For most of us in managed care, the mention of Pompe disease is likely to bring back long-faded memories from a genetics, cellular biology, or biochemistry course. We will perhaps remember Pompe disease as one of the rare autosomal recessive genetic diseases resulting from a lack of, or a defect in, the ability to synthesize the enzyme alpha-glucosidase.
We learned that the lack of alpha-glucosidase would lead to an accumulation of glycogen within the lysosomes. This enzyme is the first in the metabolic pathway leading to the breakdown of glycogen to glucose.
Our instructors may have chosen Pompe disease to use as an example in one of those "big B, little b" genetic inheritance grids to demonstrate the outcome of Mendel's classic pea experiment. If both parents were carriers, then one in four offspring would suffer from the disease, two would be carriers, and one would be free of the defective gene.
During our pediatric rotation, we learned about it again from a different perspective — as a differential diagnosis for any infant who failed to thrive or presented with rapid onset of profound hypotonia (muscle weakness or "floppy baby" syndrome), or had evidence of marked cardiomegaly on chest X-ray and respiratory problems.
At that time it was one of those "diagnose and adios" diseases. Since it was a genetic disorder with no available definitive treatment, there were more important diseases on which to focus — diseases that we could actually diagnose and treat. With an incidence of about one in every 138,000 births, it is unlikely that any readers of this column have ever seen the infantile form of Pompe disease during their clinical career. Those who did would refer the parents to a genetic counselor.
That has all changed. As with several other rare genetic diseases such as MPS III, Gaucher's, and Fabry's, parents of children with Pompe's disease now will be told that their child has some hope for survival. The FDA approval of alglucosidase alfa (Myozyme) has given these infants a replacement for their defective enzyme.
Myozyme's approved indication is "for use in patients with Pompe disease (GAA deficiency)." Myozyme has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease compared to untreated historical controls. Myozyme, a lyophilized powder produced by recombinant DNA technology in a Chinese hamster ovary cell line, is administrated intravenously every two weeks over approximately four hours in a dose of 20 mg/kg. The initial infusion rate should be no more than 1 mg/kg/hr and can be increased every 30 minutes to a maximum of 7 mg/kg/hr after tolerance to the infusion is established.
After infusion, the enzyme binds to receptors on the cell surface and is transported into the cell where it undergoes proteolytic cleavage and exerts its enzymatic activity on glycogen.
The prescribing information for Myozyme describes the following studies — two pharmacokinetic studies involving 13 patients and 14 patients respectively, and two separate clinical trials in 39 patients with Pompe disease ranging in age from 1 month to 3.5 years. The first clinical trial was an international, multicenter, open-label trial with 18 infantile-onset patients with cardiac hypertrophy under the age of 7 months who did not require ventilatory support. The trial randomized the patients to either 20mg/kg or 40 mg/kg doses every two weeks with the length of therapy ranging from 52 to 104 weeks. Efficacy was assessed by comparing the proportions of Myozyme-treated patients who died or needed invasive ventilatory support with patients of similar age and disease severity.
In the historical control, of 61 patients, only one was still alive by age 18 months. In the treated group, 3 of 18 patients required invasive ventilatory support and all were still alive. With continued treatment beyond 12 months, four additional patients required invasive ventilatory support after receiving between 13 and 18 months of active therapy. Two of these four patients died after receiving 14 and 25 months of therapy. No other deaths have been reported through a median follow-up of 20 months.
The second clinical trial is an ongoing, international, multicenter, nonrandomized, open-label trial with 21 patients ages 3 months to 3.5 years at the time of the first treatment. Of the 21, five were receiving invasive ventilatory support at the time of the first infusion of Myozyme. At the 52-week interim analysis, 16 of 21 patients were still alive. Further analysis is pending upon completion of the trial.
There are numerous implications for managed care decision makers. First, acid alpha glucosidase (GAA) enzyme activity testing is likely to increase now that there is a therapy available. Progressive health plans will develop standards for the testing and integrate these standards into their overall management strategy for genomic-based disorders.
Results of long term replacement with Myozyme are unknown. Will it lead to a normal lifespan and normal development, or will these children experience ongoing difficulties leading to progressive disability? The studies only hint at the answer to these questions.
The demand for this drug will probably expand beyond the infantile age group to the late onset population. It is likely that soon after introduction, most plans will be faced with requests for use in teenagers and older adults. How should you react? The prescribing information clearly states that approval by the FDA was based only on infantile-onset Pompe disease, but as with all enzyme deficiencies, replacing the enzyme to reach normal physiological activity is logical and likely to be requested by both physicians and patients.
Should you deny payment for other forms of the disease based upon lack of studies, or will your understanding of the basic genetic and pathophysiologic characteristics of the disease lead you to approve replacement for all patients with proven deficiency of the enzyme? At what level of enzyme activity will you approve it? How will you follow the outcome of the disease? These questions will become more acute after looking at the cost of therapy. For a hypothetical infant weighing 5 kilograms, at 20 mg/kg per dose, with 26 doses per year at the manufacturer's price of $600 per 50 mg, the yearly cost is $31,200.
In a 70 kg adult, assuming the mg/kg dose remains constant, the cost jumps to $436,800 per year. Although this number is staggering, with an incidence of 1 in 57,000 people, the late onset form of the disease will add about $7.50 per member per year to the overall cost of care. Is it worth it? Will managed care plans pay it? How will employers react? What will happen in the benefit design arena related to costly drugs?
As mankind explores deeper into the human genome, we will develop therapies for ever increasingly rare disorders. Managed care decision makers will be faced with these as well as numerous other ethical and financial questions, making for many more discussions about and within Tomorrow's Medicine.