in pictures and a few words
What it is and why it matters
Migalastat is a capsule medicine for adults with Fabry disease. One capsule every other day instead of an infusion every two weeks.
- Before, there was only one treatment — a lifelong infusion of ready-made enzyme
- It suits those whose gene test showed a suitable variant
What goes wrong in Fabry disease
Every cell has a compartment where used-up substances are broken down. In Fabry disease one enzyme is missing there, and a fat-like substance builds up in the cells.
- The kidneys, heart, blood vessels and nerves suffer most
- From childhood — burning pain in the hands and feet, heat is poorly tolerated
- Many women develop the disease too — they are not just carriers
How the medicine works
With many gene faults the enzyme is still made, but it comes out wobbly, and the cell throws it away as a reject. The medicine holds it in the right shape — and the enzyme reaches its place of work.
- It is not a foreign enzyme from outside but help for your own — like a crutch for your own worker
First — a gene test
The medicine only helps the enzyme your body makes. A lab test of your gene variant shows in advance whether it will suit you.
- If a gene fault means there is no enzyme at all, the medicine has nothing to work on
- In men, the test predicted well whether treatment would help
Kidneys and heart
In people with a suitable gene variant, kidney function stayed stable in the study, and heart muscle mass went down.
- There were fewer complaints of diarrhoea, reflux from the stomach into the gullet and heaviness after meals
Tested in people. Tested in people: a study in people with Fabry disease and a suitable gene variant.
From infusions to capsules
Some adults who were already on infusions were switched to capsules. Their kidney function changed the same way as in those who stayed on infusions, and heart muscle mass went down.
- In those who stayed on infusions, heart muscle mass did not change noticeably
- With longer follow-up, kidney function stayed stable
- Whether to switch is decided by a doctor at a specialist centre after the gene test
Tested in people. Tested in people: adults with Fabry disease who were switched from infusions to capsules.
How to take it
One 123 mg capsule every other day, not every day. Strictly on an empty stomach: no food for two hours before and two hours after.
- Don’t skip or double a dose — the pack has a calendar
- The kidneys and heart are checked the same way as on infusions
How it is tolerated
The most common are headache, inflammation of the nose and throat, urinary tract infection, nausea and fever.
- When people were followed for longer, no new safety concerns appeared
Who should see a doctor first
Treatment is started only after a test has confirmed a suitable gene variant. Capsules replace infusions, they are not added to them.
- Kidney filtration below 30 mL/min/1.73 m² or dialysis — not studied and not recommended
- Under 18, safety and benefit have not been established
- Pregnancy and breastfeeding — too little data to judge the risk
Important. If the gene variant is not suitable, the medicine will not work — it’s not a matter of dose.
In one sentence
Migalastat helps your own enzyme reach its place of work: in people with a suitable gene variant, a capsule every other day replaces infusions, and the kidneys worked stably in studies.
- First the gene test, then a capsule every other day on an empty stomach
Key points
Migalastat (Galafold, approved by the FDA in August 2018 for adults) is the first oral treatment for Fabry disease. It delivers no enzyme from outside; it stabilises the patient's own — a capsule every other day instead of an infusion every two weeks.
| Where | How it helps | What human trials showed |
|---|---|---|
| Fabry disease with an amenable GLA variant | stabilises the patient's own enzyme so that it reaches the lysosome and works | FACETS, 24 months: kidney function stable — annualised change in estimated GFR −0.30 ± 0.66, measured GFR −1.51 ± 1.33 mL/min/1.73 m²; left ventricular mass index −7.7 g/m² (95% CI −15.4 to −0.01) |
| Switching from enzyme replacement infusions | a capsule every other day instead of an infusion every two weeks | ATTRACT, 57 adults, 18 months: kidney function changed comparably with infusions; left ventricular mass index −6.6 g/m² (−11.0 to −2.2), no significant change on infusions; plasma lyso-Gb3 remained low and stable |
| Gastrointestinal complaints | less diarrhoea, reflux and indigestion | improved in FACETS |
| Choosing whom to treat | a laboratory assay shows in advance whether the variant is amenable | in men the assay predicted the real-life response with sensitivity, specificity and predictive values of at least 0.875 |
How it helps
What breaks in Fabry disease
Every cell contains a lysosome, the compartment where spent material is taken apart. One of its enzymes, alpha-galactosidase A, dismantles a fat-like substance called globotriaosylceramide.
