Treatment of Anderson–FabrydiseaseAles Linhart

Anderson–Fabry disease (AFD) (OMIM301500), is an X-linked, metabolic dis-order characterised by a defect in thedegradation of glycosphingolipids withterminal a-galactose residues that leadsto progressive intralysosomal accumula-tion of globotriaosylceramide (Gb3) invarious tissues of the human body(mainly skin, nervous system, eye, kidneyand heart). The underlying cause is amutation in the gene encoding the lyso-somal enzyme a-galactosidase A. Themultisystemic involvement in classicallyaffected men leads to premature deathduring the fourth or fifth decade due torenal failure, cerebrovascular and cardiaccomplications. Heterozygous femalepatients may have a wide range of diseaseseverity, ranging from a relatively benigncourse to manifestations comparable withthose of hemizygous men.1

Cardiovascular involvement is complexas Gb3 storage occurs in a wide spectrumof myocardial tissues, including endothe-lial cells and vessel walls, cardiomyocytes,conduction system cells and valvularfibroblasts. Main clinical manifestationsinclude left ventricular hypertrophy asso-ciated with diastolic dysfunction andsymptoms of heart failure; decreasedcoronary flow reserve caused either byfunctional impairment or fixed stenoticlesions of large epicardial coronaryarteries; and arrhythmias.2

Recent advances in molecular genetictechniques have led to the development ofenzyme replacement therapy (ERT) byrecombinant a-galactosidase A. Based onhuman studies showing promising histo-logical and clinical changes, two enzymepreparations have been approved for thetreatment of AFD in Europe: agalsidasealfa (Replagal, Shire Human Genetics,Cambridge, MA, USA) and agalsidase beta(Fabrazyme, Cambridge, MA, USA). Inthe United States only agalsidase beta hasbeen approved. Agalsidase alfa is theproduct of a continuous line of humanfibroblasts, given biweekly in a dose of0.2 mg/kg. Agalsidase beta is produced bycDNA transduction in Chinese hamster

ovary cells, administered biweekly in adose of 1.0 mg/kg. Although both pro-teins have identical amino acid sequences,they differ in their glycosylation owing topost-translational changes. A controversypersists about whether the enzymes differin their ability to reach relevant targetcells. Both enzymes have been shown toinduce cross-reactive IgG antibody forma-tion in up to 70% of male patients. Thecross-reactivity indicates that antibodiesare focused on an epitope that is evenlyexpressed in both preparations. Althoughthese antibodies exhibit neutralising capa-cities in vitro, their relevance in vivoremains unknown.3

Until now, several clinical trials andmany observational studies documentingERT efficacy and safety have been pub-lished. Unfortunately, none of the rando-mised trials focused primarily on cardiacmanifestations.

In the 24-week randomised trial usingagalsidase alfa in 26 male patients, thetreatment reduced the level of Gb3 inplasma, improved kidney histologicalfindings, stabilised renal function andameliorated pain scores and pain-relatedquality of life. The only cardiovascularobservation included a narrowing of theQRS complex and one patient resolved aright-bundle branch block in the open-label extension of the study.4

Cardiac microvascular endothelialdeposits were set as a secondary objectivein the phase 3 randomised trial usingagalsidase beta including 58 patients withAFD. The treatment led to a steepdecrease in plasma Gb3 and improvementin pain and quality of life. After 20 weeksof treatment an effective clearance ofendothelial Gb3 deposits was shown inthe kidney, skin and heart biopsy sam-ples.5

A recently published randomised pla-cebo-controlled trial using agalsidase betaincluded 82 patients with mild to moder-ate kidney disease randomised in a 2:1ratio with median time in treatment of18.5 months. The primary composite endpoint included renal, cardiac and cerebro-vascular events. After adjustment forbaseline proteinuria, the treatment wasshown to delay the time to first clinical

event. However, the difference in cardiacend points alone, although showing ahazard ratio of 0.42, did not reachsignificance (95% CI 0.058 to 2.7,p = 0.42).6

Observational data from registries andopen-label studies have repeatedly showna decrease in left ventricular mass (LVM).7

A significant improvement of cardiacsystolic performance was shown in asingle-centre study using strain rate ima-ging.8 Disappointing results were obtainedby two small independent observationalstudies evaluating the effects of ERT oncoronary flow reserve.9 10 Several short-comings limit the usefulness of theobservational data at our disposal.Single-centre studies constantly havesmall study samples. Data from registriesare supported by assessments frequentlyrelying on imaging techniques, echocar-diography in particular. These are knownto have limited reproducibility, even moreso if data are provided from many centres.Another limitation is the uncontrollednature of the data and inevitable incom-pleteness of the follow-up. Moreover,most observational studies rely only onsurrogate end points, such as reductionsin LVM. Unfortunately, as yet very littleis known about changes in cardiac clinicalevents and functional capacity induced bythe ERT. Last but not least, many studiesincluded not only hemizygous men butalso heterozygous women. In women, thedisease severity is more heterogeneousand most clinical end points occur lateror in milder forms. In addition, owing topersistent residual enzyme activity,women are not prone to develop anti-bodies against ERT. Therefore, includingwomen in clinical studies may produceunpredictable effects on their final out-come.

