CD&D National Editor and Staff Reports

Sanofi-aventis (Bridgewater, New Jersey) and Bristol-Myers Squibb (BMS; Princeton, New Jersey) reported findings from what they called "a landmark investigational study," demonstrating that, for patients with atrial fibrillation (AF), at increased risk for stroke and unable to take oral anticoagulant (OAC) medication, Plavix (clopidogrel bisulfate) plus aspirin significantly reduced major vascular events by 11% over aspirin alone.

The result looked at a median of 3.6 years of follow-up (6.8% vs. 7.6% per year). The greatest benefit was seen in the reduction of stroke, by 28% (2.4% vs. 3.3% per year), the primary goal of physicians treating patients with AF. Other components of major vascular events — non-CNS systemic embolism, heart attack or vascular death — did not reach statistical significance.

Compared to aspirin alone, however, Plavix in addition to aspirin significantly — and as expected, the companies said – did increase the rate of major bleeding (2.0% vs. 1.3% per year). The study results, from the trial called ACTIVE A, were presented at a late-breaking session during the 58th annual scientific session of the American College of Cardiology (Washington) in Orlando.

"For patients with atrial fibrillation who are at increased risk for stroke but cannot take oral anticoagulants, these findings suggest a potential change in clinical practice," said ACTIVE A principal investigator Stuart Connolly, MD, department of medicine, McMaster University (Hamilton, Ontario).

In AF, blood can pool in the atria and form clots, which can be released into the bloodstream, producing a five-fold greater risk for stroke. The companies cited statistics that AF patients account for about 15% of all strokes. Thus, they said, "In addition to therapies to normalize heart rhythm, treatment guidelines recommend AF patients at moderate-to-high risk for stroke also receive OAC therapy, which is effective in preventing vascular events in these patients." However, they note that many patients cannot take OACs without the risk of increased bleeding and that "less than half of AF patients overall use OACs."
ACTIVE A was a Phase III, double-blind, placebo-controlled trial designed to compare the combination of Plavix 75 mg once daily plus aspirin (75-100 mg) to aspirin alone (75-100 mg daily) for preventing the first occurrence of a major vascular event, the primary endpoint, during the trial, with a median of 3.6 years of follow-up.

Major vascular events included stroke, non-central nervous system (non-CNS) systemic embolism, heart attack, or vascular death. The trial included 7,554 patients with AF who could not take OACs and had at least one major risk factor for stroke.

Cardio smokers helped by Chantix/Champix

Pfizer (New York) reported at the ACC annual meeting the results of a study that found that 47% of smokers with a history of cardiovascular disease who took Chantix/Champix (varenicline) were able to quit smoking and remain abstinent during the last four weeks of treatment (weeks nine to12) compared with just 13.9 % of those given placebo.

"These data are consistent with the findings from the pivotal varenicline trials, which showed that varenicline was more effective than placebo among smokers who were generally healthy," said Nancy Rigotti, MD, professor of medicine at Harvard Medical School (Boston), director of the Tobacco Research and Treatment Center at Massachusetts General Hospital (also Boston) and lead study investigator. "This study demonstrates that varenicline is effective in helping smokers with cardiovascular disease quit smoking. The safety profile of varenicline in this study also resembles that of the pivotal studies."

The company said that in the U.S. roughly 130,000 adults die each year from smoking-related cardiovascular disease, representing roughly one-third of all smoking-related deaths among adults 35 and older.

The multicenter, double-blind, placebo-controlled trial included 714 adult patients (ages 35-75) who had smoked an average of 10 or more cigarettes daily in the year before enrollment. Eligible cardiovascular disease diagnoses included history of heart attack, a certain type of heart surgery, chest pain, peripheral arterial vascular disease, and stroke or transient ischemic attack.

At 52 weeks, 19.2% of patients who were randomized to take varenicline during the treatment phase remained abstinent, compared with 7.2% of patients randomized to take placebo. Pfizer said that Varenicline was generally well-tolerated. In the varenicline group, 7.4% of patients experienced cardiovascular events vs. 6.6% in the placebo group (difference 0.8, 95% CI: -3.0 to 4.6). Serious adverse events occurred in 6.5% patients treated with varenicline compared with 6% percent of those given placebo. None of the serious adverse events involved depression, suicidality, or abnormal behavior.

However, some patients have had changes in behavior, agitation, depressed mood, suicidal thoughts or actions when attempting to quit smoking while taking varenicline, or after stopping varenicline.

The most common side effects include nausea (30%), sleep problems, constipation, gas, and/or vomiting. Patients also may have trouble sleeping, or may have vivid, unusual or strange dreams while taking varenicline. Patients should be advised to use caution driving or operating machinery until they know how quitting smoking with varenicline may affect them.

In brief ….

