Almost exactly a year after acquiring the pharmaceutical assets of IBEX Technologies Inc., including its injectable heparinase Neutralase, BioMarin Pharmaceutical Inc. said Phase III plans for the product are marching ahead.
"We haven't enrolled the first patient yet, but we expect to shortly," said Joshua Grass, manager of investor and financial relations for Novato, Calif.-based BioMarin, adding that the company expects to have data in the fourth quarter of next year.
A protocol has been submitted, 30 testing sites have been prepared, and manufacturing arrangements have been ironed out, but the company is still awaiting comment from the FDA.
The agency "could potentially" demand revisions to the protocol and delay trials, "but we don't think it's a strong possibility," Grass told BioWorld Today.
"They've approved a protocol that has many of the same elements before," he said.
The therapeutic enzyme Neutralase has fizzled once already in a Phase III trial - apparently due to dosing - by Montreal-based IBEX, which tested the drug in patients who have undergone coronary artery bypass graft surgery. BioMarin will try Neutralase for reversing the anticoagulant action of heparin in CABG patients, but at a different dose.
Further experiments will use Neutralase in cardiology procedures such as percutaneous transluminal coronary angioplasty, as well as other operations where heparin or heparin-like compounds are used.
But first comes the CABG trial, which (if the FDA goes along) will be the first of two. It will enroll about 600 patients at 30 sites, 24 in the U.S. and six in Canada, testing patients undergoing CABG surgery on the bypass pump and off the pump.
The procedure can be done both ways and "the market seems to be moving more toward off-pump CABG," Grass said. "There's speculation that there are fewer strokes and adverse events related to problems with the pump."
He said a protocol has been established that specifies how many trial patients will be on the pump and how many off, but such details are not being disclosed until BioMarin gets a final nod from the FDA.
The primary endpoint in the Neutralase trial will be non-inferiority of Neutralase to protamine, measured by cumulative chest tube drainage.
Heparin is necessary in all CABG procedures - about 1 million of which are done annually worldwide - to avoid potentially fatal complications arising from blood clotting during the operations, but the drug can cause excessive bleeding after surgery and must be somehow reversed.
Today, protamine is the only drug available for the purpose, although it's never been approved by the FDA for that indication and carries side effects such as systemic hypotension and pulmonary hypotension, both of which can be life threatening.
Protamine has also been associated with platelet dysfunction, which can lead to excessive bleeding; complement activation, which can cause organ dysfunction; and thrombus formation, which can bring about a stroke.
Phase II results with Neutralase have been encouraging, and BioMarin expects results of the planned Phase III study to give investigators a good idea of how the drug compares with protamine in reversing heparin's effects after surgery. BioMarin also will monitor a variety of adverse hemodynamic events, evaluating morbidity and mortality in each treatment group.
IBEX stopped a Phase III study of Neutralase in July 1998, noting that an analysis of the data indicated the dose was too low to reverse heparin's effects. A Phase II/III trial was begun the following year, and a year later, IBEX said it had completed an interim analysis but was awaiting a corporate partner before going further. That's where BioMarin stepped in and acquired the pharmaceutical assets.
As for manufacturing of Neutralase, BioMarin has refined the process to the point of a 40-fold improvement in the production yield since the $20 million IBEX deal. (See BioWorld Today, Oct. 11, 2001.)
BioMarin has signed a contract with Diosynth RTP Inc., a subsidiary of Akzo Nobel NV, of Oss, the Netherlands, which will manufacture the enzyme for the Neutralase program. Production of the technology will be transferred from BioMarin to Diosynth.
Also gained in the IBEX purchase, among others, was Phenylase, an orally active enzyme designed to treat phenylketonuria.
"It's still in the preclinical stages," Grass said. After Neutralase, Phenylase is the furthest along in the pipeline bought from IBEX by BioMarin, which has its own products at center stage.
"Right now, most of our resources are focused on Aldurazyme, Neutralase and Aryplase," Grass said.
BioMarin - with partner Genzyme General, of Cambridge, Mass. - is awaiting approval in the U.S. and Europe of Aldurazyme, an enzyme replacement therapy for mucopolysaccharidosis 1.
"We're expecting to hear back from both agencies in the first quarter" of next year, Grass said.
The company reported positive Phase I results in June with Aryplase (recombinant human N-acetylgalactosamine 4-sulfatase or arylsulfatase B), an enzyme replacement therapy to treat mucopolysaccharidosis VI. This spring, dosing began in a Phase II trial.
BioMarin's stock (NASDAQ:BMRN) closed Monday at $5.79, up 23 cents.