.T454A Y152Nc.454T>C c.T454C Y152Hc.454T>G c.T454G Y152D

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.455A>C c.A455C Y152Sc.455A>G c.A455G Y152Cc.455A>T c.A455T Y152Fc.457G>A c.G457A D153Nc.457G>C c.G457C D153Hc.457G>T c.G457T D153Yc.458A>C c.A458C D153Ac.458A>T c.A458T D153Vc.465T>A or c.465T>G c.T465A or c.T465G D155Ec.466G>A c.G466A A156Tc.466G>T c.G466T A156Sc.467C>G c.C467G A156Gc.467C>T c.C467T A156Vc.469C>A c.C469A Q157Kc.469C>G c.C469G Q157Ec.470A>C c.A470C Q157Pc.470A>T c.A470T Q157Lc.471G>C or c.471G>T c.G471C or c.G471T Q157Hc.472A>G c.A472G T158Ac.472A>T c.A472T T158Sc.473C>A c.C473A T158Nc.473C>T c.C473T T158Ic.475T>A c.T475A F159Ic.475T>G c.T475G F159Vc.476T>A c.T476A F159Yc.476T>G c.T476G F159Cc.477T>A c.T477A F159Lc.478G>A c.G478A A160Tc.478G>T c.G478T A160Sc.479C>A c.C479A A160Dc.479C>G c.C479G A160Gc.479C>T c.C479T A160Vc.481G>A c.G481A D161Nc.481G>C c.G481C D161Hc.481G>T c.G481T D161Yc.482A>T c.A482T D161Vc.484T>G c.T484G W162Gc.485G>C c.G485C W162Sc.490G>A c.G490A V164Ic.490G>T c.G490T V164Lc.491T>C c.T491C V164Ac.493G>A c.G493A D165Nc.493G>C c.G493C D165Hc.494A>C c.A494C D165Ac.494A>G c.A494G D165Gc.495T>A c.T495A D165Ec.496_497delinsTC c.496_497delinsTC L166Sc.496C>A c.C496A L166Mc.496C>G c.C496G L166Vc.[496C>G; 497T>G] c.C496G/T497G L166G

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.497T>A c.T497A L166Qc.499C>A c.C499A L167Ic.499C>G c.C499G L167Vc.505T>A c.T505A F169Ic.505T>G c.T505G F169Vc.506T>A c.T506A F169Yc.506T>C c.T506C F169Sc.506T>G c.T506G F169Cc.507T>A c.T507A F169Lc.511G>A c.G511A G171Sc.512G>C c.G512C G171Ac.512G>T c.G512T G171Vc.517T>C c.T517C Y173Hc.518A>C c.A518C Y173Sc.518A>G c.A518G Y173Cc.518A>T c.A518T Y173Fc.520T>C c.T520C C174Rc.520T>G c.T520G C174Gc.523G>C c.G523C D175Hc.523G>T c.G523T D175Yc.524A>G c.A524G D175Gc.524A>T c.A524T D175Vc.525C>G or c.525C>A c.C525G or c.C525A D175Ec.526A>T c.A526T S176Cc.528T>A c.T528A S176Rc.529T>A c.T529A L177Mc.529T>G c.T529G L177Vc.530T>C c.T530C L177Sc.530T>G c.T530G L177Wc.531G>C c.G531C L177Fc.532G>A c.G532A E178Kc.532G>C c.G532C E178Qc.533A>C c.A533C E178Ac.533A>G c.A533G E178Gc.538T>A c.T538A L180Mc.538T>G c.T538G L180Vc.539T>C c.T539C L180Sc.539T>G c.T539G L180Wc.540G>C or c.540G>T c.G540C or c.G540T L180Fc.541G>A c.G541A A181Tc.541G>C c.G541C A181Pc.542C>T c.C542T A181Vc.544G>T c.G544T D182Yc.545A>C c.A545C D182Ac.545A>G c.A545G D182Gc.545A>T c.A545T D182Vc.546T>A c.T546A D182Ec.548G>A c.G548A G183Dc.548G>C c.G548C G183Ac.550T>A c.T550A Y184N

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.550T>C c.T550C Y184Hc.551A>C c.A551C Y184Sc.551A>G c.A551G Y184Cc.551A>T c.A551T Y184Fc.553A>C c.A553C K185Qc.553A>G c.A553G K185Ec.554A>C c.A554C K185Tc.554A>T c.A554T K185Mc.555G>C c.G555C K185Nc.556C>A c.C556A H186Nc.556C>G c.C556G H186Dc.556C>T c.C556T H186Yc.557A>T c.A557T H186Lc.558C>G c.C558G H186Qc.559_564dup c.559_564dup p.M187_S188dupc.559A>T c.A559T M187Lc.559A>G c.A559G M187Vc.560T>C c.T560C M187Tc.561G>T or c.561G>A or c.G561T or c.G561A or c.G561C M187Ic.561G>Cc.562T>A c.T562A S188Tc.562T>C c.T562C S188Pc.562T>G c.T562G S188Ac.563C>A c.C563A S188Yc.563C>G c.C563G S188Cc.563C>T c.C563T S188Fc.565T>G c.T565G L189Vc.566T>C c.T566C L189Sc.567G>C or c.567G>T c.G567C or c.G567T L189Fc.568G>A c.G568A A190Tc.568G>T c.G568T A190Sc.569C>A c.C569A A190Dc.569C>G c.C569G A190Gc.569C>T c.C569T A190Vc.571C>A c.C571A L191Mc.571C>G c.C571G L191Vc.572T>A c.T572A L191Qc.574A>C c.A574C N192Hc.574A>G c.A574G N192Dc.575A>C c.A575C N192Tc.575A>G c.A575G N192Sc.576T>A c.T576A N192Kc.577A>G c.A577G R193Gc.577A>T c.A577T R193Wc.578G>C c.G578C R193Tc.578G>T c.G578T R193Mc.[578G>T; 936G>C] c.G578T/G936C R193M/Q312Hc.580A>C c.A580C T194Pc.580A>G c.A580G T194Ac.580A>T or c.581C>G c.A580T or c.C581G T194S