• Ablynx (Ghent, Belgium) reported results from a 25-patient Phase Ib study of antithrombotic ALX-0081 showing that all subjects with stable angina undergoing elective percutaneous coronary intervention who received the drug had complete inhibition of the biomarker, which indicated the complete inhibition of von Willebrand Factor and its mediated effect on platelet aggregation and clotting in coronary arteries. Complete inhibition of the biomarker was seen with a duration of four to 18 hours in the single-dose group and for at least 24 hours in the multiple-dose group. The trial met its primary endpoint in December. Ablynx said it expects to start Phase II testing of ALX-0081 in 3Q09.

• Amylin Pharmaceuticals (San Diego), Alkermes (Cambridge, Massachusetts) and Eli Lilly & Co. (Indianapolis) said a meta-analysis showed no increased risk of cardiovascular events associated with Byetta (exenatide), an incretin mimetic for Type II diabetes. The relative risk of cardiovascular events in exenatide-treated patients, compared to controls, was 0.70 with a 95% confidence interval of 0.38 - 1.31. The data will support a new drug application filing for once-weekly exenatide, expected in the second quarter. The companies also said they have initiated a 240-patient Phase IIIb study comparing the once-weekly product to its approved, immediate-release counterpart and they unveiled plans for a large cardiovascular outcomes study.

• Archemix (Cambridge, Massachusetts) has initiated a Phase IIa clinical trial of its anti-von Willebrand Factor aptamer, ARC1779. The trial is designed to evaluate the safety and efficacy of ARC1779 as a potential first-in-class anti-platelet agent in patients with carotid artery disease undergoing a surgical procedure known as carotid endarterectomy. The trial is a randomized, placebo-controlled study in about 100 patients.

The primary objectives will be to measure the effectiveness of ARC1779 in reducing the number of small blood clots which form immediately following the operation and then flow to the brain, and to assess the bleeding risk of ARC1779 in this setting.

The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 10 to 2 that the data supporting the new drug application for ONGLYZA (saxagliptin) for the treatment of adults with Type 2 diabetes were sufficient to rule out unacceptable cardiovascular risk, relative to comparators in the program. The drug was developed by The committee unanimously recommended that the sponsors, Bristol-Myers Squibb (BMS; Princeton, New Jersey) and AstraZeneca (Wilmington, Delaware), perform a post-marketing trial to confirm the cardiovascular profile of ONGLYZA. BMS and AstraZeneca said they are working on a series of Phase IIIb and IV studies to further characterize long-term clinical effect and the cardiovascular profile of ONGLYZA. The companies entered a collaboration in 2007 to develop and commercialize two investigational drugs for Type 2 diabetes – saxagliptin and dapagliflozin.

• Celladon (San Diego) said results of a Phase I/II trial showed that Mydicar (AAV1/SERCA2a), a genetically targeted enzyme replacement therapy for advanced heart failure, demonstrated acceptable safety and produced quantitative evidence of biological activity across a number of parameters important for assessing heart failure. Data were published in the Journal of Cardiac Failure. Mydicar is designed to restore levels of the enzyme SERCA2a, which is known to play a role in the progression of heart failure, and animal studies have shown that repairing that molecular defect could reverse the disease and restore cardiac function.

• Cordex Pharma (La Jolla, California) said it will collaborate with biomarker company BG Medicine (Waltham, Massachusetts), to measure Galectin-3 levels in Cordex's Phase II trial of CDP-1050 in heart failure patients. Galectin-3 is a biomarker for cardiac remodeling associated with advanced stages of heart failure. CDP-1050 targets the redox-nitiric oxide imbalance that is associated with poor contractile efficiency. Financial terms were not disclosed.

• Cubist Pharmaceuticals (Lexington, Massachusetts) said it began dosing in a Phase II trial of ecallantide. The study, called CONSERV-1, is evaluating the safety/efficacy and clinical outcomes of various doses of ecallantide for the reduction of blood loss volume during on-pump cardiothoracic surgery. The trial is expected to enroll more than 300 patients undergoing on-pump cardiothoracic surgery.

• Epix Pharmaceuticals (Lexington, Massachusetts) said its annual financial statements contained a going concern qualification. The firm ended 2008 with $24.6 million in cash and a long-awaited FDA approval of its cardiovascular imaging agent Vasovist (gadofosveset trisodium), and it cut half of its workforce earlier this month.

• Flamel Technologies (Lyon, France) earned a $4 million milestone payment from GlaxoSmithKline (London), related to Flamel's production of a Micropump-based microparticle formulation of GSK's cardiovascular drug Coreg CR (carvedilol phosphate extended release capsules). Flamel and GSK entered a supply agreement in 2004.

