Chaperone Therapy in Fabry Disease.

Fabry disease is an X-linked lysosomal multisystem storage disorder induced by a mutation in the alpha-galactosidase A (GLA) gene. Reduced activity or deficiency of alpha-galactosidase A (AGAL) leads to escalating storage of intracellular globotriaosylceramide (GL-3) in numerous organs, including the kidneys, heart and nerve system. The established treatment for 20 years is intravenous enzyme replacement therapy. Lately, oral chaperone therapy was introduced and is a therapeutic alternative in patients with amenable mutations. Early starting of therapy is essential for long-term improvement. This review describes chaperone therapy in Fabry disease.

Premature ovarian insufficiency - novel hormonal approaches in optimizing fertility.

Premature ovarian insufficiency (POI) is a delicate medical problem in young women. This condition is not unchangeable and permanent but is associated with intermittent and unpredictable ovarian activity, resulting in low conception rate. Over the period of 8 years, the evaluation of secondary amenorrhea was conducted in 90 patients below the age of 40 who wished to restore fertility. Having confirmed the diagnosis and investigated the etiology of POI, hormone replacement therapy was applied (sequential administration of estradiol and norethisterone acetate) in the first 30 patients (group A). Estrogen-progestogen therapy with daily supplementation of 25 mg of micronized oral dehydroepiandrosterone (DHEA) was conducted in 44 patients (group B), whereas a combined regime (estrogen-progestogen therapy, DHEA supplementation in daily dose of 25 mg, and melatonin supplementation in daily dose of 3 mg) was conducted in 16 patients (group C). In the course of our study, 16 pregnancies were realized (18% of all cases: 17% in group A; 18% in group B; 19% in group C) 6 to 20 months after the initiation of hormone therapy, and there have been 13 completed term pregnancies so far with normal fetal growth and development. We concluded that estrogen-progestogen therapy combined with DHEA and melatonin could optimize fertility and lead to successful pregnancy in POI patients.

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations. TRIAL REGISTRATION NUMBER: NCT00925301; Pre-results.

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat.

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Soluble guanylate cyclase modulators in heart failure.

This review summarizes the role of soluble guanylate cyclase (sGC)-cyclic guanosine 3', 5'-monophosphate pathways in heart failure and several new drugs that modify guanylate cyclase. The sGC activators and stimulators as modulators of sGC are promising drugs in the therapy for decompensated heart failure and pulmonary hypertension. Cinaciguat is a nitric oxide (NO)-independent direct activator of sGC, which also may be effective under oxidative stress conditions resulting in oxidized or heme-free sGC refractory to organic nitrates. Riociguat is an NO-independent direct stimulator of sGC with beneficial effects in patients with decompensated heart failure and pulmonary hypertension. The sGC modulators play an important role in patients with heart failure and pulmonary hypertension.