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.581C>A c.C581A T194Nc.581C>T c.C581T T194Ic.583G>A c.G583A G195Sc.583G>C c.G583C G195Rc.583G>T c.G583T G195Cc.584G>T c.G584T G195Vc.586A>G c.A586G R196Gc.587G>A c.G587A R196Kc.587G>C c.G587C R196Tc.587G>T c.G587T R196Ic.589A>G c.A589G S197Gc.589A>T c.A589T S197Cc.590G>A c.G590A S197Nc.590G>C c.G590C S197Tc.590G>T c.G590T S197Ic.593T>C c.T593C I198Tc.593T>G c.T593G I198Sc.594T>G c.T594G I198Mc.595G>A c.G595A V199Mc.595G>C c.G595C V199Lc.596T>A c.T596A V199Ec.596T>C c.T596C V199Ac.596T>G c.T596G V199Gc.598T>A c.T598A Y200Nc.599A>C c.A599C Y200Sc.599A>G c.A599G Y200Cc.601T>A c.T601A S201Tc.601T>G c.T601G S201Ac.602C>A c.C602A S201Yc.602C>G c.C602G S201Cc.602C>T c.C602T S201Fc.[602C>T; 937G>T] c.C602T/G937T S201F/D313Yc.607G>C c.G607C E203Qc.608A>C c.A608C E203Ac.608A>G c.A608G E203Gc.608A>T c.A608T E203Vc.609G>C or c.609G>T c.G609C or c.G609T E203Dc.610T>G c.T610G W204Gc.611G>C c.G611C W204Sc.611G>T c.G611T W204Lc.613C>A c.C613A P205Tc.613C>T c.C613T P205Sc.614C>T c.C614T P205Lc.616C>A c.C616A L206Ic.616C>G c.C616G L206Vc.616C>T c.C616T L206Fc.617T>A c.T617A L206Hc.617T>G c.T617G L206Rc.619T>C c.T619C Y207Hc.620A>C c.A620C Y207S

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.620A>T c.A620T Y207Fc.623T>A c.T623A M208Kc.623T>G c.T623G M208Rc.625T>A c.T625A W209Rc.625T>G c.T625G W209Gc.627G>C c.G627C W209Cc.628C>A c.C628A P210Tc.628C>T c.C628T P210Sc.629C>A c.C629A P210Hc.629C>T c.C629T P210Lc.631T>C c.T631C F211Lc.631T>G c.T631G F211Vc.632T>A c.T632A F211Yc.632T>C c.T632C F211Sc.632T>G c.T632G F211Cc.635A>C c.A635C Q212Pc.636A>T c.A636T Q212Hc.637A>C c.A637C K213Qc.637A>G c.A637G K213Ec.638A>G c.A638G K213Rc.638A>T c.A638T K213Mc.640C>A c.C640A P214Tc.640C>G c.C640G P214Ac.640C>T c.C640T P214Sc.641C>A c.C641A P214Hc.641C>G c.C641G P214Rc.641C>T c.C641T P214Lc.643A>C c.A643C N215Hc.643A>G c.A643G N215Dc.643A>T c.A643T N215Yc.644A>C c.A644C N215Tc.644A>G c.A644G N215Sc.[644A>G; 937G>T] c.A644G/G937T N215S/D313Yc.644A>T c.A644T N215Ic.645T>A c.T645A N215Kc.646T>A c.T646A Y216Nc.646T>C c.T646C Y216Hc.646T>G c.T646G Y216Dc.647A>C c.A647C Y216Sc.647A>G c.A647G Y216Cc.647A>T c.A647T Y216Fc.649A>C c.A649C T217Pc.649A>G c.A649G T217Ac.649A>T c.A649T T217Sc.650C>A c.C650A T217Kc.650C>G c.C650G T217Rc.650C>T c.C650T T217Ic.652G>A c.G652A E218Kc.652G>C c.G652C E218Qc.653A>C c.A653C E218A

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.653A>G c.A653G E218Gc.653A>T c.A653T E218Vc.654A>T c.A654T E218Dc.655A>C c.A655C I219Lc.655A>T c.A655T I219Fc.656T>A c.T656A I219Nc.656T>C c.T656C I219Tc.656T>G c.T656G I219Sc.657C>G c.C657G I219Mc.659G>A c.G659A R220Qc.659G>C c.G659C R220Pc.659G>T c.G659T R220Lc.661C>A c.C661A Q221Kc.661C>G c.C661G Q221Ec.662A>C c.A662C Q221Pc.662A>G c.A662G Q221Rc.662A>T c.A662T Q221Lc.663G>C c.G663C Q221Hc.664T>A c.T664A Y222Nc.664T>C c.T664C Y222Hc.664T>G c.T664G Y222Dc.665A>C c.A665C Y222Sc.665A>G c.A665G Y222Cc.670A>C c.A670C N224Hc.671A>C c.A671C N224Tc.671A>G c.A671G N224Sc.673C>G c.C673G H225Dc.679C>G c.C679G R227Gc.682A>C c.A682C N228Hc.682A>G c.A682G N228Dc.683A>C c.A683C N228Tc.683A>G c.A683G N228Sc.683A>T c.A683T N228Ic.685T>A c.T685A F229Ic.686T>A c.T686A F229Yc.686T>C c.T686C F229Sc.687T>A or c.687T>G c.T687A or c.T687G F229Lc.688G>C c.G688C A230Pc.689C>A c.C689A A230Dc.689C>G c.C689G A230Gc.689C>T c.C689T A230Vc.694A>C c.A694C I232Lc.694A>G c.A694G I232Vc.695T>C c.T695C I232Tc.696T>G c.T696G I232Mc.698A>C c.A698C D233Ac.698A>G c.A698G D233Gc.698A>T c.A698T D233Vc.699T>A c.T699A D233Ec.703T>A c.T703A S235T

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.703T>G c.T703G S235Ac.710A>T c.A710T K237Ic.712A>G c.A712G S238Gc.712A>T c.A712T S238Cc.713G>A c.G713A S238Nc.713G>C c.G713C S238Tc.713G>T c.G713T S238Ic.715A>T c.A715T I239Lc.716T>C c.T716C I239Tc.717A>G c.A717G I239Mc.718A>G c.A718G K240Ec.719A>G c.A719G K240Rc.719A>T c.A719T K240Mc.720G>C or c.720G>T c.G720C or c.G720T K240Nc.721A>T c.A721T S241Cc.722G>C c.G722C S241Tc.722G>T c.G722T S241Ic.724A>C c.A724C I242Lc.724A>G c.A724G I242Vc.724A>T c.A724T I242Fc.725T>A c.T725A I242Nc.725T>C c.T725C I242Tc.725T>G c.T725G I242Sc.726C>G c.C726G I242Mc.727T>A c.T727A L243Mc.727T>G c.T727G L243Vc.728T>C c.T728C L243Sc.728T>G c.T728G L243Wc.729G>C or c.729G>T c.G729C or c.G729T L243Fc.730G>A c.G730A D244Nc.730G>C c.G730C D244Hc.730G>T c.G730T D244Yc.731A>C c.A731C D244Ac.731A>G c.A731G D244Gc.731A>T c.A731T D244Vc.732C>G c.C732G D244Ec.733T>G c.T733G W245Gc.735G>C c.G735C W245Cc.736A>G c.A736G T246Ac.737C>A c.C737A T246Kc.737C>G c.C737G T246Rc.737C>T c.C737T T246Ic.739T>A c.T739A S247Tc.739T>G c.T739G S247Ac.740C>A c.C740A S247Yc.740C>G c.C740G S247Cc.740C>T c.C740T S247Fc.742T>G c.T742G F248Vc.743T>A c.T743A F248Yc.743T>G c.T743G F248C

