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Galafold 123 mg hard capsules

Active Ingredient:
migalastat hydrochloride
Company:  
Amicus Therapeutics UK Ltd See contact details
ATC code: 
A16AX14
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About Medicine
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Prescription only medicine
Healthcare Professionals (SmPC) Patient Leaflet (PIL) HCP Med Info
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{healthcare_pro_orange} This information is for use by healthcare professionals
Last updated on emc: 18 Dec 2023

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Undesirable Effects Pharmacological Properties Interactions Posology Contraindications Excipients Storage precautions
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1. Name of the medicinal product

Galafold 123 mg hard capsules

2. Qualitative and quantitative composition

Each capsule contains migalastat hydrochloride equivalent to 123 mg migalastat.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

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.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

Posology

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

Missed dose

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

Special populations

Elderly population

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

Renal impairment

Galafold is not recommended for use in patients with Fabry disease who have estimated GFR less than 30 mL/min/1.73 m2 (see section 5.2).

Hepatic impairment

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

Paediatric population

Adolescents aged 12 to <18 years and weighing ≥ 45 kg

123 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.

Method of administration

For oral use.

Galafold exposure is decreased by approximately 40% when taken with food and 60% when taken with coffee (see sections 4.5 and 5.2). Food and caffeine should not be consumed at least 2 hours before 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 beverages can 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 the patient.

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

It is advised to periodically monitor renal function, echocardiographic parameters and biochemical markers (every 6 months) in patients initiated on or switched to migalastat. In case of meaningful clinical deterioration, further clinical evaluation or discontinuation of treatment with Galafold should be 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 enzyme replacement therapy infusion results in an increased exposure to agalsidase of up to 5-fold. This study also indicated that agalsidase has no effect on the pharmacokinetics of migalastat. Galafold is not intended for concomitant use with enzyme replacement therapy.

Paediatric population

123 mg migalastat capsules are not for children (≥ 12 years) weighing less than 45 kg, (see section 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

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, or 3A4/5. 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 with caffeine at least 2 hours before and 2 hours after taking Galafold (see section 4.2).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

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

Pregnancy

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

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

Table 1: Adverse reactions with Galafold

System organ class

Very common

Common

Psychiatric disorders

Depression

Nervous system disorders

Headache

Paraesthesia

Dizziness

Hypoaesthesia

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Palpitations

Respiratory, thoracic, and mediastinal disorders

Dyspnoea

Epistaxis

Gastrointestinal disorders

Diarrhoea

Nausea

Abdominal pain

Constipation

Dry mouth

Defaecation urgency

Dyspepsia

Skin and subcutaneous tissue disorders

Rash

Pruritus

Musculoskeletal and connective tissue disorders

Muscle spasms

Myalgia

Torticollis

Pain in extremity

Renal and urinary disorders

Proteinuria

General disorders and administration site conditions

Fatigue

Pain

Investigations

Blood creatine phosphokinase increased

Weight increased

Adolescent population

The safety assessment in 21 adolescents (12 to <18 years of age and weighing ≥ 45 kg) is based on 1-year safety data from the open label AT1001-020 trial in which subjects received the same dosage regimen as adults (see section 5.2). No age-specific differences in adverse reactions were observed between adolescent and adult subjects. The frequency, type and severity of adverse reactions in adolescents are expected to be the same as in adults based on these data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and 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 α -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 of substrate in vulnerable organs and tissues, which leads to the morbidity and mortality associated with Fabry disease.

Mechanism of action

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

The GLA mutations amenable to treatment with Galafold are listed in Table 2 below. The GLA mutations 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 acid mutation. The amino acid mutation (protein sequence change) is most relevant when determining amenability. If a double mutation is present on the same chromosome (males and females), that patient is amenable if the double mutation is present in one entry in Table 2 (e.g., D55V/Q57L). If a double mutation is present on different chromosomes (only in females) that patient is amenable if either one of the individual mutations is present in Table 2.

Table 2: Galafold (migalastat) amenability table

Nucleotide change

Nucleotide change

Protein sequence change

c.7C>G

c.C7G

L3V

c.8T>C

c.T8C

L3P

c.[11G>T; 620A>C]

c.G11T/A620C

R4M/Y207S

c.13A>G

c.A13G

N5D

c.15C>G

c.C15G

N5K

c.16C>A

c.C16A

P6T

c.16C>T

c.C16T

P6S

c.17C>A

c.C17A

P6Q

c.17C>G

c.C17G

P6R

c.17C>T

c.C17T

P6L

c.19G>A

c.G19A

E7K

c.20A>T

c.A20T

E7V

c.21A>T

c.A21T

E7D

c.22C>A

c.C22A

L8I

c.23T>A

c.T23A

L8Q

c.23T>C

c.T23C

L8P

c.25C>T

c.C25T

H9Y

c.26A>G

c.A26G

H9R

c.26A>T

c.A26T

H9L

c.27T>A

c.T27A

H9Q

c.28C>A

c.C28A

L10M

c.28C>G

c.C28G

L10V

c.29T>A

c.T29A

L10Q

c.29T>C

c.T29C

L10P

c.29T>G

c.T29G

L10R

c.31G>A

c.G31A

G11S

c.31G>C

c.G31C

G11R

c.31G>T

c.G31T

G11C

c.32G>A

c.G32A

G11D

c.32G>T

c.G32T

G11V

c.34T>A

c.T34A

C12S

c.34T>C

c.T34C

C12R

c.34T>G

c.T34G

C12G

c.35G>A

c.G35A

C12Y

c.37G>A

c.G37A

A13T

c.37G>C

c.G37C

A13P

c.38C>A

c.C38A

A13E

c.38C>G

c.C38G

A13G

c.40C>G

c.C40G

L14V

c.40C>T

c.C40T

L14F

c.41T>A

c.T41A

L14H

c.43G>A

c.G43A

A15T

c.44C>G

c.C44G

A15G

c.49C>A

c.C49A

R17S

c.49C>G

c.C49G

R17G

c.49C>T

c.C49T

R17C

c.50G>A

c.G50A

R17H

c.50G>C

c.G50C

R17P

c.52T>A

c.T52A

F18I

c.53T>G

c.T53G

F18C

c.54C>G

c.C54G

F18L

c.58G>C

c.G58C

A20P

c.59C>A

c.C59A

A20D

c.59C>G

c.C59G

A20G

c.62T>A

c.T62A

L21H

c.64G>A

c.G64A

V22I

c.64G>C

c.G64C

V22L

c.64G>T

c.G64T

V22F

c.65T>C

c.T65C

V22A

c.65T>G

c.T65G

V22G

c.67T>A

c.T67A

S23T

c.67T>C

c.T67C

S23P

c.[70T>A; 1255A>G]

