A study published in a recent issue of the Journal of the American Society of Hypertension demonstrates that the hypertension treatment olmesartan medoxomil was effective in reversing the narrowing of the arteries that occurs in patients with hypertension. The study, Vascular Improvement with Olmesartan medoxomil Study (VIOS), was a one-year, exploratory trial that evaluated the effects of an angiotensin receptor blocker (olmesartan medoxomil) vs. a beta-blocker (atenolol) on vascular function and structure in patients with Stage 1 hypertension, independent of the blood pressure lowering effects of these agents.

In VIOS, olmesartan medoxomil, through early blockade of angiotensin II, improved the structure abnormalities of resistance arteries in patients with hypertension as measured by arterial wall to lumen ratio (W/L), returning arterial architecture to normal levels after one year of treatment.

This effect was not seen with the comparator agent in the study, atenolol.

"We believe the VIOS data add to the growing evidence for the role of angiotensin receptor blockers in preventing or reversing vascular damage at many stages during this disease process," said Carlos Ferrario, MD, one of the study's lead investigators and professor and director of hypertension and vascular research center, Wake Forest University School of Medicine (Winston-Salem, North Carolina).

Olmesartan medoxomil is marketed in the U.S. by Daiichi Sankyo (Parsippany, New Jersey) as Benicar. Benicar and Benidar HCT (olmesartan medoxomil/ hydrochlorothiazide) are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.

VIOS was a randomized, controlled, open-label, one-year study, its primary endpoint the change in the morphological characteristics of resistance arteries as determined by differences in the wall (media)/lumen (W/L) ratio. This parameter was measured using a pressurized myograph procedure on arteriole biopsy samples obtained from a sub-group of 49 patients receiving treatment (27 were on olmesartan and 22 were on atenolol) and from 11 normotensive control subjects.(19)

Non-diabetic patients with Stage 1 hypertension (61% male; age 38 to 67 years) were randomized after a four-week washout period to olmesartan medoximil 20 mg to 40 mg or atenolol 50 to 100 mg plus additional agents (hydrochlorothiazide 12.5-25 mg, amlodipine 5-10 mg, or hydralazine 50-100 mg twice daily) as needed for a goal BP of < 140/90). Stage 1 hypertension is defined by the JNC 7 as systolic blood pressure (SBP) of 140-159 mm Hg or diastolic blood pressure (DBP) of 90-99 mm Hg.

The arteriolar dimensions (W/L Ratios) in the olmesartan medoxomil and atenolol-based treatment groups were similar prior to drug treatment (14.9% and 16% respectively), whereas arteries from the normotensive subjects had significantly smaller W/L ratios (11%).

At the end of the study the W/L ratio in the olmesartan medoxomil-based treatment group was significantly reduced (from 14.9% to a mean of 11.1%; P<0.01). No significant change was observed in arteries of atenolol-treated patients (from 16.0% to 15.5%; P=NS).

The difference between olmesartan medoxomil-treated and atenolol-treated patients at 1 year was significant (11.1% vs. 15.5%; P<0.001).

Blood pressure reductions from baseline occurred within 12 weeks for both treatments and were statistically significant (P<0.05); blood pressure reductions were similar between the two treatments for the remainder of the study.

Benicar HCT is not indicated for initial therapy. Benicar and Benicar HCT have not been FDA approved for other indications such as end organ disease or other hypertension-related morbidity.

Angiotensin II has been linked to vascular dysfunction and end-organ damage, including cardiac hypertrophy and renal injury. Previous studies have demonstrated a beneficial effect of ACE inhibitors or other angiotension II receptor blockers (ARBs) in the reversal of vascular hypertrophy in hypertensive subjects.

Study data backs Regado's two-component system

The journal Circulation has published clinical data concerning the use of the REG1 anticoagulation system from Regado Bioscience (Durham, North Carolina), in a Phase Ib dose-escalation study. REG1 is a two-component system comprised of an aptamer-based anticoagulant, RB006, and its matched antidote, RB007, which binds to and neutralizes RB006.

Regado said that the study is the first to show that RB006 effectively inhibited, in patients, the activity of Factor IXa, a protein essential to blood clotting and that RB006's activity was reversed rapidly and safely by RB007.

