BioMarin Pharmaceuticals Inc.'s word in January that Phenoptin let juvenile phenylketonuria patients ease off their low-protein, high-carbohydrate diets beefed the company's stock somewhat, but the real meat is due later this month.

Disclosing the Phase III data on Phenoptin (sapropterin dihydrochloride), BioMarin said the drug knocked down phenylalanine (Phe) levels in subjects aged 4 years to 12 years who are afflicted with the genetic disorder that hits about 50,000 in the developed world.

Specifically, daily Phenoptin at 20 mg/kg garnered a mean increase of 20.9 mg/kg per day in Phe supplementation compared to placebo (p<0.001). On average, Phenoptin patients 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. This average Phe tolerance works out to about half the amount of daily Phe in a normal diet, which ranges between 80 mg/kg and 100 mg/kg. The trial met a pair of secondary endpoints, too.

Medical foods for PKU patients cost about $10,000 to $15,000 per year, and analysts are projecting BioMarin's drug to cost about twice that much. Jean-Jacques Bienaime, BioMarin's CEO, did not provide further guidance during last week's talk at a New York conference sponsored by Merrill Lynch, but he gave a few clues.

"We're doing pricing research right now," he said. "The out-of-pocket cost [for existing PKU treatment] is pretty substantial, about $5,000 per patient in the U.S., based on our research," because the necessary food is very expensive compared to regular food, and is not reimbursed by payers.

"We believe we have some pricing flexibility, specifically after the diet study, where we were able to demonstrate that some [Phenoptin] patients are going to be able to get to a normal diet," Bienaime said. "It's not going to be like [BioMarin's marketed products] Aldurazyme or Naglazyme, which are $200,000 to $300,000 per year for patients, but it's gong to be more than $10,000."

Phenoptin, a highly purified formulation of the 6R isomer of tetrahydrobiopterin, is partnered with Merck Serono, and BioMarin expects to file for FDA approval by the end of June, with the overseas collaborator filing for European clearance in the third quarter. Approval in the U.S. could come by the end of the year. Daiichi Suntory Pharma Co. Ltd. holds Japanese rights. Tetrahydrobiopterin, or 6R-BH4, that works in conjunction with phenylalanine hydroxylase to metabolize Phe.

Another in the PKU space - though far behind BioMarin - is Altus Pharmaceuticals Inc., which has preclinical ALTU-236, an enzyme-replacement therapy to reduce the long-term effects of excess phenylalanine, also known as hyperphenylalanemia (the most severe form of which is PKU).

Sheldon Berkle, Altus' president and CEO, told BioWorld Financial Watch in December that he was "happy they're ahead of us," since BioMarin's approval will help clarify the regulatory path. BioMarin has claimed Phenoptin works in about 50 percent of PKU patients at the upper range, "but we think it's going to be about 30 percent," he added.

BioMarin's Aldurazyme (laronidase, in a joint venture with Genzyme Corp.) and Naglazyme (gasulfase) treat extremely rare lysosomal storage disorders (LSDs). Naglazyme, which targets mucopolysaccharidosis VI (MPS VI), was launched last June and sold $3.7 million in the fourth quarter. Aldurazyme is designed for MPS I, and BioMarin got a $3.1 million share of $21.2 million in fourth-quarter sales.

In August, Alliant Pharmaceuticals Inc. started selling Orapred (prednisolone). The orally disintegrating tablet is primarily for acute exacerbations of asthma in children, and is used to control severe, persistent forms of the disease as well as to reduce inflammation. Alliant signed a North American license and acquisition agreement from earlier in 2006. That deal brought BioMarin $7.5 million upon FDA approval and $4 million at launch, with another $4 million due on the first anniversary of approval and royalties ranging from 25 percent to 30 percent. BioMarin gained Orapred in the summer 2004 buyout of Ascent Pediatrics Inc., but a year later laid off most of the sales team when two generic forms of the corticosteroid were launched.

Trading at just above $19 last week - and already up 16 percent for the year - BioMarin's shares might be in line for another uptick or two later this month. Earnings are due to report on Feb. 22, and might contain even better news about Naglazyme. Chris Raymond, analyst with Robert Baird & Co., noted that heavier patients (hence the need for more drug) could mean a satisfying sales hike.

Naglazyme dosing is 1mg/kg of patient weight, per weekly infusion. "Last quarter, we spoke with one high-volume treatment center in Europe, and noted the average weight of their patients was closer to 30 kg, higher than our estimated average patient weight," Raymond wrote in a research report. "Even after we raised our Naglazyme estimates last quarter, we note that BioMarin still beat them by nearly $1 million."

He estimated that, for every $1 million in sales upside, a penny could be added to BioMarin's earnings per share, "and this added revenue could be garnered by treating just a few heavier-than-average patients."

Another driver due any day: Data from an 84-patient, Phase II trial with 6R-BH4, Phenoptin's active ingredient and a potential booster of nitric oxide, against hypertension that is not well controlled. The primary endpoint is a 5-6 mm Hg drop in systolic blood pressure, with a drop in diastolic pressure the secondary goal. The drug is given at 5 mg/kg per day, twice daily.

A Merrill Lynch meeting attendee asked if BioMarin would consider going after resistant hypertension if 6R-BH4 works in poorly controlled disease.

"Other companies in the past have been developing drugs for truly resistant, fourth to sixth-line therapy, because I think they might have been facing different issues than we are," Bienaime said, citing the BioMarin drug's clean safety profile.

What's more, the definition of "resistant" is not an FDA tag. "Most of the clinicians we talked to have a pretty systematic approach" to hypertension, he said. "After the first two drugs [fail], anything goes."

Analyst Raymond set his target price for BioMarin at $22. In December, Rodman & Renshaw raised its price target from $17 to $22.50. As far back as October, Peter McDonald of American Technology Research, initiating coverage of the stock with a "buy" rating, put the target price at $22 and predicted various catalysts would help the stock rise in the next 12 months.

Bienaime acknowledged changes at BioMarin since its inception, especially the shift from niche/orphan-type products to those with a potentially much broader patient base, such as the cardiovascular candidate 6R-BH4.

"There are just so many LSDs," he pointed out. "That doesn't mean we're abandoning genetic therapy and our focus in that area, we're not. But I think for long-term growth, we need to move beyond that. That's exactly what Genzyme has done."