A CD&D

Researchers at the University of Florida (UF; Gainesville) says they have identified a drug compound that they say "dramatically" works to lower blood pressure (BP), improves heart function and prevents damage to the heart and kidneys in rats with persistent hypertension.The latter of these findings they term "remarkable."

The drug unlocks the enzyme ACE2 that helps protect the cardiovascular system.

In the report, in the May 1 issue of the journal Hypertension, a publication of the American Heart Association (AHA; Dallas), the researchers say the finding could lead to a new class of anti-hypertensive drugs designed to address two major problems associated with cardiovascular disease: high BP and fibrosis, the tissue damage associated with high BP.

"When people have heart attacks — or suffer from hypertension — the blood vessels get more rigid," said study author David Ostrov, PhD, an assistant professor in the department of pathology, immunology and laboratory medicine at the the UF College of Medicine. "We discovered a compound [yet to be named] that reverses the fibrosis that makes the blood vessels more rigid."

The ressearchers noted that angiotensin-converting enzyme plays a key role in the development of high BP. It produces angiotensin II, a hormone that triggers the condition and contributes to the development of cardiovascular disease by constricting blood vessels, causing blood pressure to rise.

This is dealt with via ACE inhibitors, but these have only a limited capacity to repair heart function or reverse tissue damage.

In contrast, the researchers say, the enzyme ACE2 not only lowers levels of angiotensin II but also converts it to a hormone that helps protect the cardiovascular system.

"Only recently has it come to be appreciated that ACE and ACE2 play a very important role in balancing the activity of the other one to maintain normal blood pressure," Ostrov said. "They work in harmony."

Hypothesizing that activating ACE2 could be beneficial, the UF scientists set out to discover a compound that enhances the enzyme's activity, using a supercomputer to process 140,000 prospective drug compounds in a matter of weeks. The computer predicted which molecules would be most likely to enhance the activity of ACE2, rotating them in thousands of different orientations to see how they would bind to certain pockets on the enzyme's surface.

"This project had a very small likelihood of succeeding because it's much easier to inhibit activity rather than to enhance it," Ostrov said. "By analogy, it's easier to break something than to build it. If you consider the structure of an enzyme's active site, it's easy to see that if you plug up the active site it's not going to work. But how can one make the enzyme actually work better?

"This seemed to be a very significant challenge we were probably not likely to overcome. We tried anyway."

After hitting on the "lead" compound, the researchers then tested it in hypertensive rats that had developed fibrosis of the heart and kidney. The animals received the drug for two weeks.

Tissue samples from treated animals revealed a significant decrease in fibrosis of the heart, kidney and blood vessels, said Ostrov, who described the findings as "striking and reproducible."

Ostrov said the enzyme exists in two forms: like a Pac-Man with a mouth that has chomped closed, and like a Pac-Man with a mouth that remains wide open. The molecule that worked best fit in a structural pocket in the enzyme's open conformation. "So, in other words, stabilizing the open conformation may be the reason why we enhance the activity of the enzyme."

In describing the team's discovery process, Ostrov said that no one had ever been able to identify a compound "that enhances the activity of an enzyme using a rational structure-based approach ... on purpose. People have discovered molecules that enhance the activity of enzymes by trial and error, but no group has ever done it in a specifically pointed way like this."

The researchers said they will conduct additional studies to explore the compounds activity in animals and humans.

The study was funded by grants from the National Institutes of Health and the AHA.

Study identifies 6.2% bleeding claims with use of plavix

A review of medical claims from more than 70 managed care plans showed that 6.2% of patients prescribed the anti-platelet medicine clopidogrel (marketed as Plavix) submitted at least one insurance claim for ulcer or gastrointestinal bleeding, according to data from Cogentus Pharmaceuticals (Menlo Park, California), released at the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research (Lawrenceville, New Jersey).

The retrospective study tracked insurance claims for gastrointestinal adverse events among more than 368,000 patients in the 12 months following their first prescription for clopidogrel.

"This study provides important new information about the frequency of medical attention for gastrointestinal events required by an insured population on antiplatelet therapy," said lead author Pablo Lapuerta, MD, chief medical officer and senior VP for clinical strategy at Cogentus. "Inhibition of normal platelet function by clopidogrel likely contributed to gastrointestinal complications, particularly in such a real-world setting in which patients often have multiple risk factors."

Lapuerta added: "While it is important for patients to stay on clopidogrel to prevent the progression of coronary heart disease, ulcers and bleeding can result in patients not taking their heart disease medicine."