The study article, titled, "A Phase Ib Randomized Study of Antidote-Controlled Modulation of Factor IXa Activity in Patients with Stable Coronary Artery Disease," was authored by researchers from the Duke Clinical Research Institute (also Durham) and Regado.

The study showed an intravenous (IV) bolus injection of RB006 achieved a prompt, consistent, and dose-dependent prolongation of activated partial thromboplastin time (aPTT), a surrogate marker of the blood's ability to clot. In addition, a 1 mg/kg dose of RB006 resulted in essentially complete Factor IXa inhibition.

The study also demonstrated an IV bolus injection of RB007 administered in a 2:1 antidote:drug ratio successfully reversed prolonged aPTT within a median of one minute, with no rebound for up to seven days. There were no major bleeding or other serious adverse events observed in the study, which included 19 subjects who received dual antiplatelet therapy.

"The data published in Circulation provide further evidence of the REG1 system's ability to rapidly and predictably anticoagulate and then to reverse this effect as needed in a reproducible manner," said Doug Gooding, CEO of Regado. "The results also show the pharmacologic data translated well from healthy volunteers to the CAD patient population."

Following the completion of a Phase I program in a total of 173 patients, Regado now is evaluating this first-in-class antidote-reversible therapeutic system in a Phase IIa trial in patients undergoing elective percutaneous coronary intervention.

"If the results of this study further confirm the Phase I data, we are confident this system may be able to transform the way anticoagulation is approached in coronary revascularization procedures and other acute care settings," Gooding said.

Regado's Phase I program included three studies.

A PhaseIa study enrolled 84 healthy volunteers, while the Phase Ib study reported above enrolled 50 patients with stable coronary artery disease who were receiving aspirin with or without clopidogrel. In addition, the company conducted a Phase Ic clinical study, in which 39 healthy volunteers were randomized to receive either three consecutive REG1 treatment cycles or placebo.

The Phase Ic study further demonstrated RB007's ability to reverse the anticoagulant effect of RB006 either completely or partially, depending on the level of dosing of RB007.

Based upon the combined results of the company's Phase Ia, Ib and Ic studies, Regado initiated REVERSAL-PCI, a multi-center, open-label, randomized Phase IIa clinical study of the REG1 anticoagulation system.

The Phase IIa study is enrolling 26 patients undergoing elective percutaneous coronary intervention to assess whether REG1 can replace standard heparin therapy during the performance of coronary balloon angioplasty dilatation and stenting in patients at low risk for complications associated with therapy-related bleeding or heart attack.

Regado says that REG1, its lead product candidate, is the first specific, direct-acting, antidote-controlled anticoagulant ever described. Regado is developing REG1 for use in patients suffering from acute coronary syndrome who undergo coronary revascularization procedures.

These procedures, which include coronary artery bypass grafting (CABG) and PCI, put patients at a high-risk for therapy-related bleeding complications. REG1 is being developed initially to increase therapeutic flexibility and improve patient outcomes in coronary revascularization procedures.

REG1 is a two-component system, consisting of an aptamer-based anticoagulant and its matched antidote.

The RB006 anticoagulant component is a single-stranded, nucleic acid aptamer that selectively and binds to and inhibits Factor IXa, a protein that is critical to blood coagulation, Regado says. The antidote component, RB007, is a complementary nucleic acid that binds to and neutralizes RB006. The binding of RB007 to RB006 causes the predictable and rapid reversal of RB006 that allows the patient's blood to return to normal.

Regado says that its drug:antidote systems are designed to give physicians the ability to fine-tune therapeutic effect. Regado is a spin-out of the department of surgery at Duke University Medical Center.

Duska licenses drugs from Duke and Johns Hopkins

Duska Therapeutics (Bala Cynwyd, Pennsylvania) reported an exclusive, worldwide license from Duke University (Durham, North Carolina) and Johns Hopkins University (Baltimore) to develop the rights to the two universities' portfolio of investigational cardiovascular drugs for the treatment of heart failure.

The most advanced drug in the portfolio is expected to enter a Phase II clinical study later this year. The drug portfolio was developed in part by Jonathan Stamler, MD, George Barth Geller, professor of research in cardiovascular diseases and professor of medicine and biochemistry at Duke University, and Joshua Hare, MD, Louis Lemberg Professor of Medicine, chief of the division of cardiology and director of the Interdisciplinary Stem Cell Institute at University of Miami. Hare formerly was associated with Johns Hopkins University.

