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Emisphere Technologies Demonstrates Safety and Efficacy of Oral Insulin in Phase 2 Trial in Type 2 Diabetics
Monday October 30, 9:21 am ET
Company to Hold Conference Call at 10:30 am Eastern Time Today
data looks pretty darn good to me
TARRYTOWN, N.Y.--(BUSINESS WIRE)--
Oral insulin had no statistical difference in hypoglycemic episodes, serious adverse events, or insulin antibodies versus placebo
A dose response was observed for the active arms versus placebo in the diabetic patients on the highest doses of metformin enrolled in the study
Emisphere Technologies, Inc. ("Emisphere", NASDAQ: EMIS) announced today results from its 90-day, Phase 2 study of its oral insulin product utilizing its eligen® oral delivery technology. The four-arm study evaluated the safety and efficacy of low and high fixed doses of oral insulin tablets versus placebo in patients with Type 2 Diabetes Mellitus on existing oral metformin monotherapy. The trial focused on the safety of oral insulin, specifically noting incidents of hypoglycemia, as well as the occurrence of insulin antibodies. The efficacy component of the trial was designed to measure changes in Hemoglobin A1c (HbA1c) over 90 days, the standard for evaluating glucose control in Type II diabetics. An additional objective was to confirm that insulin delivered orally could be administered as a fixed dose product without the need to conduct glucose monitoring or titrate the insulin dose. The study met the Company's objectives for both safety and efficacy.
The four arms of the study consisted of three doses of oral insulin (10mg QID, 5 mg QID and 10 mg BID) and placebo. There were 35 patients enrolled in each oral insulin arm of the trial, and 36 in placebo. Results showed that the total number of patients achieving a hemoglobin A1c (HbA1c) decrease of more than 1.1% among the 35 patients dosed at the 10 mg QID dose of oral insulin was statistically significantly higher than in the 36 placebo patients (p=0.0368). The study also demonstrated it was possible to deliver a fixed dose of insulin without the need to frequently monitor the patients' blood glucose or to titrate the dose for any reason. Blood glucose was measured on a monthly basis. A dose response was observed in Hba1c for the 10 mg QID and 5 mg QID doses of oral insulin versus placebo in patients enrolled with Hba1c values above 7.5% and being treated with 1,500 mg per day or more of metformin; however, these values did not reach statistical significance.
Emisphere believes its oral insulin product had a very encouraging safety profile. During the study, there were no significant differences in number of hypoglycemic events, serious adverse events, or insulin antibody formation for the orally administered insulin compared to placebo. There were no hypoglycemic events in any of the high responder patients as measured by HbA1c. There were no insulin antibodies in any of the three oral insulin arms. The patients in all three active arms saw no change in weight and no nighttime hypoglycemic events.
"We are very pleased with these study results. The goal of this study was to demonstrate that orally dosed insulin can be effective and safe in a real world setting over a protracted period of time, 90 days, without the need to titrate the dose or frequently monitor the blood glucose levels. Such a product can improve both the quality of care and the quality of life for many diabetics" said Michael M. Goldberg, M.D., Chairman and CEO of Emisphere Technologies. "The oral delivery of insulin has been an important goal of the pharmaceutical industry since insulin's discovery over 80 years ago. The results from this Phase 2 study represent a major milestone in Emisphere's efforts toward the accomplishment of that goal. The Phase 2 clinical trial was also designed to evaluate the safety and efficacy of various dosage strengths of our product compared to placebo. In- depth analysis of the data from this study should better define the patient populations most likely to benefit from the unique characteristics of oral insulin"
"This important achievement could not have been accomplished without the dedication and commitment of our staff and our expert collaborators from around the world. We were pleased with the quality and performance of our contract research organization, iGate, whose execution skills were excellent throughout the study. We look forward to extending our clinical database to further investigate the principal subpatient populations that would most benefit from the oral insulin product. We believe that these results will support our efforts to partner this program with a major pharmaceutical company. Finally while the phase 2 study was being conducted we tested several new oral insulin formulations in humans, which are more efficient in delivering insulin as compared to the formulation used in the phase 2." Dr. Goldberg concluded.
"We were very pleased to have had the opportunity to work on such an exciting and novel product. The investigators involved in the study consistently commented on the excellent safety and tolerability of the Emisphere oral insulin product. Significant interest was expressed by the investigators and their patients in an oral insulin product, which will not require dose titration or frequent glucose monitoring" said Vasu Ginde M.D., CEO of iGate Clinical Research International.
Conference Call/Webcast Information
The Company will hold a conference call today at 10:30 am to discuss these results. The dial-in information is as follows:
U.S. Dial-In: (866) 541-8090
International Dial-In: (706) 758-0055
Passcode: 1095920
This conference call will also be broadcast live via the Internet. You may access the presentation by visiting the Investor Relations portion within the Emisphere Technologies' website, http://www.emisphere.com/ir.asp.
Please visit the site at least five minutes prior to start time for instructions. A replay will be available through November 29, 2006. To access the replay, callers are requested to dial (800) 642-1687 from the U.S. and (706) 645-9291 internationally. Callers should use passcode 1095920.
About Diabetes
According to statistics provided by the World Health Organization and the American Diabetes Association, approximately 177 million people worldwide are afflicted by diabetes, with approximately 18 million of those afflicted residing in the United States. Nearly one-third of all individuals in the United States suffering from diabetes are unaware that they have this chronic disease. Type 2 diabetics account for approximately 90-95% of diabetes cases. According to the publicly filed annual reports of leading insulin manufacturers, worldwide sales of insulin were approximately $5.6 billion in 2004. Currently, there are no approved insulin therapies in oral form.
About EMISPHERE® Oral Insulin
Emisphere's oral insulin mimics the natural physiology of insulin release, by targeting the liver prior to being distributed to the peripheral circulation, so that both the timing and location of naturally secreted (endogenous) insulin release are replicated. Orally delivered insulin, with the appropriate clinical attributes, may provide for an effective diabetes therapy with fewer side-effects as compared to existing therapies, and may be useful in halting the progression of diabetes.
About the eligen® Technology
Emisphere's broad-based oral drug delivery technology platform, known as the eligen® technology, is based on the use of proprietary, synthetic chemical compounds, known as EMISPHERE® delivery agents, or "carriers". These molecules facilitate or enable the transport of the therapeutic macromolecules across biological membranes such as those of the gastrointestinal tract, and exert their desired pharmacological effect. Emisphere's eligen® technology makes it possible to orally deliver a therapeutic molecule without altering its chemical form or biological integrity.
About Emisphere Technologies, Inc.
Emisphere Technologies, Inc. is a biopharmaceutical company pioneering the oral delivery of otherwise injectable drugs. Emisphere's business strategy is to develop oral forms of injectable drugs, either alone or with corporate partners, by applying its proprietary eligen® technology to those drugs or licensing its eligen® technology to partners who typically apply it directly to their marketed drugs. Emisphere's eligen® technology has enabled the oral delivery of proteins, peptides, macromolecules and charged organics. Emisphere and its partners have advanced oral formulations or prototypes of salmon calcitonin, heparin, insulin, parathyroid hormone, human growth hormone and cromolyn sodium into clinical trials. Emisphere has strategic alliances with world-leading pharmaceutical companies. For further information, please visit http://www.emisphere.com.
Safe Harbor Statement Regarding Forward-looking Statements
The statements in this release and oral statements made by representatives of Emisphere relating to matters that are not historical facts (including without limitation those regarding the timing or potential outcomes of research collaborations or clinical trials, any market that might develop for any of Emisphere's product candidates and the sufficiency of Emisphere's cash and other capital resources) are forward-looking statements that involve risks and uncertainties, including, but not limited to, the likelihood that future research will prove successful, the likelihood that any product in the research pipeline will receive regulatory approval in the United States or abroad, the ability of Emisphere and/or its partners to develop, manufacture and commercialize products using Emisphere's drug delivery technology, Emisphere's ability to fund such efforts with or without partners, and other risks and uncertainties detailed in Emisphere's filings with the Securities and Exchange Commission, including those factors discussed under the caption "Risk Factors" in Emisphere's Annual Report on Form 10-K (file no. 1-10615) filed on March 16, 2006.
Contact:
Investor Relations:
Emisphere Technologies, Inc.
Stewart Siskind, 914-785-4742
or
Media:
BMC Communications
Dan Budwick, 212-477-9007 ext. 14
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Source: Emisphere Technologies, Inc.
Not only are you correct about collateral therapeutics having that product but christoper Reinhardt was the ceo of Collateral Therapeutics.
So he sold the company to shering and bought the product back to sell it to someone else
La times article
The saliva of a bat species has an enzyme that may help prevent brain damage in more stroke victims. A new drug holds promise.
By Regina Nuzzo, Special to The Times
October 30, 2006
JUST for the record, vampire bats don't suck. They lap.
Under the cover of darkness, the mouse-sized Desmodus rotundus flies out from rocky caves to find a sleeping horse or cow. Its razor-sharp incisors carve out a tidy crater of flesh, no bigger than a Halloween M&M, usually without waking its prey.
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Then, perched over the welling wound, the vampire bat laps up about a tablespoon of blood — its sole source of nourishment — with a delicate, bright-pink tongue.
Normally, wounds like these would start to heal within minutes. But dinnertime for a vampire bat lasts as long as half an hour. Its saliva contains a special enzyme that immediately liquefies blood clots, keeping the vampire bat's meal smooth and fresh.
The same problem facing vampire bats — the need to keep blood vessels clot-free — also faces cardiovascular researchers. Now some of them are hoping the enzyme that allows vampire bats to avoid feeding on mouthfuls of coagulated blood might also help prevent brain damage in stroke victims.
Since last year, clinical trials have been underway to test the effectiveness of a genetically engineered, bat-saliva enzyme in a new clot-busting drug to be used for emergency treatment of ischemic stroke, in which blood supply to the brain is cut off. If approved, the drug would allow doctors to treat patients up to nine hours after symptoms begin, extending the current three-hour limit for stroke medication.
Earlier studies in humans and animals have found the drug, called desmoteplase, to be safe and accompanied by fewer side effects than existing treatments. The hope is that desmoteplase acts to dissolve only the clotted area blocking blood flow to the brain and causing stroke — thus leaving fragile blood vessels in the brain intact.
Although researchers are still hopeful about desmoteplase, more information is needed about its safety. On Wednesday, the study's coordinators announced that they were temporarily halting enrollment of new patients to allow time for more patient safety data to be analyzed.
In 2004, the Food and Drug Administration granted desmoteplase's developers, Paion in Germany and Forest Laboratories Inc. in New York, a fast-track application. These applications aim to speed the development process of products addressing unmet medical needs.
About 700,000 people suffer a stroke every year in the United States, according to the American Stroke Assn., and about 1 in 5 of them die within a month. Untreated, a stroke lasts about 10 hours and kills 1.9 million brain cells every minute — usually resulting in a region of dead brain tissue bigger than a ping-pong ball.
Quick treatment of stroke is crucial, says Dr. David S. Liebeskind, associate neurology director at UCLA Stroke Center and a researcher in the desmoteplase trial. "Every minute counts," he says. "It can make the difference not just between life and death but also between an independent life or a dependent, disabled life for many years thereafter."
