Cardiologists at Rush University Medical Center (Chicago) are studying an investigational medication for the prevention of amputations in patients suffering the most severe form of peripheral arterial disease (PAD). The study involves use of a gene therapy approach to promote new blood vessel growth in the legs of patients with critical limb ischemia. The researchers are enrolling patients in a Phase III clinical trial dubbed TAMARIS.
Narrowed arteries in the legs result in plaque formation and clots, the tissues starved of blood flow produce skin ulcers. This results in PAD and then the more serious critical limb ischemia and potentially amputation. The target population is those patients with these skin ulcers.
"At this time there are no prescription drugs available to effectively treat critical limb ischemia, and there are limited treatments available that will delay or prevent amputation," said Jeffrey Snell, MD, an interventional cardiologist at Rush and the study's principal investigator. "The goal of gene therapy is to stimulate the growth of new blood vessels. The additional blood vessels will carry more blood into the legs, alleviating pain and healing ulcers."
The trial involves an angiogenesis therapy developed by Sanofi-Aventis (Paris), based on a non-viral DNA delivery technology from Vical (San Diego). The plasmid DNA therapy induces the production of a protein called fibroblast growth factor (FGF-1) which stimulates the growth of blood vessels at the site of injection. During the 12-month study, participants will receive four injections of the investigational study medication or a placebo into the leg muscle at two-week intervals.
A primary outcome of the trial is time to major amputation of the treated leg or death from any cause; secondary outcomes include adverse events and various laboratory parameters.
Qualified participants will receive all study-related care at no cost, including physical exams, study medication, eye exams, and cancer screenings at no cost. Estimated completion date for the study is July 2010.
Panel recommends transgenic-derived drug
The Blood Products Advisory Committee of the FDA voted that the anti-clotting drug ATryn, made from the milk of genetically engineered goats, is safe and effective and may be approved for the treatment of people with an inherited disorder that makes them susceptible to life-threatening blood clots.
Atryn, made by GTC Biotherapeutics (Framingham, Massachusetts), is produced from a human protein extracted from the milk of goats that have been genetically altered to produce it. If approved, the drug will be the first commercially available pharmaceutical in the U.S. to be made from transgenic animals. The drug was previously approved in Europe.
GTC is licensing the drug to Ovation (Deerfield, Illinois) for U.S. marketing. The two companies are seeking FDA approval for the drug in the "prevention and treatment of venous thromboembolism in hereditary antithrombin deficient patients undergoing surgery or childbirth procedures," said a recent statement from GTC.
A majority of the 19-member FDA advisory panel voted that the drug was safe and effective.
Geoffrey Fox, CEO and chairman of GTC, said that the drug has the potential to provide "an important new treatment option for patients with hereditary antithrombin deficiency."
People with hereditary antithrombin deficiency are more susceptible to venous blood clots, including pulmonary embolism and deep vein thrombosis. About one in two to three thousand of the general population has the disorder, half of whom are likely to experience a thrombosis by the time they are 25 years old, and according to one study cited by GTC, up to 85% may experience an embolism before they are 51.
GTC warned that "as with any intravenous protein product, allergic type hypersensitivity reactions are possible." Two studies of heart patients showed that the blood thinner clopidogrel was less effective in carriers of certain variants of a gene known to affect how the drug prevents blood clots than non-carriers.
Cytokineticss reports on CK-1827452 trials
Cytokinetics (South San Francisco, California) has reported top-line results from a Phase IIa clinical trial evaluating the safety of its product CK-1827452 in patients with ischemic cardiomyopathy and angina. The primary safety endpoint was defined as stopping an exercise test during treatment with CK-1827452 (vs. placebo) due to unacceptable angina at an earlier exercise stage than at baseline. This endpoint was observed in one patient receiving placebo and did not occur in any patient receiving CK-1827452.
Andrew Wolff, MD, senior VP of clinical R&D and chief medical officer for the company, said that with this trial, "together with pharmacokinetic and pharmacodynamic data from other recent trials of CK-1827452, we intend to initiate in mid-2009 a Phase IIb clinical development program in patients hospitalized for heart failure and higher-risk chronic heart failure outpatients. This Phase IIb program will be designed to select appropriate dose regimens for clinical endpoint-driven trials to support potential registration."
CK-1827452 is a cardiac myosin activator and the subject of a collaboration and option agreement between Cytokinetics and Amgen (Thousand Oaks, California). The drug is being developed in both intravenous and oral formulations for the treatment of patients hospitalized for heart failure and outpatients with chronic heart failure.
Cytokinetics said that it will complete the delivery, early this year, of the clinical data required to inform the potential exercise of Amgen's option under the companies' strategic alliance.
The Phase IIa clinical trial was designed to evaluate both intravenous and oral formulations of CK-1827452 in patients with ischemic cardiomyopathy and angina. The primary objective was to assess the effect of intravenous CK-1827452 on symptom-limited treadmill exercise tolerance in this patient population; the secondary objective was to asess the tolerability and resulting plasma concentrations of CK-1827452 administered as an oral formulation.
Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction.
Cardiac contractility is driven by the cardiac sarcomere, a highly ordered cytoskeletal structure composed of cardiac myosin, actin and a set of regulatory proteins, and is the fundamental unit of muscle contraction in the heart.
