Vascular Diseases

March 4, 2013

Boehringer Ingelheim published results from a phase II trial of dabigatran compared to warfarin for the treatment of venous thromboembolism (VTE) in the New England Journal of Medicine. This randomized study, RE-MEDY, enrolled 2,856 patients with recurrent VTE. Subjects received dabigatran 150mg twice daily or warfarin for six to 36 months. Data demonstrated that dabigatran 150mg was non-inferior to warfarin in preventing recurrent VTE, including VTE-related death (26 patients,1.8% versus 18 patients, 1.3%, respectively; p=0.01). In addition, there were fewer major bleeding events in patients with a prior history of VTE receiving dabigatran compared with those receiving warfarin. There also was a significantly lower risk (46%; p<0.001) of major or clinically relevant bleeding events in this same set of patients. The drug was well tolerated. Boehringer Ingelheim did not note its plans for dabigatran.

October 29, 2012

Bayer HealthCare released data from a phase III trial of riociguat for pulmonary arterial hypertension (PAH). This randomized, double-blind, placebo-controlled, multinational study enrolled 445 patients with symptomatic PAH. Subjects received titrated doses of riociguat three times daily in increments of 0.5mg, with doses as low as 1.0mg and as high as 2.5mg, over eight weeks, followed by a four-week follow-up period. The study met its primary endpoint by demonstrating a statistically significant improvement in the six-minute walk distance (6MWD) with patients treated with riociguat showing an improvement of 36 meters 95%-CI [20-52 meters] (p<0.0001) after 12 weeks compared with placebo. Results also showed a statistically significant improvement in 6MWD, both in the treatment-naive patient group (38 meters after 12 weeks compared with placebo [95%-CI 15-62 meters]) and the pre-treated patient group (36 meters after 12 weeks compared with placebo [95%-CI 15-56 meters]). The drug was well tolerated.

September 10, 2012

The American Journal of Medicine published results from a phase III adjunctive trial of chlorthalidone for the treatment of hypertension. This 10-week, randomized, double-blind, titrate-to-target study enrolled 609 patients with stage two hypertension. Subjects received azilsartan medoxomil 40mg alone for two weeks, then 12.5mg of either diuretic, chlorthalidone or hydrochlorothiazide, for four weeks. At week six, subjects were titrated to 25mg chlorthalidone or hydrochlorothiazide for another four weeks. At week six, the clinic systolic blood pressure (SBP) reductions of the fixed dose combination of azilsartan medoxomil and chlorthalidone were -35.1mmHg. These data were statistically significantly (p<0.001) greater than those of azilsartan medoxomil and hydrochlorothiazide (-29.5mmHg), with a mean difference of -5.6mmHg. At the end of 10 weeks, greater clinic SBP reductions were maintained in patients taking the fixed-dose combination of azilsartan medoxomil and chlorthalidone (-37.8mmHg) versus those taking azilsartan medoxomil and hydrochlorothiazide (-32.8mmHg) with a mean difference of -5.0mmHg. Chlorthalidone was well tolerated.

June 14, 2010

PolyMedix issued positive results from a phase Ib trial evaluating PMX-60056 for reversing the anticoagulant activity of low molecule weight heparin (LMWH). This double-blind, crossover study enrolled six subjects at a single site in the United States. The subjects were randomized into two cohorts and given a subcutaneous injection of tinzaparin (Innohep), an FDA approved LMWH, followed five and eight hours later by a ten-minute intravenous infusion of PMX-60056 or placebo. With the crossover design, on the second treatment day, each subject received the alternate treatment. PMX-60056 neutralized the anticoagulant activity of LMWH tinzaparin and normalized blood clotting time. PMX-60056 was safely administered with no serious adverse events.

September 7, 2009

AstraZeneca reported results from a head-to-head study evaluating ticagrelor versus clopidogrel for the prevention of complications due to acute coronary syndrome. This international, double-blind, randomized trial, PLATO (A Study of Platelet Inhibition and Patient Outcomes), enrolled 18,624 patients with ACS with or without ST-segment elevation. The subjects received ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter). The primary endpoint was percentage of reported cardiovascular events (CV death, myocardial infarction, stroke) at 12 months. Ticagrelor achieved greater efficacy over clopidogrel (9.8% vs. 11.7%; p<0.001), without an increase in major bleeding (11.6% vs. 11.2%, p≡0.43). A statistically significant reduction in both CV death (4.0% vs. 5.1%, p≡0.001) and heart attacks was also observed (5.8% vs. 6.9%, p≡0.005) with no difference in stroke (1.5% vs. 1.3%, p≡0.22). Ticagrelor also demonstrated significant results across multiple secondary efficacy endpoints including all-cause mortality, transient ischemic attack, recurrent cardiac ischemia, severe recurrent cardiac ischemia, and other arterial thrombotic events. When minor bleeding was added to the major bleeding results, ticagrelor showed an increase versus clopidogrel (16.1% vs. 14.6%, p≡0.008). There was also an increase in non-procedural related bleeding with ticagrelor.

