CDU Washington Editor
And CDUs

Editor's note: While Cardiovascular Device Update is obviously directed toward manufacturers of medical devices and organizations that track these companies, this sector of med-tech also should be interested in the competitive pressures of new cardiovascular drugs. This feature is focused on that interest.

BioVascular (San Diego) has merged with Revitus (Portland), a firm founded by an Oregon biomedical engineering professor, giving the San Diego-based firm its second compound in clinical development for thrombotic vascular diseases. BioVascular acquired the full worldwide rights to BVI-007, a thrombopoeitin antagonist that reduces platelet production without impacting platelet function.

Stephen Hanson, CEO of Revitus and head of the department of biomedical engineering at Oregon Health & Science University (Beaverton), will join BioVascular's board.

The firms announced the merger just days after the first human subject was dosed in a Phase Ia clinical trial of BVI-007, said John Parrish, CEO of BioVascular. BVI-007 is being developed for the prevention of myocardial infarction, thrombotic stroke and death in patients who have had a previous cardiovascular event, he told Cardiovascular Device Update's sister publication BioWorld Today.

Parrish said that BVI-007 is a compound that reduces platelet production and is very different than products that are used to control platelet aggregation-the clumping together of platelets in the blood, which leads to blood clots. Product safety and tolerability is being tested in 12 healthy volunteers, Parrish said. The firm plans to test dose escalation of the orally administered product in 50 participants in a Phase Ib trial expected to start in the fourth quarter of 2007, Parrish said, adding that both studies are being conducted in Europe.

Results of recent studies in survivors of a first myocardial infarction showed that patients with high platelet counts had a higher risk of a second heart attack compared with those with average or low platelet counts, he noted.

"We believe that a new cardiovascular risk factor has been identified," Parrish said, adding that reducing platelet counts has been shown to reduce a second heart attack and death. BVI-007 also complements BioVascular's Saratin, a polypeptide derived from leech saliva. Saratin is currently being studied in Europe in two Phase I/II clinical trials for vascular graft failures due to intimal hyperplasia, the thickening of a blood vessel in response to an injury. Intimal hyperplasia is one of the most common reasons for vascular graft failures, Parrish noted.

The first of the two Phase I/II studies involves about 50 patients undergoing hemodialysis vascular access graft surgery, and the second involves about 100 patients with peripheral arterial disease undergoing bypass graft surgery, Parrish said.

The product, applied during surgery to the endovascular surface to prevent intimal hyperplasia, is expected to extend the life of those grafts, which have a high rate of failure, he said.