The sarcomere represents one of the most thoroughly characterized protein machines in human biology.
Cytokinetics' cardiovascular program is focused towards the discovery and development of small molecule cardiac myosin activators in order to create next-generation treatments to manage acute and chronic heart failure.
Cytokinetics' program is based on the hypothesis that activators of cardiac myosin may address certain mechanistic liabilities of existing positive inotropic agents by increasing cardiac contractility without increasing intracellular calcium.
Cardio drug teamed with diag approach
Molecular Insight Pharmaceuticals (Cambridge, Massachusetts) reported results from a recently completed Phase II clinical study (BP-23) suggest that Zemiva, when combined with the standard of care for the diagnostic evaluation of the chest pain patient, significantly improved the detection of cardiac ischemia when compared to the standard of care alone. The improved sensitivity was more than 50% greater than the standard of care alone and was evident even in patients whose chest pain symptoms had subsided up to 30 hours prior to the Zemiva scan.
The results were consistent for the subset of patients with acute coronary syndrome, the most severe form of cardiac ischemia. In both cases, sensitivity and negative predictive value was improved while specificity was maintained. In patients with a negative Zemiva scan, there were no hard cardiac events, including myocardial infarctions or death from cardiac causes during the 30-day follow up.
The trial enrolled 510 patients over 14 months at 50 hospitals throughout North America. The primary objective was to evaluate the ability of Zemiva to identify myocardial ischemia in patients who present to the emergency department with suspected acute coronary syndrome.
The company said that these top-line efficacy results are consistent with previously released Phase II clinical data (BP-21) presented at last November's American Heart Association (Dallas) annual meeting, which showed Zemiva provides incremental clinical value by improving the detection of cardiac ischemia compared to today's standard of care.
Sucampo drug studied for PAD
Sucampo Pharma of Japan, a subsidiary of Sucampo Pharmaceuticals (Bethesda, Maryland), reported that it has initiated dosing in a first-in-human clinical safety study of a proprietary prostone, SPL-017, a potential treatment for peripheral arterial disease (PAD).
The randomized, double-blind, placebo-controlled, single-center, single ascending dose study will evaluate the safety and pharmacokinetic profile of SPL-017. A total of 74 healthy adult male subjects will be enrolled in eight dose groups, receiving intravenous doses of SPL-017 ranging from 3 mcg to 360 mcg.
While many patients with early stages of PAD have mild or no symptoms, as PAD progresses, some experience leg pain while walking or climbing stairs (claudication) and in some cases even at rest. In extreme cases, PAD can lead to critical ischemic lesion and eventually to loss of a leg by amputation.
Gayle Dolecek, PhD, senior VP of R&D, Sucampo, said, "We believe that SPL-017 has potential for treatment of a variety of vascular diseases, including PAD. In pre-clinical animal studies, intravenously administered SPL-017 improved peripheral circulation without significantly affecting systemic blood pressure. In addition, in other animal studies, SPL-017 had no effect on platelet aggregation and protected endothelial barrier function."
In brief ...
• Anthera Pharmaceuticals (Hayward, California) reported the completion of enrollment in its Fewer Recurrent Acute coronary events with Near-term Cardiovascular Inflammation Suppression (FRANCIS) trial designed to examine the impact of varespladib (A-002) when administered to patients within 96 hours of an acute coronary syndrome (ACS) event. The trial is designed to assess the impact of oral varespladib on known biological markers of cardiovascular risk.
• ARYx Therapeutics (Fremont, California) reported further results from a Phase IIb trial testing the safety and efficacy of its oral anti-arrhythmic therapy, ATI-2042, in patients with atrial fibrillation 9AF). Previous results reported this past December showed that ATI-2042 reached statistical significance at its primary end point in the two highest of three doses tested.
Those results are now reinforced by these additional findings indicating, in part, that patients in the study quickly returned to their pre-treatment level of AF once the treatment ended.
The complete safety results from this study are still not finalized but are expected by the end of March.
• BioLineRx (Jerusalem, Israel) said that an Independent Safety Monitoring Board for the BL-1040 pilot study authorized the completion of the Phase I/II study and enrollment of the additional 25 patients. The decision is based on safety assessments of the first five patients to complete at least 30 days of follow up following treatment with BL-1040 without noticeable adverse events.
BL-1040 is a treatment for preventing further heart damage following acute myocardial infarction.
• Synvista Therapeutics (Montvale, New Jersey) reported completing enrollment of its chronic systolic heart failure BENEFICIAL study, a Phase II double-blind, placebo-controlled, randomized trial of alagebrium. The study will measure the effect of alagebrium on exercise tolerance in patients with.
In addition, the company anticipates completing enrollment of its Beginning a Randomized Evaluation of the A.G.E. [Advanced Glycation End Product] Breaker Alagebrium in Diastolic Heart Failure (BREAK) study in the first quarter this year.
BREAK, a randomized, double-blind, placebo controlled study, is evaluating whether alagebrium (200 mg twice daily) can improve exercise tolerance, as measured by the six-minute walk test, in patients diagnosed with diastolic heart failure.