In Fabry disease the gene for that enzyme is damaged. The substance is no longer broken down and accumulates inside cells, year after year, from birth. The cells of the renal glomeruli, heart muscle, vessel walls and nerve ganglia suffer most.
Hence the recognisable sequence: in childhood, burning pain in hands and feet, heat intolerance, absent sweating and a characteristic rash; in adulthood, protein in the urine and declining kidney function, thickened heart walls, rhythm disturbances and early strokes. The gene sits on the X chromosome, so men are affected earlier and more severely — but women are not merely carriers: many develop full disease, more often with the heart predominating.
How it was treated before
Since the early 2000s there has been one answer — enzyme replacement therapy: the missing enzyme is manufactured biotechnologically and infused intravenously every two weeks. For life.
It works, but the price is high, and not only in money:
▸an infusion of several hours every fortnight, tied to a centre or a visiting nurse; ▸infusion reactions and antibodies against the foreign protein in some patients; ▸the infused enzyme distributes unevenly and penetrates some tissues poorly; ▸adolescents and young adults drop out of the schedule — and a missed dose means accumulation resumes.
The idea: repair your own enzyme rather than deliver another
The key observation is this. With many mutations the enzyme is in fact assembled — but it comes out unstable. The cell checks every new protein for correct folding; an unstable molecule fails that check and is sent for destruction before it ever reaches the lysosome. The enzyme is not so much absent as unable to reach its workplace.
Migalastat is a small molecule resembling the terminal fragment of the very substance the enzyme should break down. It sits in the active site and acts as a strut: it holds the protein in the correct shape, the protein passes quality control and reaches the lysosome — where the acidic environment and the excess of substrate displace the strut and free the enzyme to work.
The comparison that fits: enzyme replacement therapy means bringing in a new worker to replace one who dropped out. A chaperone means giving your own worker a crutch so that he can walk to the workshop. The second is cheaper and more convenient — but it requires that a worker exist at all.
Who it suits: an amenable variant
Prescription is preceded by a mandatory amenability assay. The variant is expressed in cultured cells, migalastat is added, and any increase in enzyme activity is measured. The study that validated this assay tested 600 disease-causing mutations: 268 proved amenable. In men the assay predicted the real-life response well — sensitivity, specificity and predictive values were all at least 0.875.
The assay is needed because only something that exists can be stabilised. If the mutation truncates the protein — a large deletion, a nonsense mutation, a frameshift — there is physically no enzyme, and no dose will help.
What the FACETS trial showed
Sixty-seven people with Fabry disease were enrolled: six months of double-blind comparison against placebo, then open-label treatment. Among those whose variant proved amenable, kidney function stayed stable over 24 months and left ventricular mass index fell (the numbers are in the Key points table).
Gastrointestinal complaints — diarrhoea, reflux, indigestion — improved separately. For Fabry patients this is no small matter: persistent bowel trouble often bothers them more than their kidney numbers do.
Switching from infusions: ATTRACT
The second question was practical: can someone who has received intravenous enzyme for years be moved onto capsules? ATTRACT enrolled 57 adults (56% women; 88% had multi-organ disease) and assigned them for 18 months either to migalastat or to continued infusions.
Kidney function changed comparably in both groups; left ventricular mass index fell on the capsule and did not change significantly on infusions (the numbers are in Key points). Renal, cardiac and cerebrovascular events occurred in 29% on migalastat versus 44% on infusions.
A 12-month extension produced 30-month data in 46 patients: estimated GFR remained stable in both groups, left ventricular mass fell in those switched from infusions, and 10% experienced a new clinical event. No new safety signals emerged.
How to take it
The 123 mg capsule follows a strict schedule:
▸Strictly every other day — not daily; a missed or doubled dose breaks the schedule, which is why the manufacturer prints a calendar on the carton with punch-out circles for the off days; ▸strictly on an empty stomach: two hours without food before and two hours after, a four-hour fasting window on each dosing day; ▸a mandatory genetic assay before starting — and a fresh conversation if the variant turns out not to be amenable; ▸monitoring does not stop: kidneys, heart and biomarkers are followed exactly as they were on infusions.
Who should see a doctor first
Who it is not for
▸A non-amenable variant — the drug will not work; this is not a matter of dose or duration. ▸Estimated GFR below 30 mL/min/1.73 m² and dialysis — migalastat is cleared by the kidneys, exposure rises substantially in severe impairment, and this group was never studied. ▸Children and adolescents — safety and efficacy have not been established below the age of 18. ▸Pregnancy and breastfeeding — data from three pregnancies in the trials are insufficient to judge risk. ▸Combination with enzyme replacement therapy — the drug replaces it, it is not added to it.
