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Combination Therapy Halts Kidney Function Loss in Genetic Disease


BIRMINGHAM, Ala. -- Enzyme replacement therapy plus two classes of renin inhibitors stabilized kidney function in patients with severe Fabry's nephropathy, researchers reported.

BIRMINGHAM, Ala., July 26 -- Enzyme replacement therapy plus two classes of rennin-inhibition drugs stabilized kidney function in patients with severe Fabry's nephropathy, researchers reported.

Adding agalsidase-? (Fabrazyme) to an ACE inhibitor and an angiotensin receptor blocker (ARB) produced a sustained reduction in proteinuria in six patients with severe Fabry's disease, David G. Warnock, M.D., of the University of Alabama here, and colleagues, reported in the September issue of the Journal of the American Society of Nephrology.

The treatment for Fabry's disease, an X-linked disorder caused by lysosomal-galactosidase A deficiency, carried an average yearly cost per patient of about ,000 a year, according to Genzyme, the drug's maker.

Previous placebo-controlled phase III and phase IV trials with agalsidase-? cleared globotriaosylceramide from vascular endothelia but had little effect on proteinuria or progressive loss of kidney function in Fabry's patients with overt proteinuria and/or an estimated glomerular filtration rate (GFR) of less than 60 ml/min per 1.73 m2 , the researchers said.

ACE or ARB therapy, or both, is the standard of care for patients with proteinuric kidney diseases, but their use is challenging in patients with Fabry's disease and low or low-normal baseline systemic blood pressure, said Dr. Warnock, a Genzyme consultant.

Experience with the earlier trials suggested that the beneficial effect of ACE-ARB therapy on improvement in GFR required optimal dosing of enzyme replacement therapy. ACE-ARB therapy could not be expected to slow disease progression in the absence of optimal dosing or even suboptimal doses of enzyme replacement therapy, the researchers said.

To facilitate comparison of these patients with the earlier phase IV trial, patients were originally divided into two groups, four with stages 1 and 2 chronic kidney disease, and seven with stages 3 and 4. One male patient with severe Fabry's nephropathy who developed severe pancreatitis and required dialysis dropped out.

All told, the open-label, nonrandomized, prospective study included 10 Fabry's patients with moderate or severe disease who could be fully analyzed. Patients were seen from August 2001 to October 2004, with the final visit in December 2006.

Patients received ACE or ARB therapy, or both, as well as agalsidase-?, given at 1 mg/kg body weight every two weeks for a mean of 30.3 months.

Six patients with severe Fabry's nephropathy achieved sustained reductions in proteinuria with kidney function stabilized, the researchers reported. Most of these patients were not overtly hypertensive.

The progression rate was -0.23 1.12 mL/min per 1.73 m2 per year, with 30 months of follow-up, the researchers reported.

Blood pressure reduction in patients with stages 3 and 4 severe chronic kidney disease limited the total dosing of ACE-ARB therapy, but the drugs were generally well tolerated.

There were no serious adverse events during the study other than occasional hypotensive symptoms that responded quickly to reduction in the ACE-ARB dosage.

The progression rate for patients with stage 3 and 4 (severe) chronic kidney disease (0.22 11.47 mL/min per 1.73 m2 per year) is better than that previously described in patients with moderately severe Fabry's nephropathy treated with enzyme replacement therapy but without antiproteinuric therapy, the researchers noted.

Efforts to replicate this single-center experience with a larger group of patients in a multicenter study is under way. That study is using combined agalsidase-? and ACE-ARB therapy in which the primary treatment effect will be sustained reduction in urinary protein/creatinine ratio of 0.5 g/g, or less, and the primary outcome is the rate of progression of the GFR, the researchers said.

Data collection, analysis of the results, and preparation of the manuscript were carried out independent of Genzyme.

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