Drug Trials

The management of acute coronary syndromes (with or without ST segment elevation) requires the use of anticoagulants, antiplatelet agents (aspirin, clopidogrel and/or glycoprotein (GP) IIb/IIIa inhibitors), beta-blockers, thrombolytics in some cases, and revascularization / reperfusion.

The appropriate management of ACS has been shown over the last few decades to result in a significant improvement in outcome in the short and long term. However, the combined use of these therapies, particularly antithrombotic therapies (which include anticoagulants, antiplatelet agents and thrombolytics) may result in an excess of bleeding. Until the recent past, bleeding was not considered to be a serious complication, but over the last 5 years, bleeding complications have in fact emerged as a major contributor to overall risk, with a significant increase in the rate of death, myocardial infarction and stroke in patients who suffer bleeding complications during the initial phase of ACS, as compared to those who do not. In addition, blood transfusion has been shown to result in a higher risk of death, and is suspected to have deleterious effects in selected groups of patients.

The risk factors for bleeding have been well identified. Older age, female sex and low body weight have been identified as markers of the risk of bleeding. A past history of bleeding, the presence of renal failure, the use of an early invasive approach, excess dose of antithrombotic agents, and use of GP IIb/IIIa inhibitors have also been identified as strong predictors of the risk of bleeding.

Conversely, careful selection of drugs, giving precedence to drugs with less potential for bleeding, use of a radial versus femoral approach for invasive strategy, and systematic use of proton pump inhibitors to avoid gastro-intestinal bleeding during the initial phase, are all measures that have the potential to reduce the bleeding risk.

In this context, some anticoagulants have been shown to carry a lower risk of bleeding, such as fondaparinux and bivalirudin, as compared to low molecular weight heparins or unfractionated heparin. It would also appear that more consistent inhibition of platelet aggregation leads to better clinical outcome, albeit with an increased risk of bleeding.

In all, bleeding and possibly also blood transfusion have emerged as major contributors to worse outcome in patients with ACS. Proper management of patients, with appropriate selection of doses, drugs, and arterial approach, combined with systematic evaluation of the bleeding risk prior to starting therapy may help prevent bleeding and improve patient outcome.

http://www.escardio.org

Training courses for the Undergraduate Medical Admissions Test (UMAT) are expensive, inequitable and don’t improve students’ chances of getting into medicine, according to? the Australian Medical Students’ Association (AMSA).

The courses, which cost anywhere from a few hundred dollars to over $1,700, are purported to improve students’ performance in the UMAT and therefore their chances of getting into undergraduate medicine.

AMSA President Michael Bonning said that these courses advertised themselves as providing a significant edge for entry into medical school.

“Clever, suggestive marketing, has led students to believe that these expensive coaching programs are almost mandatory for admission into undergraduate medical courses,” Mr Bonning said.

“Newly published evidence actually shows that they provide no significant benefit in the UMAT and may actually hamper some students in the interview component of the admissions process.

“The companies who run UMAT Training Courses capitalise on the fact that getting into medical school is such a high-stakes process that people will pay significant amounts of money to gain an edge,” he said.

Furthermore, the preparation courses create another barrier for rural and low socio-economic background students in their quest to access medicine.

“Because of the perception of these courses, students are unable to access them feel as if they are disadvantaged when it comes to gaining entry, and may be deterred from trying in the first place,” Mr Bonning said.

“AMSA is also calling for regulation of this industry so that prospective medical students, and their families, can know what they are getting for their money,” he said.

Access AMSA’s briefing paper on UMAT training courses at http://www.amsa.org.au/umat.

Australian Medical Students’ Association

Drug Trials

A twelve month study of treatment with darapladib concluded that,Lp-PLA₂ inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability.

These findings suggest that Lp-PLA₂ inhibition may represent a novel therapeutic approach.In contrast, despite adherence to a high level of standard of care treatment,necrotic core continued to expand among patients receiving a placebo.

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is expressed abundantly in the necrotic core of coronary lesions and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture.