c.T70A/A1255G

W24R/N419D

c.70T>C or c.70T>A

c.T70C or c.T70A

W24R

c.70T>G

c.T70G

W24G

c.71G>C

c.G71C

W24S

c.72G>C or c.72G>T

c.G72C or c.G72T

W24C

c.73G>C

c.G73C

D25H

c.77T>A

c.T77A

I26N

c.79C>A

c.C79A

P27T

c.79C>G

c.C79G

P27A

c.79C>T

c.C79T

P27S

c.80C>T

c.C80T

P27L

c.82G>C

c.G82C

G28R

c.82G>T

c.G82T

G28W

c.83G>A

c.G83A

G28E

c.85G>C

c.G85C

A29P

c.86C>A

c.C86A

A29D

c.86C>G

c.C86G

A29G

c.86C>T

c.C86T

A29V

c.88A>G

c.A88G

R30G

c.94C>A

c.C94A

L32M

c.94C>G

c.C94G

L32V

c.95T>A

c.T95A

L32Q

c.95T>C

c.T95C

L32P

c.95T>G

c.T95G

L32R

c.97G>C

c.G97C

D33H

c.97G>T

c.G97T

D33Y

c.98A>C

c.A98C

D33A

c.98A>G

c.A98G

D33G

c.98A>T

c.A98T

D33V

c.99C>G

c.C99G

D33E

c.100A>C

c.A100C

N34H

c.100A>G

c.A100G

N34D

c.101A>C

c.A101C

N34T

c.101A>G

c.A101G

N34S

c.102T>G or c.102T>A

c.T102G or c.T102A

N34K

c.103G>C or c.103G>A

c.G103C or c.G103A

G35R

c.104G>A

c.G104A

G35E

c.104G>C

c.G104C

G35A

c.104G>T

c.G104T

G35V

c.106T>A

c.T106A

L36M

c.106T>G

c.T106G

L36V

c.107T>C

c.T107C

L36S

c.107T>G

c.T107G

L36W

c.108G>C or c.108G>T

c.G108C or c.G108T

L36F

c.109G>A

c.G109A

A37T

c.109G>T

c.G109T

A37S

c.110C>A

c.C110A

A37E

c.110C>G

c.C110G

A37G

c.110C>T

c.C110T

A37V

c.112A>G

c.A112G

R38G

c.112A>T

c.A112T

R38W

c.113G>T

c.G113T

R38M

c.114G>C

c.G114C

R38S

c.115A>G

c.A115G

T39A

c.115A>T

c.A115T

T39S

c.116C>A

c.C116A

T39K

c.116C>G

c.C116G

T39R

c.116C>T

c.C116T

T39M

c.121A>G

c.A121G

T41A

c.122C>A

c.C122A

T41N

c.122C>G

c.C122G

T41S

c.122C>T

c.C122T

T41I

c.124A>C or c.124A>T

c.A124C or c.A124T

M42L

c.124A>G

c.A124G

M42V

c.125T>A

c.T125A

M42K

c.125T>C

c.T125C

M42T

c.125T>G

c.T125G

M42R

c.126G>A or c.126G>C or c.126G>T

c.G126A or c.G126C or c.G126T

M42I

c.128G>C

c.G128C

G43A

c.133C>A

c.C133A

L45M

c.133C>G

c.C133G

L45V

c.136C>A

c.C136A

H46N

c.136C>G

c.C136G

H46D

c.137A>C

c.A137C

H46P

c.138C>G

c.C138G

H46Q

c.142G>C

c.G142C

E48Q

c.143A>C

c.A143C

E48A

c.149T>A

c.T149A

F50Y

c.151A>G

c.A151G

M51V

c.152T>A

c.T152A

M51K

c.152T>C

c.T152C

M51T

c.152T>G

c.T152G

M51R

c.153G>A or c.153G>T or c.153G>C

c.G153A or c.G153T or c.G153C

M51I

c.157A>C

c.A157C

N53H

c.[157A>C; 158A>T]

c.A157C/A158T

N53L

c.157A>G

c.A157G

N53D

c.157A>T

c.A157T

N53Y

c.158A>C

c.A158C

N53T

c.158A>G

c.A158G

N53S

c.158A>T

c.A158T

N53I

c.159C>G or c.159C>A

c.C159G or c.C159A

N53K

c.160C>G

c.C160G

L54V

c.160C>T

c.C160T

L54F

c.161T>A

c.T161A

L54H

c.161T>C

c.T161C

L54P

c.161T>G

c.T161G

L54R

c.163G>C

c.G163C

D55H

c.163G>T

c.G163T

D55Y

c.164A>C

c.A164C

D55A

c.164A>G

c.A164G

D55G

c.164A>T

c.A164T

D55V

c.[164A>T; 170A>T]

c.A164T/A170T

D55V/Q57L

c.165C>G

c.C165G

D55E

c.167G>A

c.G167A

C56Y

c.167G>T

c.G167T

C56F

c.168C>G

c.C168G

C56W

c.170A>G

c.A170G

Q57R

c.170A>T

c.A170T

Q57L

c.172G>A

c.G172A

E58K

c.175G>A

c.G175A

E59K

c.175G>C

c.G175C

E59Q

c.176A>C

c.A176C

E59A

c.176A>G

c.A176G

E59G

c.176A>T

c.A176T

E59V

c.177G>C

c.G177C

E59D

c.178C>A

c.C178A

P60T

c.178C>G

c.C178G

P60A

c.178C>T

c.C178T

P60S

c.179C>A

c.C179A

P60Q

c.179C>G

c.C179G

P60R

c.179C>T

c.C179T

P60L

c.182A>T

c.A182T

D61V

c.183T>A

c.T183A

D61E

c.184_185insTAG

c.184_185insTAG

S62delinsLA

c.184T>C

c.T184C

S62P

c.184T>G

c.T184G

S62A

c.185C>A

c.C185A

S62Y

c.185C>G

c.C185G

S62C

c.185C>T

c.C185T

S62F

c.190A>C

c.A190C

I64L

c.190A>G

c.A190G

I64V

c.193A>G

c.A193G

S65G

c.193A>T

c.A193T

S65C

c.195T>A

c.T195A

S65R

c.196G>A

c.G196A

E66K

c.197A>G

c.A197G

E66G

c.197A>T

c.A197T

E66V

c.198G>C

c.G198C

E66D

c.199A>C

c.A199C

K67Q

c.199A>G

c.A199G

K67E

c.200A>C

c.A200C

K67T

c.200A>T

c.A200T

K67M

c.201G>C

c.G201C

K67N

c.202C>A

c.C202A

L68I

c.205T>A

c.T205A

F69I

c.206T>A

c.T206A

F69Y

c.207C>A or c.207C>G

c.C207A or c.C207G

F69L

c.208A>T

c.A208T

M70L

c.209T>A

c.T209A

M70K

c.209T>G

c.T209G

M70R

c.210G>C

c.G210C

M70I

c.211G>C

c.G211C

E71Q

c.212A>C

c.A212C

E71A

c.212A>G

c.A212G

E71G

c.212A>T

c.A212T

E71V

c.213G>C

c.G213C

E71D

c.214A>G

c.A214G

M72V

c.214A>T

c.A214T

M72L

c.215T>C

c.T215C

M72T

c.216G>A or c.216G>T or c.216G>C

c.G216A or c.G216T or c.G216C

M72I

c.217G>A

c.G217A

A73T

c.217G>T

c.G217T

A73S

c.218C>T

c.C218T

A73V

c.[218C>T; 525C>G]

c.C218T/C525G

A73V/D175E

c.220G>A

c.G220A

E74K

c.221A>G

c.A221G

E74G

c.221A>T

c.A221T

E74V

c.222G>C

c.G222C

E74D

c.223C>T

c.C223T

L75F

c.224T>C

c.T224C

L75P

c.226A>G

c.A226G

M76V

c.227T>C

c.T227C

M76T

c.229G>A

c.G229A

V77I

c.229G>C

c.G229C

V77L

c.232T>C

c.T232C

S78P

c.233C>T

c.C233T

S78L

c.235G>A

c.G235A

E79K

c.235G>C

c.G235C

E79Q

c.236A>C

c.A236C

E79A

c.236A>G

c.A236G

E79G

c.236A>T

c.A236T

E79V

c.237A>T

c.A237T

E79D

c.238G>A

c.G238A

G80S

c.238G>T

c.G238T

G80C

c.239G>A

c.G239A

G80D

c.239G>C

c.G239C

G80A

c.239G>T

c.G239T

G80V

c.242G>T

c.G242T

W81L

c.244A>G

c.A244G

K82E

c.245A>C

c.A245C

K82T

c.245A>G

c.A245G

K82R

c.245A>T

c.A245T

K82M

c.246G>C

c.G246C

K82N

c.247G>A

c.G247A

D83N

c.248A>C

c.A248C

D83A

c.248A>G

c.A248G

D83G

c.248A>T

c.A248T

D83V

c.249T>A

c.T249A

D83E

c.250G>A

c.G250A

A84T

c.250G>C

c.G250C

A84P

c.250G>T

c.G250T

A84S

c.251C>A

c.C251A

A84E

c.251C>G

c.C251G

A84G

c.251C>T

c.C251T

A84V

c.253G>A

c.G253A

G85S

c.[253G>A; 254G>A]

c.G253A/G254A

G85N

c.[253G>A; 254G>T; 255T>G]