The only FDA-approved medication for ischemic stroke — alteplase (Activase) — is currently limited to a three-hour window immediately after a stroke. Yet only about 3% of stroke victims arrive at the hospital within three hours, says Dr. Andrew Slivka, neurology professor at the Ohio State University Medical Center and a researcher in the trial.
"That really limits the number of patients that we can even treat," he says.
Alteplase is the genetically engineered form of a compound called tissue plasminogen activator, or tPA, a clot-dissolving enzyme naturally found in humans and other mammals. But tPA isn't perfect: It can sometimes cause bleeding in the brain, especially when treating stroke after too much time has passed, says Dr. Wolfgang Söhngen, co-founder and chief executive of Paion.
Vampire bat saliva, on the other hand, has been "super-optimized by evolution" to do a clot-busting job, Söhngen says. "If vampire bats were not good at feeding on blood, they would have disappeared, " he says. "The enzyme's only job is to break up clots."
Desmoteplase works by switching on special protein-eating enzymes in the blood called plasmins. When activated, plasmins digest the fibrous protein mesh that forms the core of blood clots. Blood can then reach the brain again.
Eighty centers in Europe, Australia, Canada and the United States, including UCLA, are participating in the phase 3 randomized clinical trial, which has been expected to end in early 2007. Researchers hope to enroll a total of 186 patients who arrive at the hospital three to nine hours after stroke onset.
Each patient enrolled in the study is closely monitored for brain hemorrhaging and other side effects. Three months after treatment, the researchers assess how well the patient's damaged brain regions have recovered.
As with all clinical trials, an outside panel also independently monitors patient safety. When the study coordinators recently suspended recruitment into the trial, they did so at the recommendation of this panel, which requested additional safety data before the trial could proceed but did not specify the nature of the issue.
The trial was put on hold on Wednesday, I believe and by Friday evening the hold was lifted and the trial was to resume
These kinds of announcements, although potentially serious, happen with some frequency, Liebeskind says. "This could perhaps be as mild and benign as a housekeeping issue," he says — if, for example, one of the study sites failed to deliver its completed data on time. "Of course," he adds, "there is also the possibility that there's a more serious safety issue."
In an earlier trial, researchers studied dosages of desmoteplase administered in 94 patients three to nine hours after the stroke's onset. A high dose of desmoteplase sufficiently increased blood flow to the brain in 62% of patients, as compared with 24% who received no medication. Sixty percent of those treated with a high dose showed an improvement in clinical outcomes such as cognition and motor control, compared with 23% in the placebo group.
Only one out of 59 patients who received the drug suffered brain-bleeding side effects.
Scientists in Germany are also performing animal studies to investigate desmoteplase for use in hemorrhagic stroke, caused by bleeding within the brain. And desmoteplase could soon be studied to treat other health problems related to blood clots, researchers say, such as heart attacks, deep vein thrombosis or pulmonary embolism.
A cure for vampirism, however, might have to wait a couple more years
your explanation explains why neuroprotectants will not work unless a clot buster is approved to allow reperfusion, which would allow neuroprotectants to come in an do their job.
Axaron is extremely excited about the potential for AX200, as work in pre-clinical models has shown that the drug has multiple modes-of-action and is not only capable of protecting brain cells from damage occurring during the acute phase of stroke, but also improves the functional performance thereafter."
All of the neuroprotectants did well in animal studies that is why they went into humans. It is my feeling that the brains of lower species allow the neuroprotectant to get around the clot so they can protect the brain tissue even though the blood can't get the oxygen where it has to go. In humans the neuroprotectant can't get around the clot so they can't do their job. When the toilet is stuffed you need a plunger to unblock it, otherwise it overflows.
A neuroprotectant may work but first you have to find a way to bust the clot without causing bleeding. I think that desmonteplase may be the clot buster
some background on stroke
Vascular Physiology and PathophysiologyMitchell S. V. Elkind, MD, MSFebruary 25, 2006Chapter 1: Stroke EpidemiologyMitchell Elkind: Thanks, Sander, for that extended introduction, which gave mea chance to get the computer stuff going. Good morning, everybody. It’s a pleas-ure to be here, and thanks again to Sander for giving me the opportunity tospeak for the next hour about stroke.Here are some disclosures, just so you can see them. And here’s an outline ofwhat I’d like to talk about, which is to start talking a little bit about epidemiology.You heard just a little bit about that from Sander. Talk about some new ideasregarding stroke and TIA [transient ischemic stroke] definitions, some pathophys-iology of acute stroke, and then we’ll talk about some more clinical issues, acutestroke management, and stroke prevention.There are about 750,000 strokes a year in the United States. And as Sander wasalluding to it’s the third leading cause of death in the US, but it actually outranksheart disease in other parts of the world, particularly in Asia. So in other coun-tries it’s an even more important problem than it is here in the US. And becausestroke often doesn’t kill people but leaves them disabled, it is the leading causeof serious long-term disability.Now we are about nine years since the FDA approved the use of intravenoushttp://neuroscienceupdate.cumc.columbia.edu1Basicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006
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tPA [tissue-type plasminogen activator] for acute ischemic stroke within threehours, and still only up to 2% of patients nationwide get treated with tPA. So thekey to reducing the burden of disease is really prevention.With regard to definitions, here’s the definition of stroke, this is the classical defi-nition: rapidly developing clinical signs of focal disturbance of brain function last-ing more than 24 hours or leading to death with no apparent cause other thanthat of vascular origin. It’s kind of a circular definition, it says that you’ll know if,when you see it, a stroke is what a stroke looks like. But the key thing to noticehere is this idea that a stroke is something that goes on for 24 hours or longer,while a TIA or a transient ischemic attack is the same symptoms but lasting lessthan 24 hours. And you’ll notice that this definition comes from the World HealthOrganization from 1980, so currently it’s about 25 years old. Using more sophis-ticated imaging that’s been available recently we can see that that definitiondoesn’t really hold water.This is just an example of a 54-year-old gentleman with atrial fibrillation, which isa major risk factor for stroke, and he had just five minutes of dysarthria; and bythe time he got to the emergency room his symptoms had fully resolved, hisexam was completely normal, and yet he went immediately for an MRI scan, andyou can see that in his right frontal lobe there’s this tiny little focus of abnormalityconsistent with a small area of ischemia or infarction. About 50% of the timethese diffusion-weighted abnormalities will resolve, but half the time they do per-sist. This is a very sophisticated imaging technique that’s become available inthe last several years that allows us to see the earliest changes of ischemia andshows that that 24-hour dividing line doesn’t make sense. In fact, people havelooked at this more systematically, as the group from UCLA did, and found that ifyou looked over here, this shows the duration of TIA on the X axis and the likeli-hood of finding an abnormality on diffusion-weighted imaging on the Y axis. Not surprisingly the longer one’s symptoms last, the more likely you are to seeabnormalities on the MRI scan. But notice that for those whose symptoms lastless than an hour a full third will have evidence of a stroke on MRI. Now this isimportant, because I think in previous days perhaps people thought of TIA asBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu2
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being a very benign condition. If a patient came in with a stroke, they had adeficit, they couldn’t function normally, they’d be brought into the hospital, every-body would kind of worry over them for several days, if nothing else. But if some-body came in with a TIA and their symptoms had resolved, you’d send themhome, have them come to see you in the office in a couple of weeks and hopethat everything went okay. But data like this shown here tells us that that’s notreally appropriate. This is from the Kaiser Permanente group, a very large HMOwith many different emergency rooms affiliated with it in northern California, andthey looked at about 1,700 patients who were diagnosed with TIA in their emer-gency rooms and then discharged. They followed those people for 90 days, andthey found that there was a very high risk of these people going on to haveanother vascular event; 25% had one event or another, 10% went on to have astroke. You can see that half of those, so just 5% of that total group, had theirevent within 48 hours of their initial TIA. So this is really a very high risk condi-tion.This is some data that was actually just presented last week at the InternationalStroke Conference in Florida by Clay Johnston who actually did that other analy-sis I showed you. He tried to come up with a scoring system, a simple scoringsystem, to determine which TIA patients were the ones who were going to go onand have an event. Together with people in Oxford they combined their data andthey came up with this little mnemonic which actually he called DDW, but some-body in the audience at his talk suggested WDD for Will Develop Disease. Butbasically using multivaried analysis they were able to determine that these threefactors—whether weakness was present; the duration of the spell, an hour orless; and whether the patient had diabetes—that these three characteristics pre-dicted the risk of somebody going on to have a stroke. If you had none of thesefactors present, your risk of having a stroke at seven days was quite low, only1%; if you had one of the factors, 4%; and then two or three, 9 and 10%. And sohe would argue that if you had at least two of these factors present you were ina higher risk group; less than that, a lower risk group. I think one could still saythat 4% over seven days is still a pretty high risk, and we’d obviously want to bedoing something about that, too. I’m not sure how useful ultimately this will beclinically, but again I think it just confirms that this is a high risk condition, andBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu3
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that there may be some features of patients that we can use to stratify that riskfurther. We’ll see what happens with that scale as we go forward. But again, TIAbeing recognized as an increasingly worrisome condition.Chapter 2: Hemorrhagic Vs. Ischemic StrokeStroke obviously comes in two major flavors, hemorrhagic and ischemic.Hemorrhagic, roughly evenly divided between parenchymal hemorrhage, wherethe bleeding is within the substance of the brain; and subarachnoid hemorrhage,where the blood is around the brain, and I’ll show you examples of these in amoment. That’s about 20% of strokes, and then about 80% or so are ischemicstrokes. You’ll notice that even within the big group of ischemic strokes there’sstill many different causes and categories. This is really very different from heartdisease, with which stroke is often lumped together I think. Heart disease, about90-95% is due to large vessel atherosclerosis affecting the coronaries. Forstroke it’s really quite different, only about 20% of strokes are due to that kind ofatherosclerotic disease. The other important thing to remember is that traditional-ly we, neurologists, neurosurgeons, vascular folks, have tended to focus on theextracranial carotid artery in the neck where, of course, the surgeons could get itand do something about it. But nowadays, now that we have interventional tech-niques and catheters that can be fed through the blood vessels, we can actuallyget into the vessels inside the skull base, and so we recognize that half of thatcategory of atherosclerotic disease is actually intracranial atherosclerosis.Clinically we don’t want to forget to look for that either. Then we have about 20%of strokes that are due to emboli, about a quarter are due to lacunar or smallvessel disease, I’ll show you in a moment. And then even after a thorough evalu-ation, about 30, sometimes as much as 40% of strokes are of unknown cause.I recognize that there’s a range of professions and experience here, and soforth, so some of this may seem very basic to some of you but maybe not to oth-ers. This is just CAT scans showing a hemorrhagic stroke here on the left,ischemic stroke here on your right, and blood shows up bright on the CT scan,and this is why a CAT scan is such a crucial test in the emergency room forpatients with stroke. Without a CAT scan there would really be no way to distin-Basicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu4