This study compared the effects of 12 months of treatment with darapladib (oral Lp-PLA₂ inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (IVUS-palpography) and plasma hs-CRP in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (IVUS-radiofrequency), atheroma size (IVUS-greyscale), and blood biomarkers.

Background therapy was comparable between groups, with no difference in LDL-cholesterol at 12 months (placebo: 88?34 and darapladib: 84?31 mg/dL, p=0.37). In contrast, Lp-PLA₂ activity was inhibited by 59% with darapladib (p=0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (p=0.22) or plasma hsCRP (p=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5?17.9 mm³, p=0.009), whereas darapladib halted this increase (-0.5?13.9 mm³, p=0.71), resulting in a significant treatment difference of -5.2 mm³ (p=0.012). These intra-plaque compositional changes occurred without a significant treatment difference in total atheroma volume (p=0.95).

http://www.escardio.org

Drug Trials

Data from a phase II study of an investigational drug designed to block formation of blood clots show potential for added protection against a second heart attack or stroke among patients who are already taking state-of-the-art prevention therapy.

While the results of the study did not show a statistically significant difference in ischemic events among any of the four doses of apixaban evaluated, trends emerged that support further study, according to researchers at the Duke Clinical Research Institute.

Apixaban targets the activity of Factor Xa, one of several enzymes involved in process of blood coagulation. The drug is just one of several new anti-clotting agents under development. Physicians say the need for safer, better anticoagulants is critical because current therapies fall short of therapeutic goals or are especially difficult to manage and increase the risk of bleeding.

“One of the most vexing problems in cardiology is identifying the right combination of drugs that can inhibit clot formation but not increase the risk of serious bleeding,” said study lead John Alexander, M.D., a cardiologist at Duke University Medical Center, who presented the findings today at the European Society of Cardiology meeting in Munich.

Millions of patients world-wide take anti-clotting drugs on a regular basis. Most are prescribed aspirin, clopidogrel (also known as Plavix or Iscover) and/or warfarin.

“Warfarin is clearly effective as an anticoagulant, but it is especially hard to manage properly and safely,” Alexander said. “What’s driving research in this area is the fact that although aspirin and clopidogrel both offer heart attack patients important protection against blood clots, there is still room for improvement. Studies show that a significant number of patients taking aspirin and clopidogrel will still experience some sort of problem related to a blood clot. Adding warfarin increases the likelihood of bleeding complications at a higher rate than anybody is comfortable with.”

Alexander, along with Professor Lars Wallentin from the Uppsala Clinical Research Center in Sweden and other colleagues, studied the use of apixaban in 1,715 patients from 14 countries throughout Europe and North America who had suffered a recent heart attack. Roughly two-thirds of the patients had undergone angioplasty to clear blocked arteries and 99 percent of them were taking either aspirin or aspirin and clopidogrel.

The study (called APPRAISE) was designed to identify the optimal dose of apixaban. Participants were randomized into one of four doses of apixaban or a placebo. Researchers tracked the incidence of bleeding and recurrent heart attack, stroke, chest pain requiring hospitalization or additional procedures or death from cardiovascular problems for the following six months.

At the end of the study, researchers discovered a non-statistically significant trend suggesting that patients taking apixaban along with their regular treatment had a lower incidence of heart attack, stroke, chest pain or death from cardiovascular problems than patients taking a placebo.

But bleeding was an issue, especially among those taking the higher doses of the drug (10 milligrams twice daily or 20 milligrams once daily). Investigators discontinued those two arms of the study because patients were experiencing unacceptable rates of bleeding. Patients in the remaining arms of the study (2.5 milligrams twice daily or 10 milligrams once daily) also experienced more bleeding than those taking a placebo.

Investigators say that while the results are not conclusive, they do warrant further study. “The data show adding 5 or 10 milligrams of apixaban to a regimen of aspirin or aspirin and clopidogrel in patients hoping to prevent a second heart attack may offer therapeutic potential,” says Alexander. “But this needs to be definitively demonstrated in a statistically significant manner in large, well-controlled studies.”