The Phase II candidate and all other drugs in the portfolio are designed to correct nitric oxide and redox disequilibrium in the failing heart and cardiovascular system. All have a dual mechanism of action of inhibiting the creation of reactive oxygen radicals and concurrently providing nitric oxide in the failing heart. The therapeutic target is the ryanodine receptor, the ion channel in the heart that provides the calcium necessary for the heart to beat.

The investigational drugs are believed to improve calcium cycling in the heart by acting on the ryanodine receptor to significantly improve the efficiency of heart contractility.

"The licensing of these novel heart failure drugs greatly strengthens our pipeline by adding a Phase II candidate with blockbuster market potential," said James Kuo, MD, CEO and chairman of Duska. "Multiple sets of data obtained in preclinical and human studies suggest that our newly licensed heart failure drugs should be safe and beneficial. We intend to initiate a randomized, double-blind and placebo-controlled Phase II clinical trial of the lead candidate later this year to expand on the earlier clinical findings," he added.

Duska is developing products based on adenosine triphosphate and nitric oxide.

Briefly ....

Cerus (Concord, California) reported results from 32 studies, at the International Congress of the International Society of Blood Transfusion in Macao SAR, China, on its Intercept Blood System. Study outcomes included clinical experience implementing the Intercept Blood System for platelets and plasma into routine practice.

Other studies demonstrated its usefulness in the inactivation of current and emerging pathogens, such as malaria and avian influenza, in donated blood, the company said. Safety/efficacy were highlighted in results from a multi-year hemovigilence surveillance program and in a study of patients with a severe congenital bleeding disorder undergoing major surgery.

The Medicines Co. (Parsippany, New Jersey), received a not approvable letter for a supplemental new drug application for an additional dosing regimen for Angiomax (bivalirudin) in acute coronary syndromes initiated in the emergency department.

The company said it has initiated discussions with the FDA to address issues relating to the appropriate use and interpretation of non-inferiority trials. Angiomax is a direct thrombin inhibitor approved in patients undergoing percutaneous coronary intervention. The company reaffirmed its 2008 Angiomax U.S. sales guidance of $310 million to $320 million.

Syndexa Pharmaceuticals (Cambridge, Massachusetts) in early June received a $15 million boost in a Series B financing round, which will allow the firm to advance its metabolic disease product platform. Syndexa, focused on developing small-molecule drugs to treat obesity-induced diseases, such as atherosclerosis and Type 2 diabetes, has raised $19 million of equity capital to date, said CEO Teo Uysal.

The company said the new funds will carry it through 2009 and possibly beyond.

The company's discovery platform targets the endoplasmic reticulum biology and the c-jun n-terminal kinase (JNK), which Uysal called the "interface of inflammation and metabolism." Syndexa, which became operational in early 2007, licensed its technologies from Harvard University (Cambridge, Massachusetts), the University of California, San Diego, and the Burnham Institute of Biomedical Research (La Jolla, California), a non-profit organization.

The round was led by new investor Yalcin Ayasli, an entrepreneur and founder of Hittite Microwave (Chelmsford, Massachusetts).

• The Agency for Healthcare Research and Quality (Washington) released a consumer publication, Your Guide to Coumadin/Warfarin Therapy, explaining what patients should watch out for while undergoing Coumadin/Warfarin therapy. Carolyn Clancy, MD, director of AHRQ, said, "Individuals respond differently to warfarin, so the dosage must be personalized to each patient, and it is necessary for patients and clinicians alike to be aware of the factors that make for safe use of the drug."

The booklet is online at www.ahrq.gov/consumer/coumadin.html and on the SOS Rx Coalitio n website http://www.mybloodthinner.org.

AHRQ said that in 2005 more than 3.8 million Americans were taking Coumadin/Warfarin at a cost of nearly $963 million. Warfarin is the second most common drug after insulin-implicated in emergency room visits for adverse drug events, the agency said.

United Therapeutics (Silver Spring, Maryland) and its wholly-owned subsidiary, Lung Rx, reported that data from seven presentations concerning the treatment of pulmonary arterial hypertension (PAH) with treprostinil were reported at the American Thoracic Society (ATS) meeting in Toronto. The ATS presentations involved treprostinil delivered by inhaled, oral, intravenous and subcutaneous routes of administration.

