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16 Jun 2009
New Study in Women with Fabry Disease, Demonstrates Significant Benefits of Treatment with REPLAGAL® (agalsidase alfa) 0.2mg/kg on Kidney Function, Heart Function and Burden of Disease

16 Jun 2009 - NOT FOR DISTRIBUTION TO U.S. MEDIA – NOT INTENDED FOR A U.S. AUDIENCE – Shire Human Genetic Therapies (HGT), a business unit of Shire plc, the global specialty biopharmaceutical company, today 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. 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

“Our study calls attention to the fact that while the onset and rate of disease expression in women may be more variable than that observed in men, women may experience a similar impact from Fabry disease and may benefit from long-term treatment with agalsidase alfa,” said Professor Christoph Kampmann.

Key findings from the study were:
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-center, 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.

About REPLAGAL (agalsidase alfa) 0.2mg/kg intravenous (iv) infusion
REPLAGAL (agalsidase alfa, Shire Human Genetic Therapies, Inc., Cambridge, MA, USA) 0.2mg/kg iv is a human form of GALA manufactured in a human cell line by gene activation, which is missing or deficient in patients with Fabry disease, a progressive and debilitating genetic disorder that interferes with the body’s ability to break down and metabolize globotriaosylceramide (Gb3). REPLAGAL is an ERT that is indicated for long-term ERT in patients with a confirmed diagnosis of Fabry disease (alfa-galactosidase A deficiency). ERT is generally well tolerated, and shows a beneficial effect over a wide range of the manifestations of Fabry disease.

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.

REPLAGAL 0.2mg/kg iv has been shown to provide significant long-term protection of kidney and cardiac structure and function and reducing the risk of heart failure. Additionally REPLAGAL 0.2mg/kg significantly improves quality of Life by reducing pain in men, women, and children (>7 years) with Fabry disease.

REPLAGAL 0.2mg/kg combines proven long-term tolerability with convenience: short infusion time
and low infusion volume

Important Safety Information

Replagal (agalsidase alfa) abbreviated prescribing information
Please consult the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Concentrate solution for IV infusion. 1 ml of concentrate for solution for infusion contains 1 mg of agalsidase alfa.

Indication: Long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency).

Dosage and administration: Replagal 0.2 mg/kg body weight by IV infusion over
40 min every other week.

Contraindications: Hypersensitivity to the active substance or any of the excipients.

Warnings & precautions: 13.7% of patients receiving Replagal in clinical trials had idiosyncratic infusion-related reactions (generally within 2–4 months of starting treatment although later onset [after 1 year] has been reported as well). These effects have decreased with time. If mild or moderate acute infusion reactions occur, seek medical attention immediately. The infusion can be temporarily interrupted (for 5–10 minutes) until symptoms subside. If severe allergic or anaphylactic-type reactions occur, discontinue Replagal immediately and initiate appropriate treatment. Patients may develop IgG antibodies to the protein. Extensive renal damage may limit the renal response to enzyme replacement therapy. Do not give Replagal together with chloroquine, amiodarone, benoquin or gentamicin because these substances can inhibit intracellular α-galactosidase activity. Studies in children aged 0–6 years have not been performed. A dose of 0.2 mg/kg is suggested for older children and adolescents (7–18 years). Caution should be exercised in pregnant or breast-feeding women.

Side effects: Most reported adverse effects have been mild to moderate. Very common (>1/10 patients): headache, flushes, nausea, rigors, pyrexia, pain/discomfort, fatigue; common (>1/100, <1/10 patients): peripheral oedema, dizziness, dysgeusia, neuropathic pain, tremor, hypersomnia, hypoesthesia, paraesthesia, increased lacrimation, tinnitus, tinnitus aggravated, tachycardia, palpitations, hypertension, cough, hoarseness, throat tightness, dyspnoea, nasopharyngitis, pharyngitis, increased throat secretion, rhinorrhoea, diarrhoea, vomiting, abdominal pain/discomfort, acne, erythema, pruritus, rash, livedo reticularis, musculoskeletal discomfort, myalgia, back pain, limb pain, peripheral swelling, arthralgia, joint swelling, aggravated fatigue, feeling hot, feeling cold, asthenia, chest pain, chest tightness, influenza-like illness, injection-site rash, malaise, decreased corneal reflex;
uncommon (>1/1000, <1/100 patients): parosmia, angioneurotic oedema, urticaria, sensation of heaviness, decreased oxygen saturation.

Package quantity and price: Vials of 5 ml (containing 3.5 ml concentrate) in pack sizes of 1, 4 or 10 vials. Price: £1068.64 for 5 ml vials.

Pharmaceutical precautions: Store in a refrigerator (2ºC–8ºC).

Marketing authorisation number and holder: EU/1/01/189/001-006. Shire Human Genetic Therapies AB, Svärdvägen 11D, 182 33 Danderyd, Sweden.

Legal category: POM
Further information is available in the Summary of Product Characteristics (SmPC), or on request from the marketing authorisation holder.

Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Shire Human Genetic Therapies on +44 (0)1256 894000 or faxed on +44 (0)1256 894715 or emailed to

For further information please contact:

Jessica Mann (Rest of the World) +44 1256 894 280
Jessica Cotrone (North America) +1 617 613 4640

Notes to editors


Shire’s strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit and hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire’s in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

For further information on Shire, please visit the Company’s website:


Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company’s Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company’s products; the Company’s ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company’s products; the Company’s ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company’s ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company’s filings with the Securities and Exchange Commission.

1. Whybra C, Kampmann C, Krummenauer F, Ries M et al. The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet 2004; 65:299 -307



16 Jun 2009 New Study in Women with Fabry Disease, Demonstrates Significant Benefits of Treatment with REPLAGAL® (agalsidase alfa) 0.2mg/kg on Kidney Function, Heart Function and Burden of Disease (90KB PDF)

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