Apixaban is under development at Bristol-Myers Squibb, the company that sponsored the study. Alexander and Wallentin have both received research support from Bristol-Myers Squibb.

http://www.escardio.org

Drug Trials

Data presented today at the European Society of Cardiology Congress demonstrates the effectiveness of a peptide called FX06 in preventing cardiac damage resulting from treatment following a heart attack.

While reperfusion is well established as a standard of care, it paradoxically causes additional damage to heart muscle in patients surviving from these attacks - a phenomenon termed “reperfusion injury”. FX06 is a novel compound intended to prevent that damage.

Professor Dan Atar, the Coordinating Investigator of the F.I.R.E. (FX06 In ischemia and REperfusion) trial, a Phase II clinical study of FX06, will present the results of the trial at

12-noon on September 2nd in the Hot Line III Session at the European Society of Cardiology Congress in Munich, Germany.

“Re-establishment of blood flow, either by catheter-based balloon-intervention (PCI) or by thrombolysis, is necessary and life-saving in the treatment of acute myocardial infarctions. However, such interventions can lead to further damage to the heart muscle due to blood vessel dysfunction and inflammation,” said Dan Atar, Professor of Cardiology at the Aker University Hospital, University of Oslo, Norway. “Based on the F.I.R.E. results, FX06 has been shown to reduce damage to the heart muscle by inhibiting inflammation and protecting vascular function. We predict that FX06 may become a novel treatment for STEMI patients undergoing PCI, representing a major advance in acute cardiac care.”

The Phase II clinical trial of FX06 (F.I.R.E. study) was completed in March 2008, with data indicating a statistically significant reduction in myocardial necrosis following intravenous application of FX06 concurrent with reperfusion. FX06 is a peptide that binds to VE-cadherin, a target on the surfaces of endothelial cells, which form the inner cell layer of blood vessels, thereby preserving blood vessel function. This leads to reduced inflammation, reduced oedema and reduced infarct sizes.

About the study:

The F.I.R.E. (FX06 In Ischemia and REperfusion) trial was conducted between October 2007 and March 2008 as a randomized, double-blind, placebo-controlled study involving 234 patients from 26 leading centres of interventional cardiology in Europe. The study evaluated infarct size in patients undergoing percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI). FX06 was administered intravenously to patients during reperfusion treatment, and the effect on heart muscle preservation was then assessed using the most advanced imaging technology: cardiac magnetic resonance imaging (CMR). The primary endpoint was reduction in infarct size at five days after myocardial infarction.

Results showed that at 5 days post-PCI, the necrotic zone of the infarct was significantly reduced by 58% and the total affected zone of the left ventricle was reduced by 21%. This was accompanied by a reduction in markers of heart muscle cell necrosis. After 4 months, the resulting scar mass was reduced by 37%, suggesting that a reduction of reperfusion injury indeed may lead to decrease in scar tissue formation. Major adverse cardiac events in the FX06 group were also lower compared to the placebo group, which may indicate an effect of the drug on adverse patient outcome after an infarction.

http://www.escardio.org

Drug Trials

Existing practice surrounding many cardiovascular medications, including anti-hypertensive and lipid-lowering agents, is based on the evaluation of response to therapy. In cases where ideal therapeutic targets (which have been identified through several previous studies) are not met in the single individual, there is evidence to support the need to intensify standard treatment so as to achieve better control of the cardiovascular risk factor under treatment (e.g. blood pressure or cholesterol levels) as this translates into a better outcome.

No such practice currently exists for anti-platelet agents. Current treatment strategies for patients with coronary artery disease ignore the individual response to antiplatelet agent(s), and likewise fail to identify therapeutic targets for platelet reactivity necessary to evaluate the intensity of treatment.

Yet, inhibition of platelet aggregation following standard oral antiplatelet agents (i.e. aspirin or clopidogrel), has limited data from dedicated trials addressing the long-term safety and efficacy of DES in high-risk subgroups like diabetics, and patients with ST and non ST segment elevation MI or complex lesions. Reaction vary greatly among healthy subjects and patients. Many previous studies have shown that poor response to oral antiplatelet agents increases 1.8-10-fold, the risk of thrombotic events, including myocardial infarction, particularly after coronary angioplasty.