December 1, 2008

Aldagen reported positive results from a phase I/II trial of ALD-301, a stem cell therapy for the treatment of critical limb ischemia. The randomized study enrolled 21 subjects; 10 of whom received ALD-301 stem cells extracted from their own bone marrow samples, and 10 of whom received multiple injections of their own untreated bone marrow. They were subsequently monitored for up to six months. The primary objective of the trial was to evaluate the safety of ALD-301. Secondary objectives included change in clinical status from baseline to 12 weeks, as measured by the Rutherford category. ALD-301 was well tolerated. Four of the 11 subjects in the ALD-301 treatment group improved in Rutherford category and were no longer categorized as having critical limb ischemia at 12 weeks. One of the 11 subjects in the ALD-301 treatment group worsened clinically over the 24-week trial. There was a statistically significant increase in mean ankle-brachial index (ABI) in the ALD-301 treatment group at 12 weeks compared to baseline (p≡.03). There was also an increase in mean transcutaneous partial pressure of oxygen (TcPO2) in the ALD-301 treatment group at 12 weeks compared to baseline.

November 17, 2008

Pervasis issued positive pooled results from phase I and II trials of Vascugel, an allogeneic cell therapy for the repair and regeneration of vasculature pathways. These studies, collectively dubbed V-HEALTH (Vascular intimal Hyperplasia: Extending Arterial and venous patency, Limiting vascular Trauma, and inhibiting Hyperplasia while re-establishing vascular health), enrolled a total of 65 subjects with end-stage renal disease undergoing placement of an arteriovenous (AV) graft or AV fistula for hemodialysis access. The phase I trial was a non-randomized, open-label study in four subjects receiving AV fistulae and four subjects receiving AV grafts. The phase II trial was a multi-center, double-blind study of Vascugel versus placebo in 57 subjects, 27 receiving an AV fistula and 30 receiving an AV graft. The primary endpoint was the incidence of local wound infection, intervention (surgical, endovascular or percutaneous) and acute thrombosis within 30 days post-surgery. Treatment with Vascugel led to a lower incidence of each endpoint compared to placebo: 6.5% and 10.9% for the Vascugel treated arms at two and four weeks, respectively, versus 21.1% and 21.1% for the control group. In the AV graft intent-to-treat population (n=61), treatment with Vascugel showed a statistically significant decrease in the incidence of early complications compared to placebo ((5.3% versus 10.5%; p=0.047) at two weeks; this trend continued at four weeks. Treatment was well tolerated and there was no difference in serious adverse events between Vascugel and placebo groups.

June 5, 2006

Millennium Pharmaceuticals announced positive results of a phase II trial of MLN1202, for the prevention of atherosclerotic cardiovascular disease. Preliminary data indicated that the drug met its primary efficacy endpoint, significantly reducing levels of C-Reactive Protein (CRP, an inflammatory biomarker) for several months following a single-dose of the drug , compared to placebo (p=0.0275). No serious adverse events were reported. This randomized, placebo-controlled study enrolled 108 patients with elevated CRP levels who were at high risk for atherosclerosis. Subjects received a single-dose of the drug or placebo, and were then followed for several months. Additional results from this study were expected at upcoming major medical meetings.

July 21, 2003

Alteon reported negative results from a phase IIb trial investigating ALT-711, a crosslink breaker for the treatment of uncontrolled systolic hypertension. Results showed that ALT-711 did not demonstrate statistical significance as compared to placebo in the primary endpoint, the reduction of systolic blood pressure by ‘office cuff pressure’ measurement. The data showed a 6-10 mm Hg drop in systolic blood pressures in all groups during the first two weeks. The dose ranging, double-blind, placebo-controlled trials, called SAPPHIRE (Systolic And Pulse Pressure Hemodynamic Improvement by Restoring Elasticity) and SILVER (Systolic Hypertension Interaction with Left VEntricular Remodeling), enrolled 768 subjects having elevated systolic blood pressure at over 60 sites nationwide. Subjects were maintained on background hypertension medication during treatment.