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.744T>A c.T744A F248Lc.745A>C c.A745C N249Hc.745A>G c.A745G N249Dc.745A>T c.A745T N249Yc.746A>C c.A746C N249Tc.746A>G c.A746G N249Sc.746A>T c.A746T N249Ic.747C>G or c.747C>A c.C747G or c.C747A N249Kc.748C>A c.C748A Q250Kc.748C>G c.C748G Q250Ec.749A>C c.A749C Q250Pc.749A>G c.A749G Q250Rc.749A>T c.A749T Q250Lc.750G>C c.G750C Q250Hc.751G>A c.G751A E251Kc.751G>C c.G751C E251Qc.752A>G c.A752G E251Gc.752A>T c.A752T E251Vc.754A>G c.A754G R252Gc.757A>G c.A757G I253Vc.757A>T c.A757T I253Fc.758T>A c.T758A I253Nc.758T>C c.T758C I253Tc.758T>G c.T758G I253Sc.760-762delGTT or c.761-763del c.760_762delGTT or p.V254delc.761_763delc.760G>T c.G760T V254Fc.761T>A c.T761A V254Dc.761T>C c.T761C V254Ac.761T>G c.T761G V254Gc.763G>A c.G763A D255Nc.763G>C c.G763C D255Hc.763G>T c.G763T D255Yc.764A>C c.A764C D255Ac.764A>T c.A764T D255Vc.765T>A c.T765A D255Ec.766G>C c.G766C V256Lc.767T>A c.T767A V256Dc.767T>G c.T767G V256Gc.769G>A c.G769A A257Tc.769G>C c.G769C A257Pc.769G>T c.G769T A257Sc.770C>G c.C770G A257Gc.770C>T c.C770T A257Vc.772G>C or c.772G>A c.G772C or c.G772A G258Rc.773G>A c.G773A G258Ec.773G>T c.G773T G258Vc.775C>A c.C775A P259Tc.775C>G c.C775G P259Ac.775C>T c.C775T P259S

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.776C>A c.C776A P259Qc.776C>G c.C776G P259Rc.776C>T c.C776T P259Lc.778G>T c.G778T G260Wc.779G>A c.G779A G260Ec.779G>C c.G779C G260Ac.781G>A c.G781A G261Sc.781G>C c.G781C G261Rc.781G>T c.G781T G261Cc.782G>C c.G782C G261Ac.787A>C c.A787C N263Hc.788A>C c.A788C N263Tc.788A>G c.A788G N263Sc.790G>A c.G790A D264Nc.790G>C c.G790C D264Hc.790G>T c.G790T D264Yc.793C>G c.C793G P265Ac.794C>A c.C794A P265Qc.794C>T c.C794T P265Lc.799A>G c.A799G M267Vc.799A>T c.A799T M267Lc.800T>C c.T800C M267Tc.802T>A c.T802A L268Ic.804A>T c.A804T L268Fc.805G>A c.G805A V269Mc.805G>C c.G805C V269Lc.806T>C c.T806C V269Ac.808A>C c.A808C I270Lc.808A>G c.A808G I270Vc.809T>C c.T809C I270Tc.809T>G c.T809G I270Sc.810T>G c.T810G I270Mc.811G>A c.G811A G271Sc.[811G>A; 937G>T] c.G811A/G937T G271S/D313Yc.812G>A c.G812A G271Dc.812G>C c.G812C G271Ac.814A>G c.A814G N272Dc.818T>A c.T818A F273Yc.823C>A c.C823A L275Ic.823C>G c.C823G L275Vc.827G>A c.G827A S276Nc.827G>C c.G827C S276Tc.829T>G c.T829G W277Gc.830G>T c.G830T W277Lc.831G>T or c.831G>C c.G831T or c.G831C W277Cc.832A>T c.A832T N278Yc.833A>T c.A833T N278Ic.835C>G c.C835G Q279Ec.838C>A c.C838A Q280Kc.839A>G c.A839G Q280R

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.839A>T c.A839T Q280Lc.840A>T or c.840A>C c.A840T or c.A840C Q280Hc.841G>C c.G841C V281Lc.842T>A c.T842A V281Ec.842T>C c.T842C V281Ac.842T>G c.T842G V281Gc.844A>G c.A844G T282Ac.844A>T c.A844T T282Sc.845C>T c.C845T T282Ic.847C>G c.C847G Q283Ec.848A>T c.A848T Q283Lc.849G>C c.G849C Q283Hc.850A>G c.A850G M284Vc.850A>T c.A850T M284Lc.851T>C c.T851C M284Tc.852G>C c.G852C M284Ic.853G>A c.G853A A285Tc.854C>G c.C854G A285Gc.854C>T c.C854T A285Vc.856C>G c.C856G L286Vc.856C>T c.C856T L286Fc.857T>A c.T857A L286Hc.860G>T c.G860T W287Lc.862G>C c.G862C A288Pc.862G>T c.G862T A288Sc.863C>G c.C863G A288Gc.863C>T c.C863T A288Vc.865A>C c.A865C I289Lc.865A>G c.A865G I289Vc.866T>C c.T866C I289Tc.866T>G c.T866G I289Sc.868A>C or c.868A>T c.A868C or c.A868T M290Lc.868A>G c.A868G M290Vc.869T>C c.T869C M290Tc.870G>A or c.870G>C or c.G870A or c.G870C or c.G870T M290Ic.870G>Tc.871G>A c.G871A A291Tc.871G>T c.G871T A291Sc.872C>G c.C872G A291Gc.874G>T c.G874T A292Sc.875C>G c.C875G A292Gc.877C>A c.C877A P293Tc.880T>A c.T880A L294Ic.880T>G c.T880G L294Vc.881T>C c.T881C L294Sc.882A>T c.A882T L294Fc.883T>A c.T883A F295Ic.883T>G c.T883G F295Vc.884T>A c.T884A F295Yc.884T>C c.T884C F295S