It is unknown whether this reflects suboptimal platelet inhibition per se which might benefit from alternative/more potent antiplatelet agents. Studies aiming at improving outcomes while intensifying platelet inhibition in these patients who are poor responders to standard oral antiplatelet gents are critical to establishing a causal relationship between poor response to a standard anti-platelet regimen and worse outcome. This may help identifying patients who are at high risk for cardiovascular recurrences because they are not fully protected by standard medications. In these patients, the tailored use of alternative anti-platelet agents may provide better protection from cardiovascular complications.

We selected patients, based on results of a point-of-care assay (VerifyNow produced by Accumetrics, Inc., San Diego, CA, USA), undergoing elective percutaneous coronary intervention who were presenting with suboptimal response to either aspirin and/or clopidogrel (these two medications together are crucial to make percutaneous coronary intervention both effective and safe). Poor responders to either aspirin and/or clopidogrel were then randomly treated with standard care (placebo on top of aspirin and clopidogrel) or with the addition of a potent intravenous antiplatelet agents (tirofiban). Neither the patients nor their doctors knew whether they were receiving the real or placebo treatment. We were primarily interested in evaluating the effect of treatment on the incidence of myocardial damage induced during percutaneous coronary intervention (periprocedural myocardial infarction). We showed that intensifying platelet inhibition with tailored infusion of tirofiban in this population results in a greater than 40 percent reduction of the degree of myocardial damage during percutaneous coronary intervention compared to standard care which translated into a better outcomes a 30 days in patients treated in the experimental arm versus the conventional one. Both patients being poor responsive to aspirin or to clopidogrel seem to derive the same benefit.

The University of Ferrara, Italy, was the study sponsor whereas the conduction of the study was partially supported by an unrestricted research grant from Merck, USA and Iroko, USA.

Our study provides proof of concept for a new treatment strategy in patients with coronary artery disease which, by assessing response to standard anti-platelet agents by a point-of-care assay, modulates intensity of treatment accordingly.

http://www.escardio.org

Drug Trials

The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study has investigated the effects of intensive cholesterol lowering with the combination of simvastatin (40 mg daily) and ezetimibe (10 mg daily) in patients with aortic stenosis.

Aortic stenosis (which involves partial blockage of the aortic valve in the heart) is a relatively common disease among older people in Western populations. Left untreated, it can progress to death from heart failure or cardiac arrest. Aortic valve replacement for severe symptoms is the second most frequent type of heart surgery. Apart from surgery, there is no medical therapy known to prevent or heal this condition. Population studies and other scientific research indicate that a high blood level of LDL-cholesterol (so called “bad cholesterol) is a risk factor for developing aortic stenosis and may be involved in the pathological process. Treatment to lower LDL-cholesterol in many other types of patient has been shown to produce substantial reductions in the rates of heart attacks, strokes and other adverse outcomes.

The SEAS study is the first large-scale randomised trial to assess the effects of lowering LDL-cholesterol in patients with aortic stenosis. The study was initiated and designed by academic researchers in Scandinavia, and carried out at 173 clinical centres in Norway, Denmark, Sweden, Finland, Germany, UK and Ireland. It included 1873 patients with mild to moderate aortic stenosis without symptoms who were not considered to have a clear indication for treatment with cholesterol-lowering drugs. Patients were randomly assigned to receive either intensive cholesterol lowering with the combination of simvastatin (40 mg daily) and ezetimibe (10 mg daily) or matching placebo. The first patient was included in 2001. The study was completed according to the study plan when the last patient included had been followed for 4 years (March 2008). Vital status at the end of the study was established for all patients. All data have been checked for completeness and the data file for analysis was closed on 30 June 2008.

The scientific leadership of the study was a Steering Committee consisting of 14 academic representatives of centres in each of the participating countries and two members (a statistician and a coordinator) representing the funders. The SEAS study is funded by the pharmaceutical companies Merck Sharp & Dohme (MSD) and Schering-Plough who market the drugs being tested. All clinical endpoint events were adjudicated by an independent committee that was blinded to the study treatment allocation. The study was monitored by an independent Data Safety and Monitoring Board. Data collection was performed by MSD, and the data were analyzed by statisticians at Ullev?University Hospital in Oslo, Norway, and at MSD.