The study by Hughes and coworkerspublished in this issue of Heart is the firstrandomised study which aims at clarify-ing the impact of ERT on cardiac struc-ture (see article on page 153).11

Therefore, their observation showing asignificant reduction in LVM is of parti-cular importance. The authors used mag-netic resonance, which is the preferredmethod and has the highest reproducibil-ity for LVM assessment. Although smalland not achieving the planned number ofpatients, the population was homoge-neous, including only male patients,mostly with left ventricular hypertrophy.Thus the main limitation of the trial wasthe short duration of its randomisedphase, lasting only 6 months.

Correspondence to: Professor A Linhart, U Nemocnice2, Prague 2, 12808 Czech Republic; ales.linhart@vfn.cz

Editorial

138 Heart February 2008 Vol 94 No 2

group.bmj.com on September 27, 2014 - Published by heart.bmj.comDownloaded from

The study also attempted to verifychanges in intramyocardial Gb3 storage.Despite the difference seen among studyarms (+10% in the placebo group vs –20%in the agalsidase alfa treatment group) theresult did not reach the statistical sig-nificance. Although this might be due tothe small number of patients and shortstudy duration, the heart appears to be apotentially difficult target for the enzymesubstitution.

A recently published autopsy reportshowed extensive Gb3 lysosomal inclu-sions in cardiomyocytes despite 2.5 yearsof ERT by agalsidase beta.12 This is inagreement with our observations fromhistological specimens taken during car-diac surgery from ERT-treated patients.Unfortunately, although cardiac biopsyspecimens were obtained also during therandomised agalsidase beta trial, onlyendothelial, but not cardiomyocyte, sto-rage changes were described.5 Thus theavailable evidence suggests that at least insome patients the enzyme has limitedaccess to non-vascular cardiac tissues.

Another factor influencing limitedclearance from cardiomyocytes is theminimal cellular turnover within themyocardium. As a consequence, the tissueclearance would require reparation ofinfiltrated cells instead of their replace-ment by new undamaged cell lines devel-oping under ERT. On the other hand,clearance of the lysosomes is not necessa-rily the ultimate goal of the treatment. Asthe total amount of Gb3 does not entirelyexplain the severity of the LVM increase,the hypertrophy probably reflects a non-specific compensatory reaction to theinitial functional impairment induced bythe storage.13 We can hypothesise that thereductions in LVM seen under ERT arenot due to the clearance of the myocar-dium but to the functional improvementat the cellular level. The supposed limitedaccess of the enzyme to the myocardialtissue raises a question about the useful-ness of treatment of the AFD cardiacvariant as in these patients storage may belimited to the cardiomyocytes.13

A large majority of the above-men-tioned trials included patients with

advanced disease. Cardiac magnetic reso-nance studies using gadolinium haveshown large areas of late enhancement,in particular within the posterolateralbasal part of the left ventricle. Thesefindings correspond to myocardial fibrosisand were seen mostly in patients withadvanced disease. Autopsy reports indi-cate that fibrosis extends even outside thelate enhancement areas and represents aubiquitous process.14 Fibrotic changes areusually considered to be irreversible andmay explain why treatment is not ade-quate for some patients.15 A similarpattern was seen in the recently publishedrandomised trial with agalsidase beta.Most of the beneficial effect of ERT wasdocumented in patients with mild renaldeterioration with glomerular filtrationrates greater than 55 ml/min per 1.73 m2.In contrast, patients whose renal functionwas below this threshold showed virtuallyno benefit of the treatment.6 This suggeststhat introduction of ERT in the early phasesof the disease would be more effective thanwaiting until measurable organ damagedevelops. Preliminary reports on the effi-cacy and safety of ERT in children suggestthat this strategy would be feasible.16 Itslong-term, organ-protective effects, how-ever, remain to be documented.

Assessment of the clinical efficacy ofERT is the major concern. The high costof lifelong treatment should be supportedby sound evidence of reduction of clinicalevents and prolongation of life expecta-tion. Recent evidence suggests that thecommon practice of treating advanceddisease might be ineffective and ERTshould be considered as preventive thancurative medication. The study byHughes and coworkers contributes signif-icantly to the effort made to determinethe extent of end-organ damage suscep-tible to respond to the available ERT.

