At the same time Nuvelo Inc. selected a second direct thrombin-inhibiting aptamer from its collaboration with Archemix Corp., the companies signed an expanded agreement to include additional aptamer-based products targeting coagulation.

They also restructured the original January 2004 agreement, which called for a 50-50 commitment, to instead divide the responsibilities to take advantage of each company's strengths.

"We will front-end load the collaboration from the standpoint of doing all of the research here, which is what we do best," said Errol De Souza, president and CEO of Cambridge, Mass.-based Archemix, which could receive as much as $54 million under the new agreement.

Once Archemix's scientists have completed preclinical work, Nuvelo will take the lead on clinical development and commercialization, relying on experience from its cardiovascular therapeutic pipeline, which features alfimeprase, a direct thrombolytic in Phase III programs in acute peripheral arterial occlusion and catheter occlusion.

That product is partnered outside the U.S. with Bayer HealthCare AG, of Leverkusen, Germany, in a potential $385 million deal signed in January, but Nuvelo intends to build its own hospital-based sales force to market the alfimeprase in the U.S. (See BioWorld Today, Jan. 6, 2006.)

"By the time a compound comes out of the Archemix collaboration, we should have a highly suitable commercial infrastructure in place," said Lee Bendekgey, senior vice president and general counsel of San Carlos, Calif.-based Nuvelo.

Under the terms, Nuvelo agreed to make an up-front payment of $4 million and could invest up to $10 million in privately held Archemix's common stock if and when the company seeks a public listing.

Beyond that, Nuvelo will provide at least $5.25 million in research funding over the next three years, and pay milestones up to $35 million per development compound. Archemix also would be entitled to royalties from any product sales, though it could opt instead for a profit-sharing arrangement by agreeing to fund a pro-rata share of the expenses and forgoing milestones and royalties.

"We get the opportunity to buy into 25 percent of the program at the beginning of Phase III," De Souza told BioWorld Today, "so for us, it divests the risk but lets us keep a good portion of the upside."

Holding on to part of the upside has become "a major theme" for Archemix in recent days, he added. Last month, the company signed a deal with Dublin, Ireland-based Elan Corp. plc to develop up to three aptamer-based drugs against autoimmune diseases that also includes a co-development option for Archemix on certain products. That deal was valued at a potential $350 million for Archemix. (See BioWorld Today, July 14, 2006.)

In addition to dividing responsibilities, the revamped collaboration also expands the scientific focus.

"It now includes short-acting aptamers that inhibit potential targets all up and down the coagulation cascade," Bendekgey said.

The most recent candidate to emerge from the collaboration is NU172, formerly ARC2172, a short-acting, second-generation direct thrombin inhibitor that has shown promising efficacy and safety profiles in preclinical studies.

It's the second compound to emerge from the collaboration. The companies began working on ARC13, a first-generation thrombin inhibitor, but while it showed proof-of-concept in the clinic, a lower-than-anticipated potency prevented the companies from proceeding with development. NU172 so far has demonstrated a superior potency to the earlier candidate.

Like all aptamers, NU172 has a short half-life after it enters the blood stream, which could make it an ideal anticoagulant for surgical procedures, such as bypass surgery, Bendekgey said.

"During that procedure, a patient's blood needs to be anticoagulated so it doesn't clot on the bypass machine," he said, "but as soon as the procedure is completed and blood is reintroduced, it's important that [coagulation] returns to normal. And aptamers are kind of perfect for that."

If developed successfully, NU172 could replace the standard of care, heparin with protomine, which have safety limitations.

Nuvelo has not yet provided a time frame for the development of NU172, but the drug is expected to be a good fit with its existing pipeline, which, besides alfimeprase, includes rNAPc2, an anticoagulant designed to inhibit the Factor VIIa and the tissue factor protease complex. That product is in Phase II development in acute coronary syndrome.

Nuvelo posted a net loss of $19.7 million, or 40 cents per share, for the first quarter. As of March 31, the company had a cash position of $200.3 million, which included proceeds from a $112 million public offering completed in February. (See BioWorld Today, Feb. 1, 2006.)

Shares of Nuvelo (NASDAQ:NUVO) closed at $16.70 Tuesday, down 30 cents.