"It has always been our goal to build a portfolio of products from the remarkable treprostinil molecule that will create viable treatment options for patients along the full continuum of this life-threatening disease," said Martine Rothblatt, PhD, United Therapeutics' chairman/CEO "The results of these diverse studies covering all four routes of delivery are bringing us just that much closer to realizing our goal."

Stem cell therapies for cardio applications

Ark Therapeutics advances Trinam and also Vitor

Ark Therapeutics (London) recently made advances in two of its programs, getting FDA go-ahead for the Phase III trial of Trinam, a gene-based therapy for preventing blood vessels blocking in vascular access grafts, and securing approval for a European Phase III pilot study of Vitor in treating cancer cachexia.

After more than a year of negotiation with the FDA, Ark has been granted a special protocol assessment for the Trinam trial. "This is very good news at the end of what has been an extremely rigorous and detailed review by the FDA," Nigel Parker, CEO, said. During the course of the review, Ark was required to conduct a further preclinical study and to provide extra biodistribution data for the product, which uses an adenoviral vector to deliver the vascular endothelial growth factor gene VEGF-D.

The company has to qualify one product release test relating to potency before it starts enrolling patients, and Parker expects the trial to start, "within the next couple of months."

At the end of access graft surgery, Ark's biodegradable collagen collar device is fitted around the outside of the joint between the vein and the graft, and the VEGF gene solution is injected into the space between the two. The method ensures delivery to the target tissue while avoiding systemic distribution.

"Graft failure is a big problem where nothing works and there is a high cost for revision surgery," Parker said. "Getting the SPA is really important because now if [Trinam] works it is acceptable for approval."

Ark also intends to apply for fast-track designation and expects the U.S. data to be suitable for filing in Europe.

The SPA includes the provision that there will be a sample sizing after 150 patients to determine the final trial size. Parker said this adaptive trial design was a useful approach for breakthrough drugs. "It is a constructive way of ensuring we don't narrowly miss the "p" value."

In the Phase II trial, which reported in March 2007, grafts treated with Trinam remained functional over three times longer on average than untreated controls.

Meanwhile, the European Phase III pilot study of Vitor in up to 64 patients is intended to inform the design of the final Phase III, to be carried out in the U.S. An earlier 167-patient Phase II/III study was positive in small-cell lung and colon cancer patients but failed in pancreatic cancer. After talks with the FDA to discuss those data, Ark backed off from moving Vitor into a full-scale Phase III trial, opting instead to gather further intelligence on endpoints.

That change, in response to the FDA's increasingly rigorous stance on clinically relevant endpoints and safety data, set back development by nine months.

As an angiotensin-converting enzyme (ACE) inhibitor currently marketed for the treatment of hypertension, Vitor has application in cachexia , based on Ark's discovery that ACE inhibitors increase the ability of mitochondria to produce energy and prevent the breakdown of the muscle proteins actin and myosin.

Covalon reports progress in its EPAS-1 project

Covalon Technologies (Mississauga, Ontario) reported reported progess in its EPAS-1 research project is to identify a breakthrough for stimulating new blood vessel growth and tissue regeneration in tissues damaged by loss of, or restricted blood flow due to congestive heart failure, diabetes, chronic wounds, peripheral vascular disease and other conditions.

Dr. Frank DiCosmo, co-founder and CEO of Covalon, said that the EPAS-1 project is expected to allow Covalon to produce "universal donor" mesenchymal stem cells that can be used by all individuals for use in myocardial preservation by therapeutic cell transplantation following loss of blood flow due to coronary vessel occlusion. He said, "Covalon's cell therapy program is designed to generate mesenchymal stem cells [EPAS1-cells] that express genes that control the production of growth factors at the site of cell transplantation that may be useful for new blood vessel formation ... ."

In pre-clinical studies, swine stem cells derived from the marrow of a single donor animal with blood group "O" could be isolated, genetically manipulated with EPAS1, frozen and thawed for use.

Mesenchymal stem cells altered with the EPAS-1 gene showed enhanced production and secretion in vitro of several protein factors essential to new blood vessel growth. And the introduction of EPAS-1 cells by intra-cardiac injection into the hearts of swines showed no significant, adverse side-effects.

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