c.G253A/G254T/T255G

G85M

c.253G>C

c.G253C

G85R

c.253G>T

c.G253T

G85C

c.254G>A

c.G254A

G85D

c.254G>C

c.G254C

G85A

c.257A>T

c.A257T

Y86F

c.260A>G

c.A260G

E87G

c.261G>C or c.261G>T

c.G261C or c.G261T

E87D

c.262T>A

c.T262A

Y88N

c.262T>C

c.T262C

Y88H

c.263A>C

c.A263C

Y88S

c.263A>G

c.A263G

Y88C

c.265C>G

c.C265G

L89V

c.265C>T

c.C265T

L89F

c.271A>C

c.A271C

I91L

c.271A>T

c.A271T

I91F

c.272T>C

c.T272C

I91T

c.272T>G

c.T272G

I91S

c.273T>G

c.T273G

I91M

c.286A>G

c.A286G

M96V

c.286A>T

c.A286T

M96L

c.287T>C

c.T287C

M96T

c.288G>A or c.288G>T or c.288G>C

c.G288A or c.G288T or c.G288C

M96I

c.289G>A

c.G289A

A97T

c.289G>C

c.G289C

A97P

c.289G>T

c.G289T

A97S

c.290C>A

c.C290A

A97D

c.290C>T

c.C290T

A97V

c.293C>A

c.C293A

P98H

c.293C>G

c.C293G

P98R

c.293C>T

c.C293T

P98L

c.295C>G

c.C295G

Q99E

c.296A>C

c.A296C

Q99P

c.296A>G

c.A296G

Q99R

c.296A>T

c.A296T

Q99L

c.301G>C

c.G301C

D101H

c.302A>C

c.A302C

D101A

c.302A>G

c.A302G

D101G

c.302A>T

c.A302T

D101V

c.303T>A

c.T303A

D101E

c.304T>A

c.T304A

S102T

c.304T>C

c.T304C

S102P

c.304T>G

c.T304G

S102A

c.305C>T

c.C305T

S102L

c.310G>A

c.G310A

G104S

c.311G>A

c.G311A

G104D

c.311G>C

c.G311C

G104A

c.311G>T

c.G311T

G104V

c.313A>G

c.A313G

R105G

c.314G>A

c.G314A

R105K

c.314G>C

c.G314C

R105T

c.314G>T

c.G314T

R105I

c.316C>A

c.C316A

L106I

c.316C>G

c.C316G

L106V

c.316C>T

c.C316T

L106F

c.317T>A

c.T317A

L106H

c.317T>C

c.T317C

L106P

c.319C>A

c.C319A

Q107K

c.319C>G

c.C319G

Q107E

c.320A>G

c.A320G

Q107R

c.321G>C

c.G321C

Q107H

c.322G>A

c.G322A

A108T

c.323C>A

c.C323A

A108E

c.323C>T

c.C323T

A108V

c.325G>A

c.G325A

D109N

c.325G>C

c.G325C

D109H

c.325G>T

c.G325T

D109Y

c.326A>C

c.A326C

D109A

c.326A>G

c.A326G

D109G

c.327C>G

c.C327G

D109E

c.328C>A

c.C328A

P110T

c.334C>G

c.C334G

R112G

c.335G>A

c.G335A

R112H

c.335G>T

c.G335T

R112L

c.337T>A

c.T337A

F113I

c.337T>C or c.339T>A or c.339T>G

c.T337C or c.T339A or c.T339G

F113L

c.337T>G

c.T337G

F113V

c.338T>A

c.T338A

F113Y

c.341C>T

c.C341T

P114L

c.343C>A

c.C343A

H115N

c.343C>G

c.C343G

H115D

c.346G>C

c.G346C

G116R

c.350T>C

c.T350C

I117T

c.351T>G

c.T351G

I117M

c.352C>T

c.C352T

R118C

c.361G>A

c.G361A

A121T

c.362C>T

c.C362T

A121V

c.367T>A

c.T367A

Y123N

c.367T>G

c.T367G

Y123D

c.368A>C

c.A368C

Y123S

c.368A>G

c.A368G

Y123C

c.368A>T

c.A368T

Y123F

c.370G>A

c.G370A

V124I

c.371T>G

c.T371G

V124G

c.373C>A

c.C373A

H125N

c.373C>G

c.C373G

H125D

c.373C>T

c.C373T

H125Y

c.374A>G

c.A374G

H125R

c.374A>T

c.A374T

H125L

c.376A>G

c.A376G

S126G

c.376A>T

c.A376T

S126C

c.377G>T

c.G377T

S126I

c.379A>G

c.A379G

K127E

c.383G>A

c.G383A

G128E

c.383G>C

c.G383C

G128A

c.385C>G

c.C385G

L129V

c.388A>C

c.A388C

K130Q

c.389A>T

c.A389T

K130M

c.390G>C

c.G390C

K130N

c.391C>G

c.C391G

L131V

c.397A>C

c.A397C

I133L

c.397A>G

c.A397G

I133V

c.397A>T

c.A397T

I133F

c.398T>C

c.T398C

I133T

c.399T>G

c.T399G

I133M

c.[399T>G; 434T>C]

c.T399G/T434C

I133M/F145S

c.403G>A

c.G403A

A135T

c.403G>T

c.G403T

A135S

c.404C>A

c.C404A

A135E

c.404C>G

c.C404G

A135G

c.404C>T

c.C404T

A135V

c.406G>A

c.G406A

D136N

c.407A>C

c.A407C

D136A

c.407A>T

c.A407T

D136V

c.408T>A or c.408T>G

c.T408A or c.T408G

D136E

c.409G>A

c.G409A

V137I

c.409G>C

c.G409C

V137L

c.410T>A

c.T410A

V137D

c.410T>C

c.T410C

V137A

c.410T>G

c.T410G

V137G

c.413G>C

c.G413C

G138A

c.415A>C

c.A415C

N139H

c.415A>T

c.A415T

N139Y

c.416A>G

c.A416G

N139S

c.416A>T

c.A416T

N139I

c.417T>A

c.T417A

N139K

c.418A>C

c.A418C

K140Q

c.418A>G

c.A418G

K140E

c.419A>C

c.A419C

K140T

c.419A>G

c.A419G

K140R

c.419A>T

c.A419T

K140I

c.420A>T

c.A420T

K140N

c.421A>T

c.A421T

T141S

c.427G>A

c.G427A

A143T

c.428C>A

c.C428A

A143E

c.428C>G

c.C428G

A143G

c.428C>T

c.C428T

A143V

c.430G>A

c.G430A

G144S

c.430G>C

c.G430C

G144R

c.430G>T

c.G430T

G144C

c.431G>A

c.G431A

G144D

c.431G>C

c.G431C

G144A

c.431G>T

c.G431T

G144V

c.433T>G

c.T433G

F145V

c.434T>A

c.T434A

F145Y

c.434T>C

c.T434C

F145S

c.434T>G

c.T434G

F145C

c.435C>G

c.C435G

F145L

c.436C>A

c.C436A

P146T

c.436C>G

c.C436G

P146A

c.436C>T

c.C436T

P146S

c.437C>A

c.C437A

P146H

c.437C>G

c.C437G

P146R

c.437C>T

c.C437T

P146L

c.440G>C

c.G440C

G147A

c.442A>G

c.A442G

S148G

c.442A>T

c.A442T

S148C

c.443G>C

c.G443C

S148T

c.446T>G

c.T446G

F149C

c.449G>A

c.G449A

G150E

c.449G>T

c.G449T

G150V

c.451T>G

c.T451G

Y151D

c.452A>C

c.A452C

Y151S

c.452A>G

c.A452G

Y151C

c.454T>A

c.T454A

Y152N

c.454T>C

c.T454C

Y152H

c.454T>G

c.T454G

Y152D

c.455A>C

c.A455C

Y152S

c.455A>G

c.A455G

Y152C

c.455A>T

c.A455T

Y152F

c.457G>A

c.G457A

D153N

c.457G>C

c.G457C

D153H

c.457G>T

c.G457T

D153Y

c.458A>C

c.A458C

D153A

c.458A>T

c.A458T

D153V

c.465T>A or c.465T>G

c.T465A or c.T465G

D155E

c.466G>A

c.G466A

A156T

c.466G>T

c.G466T

A156S

c.467C>G

c.C467G

A156G

c.467C>T

c.C467T

A156V

c.469C>A

c.C469A

Q157K

c.469C>G

c.C469G

Q157E

c.470A>C

c.A470C

Q157P

c.470A>T

c.A470T

Q157L

c.471G>C or c.471G>T

c.G471C or c.G471T

Q157H

c.472A>G

c.A472G

T158A

c.472A>T

c.A472T

T158S

c.473C>A

c.C473A

T158N

c.473C>T

c.C473T

T158I

c.475T>A

c.T475A

F159I

c.475T>G

c.T475G

F159V

c.476T>A

c.T476A

F159Y

c.476T>G

c.T476G

F159C

c.477T>A

c.T477A

F159L

c.478G>A

c.G478A

A160T

c.478G>T

c.G478T

A160S

c.479C>A

c.C479A

A160D

c.479C>G

c.C479G

A160G

c.479C>T

c.C479T

A160V

c.481G>A

c.G481A

D161N

c.481G>C

c.G481C

D161H

c.481G>T

c.G481T

D161Y

c.482A>T

c.A482T

D161V

c.484T>G

c.T484G

W162G

c.485G>C

c.G485C

W162S

c.490G>A

c.G490A

V164I

c.490G>T

c.G490T

V164L

c.491T>C

c.T491C

V164A

c.493G>A

c.G493A

D165N

c.493G>C

c.G493C

D165H

c.494A>C

c.A494C

D165A

c.494A>G

c.A494G

D165G

c.495T>A

c.T495A

D165E

c.496_497delinsTC

c.496_497delinsTC

L166S

c.496C>A

c.C496A

L166M

c.496C>G

c.C496G

L166V

c.[496C>G; 497T>G]

