It is unlikely that many people paid attention to the miracle that occurred last year with the approval and release of laronidase (alpha-L-iduronidase). Alpha-L-iduronidase is just an enzyme, and enzymes typically do not garner much attention from managed care medical and pharmacy directors. Certainly it did not attract much attention from the public. This medication is used to treat an autosomal recessive inherited disease that few health care providers ever remember hearing about. Even fewer have ever seen a person with the disease that is caused by the deficiency of this enzyme. It occurs in an estimated 1 in 100,000 to 1 in 280,000 births.
That means that the typical hospital in the United States will only oversee the birth of one affected infant every one to two decades. It means that only the largest national pediatric practices will ever see one of these children, literally only those practices with 50 to 100 physicians. To put this into perspective, cystic fibrosis, also an autosomal recessive genetic disease, occurs in 1 in 3,000 births.
The disease caused by a deficiency of alpha-L-iduronidase is also difficult to diagnose. Many of the early symptoms of this disease are common in the general population; frequent ear infections, upper airway obstruction, sleep apnea, malaise, and delayed development. Typically, the patient sees several physicians before being correctly diagnosed. The presumptive diagnosis is based on observation of the skeletal and facial features as well as history of symptoms. Obviously, a family history is helpful in some cases. A panel of laboratory tests is also helpful.
What is the disease? It is mucopolysaccharidosis I (MPS I), and it goes by several historical names: Hurler's syndrome, Hurler-Scheie syndrome, and Scheie syndrome. This is one of a family of more than 40 known inborn errors of metabolism called lysosomal storage disorders. Other mucopolysaccharidoses are numbered II, III, IV, VI, VII, and IX and are known as Hunter syndrome (MPS II), Sanfilippo syndrome (MPS III), Morquio syndrome (MPS IV), Maroteaux-Lamy syndrome (MPS VI) and Sly syndrome (MPS VII). Other lysosomal storage diseases include Gaucher disease, Fabry disease, Pompe disease, and Niemann-Pick disease. Collectively, these disorders occur in 1 in 7,700 births.
The enzyme alpha-L-iduronidase breaks down glycosaminoglycans (GAGs), complex substances found in all types of connective tissue. Without the needed enzyme, these substances start to build up at birth leading to the pathology. The manifestations are expressed in virtually all organs: brain, upper airway, lungs, heart, liver, spleen, and bones and joints, and result in profound skeletal abnormalities. The more severely affected infants are subject to severe mental retardation.
Obstructive airway disease, respiratory infections, and cardiac complications lead to death by age 10 in the most severe cases. Patients with less severe cases can live almost normal life spans and have near normal intellect and stature. Treatment, until recently, consisted of supportive care such as oxygen, physical therapy for the joints, and cardiac valve replacement. Bone marrow transplantation from a suitable non-deficient donor was also used to correct the enzyme deficiency.
The definitive diagnosis is made after assaying for alpha-L-iduronidase activity in leukocytes, cultured skin fibroblasts, or serum. This is markedly deficient in affected patients with less than 1 percent of normal activity measured. This can also be done by culturing chorionic villi or amniocytes during prenatal testing. The level of enzyme deficiency does not directly correlate with disease severity, indicating that there is still a lot to learn about the diseases caused by this deficient enzyme. A genetic mutation analysis is available but reserved for carrier detection as it is expensive and there are numerous potential point mutations that can cause the deficiency. This test has limited usefulness as the established mutations constitute only a fraction of known cases. Early diagnosis remains the key to preventing the irreversible damage.
As in most genetic diseases, there is more than one mutation that can lead to disease expression. In fact, for this disorder, there are more than 50 potential mutations that can lead to a deficiency in or decreased activity of alpha-L-iduronidase. The discovery of the fundamental flaws in the DNA again demonstrates that the advancements in the area of genetics and proteinomics are transforming medicine.
The full length of the gene coding for alpha-L-iduronidase was isolated in 1991 and production of recombinant alpha-L-iduronidase occurred in 1994. After nearly 10 years of study and testing, the FDA approved Aldurazyme, for release in the spring of 2003.
The complex protein is infused in a weekly, weight-based dosing regime. Once treatment starts, the accumulated GAGs are broken down and eliminated, leading to symptom improvement. Improvement is not uniform across all organ systems and varies from patient to patient. The endpoints in the clinical trials were improvement in forced vital capacity and 6-minute walking distance. Some damage, especially neurological, is most likely irreversible.
The best hope for most patients is early replacement with alpha-L-iduronidase to prevent the irreversible damage. Lifetime treatment is inevitable. Replacement of alpha-L-iduronidase offers hope for families who previously were helplessly watching their child deteriorate.
Obviously this therapy is expensive and unending. This offers challenges to managed care to ensure that proper access is achieved for this remarkable development in the lives of patients in a heretofore untreatable, progressive, and, in many cases, fatal childhood disease.
Aldurazyme does offer some relief to managed care from previously unavoidable costs such as tracheostomy and respiratory support, cardiac surgery, treatment of hydrocephalus, and around-the-clock nursing care. But, the overall lifetime cumulative costs are most assuredly higher than in the past. This is obviously a challenge to the long-term planners of medical benefits and trends.
The release of alpha-L-iduronidase also demonstrates the wave of future treatments for many other MPS diseases. In fact, Fabry disease also gained a new treatment last year after the FDA approved Fabrazyme, also manufactured by Genzyme. Fabry disease is an inherited disorder caused by the deficiency of the enzyme alpha-galactosidase A.
Other MPS disorders will benefit from the ongoing breakthroughs at Genzyme and other biotechnology companies over the next few years. These compounds will continue to change the lives of countless people who were destined to have a lifelong struggle with a genetic defect that would destroy their hopes, dreams, and lives. But that is not the end. In our lifetime, gene therapy will be sought for these diseases.
That is another subject for Tomorrow's Medicine.