Bottom line
▸The first oral treatment for Fabry disease — a 123 mg capsule every other day instead of an intravenous infusion every fortnight. ▸A different mechanism: not replacing the enzyme but stabilising the patient's own so that it reaches the lysosome. ▸An assay decides who it suits: an amenable variant is required; of 600 mutations tested, 268 qualified. ▸In amenable patients in FACETS kidney function stayed stable and cardiac mass declined. ▸Switching from infusions is feasible: in ATTRACT renal function changed comparably and cardiac mass fell by 6.6 g/m².
Your own case — which variant you carry, what the biopsy shows and whether switching makes sense — can be reviewed at a consultation; the drug can be ordered here.
References
1. Germain DP, et al. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016;375(6):545–555. PMID 27509102
2. Hughes DA, et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet. 2017;54(4):288–296. PMID 27834756
3. Benjamin ER, et al. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet Med. 2017;19(4):430–438. PMID 27657681
4. Feldt-Rasmussen U, et al. Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study. Mol Genet Metab. 2020;131(1-2):219–228. PMID 33012654
5. GALAFOLD (migalastat) — US Prescribing Information, Amicus Therapeutics US, LLC.
Caveats
- The FACETS primary endpoint was not met. The response rate at six months was 41% (13 of 32) on migalastat versus 28% (9 of 32) on placebo, p=0.30. The reason lies in selection: participants were recruited using an early, imperfect amenability assay, and the validated assay, applied after recruitment but before unblinding, found an amenable variant in only 50 of the 67. The other seventeen could not physically respond to treatment, yet entered the main analysis and diluted it.
- Myocardial hypertrophy. In amenable patients with baseline hypertrophy, left ventricular mass index fell by 18.6 g/m² over 24 months, but the confidence interval (95% CI −38.2 to 1.0) crosses zero: the subgroup was too small for the claim to be made with confidence.
- ATTRACT. The difference in events — 29% versus 44% — was not the primary endpoint, and the trial was open-label: both physicians and patients knew who was receiving what. The comparison with enzyme replacement therapy used surrogate measures; the 'no worse' conclusion was reached without blinding. Such data are encouraging; they do not establish superiority.
- Accelerated approval. The very first line of the label states it: approval was granted through the accelerated pathway, on the basis of reduced inclusions of the substance in kidney interstitial capillary cells — that is, on a surrogate measure, not on whether patients reach dialysis, myocardial infarction and stroke less often. Continued approval may be contingent on verification of clinical benefit in confirmatory trials.
- What cannot be claimed yet. Clinical outcomes — death, dialysis, transplantation, stroke — have never been the primary endpoint of any migalastat trial, and an effect on them has not been demonstrated. The observation horizon is 30 months, while Fabry disease unfolds over decades. Subgroups are small: estimates for women, the elderly and patients with marked hypertrophy are unstable.
- Experience so far. Tolerability is good, but the absence of contraindications in the label also reflects a modest body of experience: only 139 people received the drug across the trials.
This material is for information only and does not replace a consultation with a doctor.
Key facts
- Migalastat (brand name Galafold, Amicus Therapeutics) is the first oral treatment for Fabry disease, approved by the FDA in August 2018 for adults with a confirmed diagnosis and an amenable GLA variant.
- Migalastat is a pharmacological chaperone: it binds the patient's own defective enzyme and holds it in the correct shape so that it survives quality control and reaches the lysosome. A capsule every other day replaces an intravenous infusion of a manufactured enzyme every two weeks.
- A cell-based assay shows in advance whether the drug will suit: of 600 mutations tested, 268 proved amenable, and in men the assay predicted the real-life response with sensitivity, specificity and predictive values of at least 0.875.
- Among patients with amenable variants in FACETS, kidney function stayed stable over 24 months and left ventricular mass index fell by 7.7 g/m²; in ATTRACT (57 adults on infusions, some of whom were switched to capsules), renal function in those who switched changed comparably with those who stayed on infusions, and left ventricular mass index fell by 6.6 g/m².
- The 123 mg capsule is taken every other day on an empty stomach: at least two hours without food before and two hours after — a four-hour fast on each dosing day.