c.C496G/T497G

L166G

c.497T>A

c.T497A

L166Q

c.499C>A

c.C499A

L167I

c.499C>G

c.C499G

L167V

c.505T>A

c.T505A

F169I

c.505T>G

c.T505G

F169V

c.506T>A

c.T506A

F169Y

c.506T>C

c.T506C

F169S

c.506T>G

c.T506G

F169C

c.507T>A

c.T507A

F169L

c.511G>A

c.G511A

G171S

c.512G>C

c.G512C

G171A

c.512G>T

c.G512T

G171V

c.517T>C

c.T517C

Y173H

c.518A>C

c.A518C

Y173S

c.518A>G

c.A518G

Y173C

c.518A>T

c.A518T

Y173F

c.520T>C

c.T520C

C174R

c.520T>G

c.T520G

C174G

c.523G>C

c.G523C

D175H

c.523G>T

c.G523T

D175Y

c.524A>G

c.A524G

D175G

c.524A>T

c.A524T

D175V

c.525C>G or c.525C>A

c.C525G or c.C525A

D175E

c.526A>T

c.A526T

S176C

c.528T>A

c.T528A

S176R

c.529T>A

c.T529A

L177M

c.529T>G

c.T529G

L177V

c.530T>C

c.T530C

L177S

c.530T>G

c.T530G

L177W

c.531G>C

c.G531C

L177F

c.532G>A

c.G532A

E178K

c.532G>C

c.G532C

E178Q

c.533A>C

c.A533C

E178A

c.533A>G

c.A533G

E178G

c.538T>A

c.T538A

L180M

c.538T>G

c.T538G

L180V

c.539T>C

c.T539C

L180S

c.539T>G

c.T539G

L180W

c.540G>C or c.540G>T

c.G540C or c.G540T

L180F

c.541G>A

c.G541A

A181T

c.541G>C

c.G541C

A181P

c.542C>T

c.C542T

A181V

c.544G>T

c.G544T

D182Y

c.545A>C

c.A545C

D182A

c.545A>G

c.A545G

D182G

c.545A>T

c.A545T

D182V

c.546T>A

c.T546A

D182E

c.548G>A

c.G548A

G183D

c.548G>C

c.G548C

G183A

c.550T>A

c.T550A

Y184N

c.550T>C

c.T550C

Y184H

c.551A>C

c.A551C

Y184S

c.551A>G

c.A551G

Y184C

c.551A>T

c.A551T

Y184F

c.553A>C

c.A553C

K185Q

c.553A>G

c.A553G

K185E

c.554A>C

c.A554C

K185T

c.554A>T

c.A554T

K185M

c.555G>C

c.G555C

K185N

c.556C>A

c.C556A

H186N

c.556C>G

c.C556G

H186D

c.556C>T

c.C556T

H186Y

c.557A>T

c.A557T

H186L

c.558C>G

c.C558G

H186Q

c.559_564dup

c.559_564dup

p.M187_S188dup

c.559A>T

c.A559T

M187L

c.559A>G

c.A559G

M187V

c.560T>C

c.T560C

M187T

c.561G>T or c.561G>A or c.561G>C

c.G561T or c.G561A or c.G561C

M187I

c.562T>A

c.T562A

S188T

c.562T>C

c.T562C

S188P

c.562T>G

c.T562G

S188A

c.563C>A

c.C563A

S188Y

c.563C>G

c.C563G

S188C

c.563C>T

c.C563T

S188F

c.565T>G

c.T565G

L189V

c.566T>C

c.T566C

L189S

c.567G>C or c.567G>T

c.G567C or c.G567T

L189F

c.568G>A

c.G568A

A190T

c.568G>T

c.G568T

A190S

c.569C>A

c.C569A

A190D

c.569C>G

c.C569G

A190G

c.569C>T

c.C569T

A190V

c.571C>A

c.C571A

L191M

c.571C>G

c.C571G

L191V

c.572T>A

c.T572A

L191Q

c.574A>C

c.A574C

N192H

c.574A>G

c.A574G

N192D

c.575A>C

c.A575C

N192T

c.575A>G

c.A575G

N192S

c.576T>A

c.T576A

N192K

c.577A>G

c.A577G

R193G

c.577A>T

c.A577T

R193W

c.578G>C

c.G578C

R193T

c.578G>T

c.G578T

R193M

c.580A>C

c.A580C

T194P

c.580A>G

c.A580G

T194A

c.580A>T or c.581C>G

c.A580T or c.C581G

T194S

c.581C>A

c.C581A

T194N

c.581C>T

c.C581T

T194I

c.583G>A

c.G583A

G195S

c.583G>C

c.G583C

G195R

c.583G>T

c.G583T

G195C

c.584G>T

c.G584T

G195V

c.586A>G

c.A586G

R196G

c.587G>A

c.G587A

R196K

c.587G>C

c.G587C

R196T

c.587G>T

c.G587T

R196I

c.589A>G

c.A589G

S197G

c.589A>T

c.A589T

S197C

c.590G>A

c.G590A

S197N

c.590G>C

c.G590C

S197T

c.590G>T

c.G590T

S197I

c.593T>C

c.T593C

I198T

c.593T>G

c.T593G

I198S

c.594T>G

c.T594G

I198M

c.595G>A

c.G595A

V199M

c.595G>C

c.G595C

V199L

c.596T>A

c.T596A

V199E

c.596T>C

c.T596C

V199A

c.596T>G

c.T596G

V199G

c.598T>A

c.T598A

Y200N

c.599A>C

c.A599C

Y200S

c.599A>G

c.A599G

Y200C

c.601T>A

c.T601A

S201T

c.601T>G

c.T601G

S201A

c.602C>A

c.C602A

S201Y

c.602C>G

c.C602G

S201C

c.602C>T

c.C602T

S201F

c.607G>C

c.G607C

E203Q

c.608A>C

c.A608C

E203A

c.608A>G

c.A608G

E203G

c.608A>T

c.A608T

E203V

c.609G>C or c.609G>T

c.G609C or c.G609T

E203D

c.610T>G

c.T610G

W204G

c.611G>C

c.G611C

W204S

c.611G>T

c.G611T

W204L

c.613C>A

c.C613A

P205T

c.613C>T

c.C613T

P205S

c.614C>T

c.C614T

P205L

c.616C>A

c.C616A

L206I

c.616C>G

c.C616G

L206V

c.616C>T

c.C616T

L206F

c.617T>A

c.T617A

L206H

c.617T>G

c.T617G

L206R

c.619T>C

c.T619C

Y207H

c.620A>C

c.A620C

Y207S

c.620A>T

c.A620T

Y207F

c.623T>A

c.T623A

M208K

c.623T>G

c.T623G

M208R

c.625T>A

c.T625A

W209R

c.625T>G

c.T625G

W209G

c.627G>C

c.G627C

W209C

c.628C>A

c.C628A

P210T

c.628C>T

c.C628T

P210S

c.629C>A

c.C629A

P210H

c.629C>T

c.C629T

P210L

c.631T>C

c.T631C

F211L

c.631T>G

c.T631G

F211V

c.632T>A

c.T632A

F211Y

c.632T>C

c.T632C

F211S

c.632T>G

c.T632G

F211C

c.635A>C

c.A635C

Q212P

c.636A>T

c.A636T

Q212H

c.637A>C

c.A637C

K213Q

c.637A>G

c.A637G

K213E

c.638A>G

c.A638G

K213R

c.638A>T

c.A638T

K213M

c.640C>A

c.C640A

P214T

c.640C>G

c.C640G

P214A

c.640C>T

c.C640T

P214S

c.641C>A

c.C641A

P214H

c.641C>G

c.C641G

P214R

c.641C>T

c.C641T

P214L

c.643A>C

c.A643C

N215H

c.643A>G

c.A643G

N215D

c.643A>T

c.A643T

N215Y

c.644A>C

c.A644C

N215T

c.644A>G

c.A644G

N215S

c.[644A>G; 937G>T]