The primary endpoint of the SEAS study was “major cardiovascular events”, which is the composite of events associated with aortic valve disease and with atherosclerotic disease. The secondary endpoints were the two separate components of the primary endpoint: “aortic valve disease events” (surgical valve replacement, hospitalization because of heart failure, and cardiovascular death); and “atherosclerotic disease events” (non-fatal myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, hospitalization because of unstable angina pectoris, non-haemorrhagic stroke and cardiovascular death). Subsidiary outcomes included echocardiographic evidence of aortic stenosis progression and safety.

Compared with placebo, the combination of simvastatin and ezetimibe reduced LDL-cholesterol by an average of 61%, corresponding to a reduction of about 2 mmol/L (76 mg/dl), and this effect was sustained throughout the study. 688 patients had one or more primary endpoint events. No significant difference was observed between the treatment groups for the combined primary endpoint (333 patients with an event on LDL-lowering treatment versus 355 on placebo; hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.83 to 1.12). Nor was there a significant difference for the secondary endpoint of aortic valve disease events alone (308 versus 326; HR 0.97; 95% CI 0.83 to 1.14). The combination of simvastatin and ezetimibe did, however, produce a statistically significant 22% (95% CI 3% to 37%; p=0.02) proportional reduction in the secondary endpoint of atherosclerotic events alone: 148 (15.7%) in the simvastatin plus ezetimibe group versus 187 (20.1%) in the placebo group.

The study therapy was generally well tolerated, with no significant differences between the treatment groups in the proportions of patients who stopped taking study treatment (irrespective of whether it was active or placebo). In the subsidiary safety analyses, a total of 175 patients were recorded with a serious adverse event attributed to cancer. More of these events were observed among patients assigned the combination of simvastatin and ezetimibe than among those assigned placebo (105 [11.1%] versus 70 [7.5%]; unadjusted p=0.01), this included patients with recurrent cancer and cancer priror to reandomization as well as cancer diagnosed more than 2 weeks after withrawal from the study. There were also slightly more cancer deaths (39 [4.1%] versus 23 [2.5%]; unadjusted p=0.05). These apparent differences were not related to any particular type of cancer and did not become significantly larger with more prolonged treatment.

The observed differences in cancer in the SEAS study are based on small numbers and could have occurred as a result of chance. In order to assess their relevance, the SEAS data have been provided to an independent academic group for combined analysis with data on cancer from the two other large trials of simvastatin and ezetimibe, which are still in progress. The SHARP (Study of Heart and Renal Protection) study is a randomized placebo-controlled trial of simvastatin and ezetimibe in 9400 patients with chronic kidney disease. The IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study is a randomized double-blind trial of simvastatin and ezetimibe compared to simvastatin alone which has recruited 12,000 of a planned 18,000 patients with acute coronary disease.

In combination, the SHARP and IMPROVE-IT studies involve about 4 times as many cancers as in the SEAS study. The analysis of SHARP and IMPROVE-IT does not support the suggestion of an increase in cancer that was raised by the subsidiary analyses of the relatively small numbers of cancers in the SEAS study. Independent analysis of these data was initiated and has been conducted and interpreted by the Clinical Trial Service Unit (CTSU) at the University of Oxford, UK. The CTSU also designed and is conducting the SHARP trial, which is funded by a research grant to the University of Oxford from MSD and Schering-Plough academic. Both the SHARP study and the analyses of cancer data have been conducted by the CTSU independently of the pharmaceutical companies. Please, refer to the press release issued by the CTSU today.

In conclusion, the SEAS study has found that intensive LDL-cholesterol lowering with the combination of simvastatin and ezetimibe in patients with mild to moderate aortic stenosis does appear to reduce the risk of coronary artery disease events (as has been shown for many other types of patient in previous trials) but not the rate of progression of aortic valve disease. The use of simvastatin and ezetimibe in such patients was generally well tolerated and safe.

http://www.escardio.org

Drug Trials

REGENT is a multicenter, randomized trial for comparison of intracoronary infusion of bone marrow-derived unselected mononuclear cells (MNC) and selected CD34+CXCR4+ cells in 200 patients with acute myocardial infarction and reduced LVEF ??40%.

