From CDUs

Editor's note: While Cardiovascular Device Update is obviously directed toward manufacturers of medical devices and organizations in the med-tech sector, also of interest are the developments and competitive pressures in the pharmaceutical arean. This feature is focused on that interest.

The Agency for Healthcare Research and Quality (AHRQ; Washington) and the FDA last month said that they will collaborate on a study to examine the potential for increased cardiovascular problems related to the use of prescription drugs to treat attention deficit hyperactivity disorder (ADHD).

The agencies said they will analyze the clinical data of about 500,000 children and adults who have taken ADHD medications which are known to increase heart rate and blood pressure, and that these risks may be different for adults and children.

The analysis follows a preliminary study by the FDA that compiled information from large healthcare databases on prescription drug use, inpatient care, outpatient treatment and health outcomes, including death. That study identified people who took ADHD drugs during a seven-year period ending in 2005. AHRQ will complete the analysis of the data.

Gerald Dal Pan, MD, director of FDA's Office of Surveillance and Epidemiology, noted reports describing adverse cardiovascular events in adult and pediatric patients with certain underlying risk factors who receive drug treatment for ADHD, but that evidence is needed to determine if this is a causal relationship.

Researchers at Vanderbilt University (Nashville, Tennessee) will coordinate the study on contract through AHRQ's Effective Health Care program. Data analysis will be performed by researchers at Vanderbilt, Kaiser Permanente of California, the HMO Research Network and i3 Drug Safety, as well as from FDA and AHRQ.

The analysis will include all drugs currently marketed for treating ADHD. The study will analyze the risks of all the drugs as a whole, and risks of the drugs grouped by class. Results are expected in about two years.

Marfan/cardio issues dealt with via ACE inhibor, beta blocker

Preliminary research suggests that use of the ACE inhibitor perindopril, along with a beta-blocker, may help reduce cardiac measures such as aortic stiffness and dilation associated with the cardiovascular complications of Marfan syndrome (MFS), according to an article in the Oct. 3 issue of the Journal of the American Medical Association.

MFS is a hereditary disorder principally affecting the connective tissues of the body, often characterized by excessive bone elongation and joint flexibility and abnormalities of the eye and cardiovascular system (and a disease perhaps best known for potentiallly having afflicted President Abraham Lincoln).

Progressive aortic dilation and rupture are the most serious complications and the most common cause of premature death. Beta-blockers are currently the standard treatment for MFS, but may not be as effective as other therapies in treating aortic wall degeneration, according to background information in the article. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce arterial stiffness.

Anna Ahimastos, PhD, of the Baker Heart Research Institute (Melbourne, Australia), and colleagues conducted a study to examine the effectiveness of the ACE inhibitor perindopril to reduce arterial stiffness and aortic dilation relative to placebo in 17 adult patients with MFS taking standard beta-blocker therapy. The randomized trial began in January 2004 and was completed in September 2006. Patients were administered 8 mg/day of perindopril (n = 10) or placebo (n = 7) for 24 weeks.

The authors write: "The major novel finding of our study was that perindopril therapy for 24 weeks reduced aortic diameters relative to placebo in both systole [the contraction of the chambers of the heart] and diastole [the expanding of the chambers of the heart] in patients with MFS taking standard beta-blocker therapy. In systole, perindopril reduced the progression of aortic dilatation observed in the placebo group. However, in diastole, perindopril actually reduced aortic diameters below baseline levels by an average of between 1.2 and 3.0 mm/m .

"In conclusion, therapy with perindopril reduced both aortic stiffness and aortic root diameter in patients with MFS taking standard beta-blocker therapy. These findings warrant further investigation in a larger, longer-term clinical trial."

Proteon Therapeutics adds cash to explore dialysis access, PAD

Taking aim at access sites in dialysis patients and at peripheral arterial disease (PAD) with its vascular remodeling weaponry, Proteon Therapeutics (Waltham, Massachusetts) raised $12 million, adding to the $19 million of Series A funds raised last spring and providing the privately held firm with enough cash to put the lead product, PRT-201, into the clinic early next year.

Timothy Noyes, president/CEO of Proteon, 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.

Dialysis sites are made two ways. In arteriovenous fistulas (AVFs), the vein is surgically sewn directly to the artery. In arteriovenous grafts (AVGs), the artery and vein are connected by way of a segment of artificial tubing.

AVFs "often don't work, but once they do, they work for a long time and they work great," Noyes said. "The graft is pretty well the opposite. Half of the grafts have failed in seven to nine months, and patients undergo a series of re-works," such as angioplasties that require hospital stays.

"Very few people have done anything in fistulas," he said. "Most of the attention has been on the graft side" since, in the U.S., more grafts than fistulas are used. Still, in dialysis access, science has made "no meaningful advances since anybody can remember," he added. "Everybody's talking about trying to improve dialysis, but you can't do that until you improve access."

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.

Last month, Pervasis Therapeutics (Cambridge, Massachusetts), finished patient recruitment for its two Phase II trials of Vascugel, an allogeneic cell therapy product to restore natural repair and regeneration pathways in traumatized vasculature.

"They're looking at a very different approach, but they're also looking at fistulas and grafts," Noyes said.

Other companies, such as Angiotech Pharmaceuticals (Vancouver), are exploring whether methods used against coronary artery disease might be used in dialysis, he noted, but "the jury's out right now."

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," he said. Which indication will turn out the most lucrative, Noyes added, 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.

Plenty of other firms are working to find therapies for PAD, which afflicts as many as 8 million Americans and causes such conditions as intermittent claudication, or pain while walking, caused by occluded blood flow. The only U.S.-approved drug for claudication is Pletal (cilostazol, Otsuka America Pharmaceutical Inc.), a phosphodiesterase III inhibitor that can't be used in patients with congestive heart failure.