c.A644G/G937T

N215S/D313Y

c.644A>T

c.A644T

N215I

c.645T>A

c.T645A

N215K

c.646T>A

c.T646A

Y216N

c.646T>C

c.T646C

Y216H

c.646T>G

c.T646G

Y216D

c.647A>C

c.A647C

Y216S

c.647A>G

c.A647G

Y216C

c.647A>T

c.A647T

Y216F

c.649A>C

c.A649C

T217P

c.649A>G

c.A649G

T217A

c.649A>T

c.A649T

T217S

c.650C>A

c.C650A

T217K

c.650C>G

c.C650G

T217R

c.650C>T

c.C650T

T217I

c.652G>A

c.G652A

E218K

c.652G>C

c.G652C

E218Q

c.653A>C

c.A653C

E218A

c.653A>G

c.A653G

E218G

c.653A>T

c.A653T

E218V

c.654A>T

c.A654T

E218D

c.655A>C

c.A655C

I219L

c.655A>T

c.A655T

I219F

c.656T>A

c.T656A

I219N

c.656T>C

c.T656C

I219T

c.656T>G

c.T656G

I219S

c.657C>G

c.C657G

I219M

c.659G>A

c.G659A

R220Q

c.659G>C

c.G659C

R220P

c.659G>T

c.G659T

R220L

c.661C>A

c.C661A

Q221K

c.661C>G

c.C661G

Q221E

c.662A>C

c.A662C

Q221P

c.662A>G

c.A662G

Q221R

c.662A>T

c.A662T

Q221L

c.663G>C

c.G663C

Q221H

c.664T>A

c.T664A

Y222N

c.664T>C

c.T664C

Y222H

c.664T>G

c.T664G

Y222D

c.665A>C

c.A665C

Y222S

c.665A>G

c.A665G

Y222C

c.670A>C

c.A670C

N224H

c.671A>C

c.A671C

N224T

c.671A>G

c.A671G

N224S

c.673C>G

c.C673G

H225D

c.679C>G

c.C679G

R227G

c.682A>C

c.A682C

N228H

c.682A>G

c.A682G

N228D

c.683A>C

c.A683C

N228T

c.683A>G

c.A683G

N228S

c.683A>T

c.A683T

N228I

c.685T>A

c.T685A

F229I

c.686T>A

c.T686A

F229Y

c.686T>C

c.T686C

F229S

c.687T>A or c.687T>G

c.T687A or c.T687G

F229L

c.688G>C

c.G688C

A230P

c.689C>A

c.C689A

A230D

c.689C>G

c.C689G

A230G

c.689C>T

c.C689T

A230V

c.694A>C

c.A694C

I232L

c.694A>G

c.A694G

I232V

c.695T>C

c.T695C

I232T

c.696T>G

c.T696G

I232M

c.698A>C

c.A698C

D233A

c.698A>G

c.A698G

D233G

c.698A>T

c.A698T

D233V

c.699T>A

c.T699A

D233E

c.703T>A

c.T703A

S235T

c.703T>G

c.T703G

S235A

c.710A>T

c.A710T

K237I

c.712A>G

c.A712G

S238G

c.712A>T

c.A712T

S238C

c.713G>A

c.G713A

S238N

c.713G>C

c.G713C

S238T

c.713G>T

c.G713T

S238I

c.715A>T

c.A715T

I239L

c.716T>C

c.T716C

I239T

c.717A>G

c.A717G

I239M

c.718A>G

c.A718G

K240E

c.719A>G

c.A719G

K240R

c.719A>T

c.A719T

K240M

c.720G>C or c.720G>T

c.G720C or c.G720T

K240N

c.721A>T

c.A721T

S241C

c.722G>C

c.G722C

S241T

c.722G>T

c.G722T

S241I

c.724A>C

c.A724C

I242L

c.724A>G

c.A724G

I242V

c.724A>T

c.A724T

I242F

c.725T>A

c.T725A

I242N

c.725T>C

c.T725C

I242T

c.725T>G

c.T725G

I242S

c.726C>G

c.C726G

I242M

c.727T>A

c.T727A

L243M

c.727T>G

c.T727G

L243V

c.728T>C

c.T728C

L243S

c.728T>G

c.T728G

L243W

c.729G>C or c.729G>T

c.G729C or c.G729T

L243F

c.730G>A

c.G730A

D244N

c.730G>C

c.G730C

D244H

c.730G>T

c.G730T

D244Y

c.731A>C

c.A731C

D244A

c.731A>G

c.A731G

D244G

c.731A>T

c.A731T

D244V

c.732C>G

c.C732G

D244E

c.733T>G

c.T733G

W245G

c.735G>C

c.G735C

W245C

c.736A>G

c.A736G

T246A

c.737C>A

c.C737A

T246K

c.737C>G

c.C737G

T246R

c.737C>T

c.C737T

T246I

c.739T>A

c.T739A

S247T

c.739T>G

c.T739G

S247A

c.740C>A

c.C740A

S247Y

c.740C>G

c.C740G

S247C

c.740C>T

c.C740T

S247F

c.742T>G

c.T742G

F248V

c.743T>A

c.T743A

F248Y

c.743T>G

c.T743G

F248C

c.744T>A

c.T744A

F248L

c.745A>C

c.A745C

N249H

c.745A>G

c.A745G

N249D

c.745A>T

c.A745T

N249Y

c.746A>C

c.A746C

N249T

c.746A>G

c.A746G

N249S

c.746A>T

c.A746T

N249I

c.747C>G or c.747C>A

c.C747G or c.C747A

N249K

c.748C>A

c.C748A

Q250K

c.748C>G

c.C748G

Q250E

c.749A>C

c.A749C

Q250P

c.749A>G

c.A749G

Q250R

c.749A>T

c.A749T

Q250L

c.750G>C

c.G750C

Q250H

c.751G>A

c.G751A

E251K

c.751G>C

c.G751C

E251Q

c.752A>G

c.A752G

E251G

c.752A>T

c.A752T

E251V

c.754A>G

c.A754G

R252G

c.757A>G

c.A757G

I253V

c.757A>T

c.A757T

I253F

c.758T>A

c.T758A

I253N

c.758T>C

c.T758C

I253T

c.758T>G

c.T758G

I253S

c.760-762delGTT or c.761-763del

c.760_762delGTT or c.761_763del

p.V254del

c.760G>T

c.G760T

V254F

c.761T>A

c.T761A

V254D

c.761T>C

c.T761C

V254A

c.761T>G

c.T761G

V254G

c.763G>A

c.G763A

D255N

c.763G>C

c.G763C

D255H

c.763G>T

c.G763T

D255Y

c.764A>C

c.A764C

D255A

c.764A>T

c.A764T

D255V

c.765T>A

c.T765A

D255E

c.766G>C

c.G766C

V256L

c.767T>A

c.T767A

V256D

c.767T>G

c.T767G

V256G

c.769G>A

c.G769A

A257T

c.769G>C

c.G769C

A257P

c.769G>T

c.G769T

A257S

c.770C>G

c.C770G

A257G

c.770C>T

c.C770T

A257V

c.772G>C or c.772G>A

c.G772C or c.G772A

G258R

c.773G>A

c.G773A

G258E

c.773G>T

c.G773T

G258V

c.775C>A

c.C775A

P259T

c.775C>G

c.C775G

P259A

c.775C>T

c.C775T

P259S

c.776C>A

c.C776A

P259Q

c.776C>G

c.C776G

P259R

c.776C>T

c.C776T

P259L

c.778G>T

c.G778T

G260W

c.779G>A

c.G779A

G260E

c.779G>C

c.G779C

G260A

c.781G>A

c.G781A

G261S

c.781G>C

c.G781C

G261R

c.781G>T

c.G781T

G261C

c.782G>C

c.G782C

G261A

c.787A>C

c.A787C

N263H

c.788A>C

c.A788C

N263T

c.788A>G

c.A788G

N263S

c.790G>A

c.G790A

D264N

c.790G>C

c.G790C

D264H

c.790G>T

c.G790T

D264Y

c.793C>G

c.C793G

P265A

c.794C>A

c.C794A

P265Q

c.794C>T

c.C794T

P265L

c.799A>G

c.A799G

M267V

c.799A>T

c.A799T

M267L

c.800T>C

c.T800C

M267T

c.802T>A

c.T802A

L268I

c.804A>T

c.A804T

L268F

c.805G>A

c.G805A

V269M

c.805G>C

c.G805C

V269L

c.806T>C

c.T806C

V269A

c.808A>C

c.A808C

I270L

c.808A>G

c.A808G

I270V

c.809T>C

c.T809C

I270T

c.809T>G

c.T809G

I270S

c.810T>G

c.T810G

I270M

c.811G>A

c.G811A

G271S

c.[811G>A; 937G>T]

