This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: nihrhsc@contacts.bham.ac.uk Web: http://www.hsc.nihr.ac.uk

Migalastat for Fabry disease: update SUMMARY NIHR HSC ID: 3048 Migalastat is intended as monotherapy for the treatment of Fabry disease. If licensed, it would provide an alternative therapy for the treatment of patients with Fabry disease. Unlike existing enzyme replacement therapies (ERT), which are administered by intravenous infusion, migalastat is given orally, potentially improving quality of life for patients and their carers, and potentially reducing service costs. Migalastat is a pharmacological chaperone intended to bind to abmormal α-galactosidase A (α-Gal A) and recover native protein folding, allowing correct transportation to the lysosome and restoring protein activity. Migalastat does not currently have Marketing Authorisation in the EU for any indication. Fabry disease is caused by insufficient activity of the lysosomal enzyme α-gal A. Incidence estimates vary, with a reported incidence of 1 in 3,100 newborns in Italy and 1 in 1,500 newborn males with genetic alterations in Taiwan. The EMA estimate the EU prevalence of Fabry disease to be between 1 and 5 people per 100,000 population, though two studies in the UK using a register of all known cases diagnosed between 1980 and 1995, reported a prevalence of 0.27 cases per 100,000 population for males and 0.29 for females. This equates to approximately 170 male and 180 female cases in England and Wales, though the proportion of symptomatic females is unclear. Although clinically heterogenous, classical Fabry disease is usually a slowly progressive disease in which signs and symptoms change as the patient ages. The main causes of death are renal failure, heart disease or stroke and typically occur around the age of 50 years in hemizygous men and 70 years in obligate carrier women. Fabry disease is currently incurable. However symptoms can be managed and specific ERT allows some control of the disease. Migalastat is in three phase III clinical trials comparing its effect on renal function and safety against treatment with agalsidase or placebo. These trials are expected to complete by July 2016.

Horizon Scanning Centre March 2014

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

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TARGET GROUP • Fabry disease. TECHNOLOGY DESCRIPTION Migalastat (Amigal; GSK181413; AT-1001) is a pharmacological chaperone intended to bind to abmormal α-galactosidase A (α-Gal A) and recover native protein folding, allowing correct transportation to the lysosome and restoring protein activity. It is intended as monotherapy for the treatment of Fabry disease. Migalastat in administered orally at 150mg once, every other day on a continuing basis. Migalastat does not currently have Marketing Authorisation in the EU for any indication. INNOVATION and/or ADVANTAGES If licensed, migalastat would provide an alternative therapy for the treatment of patients with Fabry disease. Unlike existing enzyme replacement therapies (ERT), which are administered by intravenous (IV) infusion, migalastat is given orally, potentially improving quality of life for patients and their carers, and potentially reducing service costs. DEVELOPER Amicus Therapeutics. AVAILABILITY, LAUNCH OR MARKETING This is an updated briefing. The original version was submitted in December 20101. Migalastat is a designated orphan drug in the EU/USA. It is currently in phase III clinical trials. PATIENT GROUP BACKGROUND Fabry disease is a X-linked lysosomal storage disorder (LSD). All LSDs share a common pathogenesis: a genetic defect in one or more specific lysosomal enzymes, activator proteins or membrane proteins, resulting in deficient enzymatic activity2. Lysosomes contain numerous acid hydrolases that are part of a complex pathway that reduces macromolecules into smaller components. These components will be reused by the cell or eventually eliminated from the body. If a specific lysosomal enzyme is deficient, the substrate it targets accumulates in a progressive manner, interfering with normal cellular activity and potentially leading to cell death3. Fabry disease (also known as Anderson-Fabry disease) is caused by insufficient activity of the lysosomal enzyme α-galactosidase A4. The gene for α-galactosidase A is on Xq22 and more than 350 mutations have been identified. Most are small deletions or insertions and numerous single based substitutions leading to missense or nonsense mutations5. The resulting inability to catabolise glycosphingolipids causes progressive accumulation of

