Washington Editor

BioMarin Pharmaceutical Inc. put out positive Phase III data on Phenoptin (sapropterin dihydrochloride) in juvenile phenylketonuria (PKU) patients who have elevated phenylalanine (Phe) levels, underscoring the drug's ability to give them more dietary freedom.

In the genetic disorder, which afflicts about 50,000 people in the developed world, Phe reaches abnormally high levels in the blood and brain and causes a variety of serious neural complications. As a result, restrictive diets are used as a standard treatment for the lifelong disease.

The study showed that the investigational small molecule significantly increased Phe tolerance and reduced blood Phe levels in 4- to 12-year-old patients, which in turn provided a lifestyle benefit in allowing many of them to relax their low-protein, high-carbohydrate diets.

"These data represent a substantial step forward," CEO Jean-Jacques Bienaime said in a conference call on Tuesday. Noting that PKU dietary restrictions create "real challenges" for compliance, he pointed to the importance of liberalizing those limitations. Those data, he added, "will be very important for driving adoption and reimbursement" of Phenoptin.

"This study is just further proof that [Phenoptin] is safe and effective," said Eugenia Shen, the company's manager of investor relations, "and good for the younger population as well."

Medical foods cost about $10,000 per year, and analysts are projecting the drug to cost about $20,000 per year.

Wrapping up the trial, which follows on past Phase III successes, represents the end of Phenoptin's clinical program, which is partnered with Merck Serono. BioMarin, of Novato, Calif., expects to file for FDA approval by the end of June, and Merck Serono, of Geneva, is scheduled to file for European approval in the third quarter.

BioMarin plans to market the product alone in the U.S. Shen told BioWorld Today approval is expected by the end of the year. Daiichi Suntory Pharma Co. Ltd., of Tokyo, holds the drug's Japanese rights.

In the study's primary endpoint, daily Phenoptin doses of 20 mg/kg produced a mean increase of 20.9 mg/kg per day in Phe supplementation compared to placebo (p<0.001). On average, patients 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.

In addition, the study met its two secondary endpoints: Phenoptin provided a mean reduction of 148.5 micromolars per liter from a starting mean of 275.7 micromolars per liter in blood Phe level from baseline to the third week, prior to Phe supplementation (p<0.001). Also, at the end of the study, Phenoptin patients were able to increase their mean daily Phe supplement by an average of 20.9 mg/kg compared to 2.9 mg/kg for placebo patients (p<0.001). The data also showed that Phenoptin was well tolerated in younger PKU patients who were under dietary control.

The drug has orphan drug designation from the FDA and European regulators, as well as fast-track designation in the U.S. Phenoptin is the synthetic form of a naturally occurring enzyme called tetrahydrobiopterin, or 6R-BH4, that works in conjunction with phenylalanine hydroxylase to metabolize Phe. It's expected to be a potential treatment option for about 30 percent to 50 percent of PKU patients.

BioMarin, which also has a preclinical enzyme replacement therapy for those not responsive to BH4 treatment, Phenolase, enrolled patients with Phe levels below 480 micromolars per liter of blood in the 11-week study. Initially, they were screened for Phenoptin responsiveness with one week of open-label treatment. Of the 89 who completed that portion of the study, 50 demonstrated a blood Phe reduction of at least 30 percent and 45 were randomized 3:1 to receive Phenoptin or placebo. For the first three weeks, patients maintained their pre-existing restricted diet with no supplementation of phenylalanine, after which specific amounts of phenylalanine were added or removed to their restricted diets every other week, according to pre-defined blood phenylalanine levels. The maximum daily amount of Phe that could be added was 50 mg/kg.

In the prior Phase III study, daily Phenoptin doses of 10 mg/kg reduced Phe levels at six weeks by 236 micromolars compared to a 3 micromolar increase among placebo patients (p<0.0001). Those pivotal data, released last spring, boosted BioMarin's stock by 11.8 percent to $13.92. (See BioWorld Today, March 17, 2006.)

On Tuesday, the company's shares (NASDAQ:BMRN) gained 24 cents to $17.91.