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.884T>G c.T884G F295Cc.886A>G c.A886G M296Vc.886A>T or c.886A>C c.A886T or c.A886C M296Lc.887T>C c.T887C M296Tc.888G>A or c.888G>T or c.G888A or c.G888T or c.G888C M296Ic.888G>Cc.889T>A c.T889A S297Tc.892A>G c.A892G N298Dc.893A>C c.A893C N298Tc.893A>G c.A893G N298Sc.893A>T c.A893T N298Ic.895G>A c.G895A D299Nc.895G>C c.G895C D299Hc.897C>G or c.897C>A c.C897G or c.C897A D299Ec.898C>A c.C898A L300Ic.898C>G c.C898G L300Vc.898C>T c.C898T L300Fc.899T>C c.T899C L300Pc.901C>G c.C901G R301Gc.902G>A c.G902A R301Qc.902G>C c.G902C R301Pc.902G>T c.G902T R301Lc.904C>A c.C904A H302Nc.904C>G c.C904G H302Dc.904C>T c.C904T H302Yc.905A>T c.A905T H302Lc.907A>G c.A907G I303Vc.907A>T c.A907T I303Fc.908T>A c.T908A I303Nc.908T>C c.T908C I303Tc.908T>G c.T908G I303Sc.911G>A c.G911A S304Nc.911G>C c.G911C S304Tc.911G>T c.G911T S304Ic.916C>G c.C916G Q306Ec.917A>C c.A917C Q306Pc.917A>T c.A917T Q306Lc.919G>A c.G919A A307Tc.919G>C c.G919C A307Pc.919G>T c.G919T A307Sc.920C>A c.C920A A307Dc.920C>G c.C920G A307Gc.920C>T c.C920T A307Vc.922A>C c.A922C K308Qc.922A>G c.A922G K308Ec.923A>G c.A923G K308Rc.923A>T c.A923T K308Ic.924A>T or c.924A>C c.A924T or c.A924C K308Nc.925G>A c.G925A A309Tc.925G>C c.G925C A309P

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.926C>A c.C926A A309Dc.926C>T c.C926T A309Vc.928C>A c.C928A L310Ic.928C>G c.C928G L310Vc.928C>T c.C928T L310Fc.931C>A c.C931A L311Ic.931C>G c.C931G L311Vc.934C>A c.C934A Q312Kc.934C>G c.C934G Q312Ec.935A>G c.A935G Q312Rc.935A>T c.A935T Q312Lc.936G>T or c.936G>C c.G936T or c.G936C Q312Hc.937G>T c.G937T D313Yc.[937G>T; 1232G>A] c.G937T/G1232A D313Y/G411Dc.938A>G c.A938G D313Gc.938A>T c.A938T D313Vc.939T>A c.T939A D313Ec.940A>G c.A940G K314Ec.941A>C c.A941C K314Tc.941A>T c.A941T K314Mc.942G>C c.G942C K314Nc.943G>A c.G943A D315Nc.943G>C c.G943C D315Hc.943G>T c.G943T D315Yc.944A>C c.A944C D315Ac.944A>G c.A944G D315Gc.944A>T c.A944T D315Vc.946G>A c.G946A V316Ic.946G>C c.G946C V316Lc.947T>C c.T947C V316Ac.947T>G c.T947G V316Gc.949A>C c.A949C I317Lc.949A>G c.A949G I317Vc.950T>C c.T950C I317Tc.951T>G c.T951G I317Mc.952G>A c.G952A A318Tc.952G>C c.G952C A318Pc.953C>A c.C953A A318Dc.953C>T c.C953T A318Vc.955A>T c.A955T I319Fc.956T>C c.T956C I319Tc.957C>G c.C957G I319Mc.958A>C c.A958C N320Hc.959A>C c.A959C N320Tc.959A>G c.A959G N320Sc.959A>T c.A959T N320Ic.961C>A c.C961A Q321Kc.962A>G c.A962G Q321Rc.962A>T c.A962T Q321Lc.963G>C or c.963G>T c.G963C or c.G963T Q321H

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.964G>A c.G964A D322Nc.964G>C c.G964C D322Hc.965A>C c.A965C D322Ac.965A>T c.A965T D322Vc.966C>A or c.966C>G c.C966A or c.C966G D322Ec.967C>A c.C967A P323Tc.968C>G c.C968G P323Rc.970T>G c.T970G L324Vc.971T>G c.T971G L324Wc.973G>A c.G973A G325Sc.973G>C c.G973C G325Rc.973G>T c.G973T G325Cc.974G>C c.G974C G325Ac.974G>T c.G974T G325Vc.976A>C c.A976C K326Qc.976A>G c.A976G K326Ec.977A>C c.A977C K326Tc.977A>G c.A977G K326Rc.977A>T c.A977T K326Mc.978G>C or c.978G>T c.G978C or c.G978T K326Nc.979C>G c.C979G Q327Ec.980A>C c.A980C Q327Pc.980A>T c.A980T Q327Lc.981A>T or c.981A>C c.A981T or c.A981C Q327Hc.983G>C c.G983C G328Ac.985T>A c.T985A Y329Nc.985T>C c.T985C Y329Hc.985T>G c.T985G Y329Dc.986A>G c.A986G Y329Cc.986A>T c.A986T Y329Fc.988C>A c.C988A Q330Kc.988C>G c.C988G Q330Ec.989A>C c.A989C Q330Pc.989A>G c.A989G Q330Rc.990G>C c.G990C Q330Hc.991C>G c.C991G L331Vc.992T>A c.T992A L331Hc.992T>C c.T992C L331Pc.992T>G c.T992G L331Rc.994A>G c.A994G R332Gc.995G>C c.G995C R332Tc.995G>T c.G995T R332Ic.996A>T c.A996T R332Sc.997C>G c.C997G Q333Ec.998A>C c.A998C Q333Pc.998A>T c.A998T Q333Lc.1000G>C c.G1000C G334Rc.1001G>A c.G1001A G334Ec.1001G>T c.G1001T G334Vc.1003G>T c.G1003T D335Y

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.1004A>C c.A1004C D335Ac.1004A>G c.A1004G D335Gc.1004A>T c.A1004T D335Vc.1005C>G c.C1005G D335Ec.1006A>G c.A1006G N336Dc.1006A>T c.A1006T N336Yc.1007A>C c.A1007C N336Tc.1007A>G c.A1007G N336Sc.1007A>T c.A1007T N336Ic.1009T>G c.T1009G F337Vc.1010T>A c.T1010A F337Yc.1010T>C c.T1010C F337Sc.1010T>G c.T1010G F337Cc.1011T>A c.T1011A F337Lc.1012G>A c.G1012A E338Kc.1013A>C c.A1013C E338Ac.1013A>G c.A1013G E338Gc.1013A>T c.A1013T E338Vc.1014A>T c.A1014T E338Dc.1015G>A c.G1015A V339Mc.1016T>A c.T1016A V339Ec.1016T>C c.T1016C V339Ac.1021G>C c.G1021C E341Qc.1022A>C c.A1022C E341Ac.1027C>A c.C1027A P343Tc.1027C>G c.C1027G P343Ac.1027C>T c.C1027T P343Sc.1028C>T c.C1028T P343Lc.1030C>G c.C1030G L344Vc.1030C>T c.C1030T L344Fc.1031T>G c.T1031G L344Rc.1033T>C c.T1033C S345Pc.1036G>T c.G1036T G346Cc.1037G>A c.G1037A G346Dc.1037G>C c.G1037C G346Ac.1037G>T c.G1037T G346Vc.1039T>A c.T1039A L347Ic.1043C>A c.C1043A A348Dc.1046G>C c.G1046C W349Sc.1046G>T c.G1046T W349Lc.1047G>C c.G1047C W349Cc.1048G>A c.G1048A A350Tc.1048G>T c.G1048T A350Sc.1049C>G c.C1049G A350Gc.1049C>T c.C1049T A350Vc.1052T>A c.T1052A V351Ec.1052T>C c.T1052C V351Ac.1054G>A c.G1054A A352Tc.1054G>T c.G1054T A352Sc.1055C>G c.C1055G A352G

