Shares of BioMarin Pharmaceutical Inc. surged Thursday on news that Phenoptin hit statistical significance in its Phase III study as a treatment of phenylketonuria, or PKU.

An oral small molecule, the product entered the study in April. Phenoptin (sapropterin dihydrochloride) met all primary and secondary endpoints, demonstrating a reduction at six weeks in blood phenylalanine (Phe) levels (p<0.0001) when compared to placebo.

BioMarin’s stock (NASDAQ:BMRN) jumped 11.8 percent, or $1.47, to close at $13.92.

The Novato, Calif.-based company also announced a separate agreement in which it licensed North American rights to the Orapred product line to Alliant Pharmaceuticals Inc. That deal is potentially worth $18 million to BioMarin, which will receive $2.5 million up front and up to $15.5 million in milestone payments.

"Orapred no longer fits well into our core business," said Jean-Jacques Bienaime, BioMarin’s CEO, "and this agreement provides us with the opportunity to maximize the value of the Orapred business."

But that agreement was somewhat pushed aside by the Phase III results for Phenoptin. The PKU drug could become the only marketed treatment for a condition that affects 50,000 people in the developed world. A new drug application is expected to be filed in early 2007.

The Phase III trial enrolled 89 patients, ages 8 years and older, with elevated blood Phe levels at 29 sites in the U.S., Europe and Canada. All of them demonstrated a reduction in blood Phe levels of about 30 percent or more following Phenoptin treatment in a Phase II screening study.

Patients received either placebo or 10 mg/kg of Phenoptin every day for six weeks. They were evaluated every two weeks, and the primary endpoint measured the difference in mean blood Phe levels between the placebo and Phenoptin groups in the 87 patients who completed all six weeks of treatment.

Of those receiving Phenoptin, there was a mean decrease in blood Phe level of 236 mM - or 29 percent - compared with a mean increase of 3 mM, or 3 percent, in the placebo group. Before treatment, patients in the Phenoptin and placebo groups had mean blood Phe levels of 843 mM and 888 mM, respectively.

As for the secondary endpoints, 54 percent of Phenoptin-treated patients had blood Phe levels of less than or equal to 600 mM, compared to 23 percent of placebo-treated patients, and the mean blood Phe level was reduced consistently among the patients treated with Phenoptin. The drug was well tolerated with no serious adverse events, and had similar adverse events to placebo.

After completing the Phase III trial, the 87 patients were eligible to enroll in an ongoing 22-week open-label extension study to evaluate long-term safety and efficacy, as well as dose titration, of Phenoptin. Following that study and a separate diet study, BioMarin and partner Serono SA would file for approval in the U.S. and European Union in 2007. The drug has orphan drug designation from the FDA and the European Medicines Agency, as well as fast-track designation in the U.S.

BioMarin partnered ex-U.S. rights, except Japan, to Phenoptin in May of last year with Geneva-based Serono in a deal worth up to $257 million. The agreement also included BioMarin’s preclinical compound for severe forms of PKU, the enzyme-substitution therapy Phenylase (phenylalanine ammonia lyase).

Daiichi Suntory Pharma Co. Ltd., of Tokyo, holds Phenoptin rights in Japan. (See BioWorld Today, May 17, 2005.)

In the U.S., BioMarin intends to market the product alone.

"We are absolutely planning on marketing this product here," Bienaime told BioWorld Today, "because we already have a sales force in place, selling Naglazyme, calling on genetic centers."

BioMarin received approval last June for Naglazyme to treat mucopolysaccharidosis VI. The sales force currently has 12 representatives and four marketing personnel, and Bienaime believes the company needs only a "small expansion" to the force to begin marketing Phenoptin.

PKU is a rare genetic metabolic condition, diagnosed in newborns. It is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), which is required for the metabolism of Phe, an amino acid found in most protein-containing foods. Without the enzyme, Phe accumulates and can result in severe mental retardation and brain damage, as well as mental illness, seizures, tremors and cognitive problems.

The only treatment is a highly restrictive diet formula that is difficult to follow and can cost $10,000 to $15,000 a year. Insurance often doesn’t cover it, but "the alternative is to be mentally retarded," Bienaime said.

He believes BioMarin will be "able to price north of that" for Phenoptin, which is expected to work in about 40 percent of the PKU population, a third of whom - or 6,000 - are in the U.S. At $20,000 a year, the drug could bring BioMarin U.S. sales of about $120 million.

PKU is only the first indication that BioMarin is pursuing with Phenoptin, which has the synthetic form of 6R-BH4 (tetrahydrobiopterin) as its active ingredient. The company expects to move Phenoptin development into the cardiovascular space later this year, starting a Phase II trial in resistant hypertension.

As the company focuses on regulatory filings and a potential launch of Phenoptin, it made sense for BioMarin to license out North American rights to the Orapred (prednisolone sodium phosphate) product line, including the already marketed oral solution, and the orally disintegrating tablets (ODT), which are the subject of a June 1 PDUFA date.

About $14 million of the $18 million the company expects to receive from Alliant, of Alpharetta, Ga., should be received this year, with another $4 million coming in 2007. The payments are based on the ODT product’s approval, launch and level of sales.

The liquid form had 2003 sales of $49 million, but generic competition has caused those sales to drop to $6.9 million in 2005. Orapred is used to treat exacerbations of asthma and other inflammatory diseases and conditions in children.

BioMarin will receive a 25 percent to 30 percent royalty on all sales, and it is retaining commercial rights outside of North America.