Competing interests: AL is a member of the executivecommittee of the Fabry Outcome Survey, supported byShire Human Genetic Therapies (previously TranskaryoticTherapies Inc.). As an employee of Charles University,Prague, CZ, AL does not receive compensation fromShire Human Genetic Therapies. The company has paidhis travel expenses to meetings related to the researchcollaboration.

Heart 2008;94:138–139. doi:10.1136/hrt.2006.113886

REFERENCES1. Mehta A, Ricci R, Widmer U, et al. Fabry disease

defined: baseline clinical manifestations of 366patients in the Fabry Outcome Survey. Eur J ClinInvest 2004;34:236–42.

2. Linhart A, Lubanda JC, Palecek T, et al. Cardiacmanifestations in Fabry disease. J Inherit Metab Dis2001;24(Suppl 2):75–83.

3. Linthorst GE, Hollak CE, Donker-Koopman WE, et al.Enzyme therapy for Fabry disease: neutralizingantibodies toward agalsidase alpha and beta. KidneyInt 2004;66:1589–95.

4. Schiffmann R, Kopp JB, Austin HA 3rd, et al.Enzyme replacement therapy in Fabry disease: arandomized controlled trial. JAMA 2001;285:2743–9.

5. Eng CM, Guffon N, Wilcox WR, et al. Safety andefficacy of recombinant human alpha-galactosidaseA—replacement therapy in Fabry’s disease.N Engl J Med 2001;345:9–16

6. Banikazemi M, Bultas J, Waldek S, et al. FabryDisease Clinical Trial Study Group. Agalsidase-betatherapy for advanced Fabry disease: a randomizedtrial. Ann Intern Med 2007;146:77–86.

7. Beck M, Ricci R, Widmer U, et al. Fabry disease:overall effects of agalsidase alfa treatment. Eur J ClinInvest 2004;34:838–44.

8. Weidemann F, Breunig F, Beer M, et al.Improvement of cardiac function during enzymereplacement therapy in patients with Fabry disease: aprospective strain rate imaging study. Circulation2003;108:1299–301.

9. Elliott PM, Kindler H, Shah JS, et al. Coronarymicrovascular dysfunction in male patients withAnderson–Fabry disease and the effect of treatmentwith alpha galactosidase A. Heart 2006;92:357–60.

10. Kalliokoski RJ, Kantola I, Kalliokoski KK, et al. Theeffect of 12-month enzyme replacement therapy onmyocardial perfusion in patients with Fabry disease.J Inherit Metab Dis 2006;29:112–8.

11. Hughes DA, Elliott PM, Shah J, et al. Effects ofenzyme replacement therapy on the cardiomyopathyof Anderson–Fabry disease: a randomized, double-blind, placebo-controlled clinical trial of agalsidase-alfa. Heart 2008;94:153–8.

12. Schiffmann R, Rapkiewicz A, Abu-Asab M, et al.Pathological findings in a patient with Fabry diseasewho died after 2.5 years of enzyme replacement.Virchows Arch 2006;448:337–43.

13. Elleder M. Sequelae of storage in Fabry disease—pathology and comparison with other lysosomalstorage diseases. Acta Paediatr Suppl. 2003;92:46–53.

14. Moon JC, Sheppard M, Reed E, et al. The histologicalbasis of late gadolinium enhancement cardiovascularmagnetic resonance in a patient with Anderson–Fabrydisease. J Cardiovasc Magn Reson 2006;8:479–82.

15. Beer M, Weidemann F, Breunig F, et al. Impact ofenzyme replacement therapy on cardiac morphologyand function and late enhancement in Fabry’scardiomyopathy. Am J Cardiol 2006;97:1515–8.

16. Ramaswami U, Wendt S, Pintos-Morell G, et al.Enzyme replacement therapy with agalsidase alfa inchildren with Fabry disease. Acta Paediatr2007;96:122–7.

Editorial

Heart February 2008 Vol 94 No 2 139

group.bmj.com on September 27, 2014 - Published by heart.bmj.comDownloaded from

doi: 10.1136/hrt.2006.113886 2008 94: 138-139Heart

 Ales Linhart 

Fabry disease−Treatment of Anderson

http://heart.bmj.com/content/94/2/138.full.htmlUpdated information and services can be found at:

These include:

References

http://heart.bmj.com/content/94/2/138.full.html#related-urlsArticle cited in:  

http://heart.bmj.com/content/94/2/138.full.html#ref-list-1This article cites 16 articles, 3 of which can be accessed free at:

serviceEmail alerting

the box at the top right corner of the online article.Receive free email alerts when new articles cite this article. Sign up in

CollectionsTopic

(4371 articles)Clinical diagnostic tests   � (2679 articles)Hypertension   �

(923 articles)Metabolic disorders   � (7898 articles)Drugs: cardiovascular system   �

 Articles on similar topics can be found in the following collections

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.com on September 27, 2014 - Published by heart.bmj.comDownloaded from