Primary end-point was change of LV ejection fraction (LVEF) and volumes measured by MRI before and 6 months after the procedure.

In patients receiving both selected and unselected bone marrow cells, LVEF increased significantly in comparison to baseline values by 3%. This increase, however, was not significantly higher in comparison to the control group. The changes of left ventricular volumes were also comparable in all groups. Significant increase of LVEF was observed in patients treated with either type of bone marrow cells who had baseline LVEF < median. Baseline LVEF was an independent predictor of significant increase of LVEF. At 6 months clinical follow-up, major cardiovascular event rate was low, and no different between the groups.

In conclusion, treatment with intracoronary infusion of BMC did not lead to significant improvement of LVEF and LV volumes in comparison to control group, however there was a trend towards significant improvement of LVEF in patients with severely depressed baseline LVEF receiving either MNC or CD34+CXCR4+ bone marrow cells. Intracoronary infusion of unselected and selected BMC proved to be safe and feasible.

REGENT is the second-largest trial using bone marrow-derived cells in patients with acute MI and the first large trialfor head-to-head comparison of selected and unselected cells. Population of CD34+CXCR4+ cells is enriched in cardiac committed progenitor cells, but so far it has not been used in a clinical trial. The results suggest that in patients with severely depressed LVEF administration of a relatively small number of CD34+CXCR4+ cells can have the same effect as an infusion of a larger number of MNC. Therefore, this cell population deserves further studies.

• REGENT is the second-largest trial using bone marrow-derived cells in patients with acute MI and the first large trial for head-to-head comparison of selected and unselected cells
• Intracoronary infusion of unselected and selected bone marrow cells proved to be safe and feasible
• Treatment with intracoronary infusion of bone marrow cells did not lead to significant improvement of LVEF and LV volumes in comparison to control group, however there was a trend towards significant improvement of LVEF in patients with severely depressed baseline LVEF receiving either MNC or CD34+CXCR4+ bone marrow cells

http://www.escardio.org

Drug Trials

MorphoSys AG announced today the publication of a first data package for its most advanced proprietary drug development program MOR103, a fully human HuCAL antibody directed against GM-CSF, in the journal “Molecular Immunology”.

The data presented show that MOR103 is able to block disease-relevant processes such as GM-CSF dependent proliferation and signal transduction in vitro. Additionally, the publication describes that MorphoSys was able to achieve a 5,000-fold increase in affinity and a 2,000-fold increase in potency compared to the parental antibody using its established optimization technology. With a resulting affinity - or binding strength - of 400 femtomolar, MOR103 represents the first known anti-GM-CSF agent with a subpicomolar affinity for its target. Targeting of antigens, which are present only at low concentrations in patients such as GM-CSF, will require antibodies with low picomolar to subpicomolar affinities in order to reach efficacy in vivo at low dose levels. The high affinity is also expected to lead to a beneficial dosing regimen and cost of goods advantage.

MOR103 is currently tested in a Phase 1 clinical trial to assess safety, tolerability and the pharmacokinetics of this fully human high affinity anti-GM-CSF HuCAL antibody. MorphoSys intends to present pre-clinical data for MOR103 at the HAH - Human Antibodies and Hybridomas Conference on November 12, 2008 in New York, USA, as well as at the IBC’s 19th Annual International Antibody Engineering Conference on December 9, 2008 in San Diego, USA.

“We are very pleased with the results we have seen so far with MOR103 and the generation process stands out as a showcase for MorphoSys’s antibody generation capabilities using our HuCAL technology,” commented Dr. Marlies Sproll, Chief Scientific Officer of MorphoSys. “While the antibody’s affinity is merely one feature which influences its capability as a drug we believe based on the overall data we have generated so far that MOR103 represents a very promising therapeutic candidate in our pipeline.”