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guish a hemorrhagic from an ischemic stroke—and the treatment is obviouslycompletely, completely different. We really do need to image these. People havetried to come up with various rules and schemes—if the patient has headacheand nausea and vomiting it must be a hemorrhage, and so forth—but none ofthose schemes are really sufficient for clinical practice, so we have to have aCAT scan.Here’s an example of a subarachnoid hemorrhage, and in this case the bleedingis not within the substance of the brain, but around the brain itself in the sub-arachnoid space and in the fissures. These kinds of patients will typically presentwith severe headache, nausea, vomiting, they may slip into coma, they can evenhave sudden death. In this way this is very different from a parenchymal hemor-rhage where the bleeding is within the substance of the brain and patients devel-op a focal deficit. The subarachnoid patients early on do not have focal deficits.Here’s an MRI scan showing also a left middle cerebral artery infarction. This iswhat we would call a border zone or watershed infarction, which outlines verynicely the territory between the major blood vessel supply. Here is the middlecerebral artery territory, here is the anterior cerebral artery, and here is the pos-terior cerebral artery; and usually this is due to a blockage in a large blood ves-sel like the carotid artery, so that blood has the hardest time getting to the mostdistal aspects of the field that it’s supplying, and that’s where the stroke ends up,and in the other territories is relatively preserved.Here’s an example on an MRI scan of a small, deep, or lacunar infarct. Theseare the kinds of patients who usually present with loss of motor function, sensoryfunction, or balance, but typically don’t have any loss of cognitive function, noaphasia, no neglect, and so forth. So they can develop these motor, sensory, orataxic syndromes. These lacunar strokes are due to blockage in the very smallblood vessels deep within the brain. Here’s a branch of the middle cerebralartery, and then here are these tiny, thread-like vessels, and if you see them atpathology they really do look like threads that come off at right angles from thelarger vessel and supply the deep territory here. Usually these are associatedwith high blood pressure, and it’s not hard to imagine how somebody who hasBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu5
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high blood pressure; and this blood vessel here, the MCA [middle cerebralartery], will be seeing those systemic high pressures; and coming off at rightangles these tiny little thread-like vessels are subjected to a big change in bloodpressure from here into there. And so those vessels over time will thicken, theythicken and eventually occlude completely. Sometimes they can develop tinyaneurysms called microaneurysms, and those can be the source of bleeding.And so frequently lacunar strokes and hypertensive hemorrhages will occur inthe same parts of the brain, because they’re both diseases of those small bloodvessels. Here’s a small superficial infarct. It’s small, and yet it’s right at the sur-face of the brain. This is typical of an embolism to a distal branch of the middlecerebral artery.Chapter 3: Anatomy of Cerebral Blood VesselsOf course understanding stroke, it’s important to know your blood vessel anato-my. There are just a couple of points I want to make here. You have four majorblood vessels supplying the brain: you have the two carotids up front, you havethe two vertebrals in back; and it’s important to remember that of the carotidarteries, the first stop is actually not the brain but the eye, and that’s why symp-toms of loss of vision transiently are such an important warning sign of potentialstroke. They’re really a TIA affecting the eye that tells you that you’d better lookat that patient’s carotid artery and make sure there isn’t a blockage there. Thetwo vertebral arteries meet up, form the basilar artery, which then divides at thetop. This is a pretty unique situation in the body. I think it’s the only place wherethe two blood vessels come together, travel as one, and then divide again in thebody. And that has clinical implications as well. Then of course all the blood ves-sels meet up at the top in the circle of Willis, which allows collateral blood flowfrom one area of the brain to another, if one of these should be blocked. Mostpeople have an intact circle of Willis, but in some cases branches may be miss-ing. For example, a posterior communicating that connects the front and theback circulations—when that’s absent, studies have shown that patients willhave a higher risk of stroke in the setting of carotid artery disease. Similarly, ifyou’re missing an anterior cerebral artery—at least the proximal part of it, whichis not uncommon—then both of these vessels here, the anterior cerebral arter-Basicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu6
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ies, will be coming from one carotid. Here’s just an example of an interestingcase we had recently illustrating that this can actually have clinical implications.This was a 72-year-old man who was having drop attacks, so both legs wouldbecome weak, but no loss of consciousness. This was due to a stenosis in hisleft internal carotid artery. Ordinarily you would think that would only affect theleft side of the brain, why should both of his legs go weak? Well it turns out he’smissing the anterior communicating here on his right side, and so his left carotidartery through the stenosis is supplying both hemispheres in the front where theleg function is located. That’s a pretty unique situation, but you can see howsome variance of the circle of Willis can result in those kind of clinical syn-dromes.Of course understanding blood vessels is half the story. You also need to knowwhere in the brain various functions reside. Just a couple of points I want tomake about this, because I think they are important clinically. Here’s the left halfof the brain, and most of this territory here is going to be supplied by the middlecerebral artery, but it’s important to remember that the MCA actually divides intotwo branches. One will go to the front part of the brain here, and include themotor strip and the sensory strip, but the inferior division of the MCA goes to theback of the brain here, and catches this Wernicke’s area, which is responsiblefor understanding speech. And so patients with an embolism to the inferior divi-sion of the MCA, which is a very common location for an embolism, will take outWernicke’s area but completely spare the motor and sensory strips. Patients likethat may walk into the emergency room, they’ll be using their arms and legs nor-mally so they’ll look normal if you just look at them, they’ll even be talking fluent-ly, but they will just be babbling away and not making any sense. And not infre-quently those patients get sent to the psychiatrist rather than to the neurologist.So clinically we want to remember that type of syndrome.Also, as I mentioned before, the basilar artery divides into these two posteriorcerebral arteries that supply the occipital lobes. And so strokes either on one orboth sides of the brain back here can result in blindness, visual loss, and notsurprisingly, those patients often get sent to the ophthalmologist first, and it isn’tuntil several days later that they make their way to the neurologist. We don’tBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu7
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want to forget about those syndromes, which are a little bit atypical, because Ithink most people are aware of stroke as involving weakness, but they forgetabout some of these other more subtle syndromes.Chapter 4: Ischemic PenumbraNow the guiding paradigm behind acute stroke therapy has been this idea of theischemic penumbra for the last probably couple of decades now. The idea hereis that when a patient has a stroke, there’s a central core area of the brain that’sinfarcted fairly quickly, because the blood flow drops down so low that that areacan’t survive very long at all. But then there’s the surrounding area of tissue, thepenumbra or shadow, in which the tissue may be functionally impaired, it’s notworking properly, so the patient has a clinical deficit, but the tissue isn’t irre-versibly damaged or dead yet. That’s this surrounding area here. If we couldrestore blood flow to this area then we might be able to restore function. And notjust blood flow. There’s a process that’s set in motion when tissue becomesischemic that involves many different factors. This is a complicated slide that justkind of summarizes a lot of these different things, but included in here are whentissue, when brain cells, when neurons die, and they release their neurotransmit-ters—those neurotransmitters then can excite surrounding neurons, but not in anormal fashion; they overexcite them in a process called excitotoxicity, whichleads to the uptake of calcium by those surrounding cells, again in supraphysio-logic levels, and leads to the death of those additional neurons. So that may beanother mechanism through which cells in the surrounding penumbra are dam-aged. There’s also inflammatory mechanisms that contribute, so when cells inthe core die then leukocytes and inflammatory mediators are brought into theischemic tissue, and those may damage surrounding tissue. Free radicals areformed that will damage the surrounding tissue as well. Through several differentmechanisms there will be damage of the surrounding penumbra, as well as justthe lack of blood flow. And so the key is to try to interrupt those processes aswell as restoring blood flow.The brain is very good at maintaining blood flow to itself in the setting ofchanges in systemic blood pressure. That’s what this curve shows here. This isBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu8
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through the process of autoregulation, which is based on the ability of the smallarteries, the arterials, in the brain to dilate and constrict in response to changesin systemic blood pressure. So that if this is systemic blood pressure here, andthis is brain blood flow, you can see that through a wide range of systemic bloodpressures, brain flow remains constant. Obviously in some situations when sys-temic blood pressure goes way too high, like in the setting of malignant hyper-tension, or when it goes too low, in somebody who’s septic, we’re outside thebarriers of that autoregulation. But for the most part in normal people, we’re ableto maintain our brain blood flow quite well. But in the setting of stroke thatchanges, and there the tissue in the brain becomes very dependent for its bloodflow on systemic blood pressure. You develop this linear relationship here, partic-ularly in the area surrounding the stroke, so that a small change in blood pres-sure results in a big drop in brain blood flow. This is why neurologists, againunlike cardiologists, are very leery of decreasing blood pressure in strokepatients.This has been seen in post-op kinds of analyses of large clinical trials. Forexample, this is data from the International Stroke Trial, which was not looking atblood pressure, but they subsequently analyzed blood pressure levels in relationto outcomes. They found this kind of U-shaped curve suggesting that althoughvery high blood pressures may be bad, very low blood pressures may be bad aswell for stroke patients, and patients tend to do best at this intermediate rangebetween about 140 and 180 or so. Again, this is a secondary analysis of a trialdone for other purposes, and there are currently ongoing clinical trials looking atthis in a prospective fashion. But the guidelines from the American StrokeAssociation for acute stroke therapy do recommend pretty high blood pressurelevels, or at least not to treat patients when their blood pressure levels are up,even as high as 120 diastolic, 220 systolic. We tolerate very high blood pressurelevels. It’s really the body’s response to the insult of the stroke.Just to show you that this idea of the ischemic penumbra is not purely a theoreti-cal or cartoon-like concept, this is an example of an actual patient who has aright middle cerebral artery occlusion. This is an MRI scan here. This is that dif-fusion-weighted imaging that shows the earliest signs of ischemia. And so youBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu9
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can see a couple of little foci here of infarction. We can see them a little bit onthe T2-weighted image, the more typical MRI we used in the past, although it’snot as evident here as here. Then this here is the perfusion-weighted image,which is looking at the amount of blood flow getting to that area of the brain. Ifyou compare the perfusion and the diffusion, you can see that there’s a large ter-ritory here that’s getting inadequate blood flow but hasn’t yet gone onto infarc-tion. This is becoming a very important way of evaluating acute stroke patients,so that rather than just relying on these time windows, 3 hours, 6 hours, and soforth, that we have right now to determine how to treat people, we can actuallyuse the pathophysiology. The patients who have a large area at risk but haven’tyet infarcted it, those are the patients who we may be able to most help, regard-less of the time window at which they come in. So again, there are trials goingon now using this as the determining point for treatment.Chapter 5: Acute Ischemic Stroke TherapyBut for now we are pretty much dependent on these time windows for therapy.These are kind of the evidence-based treatments for acute stroke right now. Wehave in the up to 3-hour time window, intravenous tPA [tissue plasminogen activator];in the 3- to 6-hour time window, intra-arterial urokinase or tPA. There’s a studythat has shown that to be of benefit, although it’s not actually approved for useby the FDA for this purpose, but many centers, including Columbia, are doingthis. Very exciting is that there’s a new device that was just approved this pastyear by the FDA for treatment of acute stroke, and I’ll show you that in amoment. Then once we get beyond the 8-hour time window we’re really justusing aspirin and subcutaneous heparin.The idea behind the original trial that demonstrated the benefit for intravenoustPA, again following on that idea that there’s a core central area of infarction, andthen a surrounding penumbra—they really did two trials sequentially. The firsttrial was intended to show that if we gave this clot-busting drug, if we throm-bolise the patient with tPA that they would have a very dramatic and immediaterecovery. And so for the end point of that study, they looked at the outcome atjust 24 hours, the patient had to have a very good outcome at 24 hours. ThisBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu10