c.G811A/G937T

G271S/D313Y

c.812G>A

c.G812A

G271D

c.812G>C

c.G812C

G271A

c.814A>G

c.A814G

N272D

c.818T>A

c.T818A

F273Y

c.823C>A

c.C823A

L275I

c.823C>G

c.C823G

L275V

c.827G>A

c.G827A

S276N

c.827G>C

c.G827C

S276T

c.829T>G

c.T829G

W277G

c.830G>T

c.G830T

W277L

c.831G>T or c.831G>C

c.G831T or c.G831C

W277C

c.832A>T

c.A832T

N278Y

c.833A>T

c.A833T

N278I

c.835C>G

c.C835G

Q279E

c.838C>A

c.C838A

Q280K

c.839A>G

c.A839G

Q280R

c.839A>T

c.A839T

Q280L

c.840A>T or c.840A>C

c.A840T or c.A840C

Q280H

c.841G>C

c.G841C

V281L

c.842T>A

c.T842A

V281E

c.842T>C

c.T842C

V281A

c.842T>G

c.T842G

V281G

c.844A>G

c.A844G

T282A

c.844A>T

c.A844T

T282S

c.845C>T

c.C845T

T282I

c.847C>G

c.C847G

Q283E

c.848A>T

c.A848T

Q283L

c.849G>C

c.G849C

Q283H

c.850A>G

c.A850G

M284V

c.850A>T

c.A850T

M284L

c.851T>C

c.T851C

M284T

c.852G>C

c.G852C

M284I

c.853G>A

c.G853A

A285T

c.854C>G

c.C854G

A285G

c.854C>T

c.C854T

A285V

c.856C>G

c.C856G

L286V

c.856C>T

c.C856T

L286F

c.857T>A

c.T857A

L286H

c.860G>T

c.G860T

W287L

c.862G>C

c.G862C

A288P

c.862G>T

c.G862T

A288S

c.863C>G

c.C863G

A288G

c.863C>T

c.C863T

A288V

c.865A>C

c.A865C

I289L

c.865A>G

c.A865G

I289V

c.866T>C

c.T866C

I289T

c.866T>G

c.T866G

I289S

c.868A>C or c.868A>T

c.A868C or c.A868T

M290L

c.868A>G

c.A868G

M290V

c.869T>C

c.T869C

M290T

c.870G>A or c.870G>C or c.870G>T

c.G870A or c.G870C or c.G870T

M290I

c.871G>A

c.G871A

A291T

c.871G>T

c.G871T

A291S

c.872C>G

c.C872G

A291G

c.874G>T

c.G874T

A292S

c.875C>G

c.C875G

A292G

c.877C>A

c.C877A

P293T

c.880T>A

c.T880A

L294I

c.880T>G

c.T880G

L294V

c.881T>C

c.T881C

L294S

c.882A>T

c.A882T

L294F

c.883T>A

c.T883A

F295I

c.883T>G

c.T883G

F295V

c.884T>A

c.T884A

F295Y

c.884T>C

c.T884C

F295S

c.884T>G

c.T884G

F295C

c.886A>G

c.A886G

M296V

c.886A>T or c.886A>C

c.A886T or c.A886C

M296L

c.887T>C

c.T887C

M296T

c.888G>A or c.888G>T or c.888G>C

c.G888A or c.G888T or c.G888C

M296I

c.889T>A

c.T889A

S297T

c.892A>G

c.A892G

N298D

c.893A>C

c.A893C

N298T

c.893A>G

c.A893G

N298S

c.893A>T

c.A893T

N298I

c.895G>A

c.G895A

D299N

c.895G>C

c.G895C

D299H

c.897C>G or c.897C>A

c.C897G or c.C897A

D299E

c.898C>A

c.C898A

L300I

c.898C>G

c.C898G

L300V

c.898C>T

c.C898T

L300F

c.899T>C

c.T899C

L300P

c.901C>G

c.C901G

R301G

c.902G>A

c.G902A

R301Q

c.902G>C

c.G902C

R301P

c.902G>T

c.G902T

R301L

c.904C>A

c.C904A

H302N

c.904C>G

c.C904G

H302D

c.904C>T

c.C904T

H302Y

c.905A>T

c.A905T

H302L

c.907A>G

c.A907G

I303V

c.907A>T

c.A907T

I303F

c.908T>A

c.T908A

I303N

c.908T>C

c.T908C

I303T

c.908T>G

c.T908G

I303S

c.911G>A

c.G911A

S304N

c.911G>C

c.G911C

S304T

c.911G>T

c.G911T

S304I

c.916C>G

c.C916G

Q306E

c.917A>C

c.A917C

Q306P

c.917A>T

c.A917T

Q306L

c.919G>A

c.G919A

A307T

c.919G>C

c.G919C

A307P

c.919G>T

c.G919T

A307S

c.920C>A

c.C920A

A307D

c.920C>G

c.C920G

A307G

c.920C>T

c.C920T

A307V

c.922A>C

c.A922C

K308Q

c.922A>G

c.A922G

K308E

c.923A>G

c.A923G

K308R

c.923A>T

c.A923T

K308I

c.924A>T or c.924A>C

c.A924T or c.A924C

K308N

c.925G>A

c.G925A

A309T

c.925G>C

c.G925C

A309P

c.926C>A

c.C926A

A309D

c.926C>T

c.C926T

A309V

c.928C>A

c.C928A

L310I

c.928C>G

c.C928G

L310V

c.928C>T

c.C928T

L310F

c.931C>A

c.C931A

L311I

c.931C>G

c.C931G

L311V

c.934C>A

c.C934A

Q312K

c.934C>G

c.C934G

Q312E

c.935A>G

c.A935G

Q312R

c.935A>T

c.A935T

Q312L

c.936G>T or c.936G>C

c.G936T or c.G936C

Q312H

c.937G>T

c.G937T

D313Y

c.[937G>T; 1232G>A]