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globotriaosylceramide in the cells of blood vessels and other organs such as the heart, kidney and brain5. This results in a multi-systemic disorder characterised by renal, cardiac and cerebrovascular complications, failure of which are the major causes of morbidity. Patients also experience significant impacts on their quality of life due to neuropathic pain and gastrointestinal symptoms1. Despite the X-linked nature, a major fraction of female heterozygotes also suffer from significant morbidity and premature mortality5. Expert opinion indicates that for any X-linked disorder, there should be twice as many females as malesa. The disease can be as severe in females as in males, though typically has a later onset, slower progression and less severe clinical pathological changes5. NHS or GOVERNMENT PRIORITY AREA • NHS England. 2013/14 NHS Standard Contract for Lysosomal Storage Disorders

Service (Children). E06/S(HSS)/c. • NHS England. 2013/14 NHS Standard Contract for Medical Genetics (All Ages).

E01/S/a.

CLINICAL NEED and BURDEN OF DISEASE Fabry disease is a rare pan-ethnic condition and the second commonest of the 40 LSDs after Gaucher disease. Incidence estimates vary, with a reported incidence of 1 in 3,100 newborns in Italy and 1 in 1,500 newborn males with genetic alterations in Taiwan6. The EMA estimate the EU prevalence of Fabry disease to be between 1 and 5 people per 100,000 population7, though two studies in the UK using a register of all known cases diagnosed between 1980 and 1995, reported a prevalence of 0.27 cases per 100,000 population for males and 0.29 for females8. This equates to approximately 170 male and 180 female cases in England and Walesb, though the proportion of symptomatic females is unclear. In 2012-13, there were 960 hospital admissions in England due to sphingolipodosis (ICD10 E75.2, includes Fabry disease as well as other diseases), accounting for 370 bed-days and 970 finished consultant episodes9. Diagnosis of Fabry disease is often delayed; in UK males it takes a mean of 8.18 years from onset of neuropathic pain and a mean of 10.70 years from the onset of angiokeratoma to achieve a diagnosis. Although clinically heterogenous, classical Fabry disease is usually a slowly progressive disease in which signs and symptoms change as the patient ages. The main causes of death are renal failure, heart disease or stroke, and typically occur around the age of 50 years in hemizygous men and 70 years in obligate carrier women. Twenty three deaths from sphingolipodisis were registered in England and Wales during 2012 (ICD-10 E75.2, includes Fabry disease as well as other diseases)10. The population likely to be eligible to receive migalastat could not easily be estimated from available routine published sources. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance No relevant guidance identified.

a Expert personal communication. b Based on the mid-2009 UK population estimate.

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Other Guidance • NHS Specialised Services. Fabry disease standard operating procedures (adults and

children). 20135. • The Journal of Pediatrics. Guidelines to diagnosis and monitoring of Fabry disease and

review treatment experience. 200911. • Genetics in Medicine. Fabry disease: guidelines for the evaluation and management of

multi-organ system involvement. 200612. CURRENT TREATMENT OPTIONS Fabry disease is currently incurable. However symptoms can be managed and specific ERT allows some control of the disease. Guidelines recommend the following treatment options for ERT5: • Agalsidase alfa (Replagal) – human form of α-Gal A produced through gene activation of

a human fibroblast cell line. • Agalsidase beta (Fabrazyme) – human form of α-Gal A produced through recombinant

DNA technology using mammalian Chinese hamster ovary (CHO) cell culture. EFFICACY and SAFETY Trial ATTRACT, NCT01218659,

FAB-AT1001-012; migalastat hydrochloride vs agalsidase; phase III.

FACETS, NCT00925301, AT1001-011; migalastat hydrochloride vs placebo; phase III.

NCT01458119, AT1001-041; migalastat hydrochloride; phase III extension.

Sponsor Amicus Therapeutics. Amicus Therapeutics. Amicus Therapeutics. Status Ongoing. Ongoing. Ongoing. Source of information

Trial registry13. Trial registry14, manufacturer15, poster16.

Trial registry17.

Location EU (incl. UK), USA and other countries.

EU (incl. UK), USA, Canada and other countries.

EU (incl. UK), USA, Canada and other countries.

Design Randomised, active-controlled.

Randomised, placebo-controlled.

Non-randomised, uncontrolled.