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people have referred to as kind of Lazaroid effect—in other words, you give thedrug, the patient would jump up off the gurney, shake your hands, say, “Thanks,Doc, I needed that,” and walk right out of the emergency room, stroke gone. Sothat’s one possibility. The other possibility is that there’s that core area that’sgoing to infarct, may not be able to do much about that, but perhaps by givingthe clot-busting drug we can improve perfusion and restore flow to the surround-ing area, and so although the patient has their stroke, their ultimate outcome willbe much better because the stroke will be smaller than it otherwise would be.And so to do that they looked at a 3-month outcome.The important things to remember about the way the study was done was thatthey looked at stroke within 3 hours of onset, and this means that if a patientwakes up at 6 o’clock in the morning but they went to bed at midnight, theywould not have been able to be in the study and they’re still not eligible for treat-ment according to the protocol. It’s based on when they were last known to benormal. Obviously they had to have a normal CT scan. The doses and the wayof using tPA are also very different from the cardiac situation. Cardiac patients,when they were still getting tPA, got 1.1 milligrams per kilogram. The strokepatients, though, get a lower dose because it was known that higher doses usedto treat heart disease would result in hemorrhage. Also we don’t use any otherblood thinning agents together with tPA for stroke patients.Here are the results for the 24-hour outcome in this study. As you can see,there’s a slight trend, so the red are the patients who got tPA and the green arethe placebo patients, and this is the percent improved in 24 hours. There is atrend towards improvement for those who got tPA, but it’s not statistically signifi-cant in any of the time windows that it was given. They couldn’t make the claimthat this causes a patient to bounce immediately right back up. But looking at the3-month outcomes, on each of the different scales that they used there was astatistically significant benefit. The one that I like to use is the Barthel index,which measures how well patients can feed themselves, wash themselves, getaround, and so forth. For those patients, if they got placebo they had about a38% chance of getting back to functionally independent, and if they got tPA, itwent up to 50%. So there’s a 12% absolute increase. You would need to treat 8Basicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu11
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patients roughly to get one patient better, and that’s a pretty robust benefit com-pared with most of the therapies that are used.That’s the good news. The bad news, of course, is that there’s a risk of hemor-rhage. These are actually all of the hemorrhages from the NINDS trial. In fact,the risk of bleeding goes up tenfold with tPA. If you look at the placebo patients,they had a 0.6% risk of symptomatic hemorrhage, and the tPA patients it was6.4%. You see that tenfold increase in risk of hemorrhage and you think my God,you’ve got to be crazy to give tPA to a stroke patient. I think this is what’s giventPA kind of a bad name among some people who are afraid to use it. But in factif you look at the overall neurologic deterioration at 24 hours, you can see thatthe rates are actually roughly the same, if anything slightly lower in the tPA treat-ed group. So it’s a reasonable question, how can it be the case that you have atenfold increase in risk of hemorrhage and yet the risk of overall neurologic dete-rioration is any worse? Well it’s because there’s a lot of other bad things that canhappen to you besides just a hemorrhage. If you don’t get the tPA potentially youcould have recurrent stroke, you could have enlargement of the stroke, you canget edema, herniation, seizures, many other things can occur. Just focusing onhemorrhage because it’s so obvious on a CT scan is a potentially misleadingway of characterizing this. There are other things that happen as well. In fact, ifyou look at the mortality at 3 months it’s lower in the tPA treated group than inthe placebo treated group.There have been other trials as well which individually have not demonstrated abenefit of thrombolysis, but in a MET analysis that put together European andAmerican and Australian trials, they found that the potential benefit actually maygo out as far as 4 1/2 hours. This is the likelihood of having a benefit, these areconfidence intervals around the center line, and that lower confidence intervaldoesn’t cross no benefit until 4 1/2 hours. It’s possible that there’s a benefit outbeyond 3 hours as well, although it would take a much larger study to show it.The Europeans are doing a study like that now with a longer time window. Wemay be pushing that time window eventually. But currently beyond 3 hours, inthe 3- to 6-hour window, we can use intra-arterial thrombolysis. This again wasdemonstrated to be of benefit in the PROACT trial. This is just an example of aBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu12
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patient who has a right middle cerebral artery occlusion. A catheter is placed inthe groin and then passed up into the area of that middle cerebral artery. In thiscase urokinase was used in the study, is infused into the face of the clot, andhere you can see the restoration of blood flow. Again, the patient ends up with asmall stroke, they don’t get away scot-free, but the stroke is much smaller thanyou might have otherwise expected.In the results of that study there was a 15% absolute benefit in their primary out-come, the Rankin scale. And so there is evidence of benefit here. You do see,though, that same phenomenon with an increase in risk of symptomatic hemor-rhage, about fivefold in this study, although still mortality at 90 days is slightlylower in the treated group. On the basis of this data we’re using tPA intra-arterial-ly, and urokinase was not available for a long time, but now we’re using thatagain.Chapter 6: Novel Treatments: MERCIThe other very exciting thing that’s happened in just the past year is the use ofthis new device, the mechanical embolism removal in cerebral ischemia device,and some people call it MERCI and some people call it mercy, so it just dependson how you look at these things. But this is an illustration of how it works. Here’sa stroke occurring in this patient’s middle cerebral artery. This device is a clotretraction device that can be used to remove blood clot from the brain. The pro-cedure is performed initially just like doing an intra-arterial thrombolysis proce-dure in which the catheter is put into the groin and then passed up through theblood vessels. Here you can see this guide wire being advanced into the carotidartery with a larger catheter around it. Interestingly, this device has beenapproved on the basis of a trial that was really just more or less a registry—itwas treating a series of patients and then comparing how they did to historicalcontrols. It was not a randomized trial. Here you can see the device, this is theguide wire again being passed through the clot and then the catheter goesthrough the clot as well, as then this is the device itself, this is like a corkscrewthat you would use to open a bottle of wine, and it gets deployed into the clot likethis, and then more proximally a balloon is inflated in the blood vessel to arrestflow, so that when you pull back against it there isn’t blood flowing against yourBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu13
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efforts to pull it back. Then the clot can be retracted through the blood vessel likethis. I should let you know, though, that this is just a cartoon, this is not a realpatient. People always get confused about that. And then it just gets sucked rightup into the catheter, and then you can let down the balloon and blood will startflowing around it. So as I say, this device is now approved on the basis of this data here. Whatthey did was to treat 150 patients with the device, compared them with the con-trols from that PROACT study that I showed you before—that was a randomizedtrial, PROACT—so these were people who had the same kinds of strokes, andthen based on this more or less historical control group they made comparisons.These were more severe strokes in the MERCI trial, treated at slightly shortertime period, and you can see that recanalization, or opening the blood vessel upagain, occurred much more commonly in the device-treated patients. But you’llalso notice, if you look at 90-day mortality, it was not so good in those device-treated patients—44% compared with 27% in the PROACT study. You mightwonder how can a device get approved with such a lousy mortality rate? Wellbasically it was approved on the basis of its ability to open a blood vessel,because we know that in the study, patients who had recanalization occur weremuch more likely to have a good outcome than patients who didn’t. And so thisdevice is currently available, not necessarily as a treatment for stroke or toreduce mortality or even to improve functional outcomes, it’s approved to openup blood vessels in the setting of stroke. It’s a good illustration, I think, of how it’smuch easier to get a device approved than a drug approved, because you can’timagine getting tPA approved on the basis of a study like this, and yet thisdevice is now available. The way we conceive of it is as a tool that’s available forneurologists, interventionists, and so forth to use when patients have a stroke toopen their blood vessels, but it’s not necessarily indicated in every case.After interventional treatments like that, we’re primarily using aspirin. Perhapssome of you use heparin in the setting of acute stroke. There have been a num-ber of studies that have looked at heparin for this purpose, but none found anybenefit, and so it’s not currently considered indicated in acute stroke, and this isreally why. What happens is that if you use heparin or heparinoids they are alsoBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu14
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going to help to eliminate blood clot, which is good potentially and so they canreduce the risk of another ischemic stroke, but that risk is exactly counterbal-anced by an increase in risk of hemorrhage. And so overall it becomes a wash.Again we’re not using heparin for most stroke patients.Chapter 7: Emerging TherapiesSome exciting recent developments in acute stroke therapy which aren’t reallyready for primetime yet, but I guess they’re getting toward that. One is the use ofultrasound enhanced thrombolysis, so the idea here is that we know that ultra-sound delivers energy, and we use it to break up kidney stones, for example.People have begun to recognize that it can also break up clot in blood vessels.In fact, in Germany they’ve used high powered ultrasound to do this and foundthat yes, they can break up clots quite effectively, but they can also burn a holein the blood vessel wall. But using the same kind of ultrasound that we use diag-nostically, transcranial Doppler, to look at blood flows, using that together withthrombolysis with tPA improves the likelihood of recanalization. There was a pilottrial done, it was published last year in the New England Journal [of Medicine],this was done by a group in Houston. What they did was to have patients ran-domized when they came to the emergency room with stroke and got tPA—so allpatients received tPA, and then half the group had ultrasound for 2 hours andthe other half an ultrasound machine put there with a tech standing there as ifthey were getting ultrasound, but the machine was turned off. Just every 30 min-utes they would turn it on, kind of take a snapshot of how the blood was flowingand then turn it back off. In that target group the rate of recanalization was muchhigher than in the control group. This was a pilot study looking at safety, but theywere still able to show clinical efficacy so that the treated group had a much bet-ter outcome on this Rankin score as well. This is now going through larger stud-ies, and may become something that we can do again in the future.Just published in the last couple of weeks in the New England Journal were theresults of the first positive neuroprotectant trial, so the Holy Grail of strokeresearch has been to try to find a drug that can sufficiently interfere with all thoseischemic cascade processes and reduce the amount of collateral damage in theBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu15
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penumbra. We know taking a clot out of a blood vessel is going to be good, butwhat can we do to protect the surrounding tissue? Trial after trial was negativeuntil this trial called the Saint trial, which used a free radical trapping agent, anddemonstrating that using a different method of statistical analysis as well—butthey could shift the outcomes from being not as good up here on the top to bet-ter with the drug. It’s called NXY-059 or cerovive. This is a single trial that waspositive, and so they’re currently doing a second trial. If that one’s positive aswell, I think it’ll be very exciting and potentially this will be a drug that will beused as a neuroprotectant. So keep listening for that.One thing that we’re excited about here at Columbia is the use of statins to treatacute stroke. We know that statins have benefit in reducing cholesterol andreducing chance of heart disease, reducing risk of stroke as well, but it’s recog-nized recently that it may also have a role in the acute setting of stroke. This isbecause if you think back to the mevalonate pathway here, one of the majorproducts of it is cholesterol, which has obvious important functions; alsoubiquinone [Coenzyme Q10], which plays an important role in muscle and maybe why statins interfere with muscle function and lead to myalgias and rab-domyalisis, and so forth. But the statin drugs, the HMG-CoA reductase inhibitorsinhibit this pathway here, and so they can actually have effects on decreasingthe production of many other important proteins that play important roles in cellcommunication and intracellular communication as well. By doing that, they haveimportant effects on blood flow and inflammation and other things as well.Actually they can upregulate endothelial nitric oxide synthase, which improvesvascular reactivity and improves not only coronary but also brain blood flow, andthey can inhibit macrophages, lower C-reactive protein and other inflammatorymarkers as well; they may reduce free radicals, and they even seem to have arole in coagulation cascade. There’s a whole host of different effects of thestatins that appear that they might have important neuroprotective effects. Infact, in animal studies using high doses of the statins there are benefits in termsof reducing size of infarct. There have been several studies now, this is just oneexample of them—but also together with tPA, it can improve reperfusion injury,and in several different models they appear to be of benefit. We’re currentlydoing a phase I clinical trial using escalating doses of statins, really to see whatare the safest high doses we can use, so that then we can put this into a clinicaltrial in humans as well. That’s something that we think will bear fruit over theBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu16