c.G937T/G1232A

D313Y/G411D

c.938A>G

c.A938G

D313G

c.938A>T

c.A938T

D313V

c.939T>A

c.T939A

D313E

c.940A>G

c.A940G

K314E

c.941A>C

c.A941C

K314T

c.941A>T

c.A941T

K314M

c.942G>C

c.G942C

K314N

c.943G>A

c.G943A

D315N

c.943G>C

c.G943C

D315H

c.943G>T

c.G943T

D315Y

c.944A>C

c.A944C

D315A

c.944A>G

c.A944G

D315G

c.944A>T

c.A944T

D315V

c.946G>A

c.G946A

V316I

c.946G>C

c.G946C

V316L

c.947T>C

c.T947C

V316A

c.947T>G

c.T947G

V316G

c.949A>C

c.A949C

I317L

c.949A>G

c.A949G

I317V

c.950T>C

c.T950C

I317T

c.951T>G

c.T951G

I317M

c.952G>A

c.G952A

A318T

c.952G>C

c.G952C

A318P

c.953C>A

c.C953A

A318D

c.953C>T

c.C953T

A318V

c.955A>T

c.A955T

I319F

c.956T>C

c.T956C

I319T

c.957C>G

c.C957G

I319M

c.958A>C

c.A958C

N320H

c.959A>C

c.A959C

N320T

c.959A>G

c.A959G

N320S

c.959A>T

c.A959T

N320I

c.961C>A

c.C961A

Q321K

c.962A>G

c.A962G

Q321R

c.962A>T

c.A962T

Q321L

c.963G>C or c.963G>T

c.G963C or c.G963T

Q321H

c.964G>A

c.G964A

D322N

c.964G>C

c.G964C

D322H

c.965A>C

c.A965C

D322A

c.965A>T

c.A965T

D322V

c.966C>A or c.966C>G

c.C966A or c.C966G

D322E

c.967C>A

c.C967A

P323T

c.968C>G

c.C968G

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c.970T>G

c.T970G

L324V

c.971T>G

c.T971G

L324W

c.973G>A

c.G973A

G325S

c.973G>C

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c.973G>T

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c.976A>C

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c.976A>G

c.A976G

K326E

c.977A>C

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c.977A>G

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c.977A>T

c.A977T

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c.978G>C or c.978G>T

c.G978C or c.G978T

K326N

c.979C>G

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Q327E

c.980A>C

c.A980C

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c.980A>T

c.A980T

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c.981A>T

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c.985T>A

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c.986A>G

c.A986G

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c.986A>T

c.A986T

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c.988C>A

c.C988A

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c.988C>G

c.C988G

Q330E

c.989A>C

c.A989C

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c.989A>G

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c.990G>C

c.G990C

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c.991C>G

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L331V

c.992T>A

c.T992A

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c.992T>C

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c.994A>G

c.A994G

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c.995G>C

c.G995C

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c.G995T

R332I

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c.A996T

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c.997C>G

c.C997G

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c.998A>C

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c.1000G>C

c.G1000C

G334R

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c.G1001T

G334V

c.1003G>T

c.G1003T

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c.1004A>C

c.A1004C

D335A

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c.A1004G

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c.1004A>T

c.A1004T

D335V

c.1005C>G

c.C1005G

D335E

c.1006A>G

c.A1006G

N336D

c.1006A>T

c.A1006T

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c.1007A>C

c.A1007C

N336T

c.1007A>G

c.A1007G

N336S

c.1007A>T

c.A1007T

N336I

c.1009T>G

c.T1009G

F337V

c.1010T>A

c.T1010A

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c.1010T>C

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F337L

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c.G1012A

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c.1013A>C

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c.1014A>T

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c.1015G>A

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V339M

c.1016T>A

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c.1016T>C

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c.1021G>C

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c.1027C>A

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c.1028C>T

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c.1030C>G

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c.1030C>T

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c.1033T>C

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c.1036G>T

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c.1037G>A

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c.1037G>T

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G346V

c.1039T>A

c.T1039A

L347I

c.1043C>A

c.C1043A

A348D

c.1046G>C

c.G1046C

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c.1046G>T

c.G1046T

W349L

c.1047G>C

c.G1047C

W349C

c.1048G>A

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c.G1048T

A350S

c.1049C>G

c.C1049G

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c.C1049T

A350V

c.1052T>A

c.T1052A

V351E

c.1052T>C

c.T1052C

V351A

c.1054G>A

c.G1054A

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A352S

c.1055C>G

c.C1055G

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c.1055C>T

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A352V

c.1057A>T

c.A1057T

M353L

c.1058T>A

c.T1058A

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c.1061T>A

c.T1061A

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c.1061T>G

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c.1063A>C

c.A1063C

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c.1063A>G

c.A1063G

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c.1063A>T

c.A1063T

N355Y

c.1064A>G

c.A1064G

N355S

c.1066C>G

c.C1066G

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c.1066C>T

c.C1066T

R356W

c.1067G>A

c.G1067A

R356Q

c.1067G>C

c.G1067C

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c.1067G>T

c.G1067T

R356L

c.1069C>G

c.C1069G

Q357E

c.1072G>C

c.G1072C

E358Q

c.1073A>C

c.A1073C

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c.1073A>G

c.A1073G

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c.1074G>T or c.1074G>C

c.G1074T or c.G1074C

E358D

c.1075A>C

c.A1075C

I359L

c.1075A>G

c.A1075G

I359V

c.1075A>T

c.A1075T

I359F

c.1076T>A

c.T1076A

I359N

c.1076T>C

c.T1076C

I359T

c.1076T>G

c.T1076G

I359S

c.1078G>A

c.G1078A

G360S

c.1078G>C

c.G1078C

G360R

c.1078G>T

c.G1078T

G360C

c.1079G>A

c.G1079A

G360D

c.1079G>C

c.G1079C

G360A

c.1082G>A

c.G1082A

G361E

c.1082G>C

c.G1082C

G361A

c.1084C>A

c.C1084A

P362T

c.1084C>G

c.C1084G

P362A

c.1084C>T

c.C1084T

P362S

c.1085C>A

c.C1085A

P362H

c.1085C>G

c.C1085G

P362R

c.1085C>T

c.C1085T

P362L

c.1087C>A

c.C1087A

R363S

c.1087C>G

c.C1087G

R363G

c.1087C>T

c.C1087T

R363C

c.1088G>A

c.G1088A

R363H

c.1088G>T

c.G1088T

R363L

c.1090T>C

c.T1090C

S364P

c.1091C>G

c.C1091G

S364C

c.1093T>A

c.T1093A

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c.1093T>G

c.T1093G

Y365D

c.1094A>C

c.A1094C

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c.1094A>T

c.A1094T

Y365F

c.1096A>C

c.A1096C

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c.1096A>T

c.A1096T

T366S

c.1097C>A

c.C1097A

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c.1097C>T

c.C1097T

T366I

c.1099A>C

c.A1099C

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c.1099A>T

c.A1099T

I367F

c.1101C>G

c.C1101G

I367M

c.1102G>A

c.G1102A

A368T

c.1102G>C

c.G1102C

A368P

c.1103C>G

c.C1103G

A368G

c.1105G>A

c.G1105A

V369I

c.1105G>C

c.G1105C

V369L

c.1105G>T

c.G1105T

V369F

c.1106T>C

c.T1106C

V369A

c.1106T>G

c.T1106G

V369G

c.1108G>A

c.G1108A

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c.1108G>C

c.G1108C

A370P

c.1109C>A

c.C1109A

A370D

c.1109C>G

c.C1109G

A370G

c.1109C>T

c.C1109T

A370V

c.1111T>A

c.T1111A

S371T

c.1112C>G

c.C1112G

S371C

c.1117G>A

c.G1117A

G373S

c.1117G>T

c.G1117T

G373C

c.1118G>C

c.G1118C

G373A

c.1120A>G

c.A1120G

K374E

c.1121A>C

c.A1121C

K374T

c.1121A>G

c.A1121G

K374R

c.1121A>T

c.A1121T

K374I

c.1123G>C

c.G1123C

G375R

c.1124G>A

c.G1124A

G375E

c.1124G>C

c.G1124C

G375A

c.1126G>A

c.G1126A

V376M

c.1126G>C

c.G1126C

V376L

c.1127T>A

c.T1127A

V376E

c.1127T>G

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c.1129G>A

c.G1129A

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c.1129G>C

c.G1129C

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c.1129G>T

c.G1129T

A377S

c.1130C>G

c.C1130G

A377G

c.1135A>G

c.A1135G

N379D

c.1136A>C

c.A1136C

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c.1136A>T

c.A1136T

N379I

c.1137T>A

c.T1137A

N379K

c.1138C>A

c.C1138A

P380T

c.1138C>G

c.C1138G

P380A

c.1139C>A

c.C1139A

P380H

c.1139C>G

c.C1139G

P380R

c.1139C>T

c.C1139T

P380L

c.1142C>A

c.C1142A

A381D

c.1147T>A

c.T1147A

F383I

c.1148T>A

c.T1148A

F383Y

c.1148T>G

c.T1148G

F383C

c.1150A>T

c.A1150T

I384F

c.1151T>C

c.T1151C

I384T

c.1152C>G

c.C1152G

I384M

c.1153A>G

c.A1153G

T385A

c.1154C>T

c.C1154T

T385I

c.1156C>A

c.C1156A

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c.1157A>T

c.A1157T

Q386L

c.1158G>C

c.G1158C

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c.1159C>A

c.C1159A

L387I

c.1159C>T

c.C1159T

L387F

c.1160T>A

c.T1160A

L387H

c.1160T>G

c.T1160G

L387R

c.1162C>A

c.C1162A

L388I

c.1162C>G

c.C1162G

L388V

c.1162C>T

c.C1162T

L388F

c.1163T>A

c.T1163A

L388H

c.1163T>G

c.T1163G

L388R

c.1168G>A

c.G1168A

V390M

c.1171A>C

c.A1171C

K391Q

c.1171A>G

c.A1171G

K391E

c.1172A>C

c.A1172C

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c.1172A>G

c.A1172G

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c.1172A>T

c.A1172T

K391I

c.1173A>T

c.A1173T

K391N

c.1174A>G

c.A1174G

R392G

c.1174A>T

c.A1174T

R392W

c.1175G>A

c.G1175A

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c.1175G>C

c.G1175C

R392T

c.1175G>T

c.G1175T

R392M

c.1177A>C

c.A1177C

K393Q

c.1177A>G

c.A1177G

K393E

c.1178A>C

c.A1178C

K393T

c.1179G>C

c.G1179C

K393N

c.1180C>A

c.C1180A

L394I

c.1181T>A

c.T1181A

L394Q

c.1181T>C

c.T1181C

L394P

c.1181T>G

c.T1181G

L394R

c.1183G>C

c.G1183C

G395R

c.1184G>A

c.G1184A

G395E

c.1184G>C

c.G1184C

G395A

c.1186T>A

c.T1186A

F396I

c.1186T>G

c.T1186G

F396V

c.1187T>G

c.T1187G

F396C

c.1188C>G

c.C1188G

F396L

c.1189T>A

c.T1189A

Y397N

c.1189T>C

c.T1189C

Y397H

c.1190A>C

c.A1190C

Y397S

c.1190A>G

c.A1190G

Y397C

c.1190A>T

c.A1190T

Y397F

c.1192G>A

c.G1192A

E398K

c.1192G>C

c.G1192C

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c.1193A>G

c.A1193G

E398G

c.1195T>A

c.T1195A

W399R

c.1195T>G

c.T1195G

W399G

c.1198A>C

c.A1198C

T400P

c.1198A>G

c.A1198G

T400A

c.1198A>T

c.A1198T

T400S

c.1199C>A

c.C1199A

T400N

c.1199C>T

c.C1199T

T400I

c.1201T>A

c.T1201A

S401T

c.1201T>G

c.T1201G

S401A

c.1202_1203insGACTTC

c.1202_1203insGACTTC

p.T400_S401dup

c.1202C>T

c.C1202T

S401L

c.1204A>G

c.A1204G

R402G

c.1204A>T

c.A1204T

R402W

c.1205G>C

c.G1205C

R402T

c.1205G>T

c.G1205T

R402M

c.1206G>C

c.G1206C

R402S

c.1207T>G

c.T1207G

L403V

c.1208T>C

c.T1208C

L403S

c.1209A>T

c.A1209T

L403F

c.1210A>G

c.A1210G

R404G

c.1211G>A

c.G1211A

R404K

c.1211G>C

c.G1211C

R404T

c.1211G>T

c.G1211T

R404I

c.1212A>T

c.A1212T

R404S

c.1213A>G

c.A1213G

S405G

c.1216C>G

c.C1216G

H406D

c.1217A>T

c.A1217T

H406L

c.1218C>G

c.C1218G

H406Q

c.1219A>T

c.A1219T

I407L

c.1220T>C

c.T1220C

I407T

c.1221A>G

c.A1221G

I407M

c.1222A>C

c.A1222C

N408H

c.1222A>G

c.A1222G

N408D

c.1222A>T

c.A1222T

N408Y

c.1223A>C

c.A1223C

N408T

c.1225C>A

c.C1225A

P409T

c.1225C>G

c.C1225G

P409A

c.1225C>T

c.C1225T

P409S

c.1226C>T

c.C1226T

P409L

c.1228A>G

c.A1228G

T410A

c.1228A>T

c.A1228T

T410S

c.1229C>T

c.C1229T

T410I

c.1231G>A

c.G1231A

G411S

c.1231G>T

c.G1231T

G411C

c.1232G>A

c.G1232A

G411D

c.1232G>C

c.G1232C

G411A

c.1232G>T

c.G1232T

G411V

c.1234A>C

c.A1234C

T412P

c.1234A>G

c.A1234G

T412A

c.1234A>T

c.A1234T

T412S

c.1235C>A

c.C1235A

T412N

c.1235C>T

c.C1235T

T412I

c.1237G>A

c.G1237A

V413I

c.1237G>T

c.G1237T

V413F

c.1238T>G

c.T1238G

V413G

c.1240T>G

c.T1240G

L414V

c.1242G>C

c.G1242C

L414F

c.1243C>A

c.C1243A

L415I

c.1244T>A

c.T1244A

L415H

c.1246C>G

c.C1246G

Q416E

c.1247A>T

c.A1247T

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c.1248G>C

c.G1248C

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c.1249C>A

c.C1249A

L417I

c.1252G>A

c.G1252A

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c.1252G>C

c.G1252C

E418Q

c.1253A>C

c.A1253C

E418A

c.1253A>G

c.A1253G

E418G

c.1254A>T

c.A1254T

E418D

c.1255A>G

c.A1255G

N419D

c.1255A>T

c.A1255T

N419Y

c.1256A>C

c.A1256C

N419T

c.1256A>G

c.A1256G

N419S

c.1256A>T

c.A1256T

N419I

c.1258A>C

c.A1258C

T420P

c.1258A>T

c.A1258T

T420S

c.1259C>A

c.C1259A

T420K

c.1259C>G

c.C1259G

T420R

c.1261A>G

c.A1261G

M421V

c.1261A>T

c.A1261T

M421L

c.1262T>A

c.T1262A

M421K

c.1262T>C

c.T1262C

M421T

c.1262T>G

c.T1262G

M421R

c.1263G>C

c.G1263C

M421I

c.1265A>C

c.A1265C

Q422P

c.1267A>T

c.A1267T

M423L

c.1268T>A

c.T1268A

M423K

c.1268T>C

c.T1268C

M423T

c.1269G>C

c.G1269C

M423I

c.1271C>T

c.C1271T

S424L

c.1275A>C

c.A1275C

L425F

c.1279G>A

c.G1279A

D427N

c.1286T>G

c.T1286G

L429R

Pharmacodynamic effects

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

Clinical efficacy and safety

The clinical efficacy and safety of Galafold have been evaluated in two phase 3 pivotal clinical studies and two open-label extension (OLE) clinical studies. All patients received the recommended dosage of 123 mg Galafold every other day.

