In a one-two punch, FDA clears orphan drugs

Within the space of one week, Genzyme Corp. received clearance from the Food & Drug Administration to market two new drugs, Fabrazyme (agalsidase beta) and Aldurazyme (laronidase). Both are used to treat patients with rare lysosomal storage disorders. Fabrazyme offers new hope to patients with Fabry disease, and Aldurazyme may help those with mucopolysaccharidosis (MPS I). For each approval, Genzyme will receive seven years of orphan drug exclusivity.

Fabrazyme is a recombinant version of the essential enzyme alpha-galactosidase that patients with Fabry disease lack. With- out this enzyme, patients cannot break down a fatty substance called globotriasylceramide (GL-3). This substance then accumulates in cells within blood vessels in the heart, kidneys, and brain, often leading to stroke, heart attack, kidney damage, and severe pain. Occurring more often in males and affecting about 5,000 people worldwide, patients begin to show symptoms in childhood that progress into adulthood, typically resulting in death around age 50. Fabrazyme will offer the first disease-specific therapy to patients whose condition has been managed only symptomatically up until now.

The accelerated approval of Fabrazyme by the FDA was based partly on a phase III double-blind, placebo-controlled study of 58 Fabry disease patients, showing a marked decrease in GL-3 inclusions found in renal interstitial capillary endothelial cells. After six months of treatment in extension study involving the same patients, decreased GL-3 levels were also achieved in mesangial cells, glomerular capillary endothelium, interstitial cells, and noncapillary endothelium. As part of its approval commitment with the FDA, Genzyme must now complete a confirmatory safety and efficacy trial of 82 patients, verifying its clinical benefit by January 2004.

Fabrazyme was "approved on the basis of a surrogate endpoint, and we are now required to substantiate its efficacy through the completion of a postmarketing clinical trial," said Dan Quinn, associate director of public relations at Genzyme. "The trial is well under way. It is fully enrolled, and we are working very hard to ensure that is completed successfully by January," he said.

For Aldurazyme, postmarketing commitments include the completion of an ongoing study in patients under five years of age (now being conducted in Europe) as well as tracking patients' long-term experience with the drug through Genzyme's worldwide patient registry, Quinn added.

The availability of Aldurazyme, which will be manufactured by BioMarin Pharmaceutical and marketed by Genzyme, "represents the introduction of a specific treatment directed at the underlying basis of the disease," according to Gregory M. Pastores, M.D., director, neurogenetics unit, departments of neurology and pediatrics at New York University School of Medicine—in this case by replacing alpha L-iduronidase, an enzyme deficient in MPS I patients.

MPS I afflicts an estimated 3,000 to 4,000 people worldwide, including approximately 1,000 in the United States. Without the enzyme, patients lack the ability to break down a carbohydrate called glycosaminoglycan (GAG), which then accumulates, causing impaired heart and lung function, skeletal and joint deformities, delayed physical development, impaired vision, enlarged liver and spleen, and decreased mental function in severe cases. Death from complications usually occurs before adulthood.

Aldurazyme has been approved for use in both Hurler and Hurler-Scheie syndromes, the more severe forms of MPS I, and also for patients with the milder Scheie gentoype who have moderate to severe symptoms. In a phase III clinical trial and extension study of 45 patients, Aldurazyme improved lung function as measured by forced vital capacity (FVC) and improved mobility and endurance, measured by increased distance covered in a six-minute walk test. Improved ability to breathe during sleep also occurred in some patients with sleep apnea. It is anticipated that these improvements will translate into an enhanced quality of life, Pastores said, adding that he has also witnessed increased range of joint motion, improved growth pattern in prepubertal children, and reduction of liver size in some of his own patients.

Infusion-related reactions are common with both medications and for Fabrazyme can include tachycardia, fever, rigors, throat/ chest tightness, hypertension, pruritus, urticaria, dyspnea, myalgia, and abdominal pain. Infusion-reactions with Aldurazyme may include flushing, fever, headache, and rash. Pretreatment with antipyretics and/or antihistamines can help prevent these reactions.

Because Fabry disease can cause compromised cardiac function, and MPS I can lead to significant airway obstruction, many patients are at increased risk for developing severe complications from infusions of Fabrazyme and Aldurazyme, respectively. Often, however, these reactions can be minimized by slowing or temporarily stopping the infusion, or by administering additional antipyretics or antihistamines.

Other common side effects of Aldurazyme include rash, flushing, injection site reaction, and upper respiratory tract infection. Fabrazyme may cause bradycardia, ataxia, pain, stroke, cardiac arrhythmia, cardiac arrest, and nephrotic syndrome. Most patients receiving Fabrazyme or Aldurazyme will develop IgG antibodies to the medications, and although the clinical significance of this phenomenon is unknown, it will continue to be examined by Genzyme.

The recommended dosage of Fabrazyme is 1.0 mg per kilogram body weight every two weeks by intravenous infusion. The initial infusion rate should not exceed 0.25 mg per minute. The rate may be increased in subsequent infusions once patient tolerance has been established,

The appropriate initial dose of Aldurazyme is 0.58 mg per kilogram body weight administered once weekly by intravenous infusion at a rate of 10 mcg/kg/hr. As long as the patient's vital signs remain stable, this rate can be increased in 15-minute intervals to a maximum of 200 mcg/kg/hr. The entire infusion should be given over three to four hours.

Quinn estimates the annual medication cost for Fabrazyme at $180,000. He added that Genzyme has not yet released the price of Aldurazyme. The company has greatly enhanced its sales staff in recent months, he said, "building on a team that has been specializing in lysosomal storage diseases for more than a decade through the marketing and sale of Cerezyme (imiglucerase for injection, Genzyme) and its predecessor, Ceredase (alglucerase injection, Genzyme), for Type I Gaucher's disease."

Genzyme has selected TheraCom, a specialty pharmacy subsidiary of AdvancePCS, to provide a number of services to help support the introduction of both drugs in this country. These services include distribution of medication, reimbursement support, direct billing to insurers, nursing coordination, and information management.