In just more than a year, BioMarin Pharmaceutical Inc. has advanced its small-molecule drug, Phenoptin, from preclinical development into a pivotal trial to treat the genetic disorder phenylketonuria (PKU).
The company has randomized the first patient in its Phase III trial for Phenoptin (sapropterin hydrochloride), which has received orphan drug designation and could end up being the first drug to treat the mild to moderate form of the disease.
"Patients and doctors have been very excited about seeing this product moved ahead, and we're happy to make it happen for them," said Emil Kakkis, senior vice president of business operations at BioMarin, adding that the only existing treatment available consists of restrictive diets and "most patients, especially the adolescents and adults, are not able to comply with the diet."
The trial is expected to enroll about 100 PKU patients who demonstrated a reduction in blood Phe, or phenylalanine, levels in BioMarin's Phase II trial, and who have blood Phe levels greater than 600 umol/L at baseline.
Patients will be randomized into a Phenoptin treatment group to receive 10 mg/kg daily or a placebo group and will be evaluated every two weeks for six weeks for changes in Phe levels, followed by a 22-week extension study to observe long-term safety, and to corroborate dose optimization and pharmacokinetics.
"We hope this trial will demonstrate that Phenoptin will reduce blood phenylalanine levels in PKU patients, which will help them potentially reduce their need for restrictive diets," Kakkis said, while preventing damage to the brain. "By giving them Phenoptin, we hope their natural abilities to metabolize Phe will be enhanced."
PKU, which affects an estimated 50,000 diagnosed patients under the age of 40 worldwide, is caused by the lack of phenylalanine hydroxylase, which is needed to metabolize Phe, an amino acid found in protein-containing foods. Without an adequate supply of the enzyme, Phe will reach abnormally high levels and "essentially become a neurotoxin," Kakkis said.
The active ingredient in Phenoptin is a synthetic form of 6R-BH4, or tetrahydrobiopterin, a naturally occurring enzyme co-factor designed to work with the enzyme to control Phe levels.
"Investigators discovered that giving tetrahydrobiopterin to patients with PKU appears to enhance and increase the amount of a mutant enzyme that these patients have," he said. "And that increased activity allows them to start metabolizing phenylalanine normally."
BioMarin said that the primary endpoint for the Phase III trial is a comparison of Phe levels from baseline to treatment between the Phenoptin and placebo groups.
The secondary endpoint will "look at the proportion of patients who become compliant with the recommended control levels for Phe," Kakkis told BioWorld Today.
All the patients entering the trial are out of compliance.
The Novato, Calif.-based company expects to announce data from the trial during the last half of the year, with a new drug application filed as early as the first half of 2006 and the product possibly on the market in 2007, he said.
If BioMarin's drug becomes the first therapeutic approved for PKU, the company would be assured market exclusivity in the U.S. for seven years and in the European Union for 10 years.
As far as the potential market size for Phenoptin, Kakkis said the company anticipates that it "very likely could be $200 million to $300 million." BioMarin expects to commercialize the product itself in the U.S., though it might seek partners to handle marketing outside the U.S., with the exception of Japan.
In November, BioMarin entered a partnership with Tokyo-based Daiichi Suntory Pharma Co. Ltd., to exclusively receive preclinical and clinical data on 6R-BH4, and also gain access to the commercial-grade formulation. In exchange, Daiichi received the rights to market Phenoptin for PKU in Japan. (See BioWorld Today, Nov. 29, 2004.)
The company previously entered a development and manufacturing agreement with Merck Eprova AG, a wholly owned subsidiary of Merck KGaA, of Darmstadt, Germany, to supply Phenoptin to BioMarin for clinical trials and potential commercial operations. The partners agreed to share process development and clinical manufacturing costs, with BioMarin owning the 6R-BH4 product for development to treat PKU and other genetic disease indications and agreeing to pay Merck Eprova a royalty on commercial sales. (See BioWorld Today, Nov. 21, 2003.)
BioMarin also is awaiting a decision on another product. The company said a biologics license application was accepted and granted a six-month review process for rhASB (galsulfase) in the treatment of mucopolysaccharidosis VI. A PDUFA date has been set for May 31.
Shares of BioMarin (NASDAQ:BMRN) gained 12 cents Thursday to close at $5.26.