Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Amicus Therapeutics Europe Limited, Block 1, Blanchardstown Corporate Park, Ballycoolen Road, Blanchardstown, Dublin, D15 AKK1, Ireland Tel: +353 (0) 1 588 6850, Fax: +353 (0) 1 588 6851, e-mail: info@amicusrx.co.uk ...
Pharmacotherapeutic group: 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.
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 stabilizes 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 and not amenable to treatment with Galafold are listed in Table 2 and Table 3 respectively 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:
The mutations not amenable to treatment with Galafold are listed in Table 3 below.
UNKNOWN in the column of ‘protein sequence change’ indicate that the changes to the protein sequence caused by the mutations cannot be readily deduced from the nucleotide changes and need to be experimentally determined. In these cases, the question marks in the accompanying parentheses indicate that the changes provided therein have not been experimentally confirmed and may not be correct.
Table 3. Mutations not amenable to Galafold (migalastat):
Not all mutations have been tested.
Treatment with Galafold in Phase 2 pharmacodynamic trials 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.
The clinical efficacy and safety of Galafold have been evaluated in two Phase 3 pivotal trials and two open-label extension (OLE) trials. All patients received the recommended dosage of 123 mg Galafold every other day.
The first Phase 3 trial (ATTRACT) was a randomised open-label active comparator trial 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 trial entry and who have amenable mutations (ERT-experienced trial). The 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 trial (FACETS) was a 6-month randomised double-blind placebo-controlled trial (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 naïve to ERT, or had previously been on ERT and had stopped for at least 6 months and who have amenable mutations (ERT-naïve trial). The first OLE trial (AT1001-041) included patients from Phase 2 and Phase 3 studies and has completed. The mean extent of exposure to the marketed dose of Galafold 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 trial (AT1001-042) included patients that both transferred from OLE study AT1001-041 and directly from Phase 3 study ATTRACT, and is ongoing. Renal Function In the ERT-experienced trial, renal function remained stable for up to 18 months of treatment with Galafold. Mean annualised rate of change in eGFR CKD-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 eGFR CKD-EPI in patients treated for 30 months with Galafold was -1.72 mL/min/1.73 m² (95% CI: -2.653, -0.782; n=31).
In the ERT-naïve trial 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 eGFR CKD-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.
In the ERT-experienced trial, 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 migalastat 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-naïve trial, 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 in patients with left ventricular hypertrophy at baseline at Month 36 was -30.0 (95%) CI: -57.9, -2.2; n=4) and at Month 48 was -33.1 (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 trial, plasma lyso-Gb 3 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-naïve trial, Galafold showed statistically significant reductions in plasma lyso-Gb 3 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.
In the ERT-experienced trial, 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.
In the ERT-naïve trial, 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.
The European Medicines Agency has deferred the obligation to submit the results of studies with Galafold in one or more subsets of the paediatric population in the treatment of Fabry disease (see section 4.2 for information on paediatric use).
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.
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.
In healthy volunteers, the volume of distribution (Vz/F) of migalastat following ascending single oral doses (25-675 mg migalastat HCl) 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 μM.
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 trial in healthy male volunteers with 150 mg [14C]-migalastat HCl revealed that 99% of the radiolabeled dose recovered in plasma was comprised of unchanged migalastat (77%) and 3 dehydrogenated O-glucuronide conjugated metabolites, M1 to M3 (13%). Approximately 9% of the total radioactivity was unassigned.
A pharmacokinetic trial 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 (25-675 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.
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).
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.
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-naïve study population. The difference in clearance between Fabry patients ≥65 years and those <65 years was 20%, which was not considered clinically significant.
The pharmacokinetic characteristics of migalastat were not significantly different between females and males in either healthy volunteers or in patients with Fabry disease.
Non-clinical studies suggest no specific hazard for humans on the basis of single-and repeat-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.
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