In June, Indigo Pharmaceuticals (New York) licensed rights to INDI-702 (previously NM-702), an oral compound that inhibits PDE-3 and thromboxane A2 synthetase, from Nissan Chemical Industries (Tokyo) and Taisho Pharmaceutical (also Tokyo), with Phase III trials in claudication planned for the first half of next year.

About a year ago, Valentis (Burlingame, California) chalked up one of a handful of failures in PAD with the poloxamer VLTS 934, scrapped by Valentis after a Phase IIb failure. The firm's stock was hit hard by the news, and this year changed its name to Urigen Pharmaceuticals after reverse merger with the specialty pharma company Urigen NA.

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.

Nile gathers in $20 million, merges into shell company

Small biotech Nile Therapeutics (Berkeley, California) last month raised an equity round of $20 million and then merged with a public shell company to fund ongoing cardiovascular drug development.

Founded two years ago by venture firm Two River Group Holdings (New York) to develop CD-NP, a clinical-stage compound for heart failure, Nile was looking to access the capital markets and opted for a reverse merger as a "cleaner capital structure" than the more traditional initial public offering, said Peter Strumph, CEO of Nile.

The company merged with SMI, a public shell trading on the Over-the-Counter Bulletin Board and then was renamed Nile Therapeutics.

Prior to gaining a public listing, Nile secured at least two years of funding with a private equity sale of 7 million shares to a syndicate led by Wexford Capital (Greenwich, Connecticut). The $20 million round will be used for development of CD-NP and to move a second compound, the recently in-licensed 2NTX-99, into the clinic.

Strumph said the company will look for "additional business development opportunities," such as additional in-licensings, collaborations and merger and acquisition deals.

Nile employs an outsourcing model and relies heavily on its scientific advisory board of cardiac disease experts, chaired by John Burnett, professor at the Mayo Clinic College of Medicine (Rochester, New York) and co-inventor of CD-NP. Nile licensed rights to CD-NP from the Mayo Foundation for Education and Research.

A chimeric natriuretic peptide, CD-NP is a selective NPRB agonist that has shown renal enhancement and cardiac unloading properties, with minimal hypotensive effects, in preclinical studies. Nile recently completed a Phase I trial in healthy volunteers, confirming that the synthetic peptide was able to activate its target receptor in humans, and that it preserved renal function and caused increases in natriuresis and diuresis.

"We're planning additional Phase I trials" in heart failure patients, Strumph said, and could later explore CD-NP in another potential indication.

Behind CD-NP, Nile has rights to 2NTX-99, a small molecule aimed at inhibiting the synthesis and action of thromboxane, enhancing production of prostacyclin and supplying nitric oxide to the vasculature.

Based upon its mechanism, the company believes 2NTX-99 might have potential against several atherosclerotic, thrombotic and microvascular diseases, and is preparing an investigational new drug application to take the program into the clinic, "perhaps next year," Strumph said.

Strumph said that the company will seek partnerships for its drug candidates, especially for compounds targeting the large cardiovascular market."We'll probably look for a company " for help with late-stage trials and commercialization, he said.

BioVascular adds thrombotic via merger with Revitus

BioVascular (San Diego) has merged with Revitus, a drug development firm founded by an Oregon biomedical engineering professor, giving the company its second compound in clinical development for thrombotic vascular diseases. BioVascular acquired from Revitus 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, Oregon) will join BioVascular's board. No other terms were disclosed.

The firms reported the merger 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. Parrish said that BVI-007 reduces platelet production and is very different than products that are used to control platelet aggregation, which leads to blood clots.

The safety and tolerability of the product is being tested in 12 healthy volunteers. The firm plans to test dose escalation of the orally administered product in 50 participants in a Phase Ib trial expected to start in 4Q07, Parrish said, adding that both studies are being conducted in Europe.

Results of recent studies in survivors of a first MI 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, Parrish said, complements BioVascular's Saratin, a polypeptide derived from leech saliva. Saratin is 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.

Saratin was originally discovered, developed and patented by Darmstadt, and Merck KGaA (Darmstadt, Germany). Merck is licensed Saratin to BioVascular in 2005 and remains an investor in the San Diego firm, Parrish noted.

... and more

• Acusphere (Watertown, Massachnusetts) said that it continues to make progress in its efforts to file its New Drug Application (NDA) for its Imagify (perflubutane polymer microspheres) injectable suspension, a cardiovascular drug in late-stage development for use in screening for coronary artery disease.
  The company has completed a pre-NDA meeting with FDA on chemistry manufacturing and controls (CMC), and plans to incorporate FDA's feedback into the NDA.
  The company said it does not expect this feedback to impact its timeline for filing. However, given the tight timelines for the remaining operational steps to confirm that the manufacturing process is sterile, the company now believes that the NDA filing date is more likely to occur in early 2008, rather than its previous guidance of year-end 2007.
  Acusphere is a specialty pharmaceutical company that makes new drugs and improved formulations of existing drugs using its microsphere technology.
• Palatin Technologies (Cranbury, New Jersey) last month reported plans to reduce its workforce by 30% — to 64 employees — to produce savings of some $4 million.
  The company in a statement said that the cutbacks are the result of FDA concerns about "the acceptable benefit/risk ratio to support the progression of bremelanotide," its drug begin develope for male sexual dysfunction, into Phase III studies for erectile dysfunction as a first-line therapy in the general population.
  Palatin said that the downsizing will give it "the greatest opportunity for near-term success" of its major programs. It said it will continue its collaboration with AstraZeneca (London) to advance a lead clinical candidate for the treatment of congestive heart failure. It said it anticipates an Investigational New Drug (IND) application with the FDA by the end of 2007.