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.1055C>T c.C1055T A352Vc.1057A>T c.A1057T M353Lc.1058T>A c.T1058A M353Kc.1058T>C c.T1058C M353Tc.1061T>A c.T1061A I354Kc.1061T>G c.T1061G I354Rc.1063A>C c.A1063C N355Hc.1063A>G c.A1063G N355Dc.1063A>T c.A1063T N355Yc.1064A>G c.A1064G N355Sc.1066C>G c.C1066G R356Gc.1066C>T c.C1066T R356Wc.1067G>A c.G1067A R356Qc.1067G>C c.G1067C R356Pc.1067G>T c.G1067T R356Lc.1069C>G c.C1069G Q357Ec.1072G>C c.G1072C E358Qc.1073A>C c.A1073C E358Ac.1073A>G c.A1073G E358Gc.1074G>T or c.1074G>C c.G1074T or c.G1074C E358Dc.1075A>C c.A1075C I359Lc.1075A>G c.A1075G I359Vc.1075A>T c.A1075T I359Fc.1076T>A c.T1076A I359Nc.1076T>C c.T1076C I359Tc.1076T>G c.T1076G I359Sc.1078G>A c.G1078A G360Sc.1078G>C c.G1078C G360Rc.1078G>T c.G1078T G360Cc.1079G>A c.G1079A G360Dc.1079G>C c.G1079C G360Ac.1082G>A c.G1082A G361Ec.1082G>C c.G1082C G361Ac.1084C>A c.C1084A P362Tc.1084C>G c.C1084G P362Ac.1084C>T c.C1084T P362Sc.1085C>A c.C1085A P362Hc.1085C>G c.C1085G P362Rc.1085C>T c.C1085T P362Lc.1087C>A c.C1087A R363Sc.1087C>G c.C1087G R363Gc.1087C>T c.C1087T R363Cc.1088G>A c.G1088A R363Hc.1088G>T c.G1088T R363Lc.1090T>C c.T1090C S364Pc.1091C>G c.C1091G S364Cc.1093T>A c.T1093A Y365Nc.1093T>G c.T1093G Y365Dc.1094A>C c.A1094C Y365Sc.1094A>T c.A1094T Y365F

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.1096A>C c.A1096C T366Pc.1096A>T c.A1096T T366Sc.1097C>A c.C1097A T366Nc.1097C>T c.C1097T T366Ic.1099A>C c.A1099C I367Lc.1099A>T c.A1099T I367Fc.1101C>G c.C1101G I367Mc.1102G>A c.G1102A A368Tc.1102G>C c.G1102C A368Pc.1103C>G c.C1103G A368Gc.1105G>A c.G1105A V369Ic.1105G>C c.G1105C V369Lc.1105G>T c.G1105T V369Fc.1106T>C c.T1106C V369Ac.1106T>G c.T1106G V369Gc.1108G>A c.G1108A A370Tc.1108G>C c.G1108C A370Pc.1109C>A c.C1109A A370Dc.1109C>G c.C1109G A370Gc.1109C>T c.C1109T A370Vc.1111T>A c.T1111A S371Tc.1112C>G c.C1112G S371Cc.1117G>A c.G1117A G373Sc.1117G>T c.G1117T G373Cc.1118G>C c.G1118C G373Ac.1120A>G c.A1120G K374Ec.1121A>C c.A1121C K374Tc.1121A>G c.A1121G K374Rc.1121A>T c.A1121T K374Ic.1123G>C c.G1123C G375Rc.1124G>A c.G1124A G375Ec.1124G>C c.G1124C G375Ac.1126G>A c.G1126A V376Mc.1126G>C c.G1126C V376Lc.1127T>A c.T1127A V376Ec.1127T>G c.T1127G V376Gc.1129G>A c.G1129A A377Tc.1129G>C c.G1129C A377Pc.1129G>T c.G1129T A377Sc.1130C>G c.C1130G A377Gc.1135A>G c.A1135G N379Dc.1136A>C c.A1136C N379Tc.1136A>T c.A1136T N379Ic.1137T>A c.T1137A N379Kc.1138C>A c.C1138A P380Tc.1138C>G c.C1138G P380Ac.1139C>A c.C1139A P380Hc.1139C>G c.C1139G P380Rc.1139C>T c.C1139T P380Lc.1142C>A c.C1142A A381D

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.1147T>A c.T1147A F383Ic.1148T>A c.T1148A F383Yc.1148T>G c.T1148G F383Cc.1150A>T c.A1150T I384Fc.1151T>C c.T1151C I384Tc.1152C>G c.C1152G I384Mc.1153A>G c.A1153G T385Ac.1154C>T c.C1154T T385Ic.1156C>A c.C1156A Q386Kc.1157A>T c.A1157T Q386Lc.1158G>C c.G1158C Q386Hc.1159C>A c.C1159A L387Ic.1159C>T c.C1159T L387Fc.1160T>A c.T1160A L387Hc.1160T>G c.T1160G L387Rc.1162C>A c.C1162A L388Ic.1162C>G c.C1162G L388Vc.1162C>T c.C1162T L388Fc.1163T>A c.T1163A L388Hc.1163T>G c.T1163G L388Rc.1168G>A c.G1168A V390Mc.1171A>C c.A1171C K391Qc.1171A>G c.A1171G K391Ec.1172A>C c.A1172C K391Tc.1172A>G c.A1172G K391Rc.1172A>T c.A1172T K391Ic.1173A>T c.A1173T K391Nc.1174A>G c.A1174G R392Gc.1174A>T c.A1174T R392Wc.1175G>A c.G1175A R392Kc.1175G>C c.G1175C R392Tc.1175G>T c.G1175T R392Mc.1177A>C c.A1177C K393Qc.1177A>G c.A1177G K393Ec.1178A>C c.A1178C K393Tc.1179G>C c.G1179C K393Nc.1180C>A c.C1180A L394Ic.1181T>A c.T1181A L394Qc.1181T>C c.T1181C L394Pc.1181T>G c.T1181G L394Rc.1183G>C c.G1183C G395Rc.1184G>A c.G1184A G395Ec.1184G>C c.G1184C G395Ac.1186T>A c.T1186A F396Ic.1186T>G c.T1186G F396Vc.1187T>G c.T1187G F396Cc.1188C>G c.C1188G F396Lc.1189T>A c.T1189A Y397Nc.1189T>C c.T1189C Y397Hc.1190A>C c.A1190C Y397S