• Gentium (Villa Guardia, Italy) presented preliminary unaudited top-line results from the Phase II/III European pediatric prevention trial of Defibrotide. The results showed a 40% reduction in incidence of veno-occlusive disease (VOD) within 30 days after stem cell transplantation and achieved a statistical P-value of 0.0539, with a hazard ratio of 1.68 (95% confidence interval of 0.98-2.86), in the intent-to-treat analysis of 180 patients in the prophylaxis arm and 176 patients in the control arm. In addition, the analysis of data in patients who completed 30 days in the study, which included 164 patients in the prophylaxis arm and 169 patients in the control arm, showed a 40 percent reduction rate of the incidence of VOD within 30 days and achieved a statistical P-value of 0.0366, with a hazard ratio of 1.78 (95% confidence interval of 1.03-3.08). The data also demonstrated the excellent safety profile of Defibrotide showing no difference in adverse events between the prophylaxis and control arms. The results were presented at the Annual Meeting of the European Group for Blood and Marrow Transplantation (Maastricht, the Netherlands) in Goteborg, Sweden.

• Gilead Sciences (Foster City, California) has begun enrolling patients in a Phase II trial of cicletanine hydrochloride (cicletanine), an oral agent in development for the treatment of pulmonary arterial hypertension. The study is designed to compare the efficacy, safety and tolerability of cicletanine to placebo in patients with PAH and will enroll 160 patients at approximately 60 investigational sites worldwide. The study is a randomized, double-blind, placebo-controlled, multicenter, dose-ranging study designed to evaluate the safety, efficacy and tolerability of cicletanine. The primary efficacy endpoint is the change from baseline in six-minute walk distance after 12 weeks of treatment.

• GTC Biotherapeutics (Framingham, Massachusetts) said it received a $3 million milestone payment from Lundbeck (Deerfield, Illinois), a subsidiary of H. Lundbeck (Copenhagen), as a result of FDA approval of ATryn (antithrombin [recombinant]). Manufacture and release of product to support the commercial launch of ATryn has been completed, and an additional $1 million payment will be made by Lundbeck for that inventory to support the drug's launch in the second quarter for the prevention of peri-operative and per-partum thromboembolic events in hereditary antithrombin deficient patients.

• Interleukin Genetics (Waltham, Massachusetts) said it has granted Labec Pharma (Madrid, Spain) the rights to market and sell throughout Spain and Portugal its Heart Health genetic test for identifying people at an elevated risk for heart attacks. No financial terms were disclosed.

• Medgenics (Misgav, Israel) reported positive results its ongoing Epodure Biopump Phase I/II trial. The latest results show that in the first two patients treated, the hemoglobin level has remained continuously in the target range of 10-12 g/dl for more than five months following a single Epodure treatment using the lowest dose of 20 IU/kg/day, thus effectively treating their anemia without receiving any injections of erythropoietin (EPO). One patient received his last EPO injection more than 200 days ago. This is contrasted with the FDA approved standard regimen of three weekly EPO injections, in which typical patients would expect to receive up to 85 injections in this timeframe. A total of seven patients have now been treated, with six patients receiving treatment for more than one month. Data were presented at the conference of the Israeli Society of Nephrology and Hypertension.

• The Medicines Co. (Parsippany, New Jersey) said its marketing authorization application for injectable antihypertensive drug Cleviprex (clevidipine butyrate) has been accepted for review in Europe. A decision is expected in 2010; the product was approved by the FDA last year.

• NicOx (Sophia Antipolis, France) presented new results on naproxcinod's blood pressure profile. In the patients with controlled hypertension who were treated with renin-angiotensin system blockers, naproxcinod 750 mg bid showed a mean reduction in systolic blood pressure (SBP) of 5.0 mmHg from baseline at week 13, while naproxen 500 mg bid showed an increase of 1.5 mmHg, resulting in a statistically significant difference of 6.5 mmHg in favor of naproxcinod (p<0.02, post hoc analysis). Likewise, the SBP reduction from baseline was 2.7 mmHg in the naproxcinod 375 mg group and 4.6 mmHg in the placebo group. The company said it expects to file a new drug application in osteoarthritis with the FDA in mid-2009.

• Nile Therapeutics (San Francisco) reported the FDA placing a clinical hold on the company's product CD-NP, for treatment of acute heart failure. The decision came as the FDA reviewed the investigational new drug application materials that Nile submitted to the FDA to support the initiation of a Phase IIb trial. The FDA requested additional data from the recently completed Phase IIa trial and modifications to CD-NP's investigator brochure. The company said it expects to be able to file a complete response. CD-NP, a novel chimeric natriuretic peptide, was designed to have direct hemodynamic and renal activity to reduce symptoms of dyspnea, be diuretic and natriuretic and preserve or enhance renal function in heart failure patients.

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