Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat
Por:
Germain, DP, Hughes, DA, Nicholls, K, Bichet, DG, Giugliani, R, Wilcox, WR, Feliciani, C, Shankar, SP, Ezgu, F, Amartino, H, Bratkovic, D, Feldt-Rasmussen, U, Nedd, K, El Din, US, Lourenco, CM, Banikazemi, M, Charrow, J, Dasouki, M, Finegold, D, Giraldo, P, Goker-Alpan, O, Longo, N, Scott, CR, Torra, R, Tuffaha, A, Jovanovic, A, Waldek, S, Packman, S, Ludington, E, Viereck, C, Kirk, J, Yu, J, Benjamin, ER, Johnson, F, Lockhart, DJ, Skuban, N, Castelli, J, Barth, J, Barlow, C, Schiffmann, R
Publicada:
11 ago 2016
Resumen:
BACKGROUND
Fabry's disease, an X-linked disorder of lysosomal alpha-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of alpha-galactosidase, increasing enzyme trafficking to lysosomes.
METHODS
The initial assay of mutant alpha-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 alpha-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 alpha-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 alpha-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 alpha-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].)
Filiaciones:
Germain, DP:
Paris Saclay Univ, Univ Versailles, Div Med Genet, Versailles, France
AP HP, Paris, France
Hughes, DA:
Royal Free & Univ Coll, Sch Med, Dept Acad Haematol, London, England
Nicholls, K:
Royal Melbourne Hosp, Dept Nephrol, Parkville, Vic, Australia
Bichet, DG:
Hop Sacre Coeur, Div Clin Res, Montreal, PQ H4J 1C5, Canada
Giugliani, R:
Clin Hosp Porto Alegre, Med Genet Serv, Porto Alegre, RS, Brazil
Wilcox, WR:
Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA
Feliciani, C:
Univ Parma, Dermatol Unit, Parma, Italy
Shankar, SP:
Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA
Emory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USA
Ezgu, F:
Gazi Univ, Dept & Lab Pediat Metab Disorders, Fac Med, Ankara, Turkey
Amartino, H:
Hosp Aleman, Dept Pediat, Buenos Aires, DF, Argentina
Bratkovic, D:
Womens & Childrens Hosp, Metab Clin, Adelaide, SA, Australia
Feldt-Rasmussen, U:
Copenhagen Univ Hosp, Rigshosp, Dept Med Endocrinol, Copenhagen, Denmark
Nedd, K:
Infus Associates, Grand Rapids, MI USA
El Din, US:
Kasr El Ainy Hosp, Fac Med, Cairo, Egypt
Lourenco, CM:
Univ Sao Paulo, Fac Med, Hosp Clin, Ribeirao Preto, Brazil
Banikazemi, M:
New York Presbyterian Hosp, New York, NY USA
Charrow, J:
Ann & Robert H Lurie Childrens Hosp Chicago, Div Genet, Chicago, IL 60611 USA
Northwestern Univ, Sch Med, Chicago, IL USA
Dasouki, M:
Univ Kansas, Med Ctr, Dept Urol, Kansas City, KS 66103 USA
Finegold, D:
Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA
Giraldo, P:
Hosp Miguel Servet, Zaragoza, Spain
Goker-Alpan, O:
O&O Alpan, Springfield, VA USA
Longo, N:
Univ Utah Hosp & Clin, Dept Pediat Genet, Salt Lake City, UT USA
Scott, CR:
Univ Washington, Dept Pediat, Seattle, WA 98195 USA
Torra, R:
Univ Autonoma Barcelona, Fundacio Puigvert, E-08193 Barcelona, Spain
Tuffaha, A:
Univ Kansas, Med Ctr, Dept Urol, Kansas City, KS 66103 USA
Jovanovic, A:
Salford Royal NHS Fdn Trust, Salford, Lancs, England
Waldek, S:
Univ Sunderland, Sunderland, England
Packman, S:
Univ Calif San Francisco, Div Pediat, San Francisco, CA 94143 USA
Ludington, E:
Agil Clin, Carlsbad, CA USA
Viereck, C:
Amicus Therapeut, Cranbury, NJ USA
Kirk, J:
Amicus Therapeut, Cranbury, NJ USA
Yu, J:
Amicus Therapeut, Cranbury, NJ USA
Benjamin, ER:
Amicus Therapeut, Cranbury, NJ USA
Johnson, F:
Amicus Therapeut, Cranbury, NJ USA
Lockhart, DJ:
TranscripTx, Sunnyvale, CA USA
Skuban, N:
Amicus Therapeut, Cranbury, NJ USA
Castelli, J:
Amicus Therapeut, Cranbury, NJ USA
Barth, J:
Amicus Therapeut, Cranbury, NJ USA
Barlow, C:
Parkinsons Inst & Clin Ctr, Sunnyvale, CA USA
Schiffmann, R:
Univ Calif San Francisco, Div Pediat, San Francisco, CA 94143 USA
Baylor Res Inst, Inst Metab Dis, Dallas, TX USA
Bronze, Green Published
|