Thomas Morrow, MD

When diet is not enough, a well known metabolic disorder can now be managed better through medication

Thomas Morrow, MD

Phenylketonuria (PKU) is a disease that most of the readers of this column have probably heard about as a result of having their own children screened for the condition at birth.

It is an inherited disease that follows simple Mendelian genetic inheritance patterns (remember the classroom discussions involving the Punnett square?) with 1 in 4 children who are born to carriers inheriting the disease. Prevalence varies from 1 in 12,000 to 1 in 25,000 births in the United States, with those of northern European and native American descent having a higher probability of having PKU than those of African, Hispanic, or Asian ancestry. There are an estimated 50,000 patients diagnosed with PKU in the developed world.

The cause of the disorder is a damaging mutation of the phenylalanine hydroxylase (PAH) gene that sits on chromosome 12. This gene codes for PAH, an enzyme that converts phenylalanine (Phe), an essential amino acid, to tyrosine (see “Role of Phenylalanine” below).

Role of phenylalanine

Phenylalanine is one of several amino acids that are critical to normal brain development and function. If the levels of Phe rise, as is the case for this disease, the brain can be irreparably damaged in early infancy. It appears that the amount of damage is related to the absolute levels of phenylalanine. Signs and symptoms include mental retardation, behavioral and social problems, seizures, tremors, hyperactivity, stunted growth, skin rashes, and microcephaly. A musty odor emanates from children afflicted with PKU. The distinctive odor is due to the secretion of phenylpyruvate, a ketone, which is excreted in increased amounts because of a secondary Phe metabolic pathway that converts Phe to phenylpyruvate.

PKU affects gray as well as white matter in the brain. Phe crosses the blood-brain barrier via specialized receptors that transport a number of large neutral amino acids. Phe has the greatest affinity for this receptor, and hence as phenylalanine levels increase, it appears that other amino acids, also essential for brain development and function, are prevented from entering the brain. This receptor also appears to transport neurotransmitter precursors such as L-DOPA. The end result of decreased essential amino acids and lack of precursors for neurotransmitters appears to explain the multiple central nervous system manifestations of PKU.


Until recently, the only treatment for those affected by PKU was a low phenylalanine diet, meaning a diet low in all major sources of protein, as well as foods containing flour and corn and some fruits and vegetables. For infants, this means a special formula with little or no breast milk. For older children and teenagers, food preparation involves careful measuring, calculating, and monitoring of day-to-day intake of phenylalanine. It also calls for routine monitoring of blood levels of phenylalanine to maintain levels within strict limits.

Diet therapy was originally thought to be needed only during early childhood development. It is now recommended that adults also follow a strict Phe diet.

But a Phe-controlled diet results in an increased carbohydrate intake that can lead to weight gain. Noncompliance is a huge problem because of the limits on the types and amounts of foods, as well as the palatability of the foods that are available.

New treatment

In December 2007, the FDA approved a new drug, sapropterin dihydrochloride (trade name Kuvan), just three years after the submission of the IND (investigational new drug) application. Kuvan is indicated to reduce blood levels of phenylalanine in patients with hyperphenylalaninemia because of BH4-responsive phenylketonuria. Kuvan is to be used in conjunction with a low-Phe diet. Kuvan works with the enzyme PAH to reduce Phe levels. Thus, if there is a total absence of PAH, or if the enzyme is damaged to a great extent, treatment with Kuvan will not lower Phe levels.

The recommended starting dose is 10 mg/kg/day taken once daily. Kuvan is available in 100 mg tablets. These are dissolved in either water or apple juice and taken at approximately the same time each day.

Phe serum levels should be measured before therapy is initiated, after one week of treatment, and periodically during the first month of treatment. If a dramatic response is noted, decreasing the dose to 5 mg/kg/day is recommended. If a response is not noted, increasing the dose to 20 mg/kg/day is recommended. Serum levels would be measured over the next month.

A >30 percent decrease in Phe level from baseline is considered a positive response. It is important to maintain a Phe-controlled diet during the initiation phase to correctly measure response to the drug. In clinical trials, 20 percent to 56 percent of PKU patients responded.

Side effects were not significantly different between the treated group and the placebo group in the double-blind, placebo-controlled study. There were slight differences in neutropenia, rhinorrhea, and pharyngolaryngeal pain. Kuvan has not been studied in pregnant women and nursing mothers or in children under 4 years of age. According to Form 8-K, released on Dec. 13, 2007, the price of Kuvan will be 29 cents per mg, which amounts to an average annual cost of $57,000 per patient.

Managed care implications

The development of Kuvan raises some interesting questions for managed care decision-makers. Should managed care restrict payment to just certain ages (study participants were ages 4–48)? Given the historical treatment with diet alone, should managed care require a supervised diet before initiating this therapy? Should patients who respond to an aggressive diet but cannot maintain compliance be denied coverage? Should long-term outcomes be proven for adults requesting therapy, as no long-term outcomes data were presented in the studies? Should a compliance program be initiated to ensure that best outcomes are maintained? Given that the endpoints did not include mental outcomes, what does a 30-percent reduction mean to the patient?

Although Kuvan does not cure PKU, and does not result in improvement of all patients with PKU, it does demonstrate how advances in the understanding of human biochemistry and genetics can lead to a successful approach to treating previously untreatable diseases. Although this product does not overcome the need for a strict diet, it does offer a therapeutic option when Phe level cannot be controlled through diet alone. It also underscores the way new developments continue to improve the hope and lives of people affected by genetic disease but add incremental costs to our already burdened payment system.

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 23 years of managed care experience at the payer or health plan level.
The author is a director in the value-based health department at Genentech Inc. During the last three years, before taking the Genentech position, he received honoraria or other financial benefits from: Amgen, Amylin Pharmaceuticals, AstraZeneca, Biogen Idec, Centocor, Galderma, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pfizer, Procter & Gamble, Q-Med, Sanofi-Aventis, Teva Pharmaceuticals Industries, UCB, and Wyeth. The views expressed in Tomorrow’s Medicine are the author’s alone.

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