  • Taking aim at peripheral arterial disease (PAD) and access sites in dialysis patients with its vascular remodeling weaponry, Proteon Therapeutics (Waltham, Massachusetts) last month raised $12 million, adding to the $19 million of Series A funds and providing the private firm with enough cash to put its lead product, PRT-201, into the clinic early next year.
    Testing PRT-201 in dialysis access and PAD gives Proteon "at least three, unique distinct patient types to figure out where this protein works best," said Timothy Noyes, president/CEO of Proteon. Which indication will turn out the most lucrative, Noyes said, is not easy. Although PAD seems like the obvious answer, the number of patients on dialysis "continues to grow so fast that it's probably a toss-up," he said.
    The only FDA-approved drug for claudication is Pletal (cilostazol), from Otsuka America Pharmaceutical (Rockville, Maryland), a phosphodiesterase III inhibitor that can't be used in patients with congestive heart failure.
    Noyes called dialysis "a prudent place to start," and said the firm is still debating when PAD trials might begin.
    "We probably wouldn't wait much longer than the end of our first-in-man [dialysis] trial to start our first PAD trial," he said. "It's possible we could start them in a slightly more staggered way." The vasodilator protein PRT-201 can be applied topically to the external surface of exposed vessels during surgery, or injected through angioplasty catheters.
    "If PRT-201 works, it will have the advantage of being entirely local. "It's one-time, it's fast and persistent, and we believe it's going to be safe," Noyes said, noting that the protein does not preclude other approaches used in tandem, as opposed to such approaches as stents.
    Noyes said efforts to treat PAD, "although they're very good at restoring blood flow, they also to some extent cause damage," as would any device that's interacting with the endothelium. "You hope that, on net, it comes out to be a benefit," he said. With PRT-201, "we're not doing anything to the endothelium —we're not disrupting it, we're not damaging it," he said.
    With dialysis and with PAD, "the underlying pathophysiology is complex," Noyes said. "It's probably going to require more than one solution. I don't think there's any silver bullet here," but Proteon hopes PRT-201 will prove benign enough to serve as part of therapies. Noyes said the company, with the new cash, has enough to operate through the end of next year.
  • Nuvelo (San Carlos, Calfifornia) last month took the first step in getting its alfimerprase development program back on track as it began enrollment in the previously discontinued SONOMA-3 trial. The single-arm trial will use a higher dosage of alfimerprase than was used in the failed SONOMA-2 Phase III trial, which also was for treating central venous catheter occlusion. That setback, in December, was accompanied by the failure of alfimerprase in a separate Phase III trial in acute peripheral arterial occlusion.
    Since then, Nuvelo lost its partner for the thrombolytic agent, a recombinant, direct-acting fibrinolytic, but officials there were encouraged enough to decide to continue development on their own.
    The SONOMA-3 trial will evaluate safety and efficacy of a single 10-mg dose of alfimeprase with a concentration of 5 mgs per milliliter in up to 100 patients. The primary efficacy endpoint is restored catheter function within 15 minutes. The failed study used a 3-mg dose with a concentration of 1.5 mg/ml.
    Data from the trial are expected in 2008, and, if positive, could support a full Phase III program in catheter occlusion. A Phase II trial in the larger indication of stroke is expected to start this year, while Nuvelo has moved back to preclinical development in peripheral arterial occlusion to optimize delivery in that indication.
    In addition to the SONOMA-3 trial and the upcoming CARNEROS-1 trial in stroke, Nuvelo intends to move NU172, an anti-thrombin aptamer, into the clinic later this year or early next year. Its other preclinical product, NU206 (R-spondin1), is a recombinant, secreted protein designed stimulate gastrointestinal epithelial cells.
  • Medicure (Winnipeg, Manitoba) plans to raise $40 million under two agreements for ongoing clinical development of a new cardioprotective agent, MC-1, and continued commercialization efforts for an approved coronary drug, Aggrastat.
    The firm has signed a term sheet to monetize a percentage of its current and potential future commercial revenues with Manchester Securities, an affiliate of Elliott Associates, for a $25 million upfront cash payment.
    Medicure says it anticipates receiving an approval decision for MC-1 by late 2008 or early 2009. The exact percentage of Aggrastat or MC-1 revenue that Elliott will receive is tiered and declines as certain revenue levels are achieved, Medicure stated. Upon conversion to MC-1, Elliott is entitled to a blended return of about 7% on the first $75 million in MC-1 revenues and 3% thereafter.
    The company expects to conclude enrollment for a Phase III study in November examining the drug in 3,000 patients undergoing coronary artery bypass graft surgery. With positive results, Medicure expects to submit a new drug application to FDA for MC-1 in mid-2008 and plans to seek priority-review status, a designation that could result in an approval within six months of an NDA submission. The drug has already achieved FDA's fast-track designation.
  • Four months after losing partner AstraZeneca (London) upon mixed cardiovascular data, AtheroGenics (Atlanta) said it plans to look for a new collaborator, as patient enrollment gets underway in a Phase III trial of its oral anti-inflammatory antioxidant drug, AGI-1067, in diabetes.
    The company anticipates beginning discussions relatively soon, likely this fall, said Mark Colonnese, executive VP and CFO. With the large diabetes market, the drug would be "served well commercially to have a partner," and, he added, the firm already has seen some interest in AGI-1067, based on "very compelling data" emerging earlier this year from a previous Phase III study in atherosclerosis.
    That study, the 6,144-patient Phase III ARISE (Aggressive Reduction of Inflammation Stops Events) showed no difference between AGI-1067 and placebo in the primary endpoint.
    The news cost AtheroGenics its 2005 whopper of a deal with AstraZeneca, which carried a potential for $650 million in milestones and a hefty royalty payment, and prompted the firm to reduce its workforce by half to cut costs.
    But further analysis of the data showed a clear improvement in glycemic control for diabetic patients receiving AGI-1067, prompting the company in June to shift gears and focus its resources on the diabetes space.
    This doesn't preclude further development of AGI-1067 in the cardiovascular space. While the previous ARISE trial missed its primary composite endpoint, it did show benefit in the "hard" cardiovascular endpoints, such as death, heart attack and stroke, Colonnese said. "That's part of our long-term view of the drug," though a cardiovascular trial likely would be longer and more expensive than the diabetes study.