An hour after beating analyst expectations for its fourth quarter and year-end earnings, BioMarin Pharmaceutical Inc. announced that a Phase IIa trial with 6R-BH4 in poorly controlled hypertension failed to show any benefit compared to placebo. The news sent its stock (NASDAQ:BMRN) down $2.45, or 12 percent, to close at $18 on Tuesday.

Christopher Raymond, analyst with Robert Baird & Co. in New York, said the hypertension indication "could have been transformative" for the company, justifying a $40 to $50 stock price. Even though BioMarin is now unlikely to move forward with that indication in the near-term, Raymond said the company has an "improving fundamental story" and pointed to an expected approval this year for Phenoptin (sapropterin dihydrochloride) in phenylketonuria (PKU) and consistently higher-than-expected sales with Naglazyme (galsulfase), an enzyme-replacement therapy for mucopolysaccharidosis VI (MPS VI).

In the Phase IIa study, 116 patients received 5 mg/kg of 6R-BH4 or placebo twice daily for eight weeks. Patients receiving 6R-BH4 experienced a 4.8 mm Hg drop in blood pressure, while those in the placebo group experienced a 6.4 mm HG drop. The difference was not statistically significant in this endpoint or in any other safety or efficacy parameter measured.

Novato, Calif.-based BioMarin had been hoping the Phase IIa trial would confirm results from a previous pilot clinical study in which treatment with 6R-BH4 reduced blood pressure. CEO Jean-Jacques Bienaime said in a conference call that the difference in outcomes between the two trials may have been due to an increase in patient compliance with background medications, the use of different background medications or other factors such as the type of patients enrolled. BioMarin plans to further analyze the data and may even conduct some additional small trials to tease out the reasons for the failure and adjust the protocols for other trials with 6R-BH4 in cardiovascular indications, as needed.

Just last month BioMarin initiated a Phase II trial with 6R-BH4 in peripheral arterial disease (PAD), and data are expected in the first half of 2008. The company also will initiate a trial of the drug in chronic sickle cell disease "in the coming weeks," Bienaime said. Ongoing investigator-initiated studies in the program include a Phase II trial in coronary artery disease and a Phase II trial in pulmonary arterial hypertension, and encouraging preclinical data were presented in heart failure last year.

Bienaime emphasized on the call that progress in the other cardiovascular indications would not be affected by the hypertension failure. BioMarin Chief Medical Officer Emil Kakkis added that the "pathophysiology is different in PAD and sickle cell."

Raymond said it's possible that the hypertension failure could increase the risk for the PAD program, adding that he's always wanted to "see the data" from BioMarin's cardiovascular trials before putting too much weight on them.

Yet both Raymond and Bienaime agreed that the failure of 6R-BH4 in hypertension has no bearing on BioMarin's progress with Phenoptin in PKU, even though 6R-BH4 is the active ingredient in Phenoptin.

In cardiovascular indications, 6R-BH4 functions as a cofactor in the production of nitric oxide, the loss of which is associated with several cardiovascular diseases. In PKU, the drug helps fold the enzyme needed to break down phenylalanine (Phe), reducing the abnormally high Phe levels that characterize this disease. Both the Phenoptin and 6R-BH4 programs are partnered with Merck Serono, of Geneva, a division of Merck KGaA. (See BioWorld Today, May 17, 2005.)

BioMarin remains on track to file a new drug application for Phenoptin next quarter, and Raymond said "there would have to be a really big, nasty surprise to not see it approved by the end of the year."

In earnings news, BioMarin reported a net loss of $10.4 million, or 11 cents per share, for the fourth quarter, and $28.5 million, or 34 cents per share, for the year. That was lower than analyst estimates of a 13-cent loss for the quarter and 36-cent loss for the year. The company brought in revenues of $84.2 million for the year, above analyst estimates of $82 million. Revenues were driven primarily by sales of Naglazyme and Aldurazyme, an enzyme replacement therapy for mucopolysaccharidosis I (MPS I). BioMarin markets Naglazyme in the United States, Europe and Latin America, using distributors for other territories, while Aldurazyme is marketed through a partnership with Genzyme General, of Cambridge, Mass. (See BioWorld Today, May 1, 2003.).