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.1190A>G c.A1190G Y397Cc.1190A>T c.A1190T Y397Fc.1192G>A c.G1192A E398Kc.1192G>C c.G1192C E398Qc.1193A>G c.A1193G E398Gc.1195T>A c.T1195A W399Rc.1195T>G c.T1195G W399Gc.1198A>C c.A1198C T400Pc.1198A>G c.A1198G T400Ac.1198A>T c.A1198T T400Sc.1199C>A c.C1199A T400Nc.1199C>T c.C1199T T400Ic.1201T>A c.T1201A S401Tc.1201T>G c.T1201G S401Ac.1202_1203insGACTTC c.1202_1203insGACTTC p.T400_S401dupc.1202C>T c.C1202T S401Lc.1204A>G c.A1204G R402Gc.1204A>T c.A1204T R402Wc.1205G>C c.G1205C R402Tc.1205G>T c.G1205T R402Mc.1206G>C c.G1206C R402Sc.1207T>G c.T1207G L403Vc.1208T>C c.T1208C L403Sc.1209A>T c.A1209T L403Fc.1210A>G c.A1210G R404Gc.1211G>A c.G1211A R404Kc.1211G>C c.G1211C R404Tc.1211G>T c.G1211T R404Ic.1212A>T c.A1212T R404Sc.1213A>G c.A1213G S405Gc.1216C>G c.C1216G H406Dc.1217A>T c.A1217T H406Lc.1218C>G c.C1218G H406Qc.1219A>T c.A1219T I407Lc.1220T>C c.T1220C I407Tc.1221A>G c.A1221G I407Mc.1222A>C c.A1222C N408Hc.1222A>G c.A1222G N408Dc.1222A>T c.A1222T N408Yc.1223A>C c.A1223C N408Tc.1225C>A c.C1225A P409Tc.1225C>G c.C1225G P409Ac.1225C>T c.C1225T P409Sc.1226C>T c.C1226T P409Lc.1228A>G c.A1228G T410Ac.1228A>T c.A1228T T410Sc.1229C>T c.C1229T T410Ic.1231G>A c.G1231A G411S

Table 2: Galafold (migalastat) amenability table

Nucleotide change Nucleotide change Protein sequence changec.1231G>T c.G1231T G411Cc.1232G>A c.G1232A G411Dc.1232G>C c.G1232C G411Ac.1232G>T c.G1232T G411Vc.1234A>C c.A1234C T412Pc.1234A>G c.A1234G T412Ac.1234A>T c.A1234T T412Sc.1235C>A c.C1235A T412Nc.1235C>T c.C1235T T412Ic.1237G>A c.G1237A V413Ic.1237G>T c.G1237T V413Fc.1238T>G c.T1238G V413Gc.1240T>G c.T1240G L414Vc.1242G>C c.G1242C L414Fc.1243C>A c.C1243A L415Ic.1244T>A c.T1244A L415Hc.1246C>G c.C1246G Q416Ec.1247A>T c.A1247T Q416Lc.1248G>C c.G1248C Q416Hc.1249C>A c.C1249A L417Ic.1252G>A c.G1252A E418Kc.1252G>C c.G1252C E418Qc.1253A>C c.A1253C E418Ac.1253A>G c.A1253G E418Gc.1254A>T c.A1254T E418Dc.1255A>G c.A1255G N419Dc.1255A>T c.A1255T N419Yc.1256A>C c.A1256C N419Tc.1256A>G c.A1256G N419Sc.1256A>T c.A1256T N419Ic.1258A>C c.A1258C T420Pc.1258A>T c.A1258T T420Sc.1259C>A c.C1259A T420Kc.1259C>G c.C1259G T420Rc.1261A>G c.A1261G M421Vc.1261A>T c.A1261T M421Lc.1262T>A c.T1262A M421Kc.1262T>C c.T1262C M421Tc.1262T>G c.T1262G M421Rc.1263G>C c.G1263C M421Ic.1265A>C c.A1265C Q422Pc.1267A>T c.A1267T M423Lc.1268T>A c.T1268A M423Kc.1268T>C c.T1268C M423Tc.1269G>C c.G1269C M423Ic.1271C>T c.C1271T S424Lc.1275A>C c.A1275C L425Fc.1279G>A c.G1279A D427Nc.1286T>G c.T1286G L429R

Treatment with Galafold in phase 2 pharmacodynamic studies generally resulted in increases inendogenous α-Gal A activity in WBCs, as well as in skin and kidney for the majority of patients. Inpatients with amenable mutations, GL-3 levels tended to decrease in urine and in kidney interstitialcapillaries.

The clinical efficacy and safety of Galafold have been evaluated in two phase 3 pivotal clinical studiesand two open-label extension (OLE) clinical studies. All patients received the recommended dosage of123 mg Galafold every other day.

The first phase 3 clinical study (ATTRACT) was a randomised open-label active comparator studythat evaluated the efficacy and safety of Galafold compared to enzyme replacement therapy (ERT)(agalsidase beta, agalsidase alfa) in 52 male and female patients with Fabry disease who werereceiving ERT prior to clinical study entry and who have amenable mutations (ERT-experiencedclinical study). The clinical study was structured in two periods. During the first period (18-months)

ERT-experienced patients were randomised to switch from ERT to Galafold or continue with ERT.

The second period was an optional 12-month open-label extension in which all subjects received

Galafold.

The second phase 3 clinical study (FACETS) was a 6-month randomised double-blindplacebo-controlled study (through month 6) with an 18-month open-label period to evaluate theefficacy and safety of Galafold in 50 male and female patients with Fabry disease who were naïve to

ERT, or had previously been on ERT and had stopped for at least 6 months and who have amenablemutations (ERT-naïve study).

The first OLE clinical study (AT1001-041) included patients from phase 2 and phase 3 studies and hascompleted. The mean extent of exposure to the marketed dose of migalastat 123 mg QOD in patientscompleting study AT1001-041 was 3.57 (±1.23) years (n=85). The maximum exposure was 5.6 years.

The second OLE clinical study (AT1001-042) included patients that either transferred from OLE study

AT1001-041 or directly from phase 3 study ATTRACT. The mean extent of exposure to the marketeddose of Galafold 123 mg QOD in patients in this study was 32.3 (±12.3) months (n=82). Themaximum exposure was 51.9 months.

In the ERT-experienced clinical study, renal function remained stable for up to 18 months of treatmentwith Galafold. Mean annualised rate of change in eGFR 2

CKD-EPI was -0.40 mL/min/1.73 m(95% CI: -2.272, 1.478; n=34) in the Galafold group compared to -1.03 mL/min/1.73 m2(95% CI: -3.636, 1.575; n=18) in the ERT group. The mean annualised rate of change from baseline ineGFRCKD-EPI in patients treated for 30 months with Galafold was -1.72 mL/min/1.73 m2(95% CI: -2.653, -0.782; n=31).

