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Peripheral Arterial Occlusive Disease
June 25, 2007
AnGes announced positive results from a phase III trialof AMG0001 for the treatment of Critical Limb Ischemia (CLI).This randomized, placebo-controlled, double blind study enrolled 40 subjects inJapan. Of the subjects, 27 received AMG 0001 8mg (4mg x 2) and 13 received placebo.The primary endpoints, improvement of rest pain ((VAS (Visual Analog Scale)) orischemic ulcer size, at 12 weeks post dosing, showed statistical significance,with a 70.4% improvement in the AMG0001 group versus a 30.8% improvement in theplacebo group (p=0.014). Treatment was well tolerated, with adverse reactionssimilar between the groups. Based on the results, AnGes stopped the trial earlyto prevent potential ethical issues against the placebo group subjects. The companyplans to move forward with filing for Japanese and US approval.
January 8, 2007
Actelion reported positive results from a clinical trial, dubbed EARLY (Endothelin Antagonist Trial in mildly Symptomatic PAH patients, NYHA modified functional class II), of Tracleer for the treatment of pulmonary arterial hypertension (PAH). This double-blind, placebo-controlled, multicenter trial enrolled 185 mildly symptomatic PAH subjects internationally. Subjects received placebo or Tracleer at an initial dose of 62.5 mg b.i.d. for four weeks and a target dose of 125 mg b.i.d. for five months, for an overall exposure to either active study drug or placebo of six months. After six months, subjects could opt to continue in an open-label extension study that was ongoing at this time. The co-primary endpoints were achieved, with the subjects on Tracleer therapy showing a significant reduction in pulmonary vascular resistance (PVR) and an improvement in 6-minute-walk test compared to those receiving placebo (p less than 0.0001and p=0.076, respectively). The secondary endpoint was met as well, with Tracleer treatment resulting in a 70% reduction in the time to clinical worsening when compared to placebo (p=0.018). Results were to be fully analyzed in anticipation of worldwide filings of Tracleer to include the treatment of mildly symptomatic PAH (NYHA modified functional class II).
Nuvelo and Bayer announced negative results from two phase III trials of alfimeprase. The first trial, dubbed NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) evaluated alfimeprase in the treatment of acute peripheral arterial occlusion. This randomized, double-blind trial enrolled 300 subjects internationally, who received 0.3 mg/kg of alfimeprase or placebo. The primary endpoint, avoidance of open vascular surgery within 30 days of treatment, was not met. The second trial, dubbed SONOMA-2 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase-2) evaluated alfimeprase in the treatment of catheter occlusion. This randomized, double-blind trial enrolled 303 subjects who received 3 mg of alfimeprase with placebo in a 2:1 ratio. The primary endpoint, restoration of function to the occluded catheter in 15 minutes, was not met. Based on these results, Nuvelo and Bayer decided to temporarily suspended enrollment in the ongoing Phase 3 trials, NAPA-3 and SONOMA-3, pending further analysis of the results.
July 17, 2006
Nuvelo announced positive results of a phase II trial of alfimeprase for the treatment of central venous catheter occlusion. This randomized, double-blind, controlled, dose-ranging study enrolled 55 patients, who received one of three doses of the drug (0.3 mg, 1 mg and 3 mg) or an approved dose of alteplase, with dosing repeated at 120 minutes if catheter patency had not been achieved. Results from the study indicated that the highest dose of the drug produced cumulative patency rates of 40% at 5 minutes, 50% at 15 minutes, 60% at 30 minutes and 120 minutes after the first dose, and 80% 120 minutes after the second dose, vs. 0%, 0%, 23%, 46%, and 62% for the approved drug, respectively. No serious hemorrhagic events were noted. Based on these results, Nuvelo initiated a pair of overlapping phase III trials of the drug.
Valentis has announced negative results of a phase IIb trial of VTLS-934 for the treatment of intermittent claudication (IC), a form of peripheral arterial disease (PAD). Trial data failed to demonstrate efficacy in the trial's primary efficacy endpoint, producing no significant difference in exercise tolerance on an escalating grade treadmill after 90 days vs. placebo. Further, no significant improvements were noted in a number of secondary endpoints, including exercise tolerance at 30 days, ankle-brachial index at 30 and 90 days, total work capacity at 30 and 90 days and quality of life at 90 days. Treatment was generally well tolerated. This randomized, double-blind, placebo-controlled study enrolled 157 patients with IC, who received intramuscular injections of the drug or placebo. Based on these results, Valentis has opted to terminate development of VLTS-934.
