Washington Editor

BioMarin Pharmaceutical Inc. filed for FDA approval of its partnered phenylketonuria (PKU) product, the newly renamed Kuvan (sapropterin dihydrochloride).

Formerly called Phenoptin, the oral small molecule could be on the market by the end of the year if it receives a priority review. The company, of Novato, Calif., has requested that six-month timeline, and the FDA has 60 days to decide if its reviewers will complete their job by then.

BioMarin is gearing up to launch Kuvan late this year or soon after for the more than 12,000 patients in the U.S. with PKU, a lifelong disease characterized by serious neural complications brought on by abnormally high levels of the amino acid phenylalanine (Phe) in the blood and brain. They lack the enzyme phenylalanine hydroxylase, which is required to metabolize Phe.

Kuvan changes that dynamic. Its active ingredient is the synthetic form of 6R-BH4 (tetrahydrobiopterin), a naturally occurring enzyme cofactor that works to metabolize Phe, and clinical data suggested that Kuvan produces significant reductions in blood Phe levels in BH4-responsive patients.

"It's going to benefit different types of patients in different ways," said Stephen Aselage, BioMarin's senior vice president of global commercial operations. "For patients who have not been able to control their phenylalanine into target range and who are responsive to BH4, this is another tool [in addition to medical foods] that a clinician can use to help them get into a target range. For patients who have been able to keep Phe levels in a target range, this gives the clinician a tool to allow them to liberalize their diet."

In short, he told BioWorld Today that Kuvan could help PKU patients live more normal lives.

Because Phe is found in so many foods, patients start on restrictive diets that limit normal food intake from the day they're born; a newborn screening test has identified PKU patients for about 40 years. But Aselage said "the vast majority" eventually abandon their diets, against medical advice, because they're "so difficult to deal with."

An estimated 50,000 people around the developed world live with PKU, which causes severe mental retardation and brain damage, mental illness, seizures and tremors, and cognitive problems if Phe levels stay too high. The special formula and low Phe foods that help them avoid those problems cost about $10,000 annually.

But even among those with well-controlled Phe levels, Aselage said other consequences of PKU impact various social aspects of their lives, limiting their intellectual and functional capabilities, job pay, marriage opportunities and other social skills. "While the diet hits the really critical piece, the severe mental retardation, it's not an all-encompassing cure for the problems that afflict PKU patients," he said. "These patients just have a very, very difficult life."

The drug has fast-track status and orphan drug designation from the FDA, and also has orphan drug designation in Europe. Those latter provisions provide for seven years and 10 years of market exclusivity in those territories, respectively, upon approval.

Analysts have projected Kuvan to cost about $20,000 per year, and while Aselage declined to put a finger on what BioMarin would charge since the company is continuing to analyze pricing research, he conceded that it would be "reasonably expensive," which is the nature of so-called orphan disease treatments. But through payment support programs, he stressed that "we are going to make very, very sure that" regardless of cost, Kuvan's price tag would not impair a patient's ability to get access for any financial reason.

The new drug application, submitted as a fully electronic document, includes a set of preclinical, clinical and manufacturing-related data on Kuvan. Company officials met with FDA staff last fall to discuss the submission, and vital to the filing are findings from six successful studies in about 650 patients.

In one Phase III trial, patients receiving daily Kuvan doses of 10 mg/kg exhibited a 29 percent mean decrease in blood Phe level, down 236 mM, compared to a mean increase of 3 mM, or 3 percent, in placebo patients. In another Phase III study, conducted in juvenile patients, daily Kuvan doses of 20 mg/kg produced a mean increase of 20.9 mg/kg per day in Phe supplementation compared to placebo, and on average, those treated with the drug were able to double their baseline intake, and at week 10 they could tolerate a mean total Phe intake of about 43.8 mg/kg per day while maintaining controlled blood Phe levels. That average Phe tolerance represents about half the amount of daily Phe in a normal diet, which ranges between 80 mg/kg and 100 mg/kg. (See BioWorld Today, March 17, 2006, and Jan. 17, 2007.)

BioMarin has applied for approval of doses ranging between 5 mg/kg and 20 mg/kg, to allow physicians to titrate as needed to get patients into target Phe levels.

Kuvan has been developed in partnership with Merck Serono, of Geneva, which expects to file for European Union approval next quarter. BioMarin stands to receive milestone payments upon European filing and approval, but none for the FDA filing or approval. Daiichi Suntory Pharma Co. Ltd., of Tokyo, holds the drug's Japanese rights.

If approved by the FDA, Aselage said BioMarin would market the product alone in the U.S. The company's portfolio already includes a pair of approved products, Naglazyme (galsulfase) for mucopolysaccharidosis VI (MPS VI) and Aldurazyme (laronidase) for MPS I. BioMarin developed and commercializes the former on its own, while the latter was developed in concert with Cambridge, Mass.-based Genzyme Corp., which markets it.

Aselage said BioMarin would add a few new representatives to its existing 10-person sales staff in the U.S. to detail Kuvan, a benefit of an existing "footprint" with metabolic specialists who prescribe Naglazyme and also would prescribe Kuvan. Also, patients are relatively concentrated at a small number of PKU centers. In anticipation of launching the drug, the company is conducting message testing, market research and dealing with payers, and also has received FDA approval for an early access program through which it will supply Kuvan at no charge to a minimum of 500 patients until approval. In addition, several hundred more patients are getting it through open-label extensions of prior clinical studies. The drug was renamed because of a similarity to the name of another drug already on the market.

On Thursday, BioMarin's stock (NASDAQ:BMRN) closed at $18.11, down 28 cents.

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