Participants n=60 (planned); adults aged 16 to 74 years; Fabry disease confirmed by α-galactosidase gene (GLA) mutation; received ERT for at least 12 months.

n=67 (planned); adults aged 16 to 74 years; Fabry disease confirmed by GLA mutation; never treated with ERT or not received ERT for 6 consecutive months.

n=100 (planned); adults aged 16 years and older; received migalastat hydrochloride in a previous study.

Schedule Randomised to migalastat hydrochloride 150mg oral once every other day alternating with placebo; or agalisdase IV given in accordance with product specification.

Randomised to migalastat hydrochloride 150mg or placebo, both given orally once every other day.

Patients receive migalastat hydrochloride 150mg oral once every other day. An inactive reminder capsule is taken on the days between migalastat hydrochloride.

Follow-up 6 month randomisation period, then 18 months extension.

18 months randomisation, then 12 months extension.

Treatment period up to 5 years.

Primary outcome/s

Renal function assessed by iohexol glomerular filtration rate.

Kidney globotriaosylceramide (GL-3) level.

Safety, withdrawal from treatment due to AEs, change in electrocardiogram (ECG)

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reading; change in echocardiography (ECHO) reading.

Secondary outcome/s

Time to occurrence of events (renal, cardiac, cerebrovascular and/or death), cardiac function, pain, quality of life.

Urine GL3 level, renal function, safety, tolerability.

Glomerular filtration rate, 24-hour urine measurement, left ventricular mass index and ejection fraction evaluations, leukocyte α-Gal A activity, patient reported assessment of pain, quality of life.

Key results Results expected Q2/3 2014.

Interim results. For migalasat hydrochloride vs placebo respectively: 50% or greater reduction in GL-3 after 6 months, 40.6% vs 28.1% (p=0.3); absolute change in GL-3, 41% vs 6% (p=0.093). Further results expected Q1/2 2014.

-

Adverse effects (AEs)

- To date, no drug-related serious AEs have been reported. Common AEs include (migalastat and placebo respectively): headache (35%, 21%), fatigue (12%, 12%), nausea (12%, 9%); nasopharyngitis, or inflammation of the nose and throat (15%, 6%); paraesthesia, or tingling sensation of the skin (9%, 12%).

-

Expected reporting date

Estimated study completion date, August 2015.

Estimated study completion date, January 2014.

Estimated study completion date, July 2016.

Trial NCT00526071, FAB-CL-205; migalastat hydrochloride; phase II extension. Sponsor Amicus Therapeutics. Status Ongoing. Source of information

Trial registry18, manufacturer and abstract19.

Location EU (incl. UK), USA, Australia and Brazil. Design Non-randomised, uncontrolled. Participants n=23; adults aged 18 to 65 years; Fabry disease confirmed by GLA mutation;

completed previous phase II trial of migalastat hydrochloride. Schedule Participants receive migalastat hydrochloride 150mg oral, every other day followed by

250mg, 300mg or 500mg, all given orally every other day for 3 days, followed by 4 days off; the continue on 150mg oral every other day.

Follow-up Treatment period 13 months. Primary outcome/s

Long-term safety and tolerability.

Secondary outcome/s

Pharmacodynamics and disease-related outcomes.

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Key results Interim results (n=23). All patients who entered extension study maintained renal function for up to 3 years18.

Adverse effects (AEs)

Interim results. Most common AEs reported were headache, arthralgia and diarrhoeac.

Trial NCT00214500, FAB-CL-

201; migalastat hydrochloride; phase II.

NCT00283959, FAB-CL-202; migalastat hydrochloride; phase II.

NCT00283933, FAB-CL-203; migalastat hydrochloride; phase II.

Sponsor Amicus Therapeutics. Amicus Therapeutics. Amicus Therapeutics. Status Complete but unpublished. Published. Published. Source of information

Trial registry20, manufacturer and poster21.

Publication22, trial registry23, manufacturer and poster20.

Publication, trial registry24, manufacturer and poster20.

Location USA. Australia and Brazil. UK, Canada and France. Design Non-randomised,

uncontrolled. Non-randomised, uncontrolled.

Non-randomised, uncontrolled.

Participants n=14; adults aged 18 to 55 years; Fabry disease confirmed by GLA mutation; never treated with ERT or stable without ERT for at least 18 weeks.

n=4; adults aged 18 to 65 years; Fabry disease confirmed by GLA mutation; never treated with ERT or stable without ERT for at least 18 weeks.

n=5; adults aged 18 to 65 years; Fabry disease confirmed by GLA mutation; never treated with ERT or stable without ERT for at least 30 weeks.