August 15, 2005
CV Therapeutics and Astellas issued positive results of a phase III trial of their selective A2A-adenosine receptor agonist regadenoson, under investigation as a pharmacologic stress agent in cardiovascular imaging procedures. Trial data met their primary efficacy endpoint, producing statistical non-inferiority to the approved diagnostic product Adenoscan in myocardial perfusion imaging (MPI). Further, the drug was generally well tolerated, with headache, chest pain, shortness of breath, flushing and gastrointestinal discomfort observed most often. This multinational, randomized, double-blind study enrolled 784 subjects undergoing MPI.
Isis Pharmaceuticals has issued positive results of a phase I study of ISIS 301012, for the treatment of hypercholesterolemia. Trial data indicated that the drug produced rapid reduction (<1 month) in serum levels of apoB-100, and concomitant reductions in LDL levels; median reductions were 60% and 54%, respectively. No treatment related serious adverse events were reported. This open- label study enrolled 6 healthy volunteers with mildly elevated cholesterol, who received 350 mg/week of ISIS 301012 for one month, with subsequent observational follow- up. Based on these results, Isis announced plans to initiate a series of phase II trials of the drug in the second half of 2005.
Nuvelo reported positive results of a phase I trial of alfimeprase, for the treatment of peripheral arterial occlusion (PAO), in the Journal of Vascular and Interventional Radiology. Preliminary safety data yielded a positive tolerability profile, with no serious adverse events reported no incidence of bleeding complications. Drug administration led to a dose-dependent reduction in serum alpha-2 macroglobulin levels (a protein associated with alfimeprase metabolism), which normalized within 14 days of drug administration. No anti-alfimeprase antibodies were detected within 3 months of drug exposure, and no changes in serum plasminogen of fibrinogen levels were detected. Secondary efficacy data indicated thrombolysis and restoration of blood flow in 40% of patients. This multicenter, open-label, dose-escalating study enrolled 20 patients with chronic lower extremity PAO, who received one of 5 intra-arterial doses of the drug (0.025, 0.05, 0.1, 0.3 and 0.5 mg/kg).
ZymoGenetics reported combined results of 4 phase II studies of their investigational surgical homeostatic agent rhThrombin. Pooled data indicated that drug administration tended to increase incidence of homeostasis at 10 minutes (90% vs. 78%), reduce the mean time to homeostasis (194 seconds vs. 250 seconds) and reduce the need for open-label rescue therapy (10% vs. 20%), compared to placebo. When rhThrombin was used as the open-label rescue agent, it was successful in 95% of patients. In addition, there was no difference in the rate of anti-rhThrombin specific antibody formation between drug (n=1) and placebo (n=1) groups. Each trial was a multi-center, randomized, double-blind, placebo- controlled study, in which subjects were administered the drug or placebo through direct application via gelatin sponge to bleed sites warranting topical homeostatic agent application.
March 7, 2005
Metabolex has issued positive results of a phase I trial of MBX-2044, their investigational oral insulin sensitizer for the treatment of type II diabetes. Trial data yielded a positive safety profile, with no serious adverse events and favorable tolerability results. The drug also yielded preliminary evidence of efficacy, with a reduction in uric acid levels after a single-dose. This open-label single-ascending-dose study enrolled 42 healthy men and women into one of 7 dose-ranging dosing cohorts (1.5 mg. to 120 mg.)The company announced plans to move the drug into proof-of-efficacy studies, based upon these results.
NiCox has reported positive results of a phase IIa trial of NCX 4016, for the treatment of platelet activation in diabetic patients. The company is also developing the drug for the treatment of peripheral arterial obstructive disease. Trial results indicated that the drug was significantly more efficacious than treatment with aspirin or placebo, as measured by O'Brien platelet filtration test closure time (p=0.0435, p=0.0386, respectively). No significant difference in efficacy was observed between aspirin and placebo. This prospective, double-blind trial enrolled 40 patients with type II diabetes at a single site in Italy, who were randomized to receive NCX 4016 (800 mg twice daily), aspirin (100 mg once daily), the combination of NCX 4016 and aspirin, or placebo for 14 days.