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next 5 years or so.Chapter 8: Stroke Prevention: Risk Factor ControlIn the last few minutes I’d like to just talk a little bit about stroke prevention. Themainstays of stroke prevention: risk factor control, carotid treatments, anticoagu-lation, and anti-platelet therapies. I think there are a few important developmentswith regard to each of these things that’s worth knowing about.This slide shows the relationship between blood pressure and stroke risk. Noweverybody knows that high blood pressure increases your risk of stroke. Here wehave a MET analysis among over 400,000 people illustrating that, and here’sdiastolic blood pressure, and you can see that as your diastolic blood pressuregoes up, your risk of having a stroke goes up. That’s not surprising. But what’sinteresting here is that if you look down in the lower range—blood pressures inthe high 70s and low 80s—there’s still a continuous relationship between bloodpressure and stroke risk. There’s no threshold, in other words, below which yourrisk just drops back to the rest of the population. It continues down even into thislow range. Based on that relationship, it was hypothesized that if there’s thiscontinuous relationship then maybe it’s the case that we really ought to be lower-ing blood pressure in all of our stroke patients. With that hypothesis in mind, theprogress trial was done. This was an Australian effort, took place mostly inAustralia and Asia, and they looked at patients who had a history of eitherischemic or hemorrhagic stroke in the last 5 years, and enrolled them regardlessof a history of blood pressure problems, and regardless of what their baselineblood pressure was. Patients were randomized to active therapy with an ACEinhibitor and a diuretic versus placebo therapy, and followed up for severalyears; and there was a statistically significant reduction in risk of them going onto have a stroke or a combined vascular event that the curve looks very muchthe same. Interestingly, the benefits here were present not only among thosewho had high blood pressure, but also those whose systolic was less than 140;they had about a 40% reduction in risk, or diastolic less than 85. Much lowerblood pressures than we would traditionally be particularly concerned about, andstill seeing a benefit with reducing the blood pressure further.Basicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu17
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In this study it did not seem to be a benefit just of being on an ACE inhibitor. Itwas really related more to the reduction in blood pressure itself than to the par-ticular agent, which is consistent with some of these really big trials in bloodpressure itself, like the ALLHAT study, which pretty much showed that the old,good blood pressure agents are just as good as more recent, fancier ones. Ithink what progress does, is provides some clinical trial confirmation of that ideaof a continuum of risk between blood pressure and stroke. I think we’re movingtoward thinking about treating all of our stroke patients with blood pressurereduction, not just those who meet some standard definition of hypertension.We see a similar kind of approach in the treatment of stroke patients for second-ary prevention with statins as well. There was a very large study called the HeartProtection Study done in Great Britain that enrolled over 20,000 people whowere considered to be at high risk of having vascular events. In that group ofpeople were 1,800 people who had a history of stroke but no heart disease.People to get into the study didn’t have to have an elevated cholesterol, they justcouldn’t have a very low cholesterol. In fact, a third of the patients had LDL lev-els—bad cholesterol levels, less than 116—and about 20% were under 100. Lowcholesterol levels in this group, and the patients were randomized to simvastatin[brand name Zocor] or to placebo, and you can see that there was about a 25%reduction in risk of these people going on to have another vascular event withthose curves diverging after about one year.But, importantly for us as stroke people is that looking at those who had a historyof stroke but no heart disease, the benefits were the same as for the heart dis-ease patients, and basically were the same with every other subgroup as well.Cardiologists and medicine people have known for some time that once youhave a heart attack you’re going to go on a statin pretty much regardless of whatyour cholesterol level may be, but that hadn’t been shown yet for stroke patients.This really shows us that stroke patients do behave very similarly to those otherpatients with regard to statins.The other interesting thing to notice here is that if you look at the actual eventBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu18
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rates in the placebo group for the stroke without heart disease patients and theheart disease patients, they’re about the same. Stroke patients are at the samehigh level of risk as are the cardiac patients. That has implications, because ifyou look at the guidelines from the National Cholesterol Education Panel theytalk about risk equivalents—these are people who have the same high risk ofhaving an MI [myocardial infarction] or a coronary event over the next 10 yearsas people who already have the disease. Included in that group are people whohave diabetes, people who have multiple risk factors, like smoking and so forth,you put them together and they have a high risk, and they also include peoplewith symptomatic carotid artery disease. But they don’t say anything aboutstroke in general. I showed you before there are many different subtypes ofstroke, and I don’t think the guidelines really capture stroke patients.In our population here in northern Manhattan, we tried to determine which strokepatients would be most likely to go on to have cardiac events. We could deter-mine that age is an important factor, and whether or not you have a history ofheart disease also an important factor in predicting this. But even for those whoare less than age 70 and have no history of heart disease, their risk still comesout to about 2% per year, which is the same level of risk as the coronary riskequivalents. So I would argue that we really shouldn’t be just thinking about car-diac risk equivalents—it’s probably cardiac and stroke risk equivalents, andstroke patients should certainly be included in that group as well.Chapter 9: Stroke Prevention: Carotid TreatmentsWhat about carotid procedures? We know that in both symptomatic and asymp-tomatic patients, surgery will reduce the risk of having a stroke, but many morepatients will need to be treated in the asymptomatic group than the symptomaticgroup because the absolute rates of events are very different.What about anticoagulation, strong blood thinners like warfarin for patients withstroke? In the old days we used to put all patients on warfarin because a stroke’scaused by a blood clot—you’ve got to get rid of the blood clot. We know nowthat for patients with atrial fibrillation there is a benefit to being on warfarin, butBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu19
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for patients with noncardioembolic stroke or TIA, we’re using antiplatelet agents.This is based on the results of two trials, one called WARSS, and that focusedon patients with intracranial disease or WASID [warfarin-aspirin symptomaticintracranial disease]. The WARSS study in about 2,000 patients followed for twoyears who were randomized to warfarin or to 325 milligrams of aspirin did notshow any statistically significant benefit for warfarin over aspirin. In fact the war-farin-treated patients did slightly worse, although fortunately their risk of majorhemorrhage was not markedly different in the WARSS study.The WASID trial looked at a group of patients that we had always been particu-larly concerned about, patients with intracranial stenosis, like basilar arterystenosis. We always worried that those patients would go on to have big brain-stem strokes. They took patients who had intracranial disease, randomized themto warfarin or to a high dose of aspirin. What happened was, though, that thestudy had to be stopped early, after only about 570 patients were enrolled,because of evidence of no benefit, and only an increase in risk of bleeding.There was no benefit for the warfarin-treated patients, they behaved almost thesame as the aspirin-treated patients in terms of risk of ischemic events, and infact there was an increase in risk of death and major hemorrhage for those treat-ed with warfarin. Unlike in the WARSS study, there was some increase in risk ofdeath.In a subsequent kind of post-hoc analysis of the data they were able to showthat for those who were kept on the target range for warfarin, the INR from 2 to3, they did have a decrease in the risk of hemorrhage and also a markeddecrease in the risk of ischemic events, suggesting that if we had the perfectanticoagulant, if you could keep people in that target window without any prob-lems, then you could say that you had a good agent. There may in the future bea role for the perfect anticoagulant like that, but at the present time we can’t rec-ommend warfarin for most patients with stroke, which leaves us using eitheraspirin, aspirin / dipyridamole, or clopidogrel [brand name Plavix] for strokepatients.Using two agents together was shown, in a trial called the European StrokeBasicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu20
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Prevention Study II, to be of benefit, so that patients who were on either extend-ed release dipyridamole or aspirin, both had a benefit compared with placebopatients. If you put patients on both of those together, there was almost an addi-tive effect of being on the two agents.Based on that additive benefit, people have suggested the use of combination ofaspirin and another antiplatelet agent clopidogrel together. In the cardiac litera-ture there’s evidence that combining those two drugs together does provide ben-efit; but in stroke patients, actually a study was called MATCH, which found thatthere was a slight trend towards a reduction in risk for patients who were on bothaspirin and clopidogrel, but this was completely offset by an increase in risk ofhemorrhage. There’s a 1% absolute benefit in terms of reducing ischemicevents, a 1% absolute increase in risk of hemorrhage. It’s the same story againthat we saw with the heparin—the antithrombotic therapy is going to reduce therisk of ischemia but increase the risk of hemorrhage—and so based on this data,we don’t recommend the addition of aspirin to clopidogrel for stroke patients.This is a very different situation again from the cardiac patients, where they’recommonly treated with both of those agents together. I think it’s important toremember that stroke is not just a heart attack of the brain—stroke patients areolder on average, they have an increased risk of not only intracerebral hemor-rhage, but also bleeding elsewhere in the body. The risk factors are different;there are many different causes of stroke, as I showed you before. And again,that trial didn’t show any benefit to using the same kind of antiplatelet approach-es we saw in cardiac patients. So we have to keep those things in mind in decid-ing on treatment.I will stop on that note. Thank you for your attention.Basicand Clinical Neurosciences28th Annual Postgraduate Review CourseDecember 3, 2005, through March 11, 2006 http://neuroscienceupdate.cumc.columbia.edu21
Desmoteplase study back
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Patient Recruitment to Resume Without Modification of Protocol for Desmoteplase Phase IIB/III Stroke Study DIAS-2
Friday October 27, 11:08 pm ET [!]
NEW YORK, Oct. 27 /PRNewswire-FirstCall/ -- Forest Laboratories, Inc. (NYSE: FRX - News) and its development partner for desmoteplase, PAION AG (Aachen, Germany), today announced that the independent Data Monitoring Committee (DMC) for the DIAS-2 Phase IIB/III study met and informed the Steering Committee and the Companies that it has reviewed the cumulative data from the study provided by the Companies and recommended the resumption of patient enrollment into DIAS-2 with no modification of the protocol. At this meeting, the DMC reviewed data from 170 randomized subjects. The DIAS-2 study is evaluating PAION's drug candidate desmoteplase in patients with acute ischemic stroke. The Companies continue to expect that enrolment will be completed by the end of 2006 and that study results will be available by the middle of 2007.
from the above press release it they were able to make the determination that the trial should be continued without breaking the blind.
Unlike the failure of Cerovive which would have added billions of dollars of increased healthcare costs if they would have reached statistical significance in a clinically meaningless benefit and failure of the drug was not a tragedy, the failure of desmoteplase which has the potential to increase the quality of life of millions of future stroke patients and end up reducing healthcare costs because rehabilitation from stoke adds billions of dollars to the cost of healthcare and early reperfusion can reduce the cost of rehabilitation, desmoteplase failure would have been a tragedy.