The first phase 3 clinical study (ATTRACT) was a randomised open-label active comparator study that 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 were receiving ERT prior to clinical study entry and who have amenable mutations (ERT-experienced clinical 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-blind placebo-controlled study (through month 6) with an 18-month open-label period to evaluate the efficacy and safety of Galafold in 50 male and female patients with Fabry disease who were naï ve to ERT, or had previously been on ERT and had stopped for at least 6 months and who have amenable mutations (ERT-naï ve study).

The first OLE clinical study (AT1001-041) included patients from phase 2 and phase 3 studies and has completed. The mean extent of exposure to the marketed dose of migalastat 123 mg QOD in patients completing 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 marketed dose of Galafold 123 mg QOD in patients completing this study was 32.3 (± 12.3) months (n=84). The maximum exposure was 51.9 months.

Renal function

In the ERT-experienced clinical study, renal function remained stable for up to 18 months of treatment with Galafold. Mean annualised rate of change in eGFRCKD-EPI was -0.40 mL/min/1.73 m2 (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 in eGFRCKD-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-naï ve clinical study and open-label extension, renal function remained stable for up to 5 years of treatment with Galafold. After an average of 3.4 years of treatment, the mean annualised rate of change in eGFRCKD-EPI was -0.74 mL/min/1.73 m2 (95% CI: -1.89, 0.40; n=41). No clinically significant differences were observed during the initial 6-month placebo-controlled period.

Data for the annualised rate of change for eGFRCKD-EPI was pooled for ERT-naï ve subjects and ERT-experienced subjects with amenable mutations in OLE clinical study AT1001-042; the results showed the durability of renal stabilization up to 8.6 years in annualised rate of change. After a mean duration of 5.2 years, ERT-naï ve patients had a mean annualised rate of change from baseline of -1.71 mL/min/1.73 m2 (CI: -2.83, -0.60; n=47). After a mean duration of 4.3 years, ERT-experienced patients had a mean annualised rate of change from baseline of -1.78 mL/min/1.73 m2 (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 a statistically 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 18 was -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. The change 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 months treatment 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 baseline was -10.0 (95% CI: -16.6, -3.3; n=10).

In the ERT-naï ve 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 change from 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 at month 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 LVMi were observed during the initial 6-month placebo-controlled period.

In the ERT-experienced and ERT-naï ve 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 an average 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 in patients with amenable mutations treated with Galafold for the 30-month duration of the study. Plasma lyso-Gb3 levels also remained low in patients on ERT for up to 18 months.

In the ERT-naï ve clinical study, Galafold showed statistically significant reductions in plasma lyso-Gb3 concentrations and kidney interstitial capillary GL-3 inclusions in patients with amenable mutations. Patients randomised to Galafold in Stage 1 demonstrated statistically significant greater reduction (± SEM) in mean interstitial capillary GL-3 deposition (-0.25± 0.10; -39%) at month 6 compared to placebo (+0.07 ± 0.13; +14%) (p=0.008). Patients randomised to placebo in Stage 1 and switched to Galafold at month 6 (Stage 2) also demonstrated statistically significant decreases in interstitial capillary GL-3 inclusions at month 12 (-0.33± 0.15; -58%) (p=0.014). Qualitative reductions in GL-3 levels were observed in multiple renal cell types: podocytes, mesangial cells, and glomerular endothelial 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. The frequency of events in patients treated with Galafold over 30 months (32%) was similar to the 18-month period.

Patient-reported outcome - gastrointestinal symptoms rating scale

In the ERT-naï ve clinical study, analyses of the Gastrointestinal Symptoms Rating Scale demonstrated that treatment with Galafold was associated with statistically significant (p<0.05) improvements versus placebo from baseline to month 6 in the diarrhoea domain, and in the reflux domain for patients with 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 of improvement in the constipation domain.

Paediatric population

In Study AT1001-020, a 1-year, Phase 3b, open-label, uncontrolled, multicenter 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 mutations of the gene encoding α -galactosidase A (GLA). Subjects were either naï ve to enzyme replacement therapy (ERT) or had stopped ERT at least 14 days before screening. The mean number of years since diagnosis of Fabry disease was 9.6 (± 4.25) years.

At 1 year, the efficacy in adolescents on the same dosing regimen as adults were consistent in renal, cardiac, and pharmacodynamic results as well as responses to patient-reported outcomes. The overall mean (SD) change from baseline in eGFR was -1.6 (15.4) mL/min/1.73 m2 (n=19). The overall mean (SD) change from baseline for LVMi was -3.9 (13.5) g/m2 (n=18). LVMi decreased in 10 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 in plasma lyso-Gb3 was -0.06 (32.9) (n=19). A reduction in plasma lyso-Gb3 from baseline was observed in ERT-naï ve 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 patient reported outcomes.

The Medicines and Healthcare products Regulatory 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 (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

The absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose or a single 2-hour 150 mg intravenous infusion was approximately 75%. Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure (AUC0-∞ ) and Cmax demonstrated dose-proportional increases at migalastat hydrochloride 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 after a 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 the fasting state (see section 4.2).

Compared to intake of a single dose of migalastat with water, intake with coffee containing approximately 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 was observed when migalastat was taken with natural (sucrose) and artificial (aspartame or acesulfame K) sweeteners (see sections 4.2 and 4.5).

Distribution

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

Biotransformation

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 that migalastat would be subject to drug-drug interactions with cytochrome P450s. A pharmacokinetic study in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that 99% of the radiolabelled dose recovered in plasma was comprised of unchanged migalastat (77%) and 3 dehydrogenated O-glucuronide conjugated metabolites, M1to M3 (13%). Approximately 9% of the total radioactivity was unassigned.

Elimination

A pharmacokinetic study in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that approximately 77% of the radiolabeled dose was recovered in urine of which 55% of was excreted as unchanged migalastat and 4% as combined metabolites M1, M2 and M3. Approximately 5% of the total sample radioactivity was unassigned components. Approximately 20% of the total radiolabeled dose was excreted in faeces, with unchanged migalastat being the only measured component.

Following ascending single oral doses (25 to 675 mg migalastat hydrochloride), no trends were found for clearance, CL/F). At the 150 mg dose, CL/F was approximately 11 to 14 L/hr. Following administration of the same doses, the mean elimination half-life (t1/2) ranged from approximately 3 to 5 hours.

Special populations

Patients with renal impairment

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

Patients with hepatic impairment

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

Elderly (>65 years)

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

Paediatric population

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

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

Gender

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

5.3 Preclinical safety data

Non-clinical studies suggest no specific hazard for humans on the basis of single-and repeat-dose studies, with the exception of transient and fully reversible infertility in male rats associated with migalastat treatment. The infertility associated with migalastat treatment was reported at clinically relevant exposures. Complete reversibility was seen after 4 weeks off-dose. Similar findings have been noted pre-clinically following treatment with other iminosugars. In the rabbit embryo-foetal toxicity study, 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 doses associated with maternal toxicity.

In a rat 104-week carcinogenicity study, there was an increased incidence of pancreatic islet cell adenomas in males at a dose level 19-fold higher than the exposure (AUC) at the clinically efficacious dose. This is a common spontaneous tumour in ad libitum-fed male rats. In the absence of similar findings 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 observation in male rats is not considered related to treatment and its relevance to humans is unknown.

6. Pharmaceutical particulars
6.1 List of excipients

Capsule contents

Pregelatinised starch (maize)

Magnesium stearate

Capsule shell

Gelatin

Titanium dioxide (E171)

Indigo carmine (E132)

Printing ink

Shellac

Black iron oxide

Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

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

6.5 Nature and contents of container

PVC / PCTFE / PVC/Al blister.

Pack size of 14 capsules.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Amicus Therapeutics UK Limited

One Globeside

Fieldhouse Lane

Marlow

Buckinghamshire

SL7 1HZ

8. Marketing authorisation number(s)

PLGB 25823/0002

9. Date of first authorisation/renewal of the authorisation

01/01/2021

10. Date of revision of the text

13/12/2023

Amicus Therapeutics UK Ltd
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