Schedule Participants receive migalastat hydrochloride 25mg, 100mg or 250mg twice daily, or 50mg once every other day; all oral.

Participants receive migalastat hydrochloride 150mg oral once every other day.

Participants receive migalastat hydrochloride 150mg oral once every other day.

Follow-up 28 day screening period followed by 12 weeks treatment period.

Treatment period 12 weeks.

Treatment period 24 weeks.

Primary outcome/s

Safety and tolerability. Safety and tolerability. Safety and tolerability.

Secondary outcome/s

Pharmokinetics and pharmacodynamics.

Pharmacodynamics and functional parameters (renal and cardiac).

Pharmacodynamics and functional parameters (renal, cardiac and nervous system).

Key results Cumulative results for phase II trials FAB-CL-201, -202, -203 and -204: No serious adverse events reported. All drug-related AEs mild to moderate and did not require intervention. Treatment with migalastat hydrochloride increased activity of α-Gal A, and reduced urinary GL-3 in the majority of responders.

Expected reporting date.

To be announced. - -

Trial FAB-CL-204, NCT00304512; migalastat hydrochloride; phase II. Sponsor Amicus Therapeutics. Status Published.. Source of information

Publication25, trial registry26, manufacturer and poster11.

Location EU (inc UK), USA, Canada, Australia and Brazil. Design Non-randomised, uncontrolled. Participants n=9; female adults aged 18 to 65 years; Fabry disease confirmed by GLA mutation;

never treated with ERT or stable without ERT for at least 18 weeks. Schedule Participants receive migalastat hydrochloride 50mg, 150mg or 250mg once every

other day, all oral.

c Results provided by manufacturer.

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Follow-up 4 week screening period followed by 12 week treatment period, with possible 36-week extension. Follow-up 2 weeks.

Primary outcome/s

Safety and tolerability.

Secondary outcome/s

Pharmacodynamics and functional parameters (renal, cardiac and CNS).

Key results See cumulative results of Phase II trials reported under FAB-CL-201.

ESTIMATED COST and IMPACT COST The cost of migalastat hydrochloride is not yet known. The cost of comparator drugs are summarised in the following table27. Drug Dose (adults) Cost per dose Replagal (agalsidase alpha) 0.2mg/kg body weight given

every 2 weeksd. £4,988

Fabrazyme (agalsidase beta) 1mg/kg body weight given every 2 weekse.

£5,023.

IMPACT - SPECULATIVE Impact on Patients and Carers

Reduced mortality/increased length of survival Reduced symptoms or disability

Other: improved quality of life for patients and carers, improved patient convenience.

No impact identified

Impact on Health and Social Care Services

Increased use of existing services Decreased use of existing services: oral administration.

Re-organisation of existing services Need for new services

Other: None identified Impact on Costs and Other Resource Use

Increased drug treatment costs Reduced drug treatment costs

Other increase in costs: Other reduction in costs:

Other: uncertain unit cost compared to existing treatments

None identified

Other Issues

Clinical uncertainty or other research question identified:

None identified

d Average adult body weight 76.9kg based on figures from Health Survey for England 2008.

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comprehensive care. Journal of Pediatrics 2004;144:3-14. 3 Meikle PJ, Hopwood JJ, Clague AE et al. Prevalence of lysosomal storage disorders. The Journal

of American Medical Association 1999;281(3):249-54. 4 El Dib RP, Nascimento P, Pastores GM. Enzyme replacement therapy for Anderson-Fabry

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2013. http://www.specialisedservices.nhs.uk/library/23/Fabry_Disease_Standard_Operating_Procedures_Adults_and_Children.pdf Accessed 27 March 2014.

6 Pisani A, Imbriaco M, Zizzo C et al. A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report. BMC Cardiovascular Disorders 2012;12:39.

7 European Medicines Agency. Fabry disease. March 2012 http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324 Accessed on 27 March 2014.

8 Connock M, Jurarez-Garcia A, Frew E et al. Health Technology Assessment NHS R&D HTA Programme, A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharoidosis type I. Health Technology Assessment 2006;10:17-25.