In the ERT-naïve clinical study and open-label extension, renal function remained stable for up to5 years of treatment with Galafold. After an average of 3.4 years of treatment, the mean annualisedrate of change in eGFR 2

CKD-EPI was -0.74 mL/min/1.73 m (95% CI: -1.89, 0.40; n=41). No clinicallysignificant differences were observed during the initial 6-month placebo-controlled period.

Data for the annualised rate of change for eGRFCKD-EPI was pooled for ERT-naïve subjects and

ERT-experienced subjects with amenable mutations; the results showed the durability of renalstabilization up to 8.6 years in annualised rate of change. After a mean duration of 5.2 years,

ERT-naïve patients had a mean annualised rate of change from baseline of -1.71 mL/min/1.73 m2(95% CI: -2.83, -0.60; n=47). After a mean duration of 4.3 years, ERT-experienced patients had amean annualised rate of change from baseline of -1.78 mL/min/1.73 m2 (95% CI: -3.76, 0.20; n=49).

Left ventricular mass index (LVMi)

In the ERT-experienced clinical study, following 18 months of treatment with Galafold there was astatistically significant decrease in LVMi (p<0.05). The baseline values were 95.3 g/m2 for the

Galafold arm and 92.9 g/m2 for the ERT arm and the mean change from baseline in LVMi at month 18was -6.6 (95% CI: -11.0, -2.1; n=31) for Galafold and -2.0 (95% CI: -11.0, 7.0; n=13) for ERT. Thechange from baseline to month 18 in LVMi (g/m2) in patients with left ventricular hypertrophy(females with baseline LVMi >95 g/m2 and males with baseline LVMi >115 g/m2) was -8.4(95% CI: -15.7, 2.6; n=13) for Galafold and 4.5 (95% CI: -10.7, 18.4; n=5) for ERT. After 30 monthstreatment with Galafold, the mean change from baseline in LVMi was -3.8 (95% CI: -8.9, 1.3; n=28)and the mean change from baseline in LVMi in patients with left ventricular hypertrophy at baselinewas -10.0 (95% CI: -16.6, -3.3; n=10).

In the ERT-naïve clinical study, Galafold resulted in a statistically significant decrease in LVMi(p<0.05); the mean change from baseline in LVMi at month 18 to 24 was -7.7 (95% CI: -15.4, -0.01;n=27). After follow-up in the OLE, the mean change from baseline in LVMi at month 36 was -8.3(95% CI: -17.1, 0.4; n=25) and at month 48 was -9.1 (95% CI: -20.3, 2.0; n=18). The mean changefrom baseline in LVMi at month 18 to 24 in patients with left ventricular hypertrophy at baseline(females with baseline LVMi >95 g/m2 or males with baseline LVMi >115 g/m2) was -18.6(95% CI: -38.2, 1.0; n=8). After follow-up in the OLE, the mean change from baseline in LVMi atmonth 36 in patients with left ventricular hypertrophy at baseline was -30.0 (95% CI: -57.9, -2.2; n=4)and at month 48 was -33.1 (95% CI: -60.9, -5.4; n=4). No clinically significant differences in LVMiwere observed during the initial 6-month placebo-controlled period.

In the ERT-experienced and ERT-naïve clinical studies, after follow up in OLE clinical study

AT1001-042, the mean change in LVMi from AT1001-042 baseline was 1.2 g/m2 (95% CI: -5.3, 7.7;n=15) and -5.6 g/m2 (95% CI: -28.5, 17.2; n=4) respectively, for patients treated with Galafold for anaverage of 2.4 and 2.9 years (up to 4.0 and 4.3 years, respectively).

Disease substrate

In the ERT-experienced clinical study, plasma lyso-Gb3 levels slightly increased but remained low inpatients with amenable mutations treated with Galafold for the 30-month duration of the study. Plasmalyso-Gb3 levels also remained low in patients on ERT for up to 18 months.

In the ERT- naïve clinical study, Galafold showed statistically significant reductions in plasmalyso-Gb3 concentrations and kidney interstitial capillary GL-3 inclusions in patients with amenablemutations. Patients randomised to Galafold in Stage 1 demonstrated statistically significant greaterreduction (±SEM) in mean interstitial capillary GL-3 deposition (-0.25±0.10; -39%) at month 6compared to placebo (+0.07 ± 0.13; +14%) (p=0.008). Patients randomised to placebo in Stage 1 andswitched to Galafold at month 6 (Stage 2) also demonstrated statistically significant decreases ininterstitial capillary GL-3 inclusions at month 12 (-0.33±0.15; -58%) (p=0.014). Qualitative reductionsin GL-3 levels were observed in multiple renal cell types: podocytes, mesangial cells, and glomerularendothelial cells, respectively, over 12 months of treatment with Galafold.

Composite clinical outcomes

In the ERT-experienced clinical study, an analysis of a composite clinical outcome composed of renal,cardiac, and cerebrovascular events, or death, showed that the frequency of events observed in the

Galafold treatment group was 29% compared to 44% in the ERT group over 18 months. Thefrequency of events in patients treated with Galafold over 30 months (32%) was similar to the18-month period.

Patient-reported outcome - gastrointestinal symptoms rating scale

In the ERT-naïve clinical study, analyses of the Gastrointestinal Symptoms Rating Scale demonstratedthat treatment with Galafold was associated with statistically significant (p<0.05) improvementsversus placebo from baseline to month 6 in the diarrhoea domain, and in the reflux domain for patientswith symptoms at baseline. During the open-label extension, statistically significant (p<0.05)improvements from baseline were observed in the diarrhoea and indigestion domains, with a trend ofimprovement in the constipation domain.

In Study AT1001-020, a 1-year, Phase 3b, open-label, uncontrolled, multicentre study, the safety, PK,pharmacodynamic (PD), and efficacy of migalastat treatment was evaluated in 21 adolescent subjects(12 to < 18 years of age and weighing ≥ 45 kg) with Fabry disease and who have amenable mutationsof the gene encoding α-galactosidase A (GLA). Subjects were either naïve to enzyme replacementtherapy (ERT) or had stopped ERT at least 14 days before screening. The mean number of years sincediagnosis of Fabry disease was 9.6 (± 4.25) years.

At 1 year, the efficacy results in adolescents on the same dosing regimen as adults were consistent inrenal, cardiac, and pharmacodynamic results as well as responses to patient-reported outcomes. Theoverall mean (SD) change from baseline in eGFR was -1.6 (15.4) mL/min/1.73 m2 (n=19). The overallmean (SD) change from baseline for LVMi was -3.9 (13.5) g/m2 (n=18). LVMi decreased in10 subjects and increased in 8 subjects, but all subjects remained within normal limits at 12 months.