It is my belief that desmoteplase, if the trial is successful, will change the treatment paradigm for stroke.
All this for a market cap under 200 million dollars
They have reviewed that data for 170 randamized patients. The trial will probably be completely enrolled withing 2 weeks. I hope they add at least 18 to 24 patients. Nothing wrong with having a little more safety data, if possible skip the 90 ug dose and just add more patients to the 125 ug dose if they can do it without delaying the trial by getting feedback from the FDA.
dpp-4 point
point is between a rock and a hard place. They need to invest some more money to get the project into humans, and they need the cash to finish their 2 phase 3's for lung cancer.
cash is king
nuvo
the drug probably would work for stroke but it would have to be delivered with a catheter
I bought more Paion
I am convinced that my research on the drug, and the fact that there was no excessive bleeding during the trial, which I consider the main risk, leads me to believe that the safety signal, whatever that may be, will be able to be overcome by the strength of the reperfusion that takes place when the drug is used.
Just my opinion. I have done a lot of work in this area.
the reason I believe that the clinical hold was not caused by excessive bleeding was because the DMB and the company would have know about bleeding as an SAE prior to the planned DSMB meeting.
Does this up the chances for NTII and their stroke drug?
depending on what the issue is it may help ntii's drug.
right now we don't know what the problem is or how big it is. if the problem turns out to be an issue about a mechanism of action that is similar it would be a problem for ntii. if ntii's drug has a different mechanism of action it would benefit them because it would have one less competitor, if dspa is really gone
PAION AG: RECRUITMENT FOR PHASE III STROKE STUDY DIAS-2 ON
HOLD
I am long the stock and this does not look good. I have not seen anything in the mechanism of action that would cause a problem but we shall see. I won't sell for the time being but that could be a mistake
Aachen (Germany), 25 October 2006 - Biopharmaceutical company PAION
AG today announced that the Steering Committee of the Phase III study
DIAS-2 with PAION’s drug candidate Desmoteplase has decided in
agreement with Forest Laboratories, Inc. and PAION to set patient recruitment
temporarily on hold until further data have been analysed.
The Steering Committee followed a recommendation by the Data Monitoring
Committee (DMC). The DMC had requested additional safety relevant data in
order to facilitate the evaluation of a potential safety signal, which was not
specified further by the DMC. The DMC had notified in its statement that no
conclusion on safety or efficacy of Desmoteplase should be drawn from this
recommendation. The requested data have been processed and will be
provided to the DMC within the next day.
Contact
Dr. Peer Nils Schroeder, Investor Relations / Public Relations
PAION AG
Martinstrasse 10-12
52062 Aachen – Germany
Tel. +49 (0)241 4453 152
Email pn.schroeder@paion.de
www.paion.de
VIVUS, Inc. VVUS – $3.57
Buy Price Target: $9.00
VVUS: Positive Clinical Update For Qnexa At NAASO
THINK ACTION:
An update on Qnexa Phase II results at the North American Association for the Study of Obesity included both the previously presented weight loss results as well as an update on improvements in blood pressure, total cholesterol and triglycerides seen in patients on Qnexa compared to placebo or, in some cases, the individual treatment arms as well. The next steps are updates on toxicology studies, formulation, and a special protocol assessment by the FDA. We continue to believe VVUS shares are undervalued based on the potential of Qnexa alone with a free call-option on the broad, late-stage product pipeline.
KEY POINTS:
Qnexa induces weight loss and improves clinical/laboratory outcomes. In the first public scientific outing for Qnexa, Dr. Kishore Gadde (Director, Obesity Clinical Trials Program, Duke University Medical Center) presented and expanded upon previously seen positive Phase II results. In addition to the strong weight loss data seen previously (a placebo-adjusted weight change of -9.2 kg over 24 weeks for Qnexa), updates focused on important clinical parameters such as blood pressure, total cholesterol, and triglyceride levels, all of which showed clinical improvements. We note that these positive outcomes were achieved with an extremely low drop out rate and an excellent safety profile.
Improved blood pressure. Patients treated with Qnexa demonstrated a greater reduction in systolic blood pressure compared to patients treated with placebo, phentermine or topiramate. While results were not statist ically significant in a Phase II study, there was a strong and promising trend. We believe this outcome further reinforces the weight loss benefits seen with Qnexa translating into improvements in overall clinical and laboratory outcomes.
Reduced total cholesterol and triglycerides. Patients treated with Qnexa also showed a greater decrease in total cholesterol compared to the placebo arm, an outcome that was statistically significant. A similar outcome was observed for triglyceride levels, where patients treated with Qnexa had a statistically significant greater decrease compared to those in the placebo arm.
Qnexa is the value driver. We believe shares of VVUS are undervalued based on the potential of Qnexa alone, which we believe could easily be a blockbuster-plus product upon approval. We expect progress in the obesity program over the next few months, starting with the updates on the toxicology studies, finalizing a formulation, obtainin g a special protocol assessment (SPA) from the FDA, and the initiation of the Phase III trial, potentially by mid-2007, to close the valuation gap between current share price and our price target.
Pipeline includes several assets. While Qnexa has taken center stage, we believe Vivus' proprietary pipeline of products targeted at sexual disorders also represents potentially monetizable assets. Of these, the most advanced are EvaMist, a differentiated estrogen that could be approved by YE07, and Testosterone MDTS for female hypoactive sexual desire disorder, an SPA which could be approved by early 2007.
Reason for Report:
Company Update
Adnan Butt
212-468-7097, adnanb@thinkequity.com
Click Here For Complete PDF Version
Changes Current Previous
Rating Buy --
Price Target $9.00 --
FY06E REV(mil) $14.8E --
FY07E REV(mil) $15.1E --
FY06E EPS ($0.64)E --
FY07E EPS ($1.20)E --
52 Week High: $5.60
52 Week Low: $2.78
Shr.O/S-Diluted (mil): 49.5
Mkt Cap (mil): $176.7
Avg Daily Vol: 196,031
Short Interest: 2.1%
Debt/Total Cap.: NA
Net Cash per Share: $0.50
P/E (12-mo. Fwd): NA
Est. LT EPS Growth: 40.0%
P/E/G: NM
Fiscal Year End: Dec
REV(mil) 2005A 2006E 2007E
Mar $0.6A $1.3A $1.2E
Jun $1.7A $3.6A $3.3E
Sep $3.3A $3.4E $3.6E
Dec $9.0A $6.8E $7.0E
FY $14.7A $14.8E $15.1E
CY $14.7A $14.8E $15.1E
FY P/S 12.0x 11.9x 11.7x
CY P/S 12.0x 11.9x 11.7x
EPS 2005A 2006E 2007E
Mar ($0.22)A ($0.20)A ($0.16)E
Jun ($0.19)A ($0.13)A ($0.31)E
Sep ($0.13)A ($0.15)E ($0.38)E
Dec ($0.02)A ($0.17)E ($0.33)E
FY ($0.56)A ($0.64)E ($1.20)E
CY ($0.56)A ($0.64)E ($1.20)E
FY P/E NM NM NM
CY P/E NM NM NM
.
Reiterate Buy Rating And $9 Price Target
precious
I am a person that doesn't take drugs unless absolutely neccessary. It is my belief that statins probably save more lives than are harmed by the drug which makes it risk vs benefit positive, unless you know of something with less side effects that does the same thing.
You have mentioned that statins deplete co enzyme 10. Is you answer that statins should be perscribed with co enzyme 10?
ConjuChem Biotechnologies Inc./
Friday October 20, 10:05 am ET
some idiot put out the wrong headline
In c2386 sent today at 07:00e please note that the headline has been revised. Full corrected copy follows.
New Study of PC-DAC(TM): Exendin-4 for Type 2 Diabetes Confirms Excellent Tolerability, Efficacy, and Extended Duration of Activity
- One Month Study in Sixty Type 2 Diabetes Patients -
MONTREAL, Oct. 20 /CNW/ - ConjuChem Biotechnologies Inc. (TSX:CJB - News) today announced results from a three-week inpatient study of PC-DAC(TM):Exendin-4 in Type 2 diabetic patients. Previously announced results from its Phase I/II single-dose clinical trial reported in September demonstrated an excellent tolerability profile, positive efficacy on glucose reduction, and extended duration of activity. ConjuChem subsequently conducted a randomized, double-blind, single-dose 3-week inpatient trial that further evaluated the pharmacokinetic and pharmacodynamic profile of the product in a controlled setting. Safety and tolerability were assessed in sixteen patients (12 active/4 placebo) at a dose of 3 mg. All patients discontinued their oral antidiabetic medications one week prior to the start of the study.
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Study Results
Safety/Tolerability:
--------------------
Safety and tolerability were excellent; no vomiting and no injection site reactions were observed. There were two cases of transient nausea presumed to be associated with the rapid decrease in glucose on day 1 that resolved with food intake; there were no cases of hypoglycemia. Low titer antibodies directed towards the peptide portion of drug were detected in 1 of 12 subjects.
Pharmacokinetic Profile:
------------------------
The pharmacokinetic profile exhibited slow absorption and prolonged exposure with plasma drug levels peaking at around 7 days and then declining thereafter with a half-life of approximately one week.
Pharmacodynamic Parameters:
---------------------------
Glucose was measured 6 times per day (fasting, 2-hour post-breakfast, pre-lunch, 2-hour post-lunch, pre-dinner and 2-hour post-dinner). The reduction in mean daily glucose from baseline for the treated group was 13% at the end of the first week, 10% at the end of the second week and 9% at the end of the third week versus a reduction of 2%, 3% and 0%, respectively, for the placebo group.
Most notably, a progressive reduction in weight was noted in the treated group over the 3-week inpatient period as recorded by daily weight measures. After a single injection, average body weight reduction in patients in the treated group reached a maximum of 5.5 lb versus 2.6 lb in the placebo group, before returning toward baseline and placebo levels at week 6.
Next Steps
ConjuChem is currently conducting a randomized, double-blind, multiple-dose Phase I/II study to evaluate the safety and tolerability of PC-DAC(TM):Exendin-4 in Type 2 diabetic patients. Pharmacokinetic and pharmacodynamic parameters will also be evaluated. The trial will enroll up to 60 patients with 15 patients randomized to one of four parallel treatment groups: 1mg, 2mg, 3mg, or placebo. Preliminary study results are expected in the first quarter of 2007.
About PC-DAC(TM):Exendin-4
Exendin-4 is a Glucagon-like peptide-1 (GLP-1) homolog and an agonist for the GLP-1 receptor. Exendin-4 decreases glucagon and increases insulin secretion in a glucose-dependent manner. Exendin-4 may stimulate beta-cell proliferation, restore beta-cell sensitivity to glucose, delay gastric emptying, and increase peripheral sensitivity to glucose. The clinical utility of Exendin-4 is somewhat limited by its relatively short half-life in plasma. Developed with ConjuChem's proprietary PC-DAC(TM) technology, PC-DAC(TM):Exendin-4 is a modified Exendin-4 analogue that is covalently bound to recombinant human albumin (Recombumin(R), provided by Delta Biotechnology Limited). The preformed albumin-peptide conjugate has a much longer half-life than the peptide alone.
