Washington Editor

Officials at BioMarin Inc. believe themselves to be fortunate in determining fairly early that their lead product, Neutralase, probably won't make it to market.

In response to a recommendation Friday from an independent Data Safety Monitoring Board (DSMB), BioMarin stopped its Phase IIIa study of Neutralase in coronary artery bypass graft surgery and has terminated further development of the experimental drug. Neutralase was being evaluated for the reversal of anticoagulation by heparin in primary CABG surgery.

The company's stock (NASDAQ:BMRN) on Monday closed at $7.93, down 66 cents.

Even though Neutralase was BioMarin's No. 1 candidate with a potentially large market, Yaron Werber, a biotechnology analyst with S.G. Cowen Securities Corp. in New York, told BioWorld Today Wall Street has been skeptical at best about the trial ending in success. Not only that, he said, the company has been criticized for allocating so much money to develop the drug. "In that regard, it is certainly encouraging that they caught it early and decided to terminate development earlier, rather than later."

The DSMB recommended that BioMarin stop enrollment due to an increasing frequency of adverse events observed in the Neutralase group, Joshua Grass, BioMarin's manager of investor relations, told BioWorld Today. The company is not prepared to release a list of the events, he said, adding, "This was late-breaking news on Friday. When we get more data, we'll be able to determine exactly what the adverse events were."

However, "the adverse events were not uncommon to those observed in CABG surgery; they were just more common in the group that was receiving Neutralase," Grass said.

Neutralase, a carbohydrate-modifying enzyme that cleaves heparin, was acquired by BioMarin in its 2001 buyout of Montreal-based IBEX Technologies Inc. Heparin is necessary in all CABG procedures to avoid potentially fatal complications arising from blood clotting during the operations, but the drug can cause excessive bleeding after surgery and must be reversed. (See BioWorld Today, Oct. 1, 2002, and Oct. 11, 2001.)

In a conference call with investors, analysts and reporters Monday morning, Fredric Price, chairman and CEO of Novato, Calif.-based BioMarin, said terminating further development of Neutralase was the best decision for both the stockholders and the company. BioMarin has worldwide rights to the drug.

"Based on our top-line analysis, the problems observed with Neutralase could not be addressed by change to the clinical protocol or study design," Price said. "There were no deaths in the study related to Neutralase, but there was one death in the protamine arm, but this isn't an unusual event given the critical nature of CABG surgery."

According to the company, 150 patients out of the targeted 600 had enrolled in the study. The primary endpoint was non-inferiority of Neutralase to protamine, measured by cumulative chest tube drainage.

Neutralase failed in a previous Phase III in CABG surgery while under the ownership of IBEX. That trial was believed to have been unsuccessful due to dosing.

But in earlier Phase I/II trials, Grass said Neutralase performed well. "Earlier trial data suggested that Neutralase was effective in stopping bleeding, and it didn't show some of the adverse events that were associated with protamine, which is the current standard of care."

BioMarin in early June offered about $125 million in convertible subordinated notes due in 2008. The company has a healthy pipeline and was looking for funds to help support its trials. (See BioWorld Today, June 18, 2003.)

As of June 30, BioMarin had about $265 million in cash and cash equivalents. On deciding to stop development of Neutralase, BioMarin revised its financial estimates. For 2003, the company reduced its forecasted net loss to $76 million to $78 million, down from $81 million to $83 million. Its cash burn rate has dropped to $74 million to $78 million, down from $80 million to $84 million.

For 2004, the company changed its forecasted net loss to $68 million to $70 million, down from $81 million to $83 million. The cash burn drops from $69 million to $73 million, down from $80 million to $84 million.

As for the good news, Werber told BioWorld Today that Aldurazyme, an enzyme replacement therapy for mucopolysaccharidosis-1 recently launched by BioMarin and partner Genzyme General, of Cambridge, Mass., is on track to meet guidance estimates of $10 million to $13 million this year.

BioMarin and Genzyme received FDA approval in May for Aldurazyme. (See BioWorld Today, May 1, 2003.)

Elsewhere in the pipeline, BioMarin is conducting a pivotal Phase III trial evaluating Aryplase in mucopolysaccharidosis-VI, also a genetic disease.

Price told conference call listeners he expects to file a new drug application for Aryplase in September or October 2004, and if all goes well, the product could reach the market in the second or third quarter of 2005. The FDA awarded Aryplase fast-track and orphan status. Price expects to partner Aryplase outside the U.S.

The company also is conducting a Phase Ib study of Vibrilase, an enzyme candidate for the treatment of serious burns. BioMarin likely will out-license Vibrilase.

Price said BioMarin believes it will enter the clinic in 2004 with a treatment for phenylketonuria (PKU), a genetic disease affecting 50,000 children in the Western world. PKU is characterized by an inability to oxidize a metabolic product of phenylalanine and by severe mental retardation.