Baseline plasma lyso-Gb3 was 12.00 ng/mL and the overall mean (SD) change from baseline inplasma lyso-Gb3 was -0.06 (32.9) (n=19). A reduction in plasma lyso-Gb3 from baseline was observedin ERT-naïve subjects (median -2.23 ng/ml, n=9) and levels remained generally stable in

ERT-experienced subjects (median 0.54 ng/ml, n=10). There were no notable changes in patientreported outcomes.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Galafold in one or more subsets of the paediatric population in the treatment of Fabry disease (seesection 4.2 for information on paediatric use).

The absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose or a single2-hour 150 mg intravenous infusion was approximately 75%. Following a single oral dose of 150 mgmigalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours.

Plasma migalastat exposure (AUC0-∞) and Cmax demonstrated dose-proportional increases at migalastathydrochloride oral doses from 50 mg to 1,250 mg in adults.

Migalastat administered with a high-fat meal, or 1 hour before a high-fat or light meal, or 1 hour aftera light meal, resulted in significant reductions of 37% to 42% in mean total migalastat exposure(AUC0-∞) and reductions of 15% to 40% in mean peak migalastat exposure (Cmax) compared with thefasting state (see section 4.2).

Compared to intake of a single dose of migalastat with water, intake with coffee containingapproximately 190 mg caffeine resulted in a significant decrease in migalastat systemic exposure(mean reduction in AUC0-∞ by 55% and mean reduction in Cmax by 60%). The rate of absorption (tmax)of migalastat was not affected by administration of caffeine in comparison to water. No effect wasobserved when migalastat was taken with natural (sucrose) and artificial (aspartame or acesulfame K)sweeteners (see section 4.2 and 4.5).

In healthy volunteers, the volume of distribution (Vz/F) of migalastat following ascending single oraldoses (25 to 675 mg migalastat hydrochloride) ranged from 77 to 133 L, indicating it is welldistributed into tissues and greater than total body water (42 litres). There was no detectable plasmaprotein binding following administration of [14C]-migalastat hydrochloride in the concentration rangebetween 1 and 100 M.

Based upon in vivo data, migalastat is a substrate for UGT, being a minor elimination pathway.

Migalastat is not a substrate for P-glycoprotein (P-gP) in vitro and it is considered unlikely thatmigalastat would be subject to drug-drug interactions with cytochrome P450s. A pharmacokineticstudy in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that 99% of theradiolabelled dose recovered in plasma was comprised of unchanged migalastat (77%) and3 dehydrogenated O-glucuronide conjugated metabolites, M1to M3 (13%). Approximately 9% of thetotal radioactivity was unassigned.

A pharmacokinetic study in healthy male volunteers with 150 mg [14C]-migalastat hydrochloriderevealed that approximately 77% of the radiolabeled dose was recovered in urine of which 55% of wasexcreted as unchanged migalastat and 5% as combined metabolites M1, M2 and M3. Approximately3% of the total sample radioactivity was unassigned components. Approximately 20% of the totalradiolabeled dose was excreted in faeces, with unchanged migalastat being the only measuredcomponent.

Following ascending single oral doses (25 to 675 mg migalastat hydrochloride), no trends were foundfor clearance, CL/F. At the 150 mg dose, CL/F was approximately 11 to 14 L/hr. Followingadministration of the same doses, the mean elimination half-life (t1/2) ranged from approximately 3 to5 hours.

Galafold has not been studied in patients with Fabry disease who have a GFR less than30 mL/min/1.73 m2. In a single dose study with Galafold in non-Fabry subjects with varying degreesof renal insufficiency, exposures were increased by 4.3-fold in subjects with severe renal impairment(GFR <30 mL/min/1.73 m2).

No studies have been carried out in subjects with impaired hepatic function. From the metabolism andexcretion pathways, it is not expected that a decreased hepatic function may affect thepharmacokinetics of migalastat.

Elderly (>65 years)

Clinical studies of Galafold included small number of patients aged 65 and over. The effect of age wasevaluated in a population pharmacokinetic analysis on plasma migalastat clearance in the ERT-naïvestudy population. The difference in clearance between Fabry patients ≥ 65 years and those < 65 yearswas 20%, which was not considered clinically significant.

The pharmacokinetics of migalastat were characterised in 20 adolescent subjects (12 to < 18 years andweighing ≥45 kg) with Fabry disease who received the same dosage regimen as adults (123 mgmigalastat capsule every other day) in an open label phase 3b study (AT1001-020).

Assessment of bioequivalence of exposure was simulated in adolescent subjects (12 to < 18 years)weighing ≥ 45 kg and receiving migalastat 123 mg once every other day compared to adults receivingthe same dosing regimen. Model derived AUCtau in adolescent subjects (12 to < 18 years) were similarto adult exposures.

The pharmacokinetic characteristics of migalastat were not significantly different between females andmales in either healthy volunteers or in patients with Fabry disease.

Non-clinical studies suggest no specific hazard for humans on the basis of single-and repeat-dosestudies, with the exception of transient and fully reversible infertility in male rats associated withmigalastat treatment. The infertility associated with migalastat treatment was reported at clinicallyrelevant exposures. Complete reversibility was seen after 4 weeks off-dose. Similar findings have beennoted pre-clinically following treatment with other iminosugars. In the rabbit embryo-foetal toxicitystudy, findings including embryo-foetal death, a reduction in mean foetal weight, retarded ossification,and slightly increased incidences of minor skeletal abnormalities were observed only at dosesassociated with maternal toxicity.

In a rat 104-week carcinogenicity study, there was an increased incidence of pancreatic islet celladenomas in males at a dose level 19-fold higher than the exposure (AUC) at the clinically efficaciousdose. This is a common spontaneous tumour in ad libitum-fed male rats. In the absence of similarfindings in females, no findings in the genotoxicity battery or in the carcinogenicity study with

Tg.rasH2 mice, and no pre-neoplastic pancreatic findings in the rodents or monkeys, this observationin male rats is not considered related to treatment and its relevance to humans is unknown.

Pregelatinised starch (maize)

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Indigo carmine (E132)

Shellac

Black iron oxide

Potassium hydroxide

Not applicable.

4 years

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from moisture.

PVC/PCTFE/PVC/Al blister.

Pack size of 14 capsules.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amicus Therapeutics Europe Limited

Block 1, Blanchardstown Corporate Park

Ballycoolin Road

Blanchardstown, Dublin

D15 AKK1

Ireland

Tel: +353 (0) 1 588 0836

Fax: +353 (0) 1 588 6851e-mail: info@amicusrx.co.uk

EU/1/15/1082/001

Date: of first authorisation: 26 May 2016

Date of latest renewal: 11 February 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.