9 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2011-12. www.hscic.gov.uk

10 Office for National Statistics. . Mortality statistics: deaths registered in 2012 (Series DR) Table 5. http://www.ons.gov.uk

11 Martins AM, D’Alemida V, Kyosen SO et al. Guidelines to diagnosis and monitoring of Fabry disease and review of treatment experiences. The Journal of Pediatrics 2008;155(4):S19-131.

12 Eng CM, Germain DP, Banikazemi M et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genetics in Medicine 2006;8:539-548.

13 ClinicalTrials.gov. A randomised open-label study to compare the efficacy and safety of AT1001 and enzyme replacement therapy (ERT) in patients with Fabry disease and AT1001-responsive GLA mutations, who were previously treated with ERT. http://clinicaltrials.gov/ct2/show/NCT01218659 Accessed 27 March 2014.

14 ClinicalTrials.gov. A double-blind, randomised, placebo-controlled study to evaluate the efficacy, safety and pharmacodynamics of AT1001 in patients with Fabry disease and AT1001-reponseive GLA mutations. http://clinicaltrials.gov/ct2/show/NCT00925301 Accessed 27 March 2014.

15 GlaxoSmithKline and Amicus therapeutics announce top-line six-month primary treatment period results from first phase III Fabry monotherapy study. http://us.gsk.com/html/media-news/pressreleases/2012/2012-pressrelease-1281220.htm Accessed 27 March 2014.

16 Barlow C, Castelli J, Benjamin E et al. Phase 3 study (FACETS) of migalastat HCl for Fabry disease: post hoc GLA mutation-based identification of subjects likely to show a drug effect. Lysosomal Disease Network 10th Annual World Symposium. February 2014. Poster presentation.

17 ClinicalTrials.gov. An open-label extension study to evaluate the long term safety and efficacy of migalastat hydrochloride monotherapy in subjects with fabry disease http://clinicaltrials.gov/ct2/show/NCT01458119 Accessed 4 April 2014.

18 ClinicalTrials.gov. Open-label extension study to evaluate the long-term safety, tolerability and pharmacodynamics of AT1001 in patients with Fabry disease http://clinicaltrials.gov/ct2/show/NCT00526071 Accessed 27 March 2014.

19 Waldek S, Castelli J, Bragat A et al. Preliminary long-term safety, tolerability and assessments of renal function of adult Fabry patients receiving treatment with AT1001, a pharmacological chaperone, for up to 3 years, abstract 276. American College of Medical Genetics annual clinical genetics meeting. March 2010.

20 ClinicalTrials.gov. A phase 2, open-label, multicentre, ascending-dose, 12-week study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AT1001 in patients with Fabry disease http://clinicaltrials.gov/show/NCT00214500 Accessed 27 March 2014.

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21 Germain D, Castelli J, Shenker A et al. Phase 2 clinical trials of the pharmacological chaperone

AT1001 for the treatment of Fabry disease, poster. Society for the Study of Inborn Errors of Metabolism annual symposium. September 2008. Poster presentation.

22 Germain DP, Giugliani R, Hughes DA et al. Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies. Orphanet Journal of Rare Diseases 2012;7:91.

23 ClinicalTrials.gov. A phase 2, open-label, single dose level, 12-week study to evaluate the safety, tolerability, and pharmacodynamics of AT1001 in patients with Fabry disease. http://clinicaltrials.gov/show/NCT00283959 Accessed 27 March 2014. .

24 ClinicalTrials.gov. A phase 2, open-label, single dose level, 24-week study to evaluate the safety, tolerability, and pharmacodynamics of AT1001 in patients with Fabry disease. http://clinicaltrials.gov/ct2/show/NCT00283933 Accessed 27 March 2014

25 Giugliani R, Waldek S, Germain DP et al. A phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamics effects. Molecular Genetics and Metabolism 2013;109(1):86-92.

26 ClinicalTrials.gov. A phase 2, open-label, multiple dose level, 12-week study to evaluate the safety, tolerability, and pharmacodynamics of AT1001 in female patients with Fabry disease http://clinicaltrials.gov/show/NCT00304512 Accessed 27 March 2014.

27 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 67. London: BMJ Group and RPS Publishing, March 2014.