Enzyme replacement therapy gives significant benefits for women with Fabry disease

18 June 2009

Shire Human Genetic Therapies (HGT), a business unit of Shire plc, has announced that results from an observational study published in the June 2009 print issue of Genetics in Medicine demonstrate that enzyme replacement therapy (ERT) with REPLAGAL 0.2mg/kg is effective in treating some of the signs and symptoms of Fabry disease in women.

Clinical benefits were measured, including stabilisation of kidney function and improvement in patients with stage 2 CKD, improvement in cardiac structure in some groups of patients, and reduction in pain and burden of disease.

The authors concluded that this observational study, which included 36 women and lasted for 4 years, indicates that women with signs and symptoms of Fabry disease should be considered for ERT with agalsidase alfa, noting that the patient population studied may not be representative of the general Fabry disease female population.

“Our research has generated meaningful, measureable data which shows that long-term treatment with agalsidase alfa stabilizes kidney function and improves heart function. This may result in important benefits for Fabry women, such as the reduced risk of heart failure.” said Professor Christoph Kampmann, MD, co-author of the study, Centre for Lysosomal Storage Diseases, Children’s Hospital of the Universitätsmedizin Johannes Gutenberg University, Mainz, Germany.

Because women are commonly described as “carriers” of Fabry disease, the true burden of their disease is often under estimated, which leads to delayed diagnosis and initiation of treatment, even though it is documented that without treatment, their lifespan is typically reduced by 15 years compared to the general population.1

“Like Dr Whybra et al physicians in the UK recognise that females can indeed carry a significant burden of Fabry disease requiring swift and correct diagnosis and management by an expert centre. This long-term study allows us to better understand how women suffering from the symptoms of Fabry disease may benefit from enzyme replacement therapy with agalsidase alpha and is consistent with our findings in the female patients we treat here” said Dr Derralynn Hughes, Senior Lecturer in Haematology, Lysosomal Storage Disorder Unit, Royal Free Hospital, London

“Until the year 2000 Fabry disease was rarely recognized as causing symptoms in women. The findings of this clinical trial recognizes that women can be symptomatic for Fabry disease and the burden of their disease can be very debilitating. This is what our Fabry members have been telling us for years “said Christine Lavery, Chief Executive, Society for Mucopolysaccharide Diseases

Key findings of the study

Agalsidase alfa stabilizes kidney function, improves heart function and reduces pain and severity of disease in Fabry women.

Kidney function

Stabilization or improvement in kidney function was found in more than 90 percent of the women in the study. Average eGFR (estimated glomerular filtration rate) was 91.0 ± 31.2 mL/min/1.73 m2/year at baseline and remained stable throughout the study. A subgroup of patients with moderately reduced renal function at baseline (Stage 2 CKD, eGFR >60 and < 90ml/min/1.73m2) demonstrated a significant increase in eGFR after 1 year of treatment, which was sustained through 4 years.

Reduction in proteinuria was also noted in patients with a baseline excretion of >300mg/day.

Cardiac structure and function

LVM was significantly reduced in patients with baseline LVH after 1 year of REPLAGAL, and remained reduced through the four years, with 52% of them showing decreases of LVM in excess of 20%. In addition, treatment with REPLAGAL resulted in clinical improvement of symptoms of heart failure for nearly one–third of the patients who were classified as having NYHA Class III heart failure at baseline. After four years of treatment with agalsidase alfa, only one patient remained in NYHA classification III, and no patients progressed to a more severe stage of heart failure.

Pain and burden of disease

Significant benefits with regard to severity of disease and quality of life were demonstrated. Mainz Severity Score Index (MSSI) significantly improved after 12 months of treatment (p< 0.01) and showed continued improvement over 4 years. Importantly, 12 out of 36 patients (33%) patients exhibited decreases in MSSI scores that moved them to a lower range of severity. Reduced Brief Pain Inventory (BPI) “pain at worst” was observed: score at baseline was 4.6± 2.9 and declined to 3.3± 2.9 after 12 months (P=0.001).

REPLAGAL was well-tolerated during the study. One patient experienced mild infusion reactions. No anti-agalsidase alfa antibodies were detected at any time during the treatment period. Five women experienced a stroke during the study (three of which had a history of stroke prior to initiating ERT).

Study limitations

The study was an open-label, observational clinical trial conducted in a single centre. This site is a referral centre, and therefore, the patient population may not be representative of the general female Fabry disease population. The study did not include a concurrently followed untreated control group, which limits the strength of the conclusions regarding the effect of agalsidase alfa on organ-system involvement in women with Fabry disease.

Study background

Published data represents analysis of a prospective, single-centre, open-label clinical trial that was performed to evaluate the long-term response of female Fabry disease patients to enzyme replacement therapy. All enrolled patients were treated with agalsidase alfa for 48 months.

Agalsidase alfa was administered at a dose of 0.2 mg/kg infused over 40 minutes every other week. Patients were assessed at baseline and at 12-month intervals. The following measurements were performed at baseline and 12-month intervals: eGFR and proteinuria, plasma Gb3 and urine Gb3, left ventricular mass and New York Heart Association functional score, Brief Pain Inventory (BPI) and Mainz Severity Score Index (MSSI).

eGFR was calculated using the abbreviated MDRD equation. A responder analyses was performed comparing final and baseline assessments and was expressed as mL/min/1.73 m2/year. Proteinuria was based on a 24-hour urine collection. LVM was assessed by standard echocardiographic techniques, calculated according to Devereux and was expressed as LVMi in g/m2.7.

About Fabry Disease

Fabry disease is a lysosomal storage disorder (LSD) that interferes with the body’s ability to break down specific fatty substances which accumulate within the body due to a specific enzyme deficiency. Fabry disease affects both males and females and can present with a number of signs or symptoms of variable degree, such as intense or burning pain, heat intolerance, skin lesions, gastrointestinal complaints, hearing loss, ocular problems, and cardiovascular and/or renal dysfunction.

The nature, severity and time of onset of signs and symptoms in patients with Fabry disease can vary considerably. Fabry disease affects an estimated 8,000 to 10,000 people worldwide and those with the disease are at risk of renal, cardiac, or cerebrovascular morbidity and premature death.

More information

REPLAGAL 0.2mg/kg iv is approved in more than 40 countries, including European countries, Canada, Argentina and Japan. REPLAGAL is not approved in the United States.

For further information on REPLAGAL for medical professionals and patients please see www.shire.com

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