Rheumatoid arthritis (RA) is traditionally considered a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints and affects in particular a membrane, called synovium, which lines each movable joint. It is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and joint destruction. As a systemic disease, RA often affects extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles. The disease affects approximately 4-6 million people worldwide. In patients suffering from RA, white blood cells move from the bloodstream into the synovium. Here, these blood cells appear to play an important role in causing the synovial membrane to become inflamed. The HuCAL-based antibody MOR103 targets GM-CSF as a means to treat inflammatory diseases such as psoriasis, multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD), asthma, and especially RA. The granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates stem cells to produce granulocytes and other macrophages and subsequently activates these differentiated immune cells. GM-CSF is part of the natural immune and inflammatory cascade but has also been identified as an inflammatory mediator in autoimmune disorders like RA leading to an increased production of pro-inflammatory cytokines, chemokines and proteases and thereby ultimately to articular destruction. By neutralizing GM-CSF the HuCAL-based antibody MOR103 reduces undesired proliferation and activation of inflammatory granulocytes and macrophages and intervenes in several pathophysiological pathways.

http://www.morphosys.com

Drug Trials

Scientists at the Blanchette Rockefeller Neurosciences Institute (BRNI) have discovered that Bryostatin– and a related class of drugs discovered at BRNI — administered 24 hours after stroke can rescue and repair brain tissue. These findings are markedly advanced compared to current stroke treatments that must be administered within three hours and are unable to repair damaged brain tissue.

In an article to be published in the September 3 issue of the Proceedings of the National Academy of Sciences (PNAS), BRNI Scientific Director and Toyota Chair Daniel Alkon, M.D. and Professor Miao-Kun Sun, PhD describe how this Alzheimer’s candidate drug repairs the brain and improves memory.

“Today’s stroke patient has precious minutes to receive care without suffering irreversible damage or death. One of the greatest challenges in modern medical practice is finding an effective treatment that extends that treatment time and repairs damage,” said BRNI Scientific Director Daniel Alkon, M.D. “Bryostatin could be an answer.”

Bryostatin could be life changing for millions of Americans who suffer neurological conditions — from Alzheimer’s disease to stroke. Each year in the United States, there are more than 780,000 strokes. It is the third leading cause of death in the country and the most common cause of long-term disability in developed countries. Nearly three-quarters of all strokes occur in people over the age of 65 and the risk of having a stroke more than doubles each decade after the age of 55.

“We’re facing an aging Babyboomer population, an influx of 55-plus Americans, and treatment that is less time-restrictive and able to repair the brain if a stroke destroys tissue is urgently needed,” said Alkon.

How Bryostatin Works

Stroke symptoms typically develop rapidly — within seconds to minutes — and as oxygen becomes depleted in the brain tissue, cells die. This means that hundreds of thousands of neurons — each linked to thousands of connections — die. In animal testing, Bryostatin completely rescues these dying neurons, stimulates the growth of new connections and restores memory capacity. Additionally, the drug can be administered up to 24 hours following a stroke, increasing the number of patients it could potentially save.

This drug, suggests Alkon, offers potential to prevent and/or reverse brain degeneration not just in stroke victims, but also Alzheimer’s disease and traumatic brain injury.

Previous studies had also shown Bryostatin’s ability to accelerate the generation of new connections in the brain when paired with learning exercises. According to Alkon, this could eventually lead to new treatment therapies for children with compromised memory activity. BRNI is in discussion with the Food and Drug Administration (FDA) to begin clinical trials of the drug.

About BRNI

BRNI is the world’s only non-profit institute dedicated to the study of both human memory and diseases of memory. Its primary mission is to accelerate the transfer of neurological discoveries from the lab to the doctor’s office where it can benefit patients who suffer from neurological and psychiatric diseases.

BRNI is operated in alliance with West Virginia University in Morgantown as well as in collaboration with other academic institutions such as Johns Hopkins University. West Virginia Senator Jay Rockefeller founded the Institute in memory of his mother, Blanchette Hooker Rockefeller, who died of Alzheimer’s disease.

http://www.brni.org/