About ConjuChem
ConjuChem, developer of next generation medicines from therapeutic peptides, is creating long-acting compounds based on bioconjugation platform technologies. When applied to peptides, the Company's systemic DAC(TM) and PC-DAC(TM) Technologies enable the creation of new drugs with significantly enhanced therapeutic properties as compared to the original peptide.
Detailed descriptions of the Company can be viewed on the Company's website www.conjuchem.com.
Forward-Looking Statements
Some of the statements made herein may constitute forward-looking statements. These statements relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause ConjuChem's actual results, performance or achievements to be materially different from those expressed or implied by any of the Company's statements. Actual events or results may differ materially. We disclaim any intention, and assume no obligation, to update these forward-looking statements.
For further information
Lennie Ryer, CA, Vice President Finance, CFO, ConjuChem Biotechnologies Inc., (514) 844-5558, ext 224, ryer@conjuchem.com
Michael Polonsky, Investor Relations, (416) 815-0700, ext. 231, (416) 815-0080, mpolonsky@equicomgroup.com
--------------------------------------------------------------------------------
Source: Conjuchem Biotechnologies Inc.
SOS, took the time to summarize TRCA's brief for all of us; INSM Lawyaers still need to post their defense. Pretty serious! Especially the part on PERMANENT INJUNCTION!
================================================================================
Interesting Points from TRCA...
Trial Brief, I can't wait to see INSM's. Those of you who are invested in either company who don't read these things are idiots:
*It talks about the advantages of Iplex (IGF/IGFBP-3) compound, longer half-life, lower risk of hypoglycemia (noting that hypoglycemic effects of naked IGF can be severe enough to cause death) (Brief, pages 1 and 2).
can insmed put tercica's court briefs in their marketing materials. the other point is that they spent 100's of millions of dollars making igf-1 but never figured out a way to attach the bp3 so that the drug would be worth something.
ENCY – The warfarin interaction remains an issue, IMO. From your SI post:
>>
The AUC0-inf of S-warfarin (25 mg) increased with sitaxentan administration with 95%, for 100 mg once daily doses of sitaxentan (study FNL02). Also the terminal half-life of warfarin increased after sitaxentan co-administration.
<<
he is correct but it is manageable. they reduce the dose of warfarin to manage the interaction. The fda should be more concerned with the higher lft's of tracleer and the fact that people can stay on the drug for a longer period of time
Cambridge Heart, Inc. (CAMH) – Outperform -- $152MM Mkt. Cap – (Jason Wittes)
I am not currently in the stock but thought you would be intereste
$B!|(B On Friday, after the close, CAMH announced the resignation of David Chazanovitz, former President, CEO, and member of the Board of Directors. Mr. Chazanovitz served as President and CEO for six years at CAMH and was the public face of CAMH.
$B!|(B As a permanent replacement, the Board of Directors has appointed Jeffrey Langan as the new President and CEO of the company, effective October 13, 2006. Mr. Langan has been a member of the Board of Directors since 1999 and is extremely familiar with the company. Mr.Langan is also an experienced executive, with extensive sales experience, previously holding CEO positions at Thermedics Detection and IDEXX—both of which were turnaround stories under his direction.
$B!|(B While we believe Mr. Chazanovitz has done a tremendous job putting the pieces in place for wide-scale adoption of CAMH HearTwave Microvolt T-Wave Alternans (MTWA) System , the challenges for the company have shifted toward building out the sales force to increase penetration and device utilization—an area where Mr. Langan's experience should prove invaluable.
$B!|(B We have had a chance to speak with both Mr. Chazanovitz and Mr. Langan. Based on our conversations, differences in philosophy between Mr. Chazanovitz and the board led to this change. Mr. Langan is meant as a permanent replacement; however, Mr. Chazanovitz will stay on as a consultant.
$B!|(B This change is not a reflection on quarterly performance—we still see upside to our current 3Q06 revenue estimate of $1.17 million. This also should not impact several near-term milestones including reimbursement decisions, and major trial results including the ABCD trial (to be presented at AHA) and MASTERS trial (at ACC). The company will not be holding a conference call, but will present 3Q results on November 2, 2006.
$B!|(B Reiterate Outperform:We would be buyers on weakness, especially since, in our view, Mr. Langan's experience is so well suited for insuring market penetration. Our valuation on CAMH is $4.25.
conjuchem
that is probably why the stock is so cheap
can they get data or a partner before that happens?
Mole rat lifespan article.
that was a great article. all the data pointing to the effect of oxidative stress would point to a short life. Yet the animal live about 7 times longer than its cousin.
that is interesting
If Insmed has the lead in the EU there is no way that siezurlex
will break iplex'x orphan status
amlyn lead on conjuchem
about a year and a half
amlyn
Study Demonstrated Once-Weekly Exenatide LAR Improved Glucose Control in Patients with Type 2 Diabetes
WASHINGTON, D.C., June 10 /PRNewswire-FirstCall/ -- Amylin Pharmaceuticals, Inc. (Nasdaq: AMLN), Eli Lilly and Company (NYSE: LLY) and Alkermes, Inc. (Nasdaq: ALKS) today announced detailed results from a safety and efficacy study of the long-acting release (LAR) formulation of BYETTA(R) (exenatide) injection. Data from the study demonstrated that 86 percent of patients using the higher of two doses of the once-weekly formulation of exenatide were able to achieve recommended levels of glucose control, as measured by hemoglobin A1C (A1C) with an average improvement of approximately 2 percent compared to placebo. These study findings were presented today at the 66th Annual Scientific Sessions of the American Diabetes Association (ADA) in Washington, D.C.
The study was conducted in 45 patients with type 2 diabetes unable to achieve adequate glucose control with metformin or a diet and exercise regimen. The patients received a once-weekly subcutaneous injection of exenatide LAR (either 0.8 mg or 2.0 mg) or placebo. After 15 weeks of treatment there was a 12-week safety monitoring period during which no study medication was administered.
Dose-dependent improvements in A1C and weight loss were observed at 15 weeks. At the beginning of the study, the average A1C of study participants was approximately 8.5 percent. In subjects receiving the 2.0 mg dose of exenatide LAR, the average reduction in A1C was 1.7 percent compared to an increase of 0.4 percent in the placebo group. Those receiving the 0.8 mg dose improved with an average decrease in A1C of 1.4 percent.
In patients administered 0.8 mg or 2.0 mg of exenatide LAR, 33 percent and 86 percent achieved A1C levels of 7 percent or less, respectively. None of the patients given placebo achieved this target level of glucose control. A1C is a reflection of a person's average glucose level over approximately three months and often used by doctors as a measure of glucose management.
Fasting blood glucose levels were reduced by an average of 39 mg/dL in the 2.0 mg arm and 43 mg/dL in the 0.8 mg arm compared to an average increase of 18 mg/dL in the placebo group at week 15. Average fasting blood glucose level at the beginning of the study was 179 mg/dL. Patients who received 2.0 mg of exenatide LAR also experienced average reductions in body weight of 8.4 pounds at week 15 with no evidence of plateau at this point in time; body weight remained essentially unchanged for the 0.8 mg and placebo groups. The most frequent adverse event was mild nausea, experienced by 27 percent of subjects in the 2.0 mg dose group and 19 percent of subjects in the 0.8 mg dose group compared to 15 percent in the placebo group. No severe hypoglycemia was observed, and no subjects receiving either dose of exenatide LAR withdrew because of adverse events. These detailed findings supplement the preliminary results released in 2005.
"In this study, the long-acting formulation of exenatide improved glycemic and weight control and was well tolerated as a combination therapy with metformin or as stand alone therapy with diet and exercise," said Dennis Kim, MD, Senior Director, Medical Affairs, Amylin Pharmaceuticals and an author of the study. "These early results suggest exenatide LAR can be clinically beneficial to patients with type 2 diabetes."
Exenatide LAR uses the proprietary Medisorb(R) drug-delivery technology developed by Alkermes. The technology encapsulates active medication into polymer-based microspheres that are injected into the body, where they degrade slowly -- gradually releasing the drug at a carefully controlled rate.
On April 28, 2005, the Food and Drug Administration (FDA) approved twice daily exenatide under the trade name BYETTA for use by people with type 2 diabetes who are unsuccessful at controlling their blood sugar levels despite using commonly prescribed oral medications metformin, a sulfonylurea or both. Amylin, Lilly and Alkermes are working together to develop a sustained release, subcutaneous injection of exenatide for the treatment of type 2 diabetes based on Alkermes' proprietary Medisorb(R) injectable long-acting release drug delivery technology. Exenatide LAR has not been approved by the FDA for marketing in the United States.
About BYETTA
BYETTA is the first incretin mimetic, a class of drugs for the treatment of type 2 diabetes. BYETTA exhibits many of the same effects as the human incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1, secreted in response to food intake, has multiple effects on the intestine, liver, pancreas and brain that work in concert to regulate blood sugar.(1)
Safety and Tolerability of BYETTA
Adverse events associated with BYETTA are generally mild to moderate in intensity. In clinical trials, the most frequently reported adverse event was mild-to-moderate, dose-dependent nausea. With continued therapy, the frequency and severity of nausea decreased over time in most patients.
Patients receiving BYETTA in combination with a sulfonylurea may be at a higher risk of hypoglycemia or low blood sugar. To reduce this risk, decreasing the dose of sulfonylurea may be considered. When patients begin taking BYETTA, the symptoms, treatment and conditions that predispose development of hypoglycemia should be explained to them, and the patient's usual instructions for hypoglycemia management should be reviewed and reinforced.
Patients should also be advised that treatment with BYETTA may lead to a reduction in appetite, food intake and/or body weight, and that there is no need to modify the dosing regimen due to such effects.
BYETTA is not a substitute for insulin in insulin-requiring patients. BYETTA should not be used in patients with type 1 diabetes. Use of BYETTA is not recommended in patients with end-stage renal disease or severe renal impairment, or in patients with severe gastrointestinal disease. BYETTA should be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption.
For complete safety profile and other important prescribing considerations, visit www.BYETTA.com.
About Incretin Mimetics
Incretin mimetics is a distinct class of treatment in the fight against diabetes. An incretin mimetic works to mimic the anti-diabetic or glucose- lowering actions of naturally occurring human hormones called incretins. These actions include stimulating the body's ability to produce insulin in response to elevated levels of blood sugar, inhibiting the release of a hormone called glucagon following meals, slowing the rate at which nutrients are absorbed into the bloodstream and reducing food intake. BYETTA is the first FDA- approved incretin mimetic.
About Diabetes
Diabetes affects an estimated 194 million adults worldwide(2) and more than 20 million in the United States.(3) Approximately 90 to 95 percent of those affected have type 2 diabetes, a condition characterized by failure of the pancreatic beta cells to adequately respond to the increased demands for insulin that occur as a result of obesity-related insulin resistance.(4) Diabetes is the sixth leading cause of death by disease in the United States(3) and costs approximately $132 billion per year in direct and indirect medical expenses. Type 2 diabetes usually occurs in adults over the age of 40, but is increasingly common in younger people.(3)
According to the Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey, approximately 60 percent of diabetes patients do not achieve target hemoglobin A1C levels (less than 7 percent according to ADA guidelines(5)) with their current treatment regimen.(6)
About Amylin, Lilly, and Alkermes
Amylin Pharmaceuticals is a biopharmaceutical company committed to improving lives through the discovery, development and commercialization of innovative medicines. Amylin has developed and gained approval for two first- in-class medicines for diabetes, SYMLIN(R) (pramlintide acetate) injection and BYETTA(R) (exenatide) injection. Amylin is located in San Diego, California with over 1200 employees nationwide. Further information on Amylin Pharmaceuticals, its marketed products, and its pipeline in metabolism is available at www.amylin.com.