Studies have shown a greatly increased risk of gastrointestinal bleeding for patients taking clopidogrel in combination with aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS). One study showed that treatment with clopidogrel augmented bleeding caused by NSAIDS, an effect attributed to the inhibition of platelets by clopidogrel.

In the insurance claim review 72% of patients were over 60 years of age; a higher incidence of bleeding side effects was seen in women: 7.2% filed medical claims for an ulcer or gastrointestinal bleeding, while 5.4% of men filed claims.

"The surprisingly high frequency of these claims raises a significant public health concern," said Dr. Byron Cryer, the John Vanatta III Professor of Medicine and associate dean for minority affairs at the University of Texas Southwestern Medical School (Dallas). "Until recently, gastrointestinal side effects in patients taking anti-platelet therapy have been largely underappreciated by physicians, who are appropriately focused on preventing future heart attacks. We need to address this problem to help keep patients on their medical treatment regimens."

Cryer is a member of the Scientific Steering Committee overseeing the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) program, evaluating the efficacy/safety of Cogentus's lead product, CGT-2168, combining clopidogrel and the gastroprotectant omeprazole. CGT-2168 is designed to maintain the cardiovascular benefits of antiplatelet therapy while reducing its potentially serious gastrointestinal side effects.

COGENT is expected to enroll more than 4,000 patients at sites in the U..S., Canada, Europe and South America.

Volibris wins European Commission okay for PAH

GlaxoSmithKline (GSK; London) reported receiving authorization from the European Commission for Volibris (ambrisentan), GSK's product for the treatment of pulmonary arterial hypertension (PAH) in patients classified as World Health Organization Class II and III, to improve exercise capacity. Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.

GSK said that ambrisentan is the first non-sulphonamide class endothelin receptor antagonist (ERA) and the first PAH medicine approved for WHO Class II patients in Europe.

"Ambrisentan represents a development in the treatment of patients with PAH," said Nazzareno Gali , professor of cardiology and head of the Pulmonary Hypertension Center at the University of Bologna (Bologna, Italy). "It has demonstrated efficacy and safety in both Functional Class II and III patients. New treatments like this ... make incremental improvements to patients' quality of life."

Combined analysis of two pivotal Phase III clinical trials demonstrated that treatment with ambrisentan resulted in significant improvements in exercise capacity (six-minute walk test) and beneficial changes in other parameters, such as time to clinical worsening, WHO Functional Class, the Borg Dyspnoea Index, SF-36 Health Survey and B-type natriuretic peptide.

Patients in these studies continued ambrisentan treatment in a long-term extension study. At one year of treatment, 95% of patients who received ambrisentan were still alive and 84% were still alive at two years. Ninety-three percent of patients were maintained on ambrisentan monotherapy at one year.

GSK said that ambrisentan is associated with a low potential to affect the metabolism of other medicines and has no significant drug-drug interactions with sildenafil or warfarin.

There was no incidence of LFT abnormalities (>3 times the upper limit of normal) with patients taking ambrisentan in the two 12-week Phase III studies. In patients receiving ambrisentan long-term (mean exposure of 79.5 weeks), the event rate of liver function abnormalities (>3 times the upper limit of normal) was 2.3 events per 100 patient years of exposure to ambrisentan.

"Ambrisentan's low risk of drug-drug interactions and low incidence of liver function test abnormalities offer important additional benefits to patients with PAH whose quality of life is already significantly compromised by this progressive life-threatening condition," said Ardeschir Ghofrani, head of the Pulmonary Hypertension Division, University Hospital Giessen (Giessen, Germany).

PAH is a disease characterised by constriction of the blood vessels in the lungs, leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs. As the heart struggles to pump against these high pressures, patients become increasingly short of breath and leads to heart failure and death for many.

Dyax inks partnership for multi-potential DX-88

In what the company called part of a "multi-step commercialization strategy" for its DX-88 product, Dyax (Cambridge, Massachusetts) has licensed North American and European rights to an intravenous formulation of a compound for use in preventing blood loss during surgery to Cubist Pharmaceuticals (Lexington, Masschusetts) in a potential $231.5 million deal.

DX-88 (ecallantide, a recombinant plasma kallikrein inhibitor), has yielded positive results in the first of two Phase III studies and, pending positive results from the second, intends to file a biologics license application. Assuming a six-month priority review process, the company has said DX-88 could gain approval for treatment of heriditary angioedema, an ortphan indication, by the end of this year.

