Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat

被引：395

作者：

Germain, D. P. ^{[1
,2
]}

Hughes, D. A. ^{[3
]}

Nicholls, K. ^{[6
]}

Bichet, D. G. ^{[8
]}

Giugliani, R. ^{[9
]}

Wilcox, W. R. ^{[11
]}

Feliciani, C. ^{[13
]}

Shankar, S. P. ^{[11
,12
]}

Ezgu, F. ^{[14
]}

Amartino, H. ^{[15
]}

Bratkovic, D. ^{[7
]}

Feldt-Rasmussen, U. ^{[16
]}

Nedd, K. ^{[17
]}

El Din, U. Sharaf ^{[18
]}

Lourenco, C. M. ^{[10
]}

Banikazemi, M. ^{[19
]}

Charrow, J. ^{[20
,21
]}

Dasouki, M. ^{[22
]}

Finegold, D. ^{[23
]}

Giraldo, P. ^{[24
]}

Goker-Alpan, O. ^{[26
]}

Longo, N. ^{[27
]}

Scott, C. R. ^{[28
]}

Torra, R. ^{[25
]}

Tuffaha, A. ^{[22
]}

Jovanovic, A. ^{[4
]}

Waldek, S. ^{[5
]}

Packman, S. ^{[29
]}

Ludington, E. ^{[30
]}

Viereck, C. ^{[33
]}

Kirk, J. ^{[33
]}

Yu, J. ^{[33
]}

Benjamin, E. R. ^{[33
]}

Johnson, F. ^{[33
]}

Lockhart, D. J. ^{[31
]}

Skuban, N. ^{[33
]}

Castelli, J. ^{[33
]}

Barth, J. ^{[33
]}

Barlow, C. ^{[32
]}

Schiffmann, R. ^{[29
,34
]}

机构：

[1] Paris Saclay Univ, Univ Versailles, Div Med Genet, Versailles, France

[2] AP HP, Paris, France

[3] Royal Free & Univ Coll, Sch Med, Dept Acad Haematol, London, England

[4] Salford Royal NHS Fdn Trust, Salford, Lancs, England

[5] Univ Sunderland, Sunderland, England

[6] Royal Melbourne Hosp, Dept Nephrol, Parkville, Vic, Australia

[7] Womens & Childrens Hosp, Metab Clin, Adelaide, SA, Australia

[8] Hop Sacre Coeur, Div Clin Res, Montreal, PQ H4J 1C5, Canada

[9] Clin Hosp Porto Alegre, Med Genet Serv, Porto Alegre, RS, Brazil

[10] Univ Sao Paulo, Fac Med, Hosp Clin, Ribeirao Preto, Brazil

[11] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA

[12] Emory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USA

[13] Univ Parma, Dermatol Unit, Parma, Italy

[14] Gazi Univ, Dept & Lab Pediat Metab Disorders, Fac Med, Ankara, Turkey

[15] Hosp Aleman, Dept Pediat, Buenos Aires, DF, Argentina

[16] Copenhagen Univ Hosp, Rigshosp, Dept Med Endocrinol, Copenhagen, Denmark

[17] Infus Associates, Grand Rapids, MI USA

[18] Kasr El Ainy Hosp, Fac Med, Cairo, Egypt

[19] New York Presbyterian Hosp, New York, NY USA

[20] Ann & Robert H Lurie Childrens Hosp Chicago, Div Genet, Chicago, IL 60611 USA

[21] Northwestern Univ, Sch Med, Chicago, IL USA

[22] Univ Kansas, Med Ctr, Dept Urol, Kansas City, KS 66103 USA

[23] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA

[24] Hosp Miguel Servet, Zaragoza, Spain

[25] Univ Autonoma Barcelona, Fundacio Puigvert, E-08193 Barcelona, Spain

[26] O&O Alpan, Springfield, VA USA

[27] Univ Utah Hosp & Clin, Dept Pediat Genet, Salt Lake City, UT USA

[28] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[29] Univ Calif San Francisco, Div Pediat, San Francisco, CA 94143 USA

[30] Agil Clin, Carlsbad, CA USA

[31] TranscripTx, Sunnyvale, CA USA

[32] Parkinsons Inst & Clin Ctr, Sunnyvale, CA USA

[33] Amicus Therapeut, Cranbury, NJ USA

[34] Baylor Res Inst, Inst Metab Dis, Dallas, TX USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2016年 / 375卷 / 06期

关键词：

ENZYME REPLACEMENT THERAPY; AGALSIDASE BETA TREATMENT; NATURAL-HISTORY DATA; ALPHA-GALACTOSIDASE; GASTROINTESTINAL SYMPTOMS; NEPHROPATHY; PROGRESSION; PREVALENCE; EVENTS; SAFETY;

D O I：

10.1056/NEJMoa1510198

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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].)

引用

页码：545 / 555

页数：11

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