EPIX Medical reported positive results from two phase III trials investigating MS-324, a blood pool contrasting agent for the use with magnetic resonance angiographs (MRA). The two trials were conducted on subjects with suspected vascular disease in the renal and pedal arteries. Results demonstrated that both studies met their primary clinical endpoint, demonstrating statistically significant improvement in accuracy for detecting renal and pedal vascular disease with MS-325 compared with non-contrast MRA. The renal study enrolled 145 subjects with suspected disease in the renal arteries and administered each a 0.03 mmol/kg dose of MS-325. Data showed that three individual MRA readers achieved an accuracy of 73%, 79% and 79%, with MS-324 enhancement compared with 45%, 56% and 51% for non-contrast MRAs. The pedal study enrolled 96 subjects with suspected pedal artery stenosis and administered each a 0.03 mmol/kg dose of MS-325. The three readers showed improved specificity of 21%, 34% and 34% with MS-325-enhanced MRA compared to non-contrast MRA. Results were announced at the 11th annual meeting of the International Society of Magnetic Resonance in Medicine (ISMRM) in Toronto.

Sanofi-Synthelabo reported positive results from a general surgery study investigating Arixtra (fondaparinux), a selective factor X inhibitor for the treatment of venous thromboembolism (VTE). Results showed that Arixtra was at least as effective and as safe as the low molecular weight heparin (LMWH) dalteparin for the prevention of VTE following major abdominal surgery. In abdominal cancer surgery subjects, fondaparinux was significantly more effective than the low molecular weight heparin. The randomized, double blind study, called PEGASUS (The PEntasaccharide in GenerAl SUrgery Study) enrolled 2,927 subjects who had undergone major abdominal surgery. Results were presented at the 19th Congress of the International Society on Thrombosis and Haemostasis.

December 2, 2002

Alexion Pharmaceuticals reported mixed results from two phase II trials investigating pexelizumab, an antibody fragment for the treatment of acute myocardial infarction (AMI). The first study, designed to evaluate the possible benefits of pexelizumab in acute myocardial infarction subjects who underwent primary percutaneous transluminal coronary angioplasty did not reach its primary endpoint of infarct size reduction. However, pexelizumab was associated with a statistically significant 70% reduction in 90 day mortality (placebo 5.9% vs. pexelizumab 1.8%), a secondary endpoint. The double blind, randomized study enrolled 814 AMI patients who had received angioplasty. The second study, designed to evaluate the possible benefits of pexelizumab in subjects who sustained an AMI and were treated with a thrombolytic did not reach its primary endpoint of reduction in infarct size. There was no reduction in mortality, but subjects outside the U.S. had greater cardiac damage at baseline and lower utilization of revascularization procedures after study entry. The trial, a double blind, randomized, multinational study enrolled 920 subjects with acute myocardial infarction who had received thrombolytics. Pexelizumab appeared to be well tolerated in both studies with the most common adverse events being headache, chest pain, hypotension, and ventricular tachycardia.

Vasogen reported positive results from a phase II trial investigating their immune modulation therapy (IMT) for the treatment of cardiovascular and other inflammatory diseases. The double blind, placebo-controlled trial demonstrated a significant reduction in the risk of death and hospitalization, improvements in a clinical composite score, and improvements in key electrocardiogram (ECG) measures among CHF patients receiving IMT. There was also a significant reduction in the risk of death (1 vs. 7 deaths) and hospitalization (12 vs. 21 hospitalizations), versus placebo. Data also showed that IMT improved key ECG measures (QTc interval and QT dispersion) and that these electrophysiological effects were consistent with the observed positive impact on mortality.

June 17, 2002

Positive results were reported from a phase I trial of AC3056, an investigational compound for the treatment of atherosclerosis and other conditions related to the obstruction of blood vessels. In the double-blind, placebo-controlled, crossover trial, 14 healthy subjects received an oral formulation of AC3056 in a dose-escalating manner. Results showed dose-dependent increases in blood levels of AC3056, as well as dose-dependent increases in serum antioxidant activity. The drug was well tolerated with no safety concerns. AC3056 is being developed by Amylin Pharmaceuticals.