Henry Blair, president and chairman of Dyax, in a conference call said that the second Phase III study (EDEMA4) is "on track and enrolling well. We remain on course for year-end market approval."

Heriditary angioedema is just one potential indication for DX-88, being explored for larger angioedema indications and the prevention of blood loss during on-pump cardiothoracic surgery, which includes coronary artery bypass graft and heart valve and replacement procedures. The company has been looking for a U.S. and European partner for the latter program, and its deal with Cubist was a "significant step toward achieving the full value of the DX-88 franchise," said Gustav Christensen, executive VP and chief business officer.

Dyax will get a $15 million cash payment up front, plus an additional $2.5 million in milestones in 2008. The company could receive up to $214 million more in clinical, regulatory and sales milestones and would get tiered, double-digit royalties based on DX-88 sales by Cubist.

The deal also includes a U.S. co-promotion option for Dyax, with Cubist assuming financial responsibility for development of DX-88 in surgical indications, including costs associated with the ongoing Phase II trial in on-pump CTS patients. That study is expected to conclude in 4Q08.

Christensen said that DX-88 will be a "perfect fit" in Cubist's acute care portfolio and will take priority as the most advanced product in the pipeline.

Dyax said there has been no product available to prevent blood loss during surgery since Bayer (Leverkusen, Germany), at the request of the FDA, pulled its clotting drug, Trasylol (aprotinin, a bovine-derived enzyme inhibitor) from shelves in November, due to increased risk of in-hospital death in patients undergoing cardiac bypass.

Dyax continues to seek partners for the angioedema indications outside the U.S., but Blair said the company will commercialize DX-88 in heriditary angioedema on its own in the U.S. Heriditary angioedema is believed to affect an estimated 10,000 people in the U.S. It's characterized by painful swelling of the face, urogenital tract, abdomen or larynx and attacks can be fatal.

Dyax is one of several firms approaching regulatory approval in heriditary angioedema. Potential competitors include Lev Pharmaceuticals (New York), which in January received an approvable letter for its C1 inhibitor, Cinryze, calling for additional information, though likely no new trials. Lev submitted its response to the FDA earlier this month.

X-88 is one of several drugs in Dyax's pipeline developed using its phage display technology, and the Cubist deal marks the second major collaboration signed so far this year. Dyax partnered its antibody platform with Sanofi-Aventis (Paris) in February in a potential $500 million deal.

That collaboration gave Sanofi rights to DX-2240, a preclinical cancer compound, as well as rights to its phage display platform. Dyax expects to receive at least $25 million this year, with $16.5 million already paid.

Dyax awaits results of its second Phase III study of DX-88 in HAE, a sector riddled with competitors, one takikng a hard knock from the FDA recently.

Jerini (Berlin) said the agency deemed its icatibant, a synthetic peptidomimetic agent, not approvable in HAE, a setback that improves DX- 88's competitive position, according to analyst Phil Nadeau, of Cowen and Co. It "puts DX-88 in the pole position to be the first subcutaneous HAE treatment on the U.S. market," Nadeau wrote in a research note.

More cardio-pharma news ...

• Duska Therapeutics (La Jolla, California) said that after a meeting with the FDA it believes the agency would consider a new drug application under section 505(b)(2) for ATPace, subject to additional clinical data to be furnished by the company. ATPace is an investigational intravenous pharmaceutical formulation of adenosine 5'-triphosphate for the acute treatment of paroxysmal supraventricular tachycardia. The company said that it has begun preparation of supplement material.

• Pfizer (New York) reported that the U.S. Patent & Trademark Office will confirm the patentability of the claims of Pfizer's '893 basic patent for Lipitor. The Patent Office conducted a re-examination of the '893 patent in response to a request by a law firm that represented the India-based generic company Ranbaxy Laboratories.

The patent, which expires in March 2010 (including pediatric exclusivity), was previously the subject of litigation against Ranbaxy, in which Pfizer prevailed in both the trial and appeal courts.

• A new analysis of data from the landmark Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA) published in Diabetes Care has identified the major predictors of new-onset diabetes (NOD) in patients with hypertension.

The data show that hypertensive patients allocated to amlodipine and the ACE inhibitor perindopril (Coversy, Servier) were 34% less likely to develop NOD compared with those allocated to a beta-blocker/diuretic combination (atenolol plus or minus thiazide).

The investigators said that it seems that the beneficial effect of the amlodipine/perindopril regimen is largely a composition of the protective effect of Coversyl, amlodipine playing a neutral role, whereas atenolol and thiazide have adverse effects.