October 4, 2004
ArtheroGenix announced positive interim results from their phase IIb study of AGI-1067, their anti-inflammatory drug for the treatment of artherosclerosis. One year data indicate that the drug demonstrated efficacy in ameliorating coronary artherosclerosis, the trial’s primary endpoint, as measured by a significant reduction in total coronary plaque volume, compared to baseline (p<0.0003). Furthermore, the drug demonstrated efficacy in its secondary endpoint, a significant reduction in total coronary plaque volume among the most seriously diseased patient population, compared to baseline (p<0.0001). The drug demonstrated a trend towards efficacy improvement over standard care, but this trend in the interim was non-significant, and was to be analyzed again at the trial’s conclusion. This placebo-controlled study randomized 266 subjects to receive one of four treatment regimens for 14 days, prior to angioplasty: placebo alone, placebo plus standard care, placebo plus AGI-1067, or AGI-1067 alone. All subjects not on the standard of care regimen received AGI-1067 for 12 months.
Valentis Inc. reported results of a phase II study of their investigational medicine Deltavasc (Del-1 gene plus PINC polymer), for the treatment of the intermittent claudication form of peripheral vascular disease. The trial failed to meet its primary endpoint, with no significant difference in exercise tolerance at 90 days between subjects receiving Deltavasc and subjects receiving PINC polymer alone (the control arm). However, both arms were observed to be clinically active compared to baseline, and both improved disease symptoms and outcomes for primary and secondary endpoint factors: exercise tolerance (p<0.00001 & p=0.0001, respectively), ankle brachial index (an indication of peripheral blood flow; p=0.00665 & p=0.00072), and in the correlation between the two (p=0.039). This double-blind, controlled, trial enrolled randomized a total of 100 intermittent claudication patients to receive Deltavasc (n=49) or PINC polymer alone (n=51) for 90 days. Valentis announced that they planned to initiate a pivotal trial of PINC polymer alone for the treatment of cardiovascular disease, and to examine additional non-cardiovascular development opportunities for Deltavasc.
January 12, 2004
NicOx SA reported positive results from a phase IIa trial investigating NCX 4016, a nitric oxide-donating derivative of aspirin for the treatment of peripheral arterial obstructive disease (PAOD). Results demonstrated that NCX 4016 showed statistical significance on the primary endpoint, which was to correct endothelium dysfunction induced by physical exercise, measured by flow mediated vasodilation compared with aspirin. Data showed that the subjects walking capacity showed a clinically meaningful increase with NCX 4016 compared with aspirin. The study enrolled 44 PAOD subjects with limitations in walking capacity due to leg pain. It was conducted at the University of Perugia, in Italy. Subjects received NCX 4016 (800 mg) or aspirin (100 mg) for one month.
December 1, 2003
Nuvelo reported positive results from a phase I trial investigating alfimeprase, a modified fibrolase for the treatment of peripheral arterial occlusion (PAO). Results showed that alfimeprase was safe and well tolerated with no drug related adverse events. Plasminogen and fibrinogen levels remained unchanged. The multi-center, open- label, dose-escalation study enrolled 20 subjects with PAO. Subjects were administered one of five escalating weight-based doses of alfimeprase (0.025, 0.05, 0.1, 0.3, and 0.5 mg/kg). Subjects were given angiograms prior to treatment and one hour after administration of the drug. Results were reported at the Advanced Interventional Management (AIM) Symposium in New York City.
September 15, 2003
AstraZeneca reported positive results from a trial investigating Atacand, an approved angiotensin receptor blocker for the new indication of chronic heart failure. Results demonstrated that Atacand reduced cardiovascular deaths or hospital admissions for heart failure by 16% when compared to placebo. The international, multi-center program, called CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) enrolled 7,601 subjects with symptoms of chronic heart failure. The program consisted of three independent, parallel, double blind, placebo-controlled trials. Treatment with Atacand was generally well tolerated but associated with a greater occurrence of discontinuation of study medication compared to placebo due to an increase in serum creatinine (6.2% vs. 3.0%) hypotension (3.5% vs. 1.7%), and hyperkalemia. Atacand is currently approved for the treatment of hypertension. Results were published in the September 6th edition of The Lancet.
NicOx reported positive results from a phase II endoscopy trial investigating NCX 4016, a nitric oxide for the treatment of peripheral arterial obstructive disease (PAOD). Data demonstrated that gastric safety, measured by endoscopy, was significantly better for NCX 4016 both as a monotherapy and in combination with aspirin compared to treatment with aspirin alone. Results also showed that NCX 4016 showed greater activity in the inhibition of inflammatory markers compared to aspirin. Endoscopic scores for NCX 4016 were similar to placebo. The study enrolled 48 subjects who were treated for 21 days. Results were reported in November 2003 at the American Heart Association meeting in Orlando.