Through a long-standing commitment to diabetes care, Lilly provides patients with breakthrough treatments that enable them to live longer, healthier and fuller lives. Since 1923, Lilly has been the industry leader in pioneering therapies to help health care professionals improve the lives of people with diabetes, and research continues on innovative medicines to address the unmet needs of patients. For more information about Lilly's current diabetes products visit http://www.lillydiabetes.com.
Conjuchem
Final Results of PC-DAC(TM):Exendin-4 Phase I/II Trial for Type 2 Diabetes Confirm Excellent Tolerability, Positive Efficacy, and Extended Duration of Activity
Tuesday September 12, 7:00 am ET
<< - New Three-Week Study Also Announced - >>
MONTREAL, Sept. 12 /CNW/ - ConjuChem Biotechnologies Inc. (TSX:CJB - News) today announced that final data from its Phase I/II single escalating dose clinical study for the treatment of Type 2 diabetes using the Company's proprietary PC-DAC(TM):Exendin-4 compound confirmed the excellent tolerability profile, positive efficacy on glucose reduction and extended duration of activity reported as preliminary data on April 26th, 2006.
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Phase I/II Trial Design
The Phase I/II trial, a randomized, double-blind, single escalating dose study, evaluated safety and tolerability of PC-DAC(TM):Exendin-4 as monotherapy in patients with stable Type 2 diabetes who had discontinued their oral anti-diabetic medications starting one week before the commencement of the trial. As secondary endpoints, pharmacokinetic and pharmacodynamic parameters were evaluated.
Six cohorts were dosed subcutaneously at 310, 620, 1250, 2500, 3750 and 5000 micrograms of PC-DAC(TM):Exendin-4. The product is a highly soluble liquid formulation that is injectable in a small volume with a small gauge needle. Each cohort consisted of 7 patients (6 active, 1 placebo). The mean glucose values at baseline of the cohorts (without placebo) were 15.6, 12.2, 12.1, 11.2, 9.6 and 16.2 mmol/L, respectively.
Phase I/II Results
Safety/Tolerability:
--------------------
There were no safety or tolerability issues reported in the first four cohorts (310, 620, 1250 and 2500 microgram doses); specifically, no nausea, no vomiting and no injection site reactions. In each of the 3750 and 5000 microgram cohorts, there was one case of vomiting observed post-lunch on day one; no anti-emetic medications were needed for either of these cases nor were any anti-emetics needed throughout the trial. Low titer antibodies directed towards the peptide portion of drug were detected in 3 of 36 subjects.
Pharmacokinetic Profile:
------------------------
The pharmacokinetic profile exhibited slow absorption and prolonged exposure with plasma drug levels peaking at around 7 days and then declining thereafter with a half-life of approximately one week. Plasma concentrations were dose linear for both Cmax (maximum drug concentration) and AUC (area under the curve).
Pharmacodynamic Parameters:
---------------------------
Glucose was measured 6 times per day (fasting, 2-hour post-breakfast, pre-lunch, 2-hour post-lunch, pre-dinner and bedtime) during the first week and 3 times per day (fasting, 2-hour post-breakfast and bedtime) for the remaining 5 weeks of the study. In addition, a placebo group was constructed for data analysis by pooling the patients (one per cohort) that received placebo during the study.
Placebo and doses of 310 micrograms and 620 micrograms of PC-DAC(TM):Exendin-4 did not produce consistent reductions in mean daily or fasting glucose levels. Doses of 1250, 2500, 3750, and 5000 micrograms of PC-DAC(TM):Exendin-4 demonstrated rapid reductions in mean daily glucose values that were sustained for at least 1 to 2 weeks after dosing. Reductions in mean daily glucose at the end of the first week (average of days 1-6) ranged from -11.8% to -24.2%. The greatest reductions in daily glucose levels were observed in the cohort with the highest mean baseline glucose value, consistent with the expectation that the glucose-lowering effect of PC-DAC(TM):Exendin-4 is glucose-dependent, and that the magnitude of the decrease in glucose will therefore be related to baseline glucose levels. Treatment with doses of 1250, 2500, 3750, and 5000 micrograms also produced decreases in fasting blood glucose and reduced post-prandial glycemic excursions. A trend towards greater reduction in body weight was noted at the end of the first week in the four active cohorts.
Commenting on these final results, Thomas Ulich, M.D., ConjuChem's Executive Vice President of Research and Development, stated: "These promising results suggest that long-term once-weekly administration of PC-DAC(TM):Exendin-4 at doses of 1250 micrograms or greater can be therapeutically useful for control of fasting and post-prandial glycemia in patients with type 2 diabetes. Most notably, neither nausea nor vomiting (the major side effects of incretins) were observed in either of the pharmacodynamically effective 1250 or 2500 micrograms cohorts of PC-DAC(TM):Exendin-4."
New Three-Week Inpatient Study Announced
As a result of the long half-life of the drug and the longer than expected duration of glucose reduction, ConjuChem has conducted a randomized, double-blind, single dose 3-week inpatient trial that further evaluated the pharmacokinetic and pharmacodynamic profile of the product in a controlled setting. Safety and tolerability were assessed in sixteen patients (12 active/4 placebo) at a dose of 3000 micrograms. Data from the study will be reported in the fourth quarter.
Next Steps
ConjuChem will be conducting a multi-dose Phase I/II trial in which the product will be administered once-a-week at three different dosages for one month. The study is expected to commence in the fourth quarter.
About PC-DAC(TM):Exendin-4
Exendin-4 is a Glucagon-like peptide-1 (GLP-1) homolog and an agonist for the GLP-1 receptor. Exendin-4 decreases glucagon and increases insulin secretion in a glucose-dependent manner. Exendin-4 may stimulate B-cell proliferation, restore B-cell sensitivity to glucose, delay gastric emptying, and increase peripheral sensitivity to glucose. The clinical utility of Exendin-4 is somewhat limited by its relatively short half-life in plasma. Developed with ConjuChem's proprietary PC-DAC(TM) technology, PC-DAC(TM):Exendin-4 is a modified Exendin-4 analogue that is covalently bound to recombinant human albumin (Recombumin(R), provided by Delta Biotechnology Limited). The preformed albumin-peptide conjugate has a much longer half-life than the peptide alone.
About ConjuChem
Ambrilia Biopharma and Merck & Co., Inc. Sign Licensing Agreement Granting Merck Worldwide Rights to Ambrilia's HIV/AIDS Protease Inhibitor Program
Thursday October 12, 7:45 am ET
Ambrilia to receive an upfront payment of $US 17 million and potential milestones of up to $US 215 million.
MONTREAL, CANADA and WHITEHOUSE STATION, NEW JERSEY--(MARKET WIRE)--Oct 12, 2006 -- Ambrilia Biopharma Inc. (TSX:AMB.TO - News), a biopharmaceutical company developing innovative therapeutics in the fields of cancer and infectious diseases, and Merck & Co., Inc., one of the world's leading pharmaceutical companies, announced today that Ambrilia has entered into an exclusive licensing agreement granting Merck - through an affiliate - the worldwide rights to Ambrilia's HIV/AIDS protease inhibitor (PI) program.
Under the terms of this agreement, Ambrilia grants Merck the exclusive worldwide rights to its lead compound, PPL-100, which has completed a Phase I single-dose pharmacokinetic study and is currently in a Phase I repeat dose pharmacokinetic study. In return Ambrilia receives an upfront licensing fee of $US 17 million on signing and is eligible for cash payments totaling up to $US 215 million upon successful completion of development, clinical, regulatory and sales milestones, and royalties on all future product sales. The first of the milestone payments ($US 3 million) will be based on the successful completion of a Phase I repeat dose pharmacokinetic study, the results of which are expected in late November. Once the Phase I repeat dose pharmacokinetic study is completed, Merck will assume all subsequent development costs related to PPL-100.
Ambrilia also stands to receive significant additional milestone-based cash payments and royalties on the future development and commercialization of each back-up compound and/or related compounds developed by Merck and which fall within the scope of the Ambrilia PI program.
"We are very pleased to partner on PPL-100 with Merck, a company that has been a leader in anti-HIV drug development, and are confident that Merck will successfully advance the development of PPL-100," said Hans J. Mader, President and Chief Executive Officer of Ambrilia. "This agreement is a significant milestone for Ambrilia; an influx of potentially over $CDN 22 million in 2006 allows the Company to be much stronger financially and provides us with the opportunity to allocate the necessary resources to further progress the development of our other technologies and product candidates."
"Merck has been a world leader in the fight against HIV/AIDS for two decades, and this agreement is a further demonstration of our continuing commitment to this field of medicine," said Merv Turner, Ph.D., Senior Vice President, Worldwide Licensing and External Research. "PPL-100 and Ambrilia's Protease Inhibitor Program represent a potentially significant advancement for patients and physicians in the treatment of HIV/AIDS."
CONFERENCE CALL INFORMATION
Ambrilia will be hosting a conference call on October 12, 2006 at 9:30 a.m. ET, to discuss its licensing agreement with Merck & Co., Inc. Interested parties may access the conference call by way of telephone or webcast. The numbers to access the conference call are 1(866) 250-4910 (toll free) or 1(416) 644-3423 (local). The webcast will be available at: www.ambrilia.com, Investors section, conference calls and webcasts, and will be archived for 365 days. A replay of the call will be available and the numbers to access the replay are 1(416) 640-1917 (local) or 1(877) 289-8525 (toll free) with access code 21206250. The replay will be available starting at 11:30 a.m., October 12, until 11:59 p.m., October 19.
ABOUT PROTEASE INHIBITORS
Protease Inhibitors (PIs) are a key component to the current HIV standard of care, the Highly Active Anti-Retroviral Treatment (HAART) consisting of a cocktail of HIV medicines. Unfortunately, many PIs are associated with side effects, a high pill burden and, as it is the case with all anti-HIV drugs, the development of viral resistance. In addition, the majority of PIs are administered in combination with a small dose of ritonavir, another protease inhibitor that is often used to increase, or boost, the amount of available drug in the system, but which also has the potential to increase adverse events. More than ever, there is a pressing need for better tolerated, more convenient and effective PIs.
ABOUT AMBRILIA BIOPHARMA
Ambrilia Biopharma Inc. (TSX:AMB.TO - News) is a biopharmaceutical company developing innovative and proprietary early- to mid-stage therapeutics in the fields of oncology and infectious diseases. Ambrilia's product portfolio includes an anti-cancer therapeutic peptide (PCK3145), a novel anti-cancer therapy (TVT-Dox), two oncology specialty generics (Octreotide, Goserelin), the first of which is late-stage and value-added, and promising anti-HIV treatments (PPL-100, Anti-HIV Peptides, Integrase Inhibitor Program). Ambrilia's head office, research and development and manufacturing facilities are located in Montreal with a regional office in France. For more information, please visit the Company's web site: www.ambrilia.com
Ambrilia Forward-looking statement
This press release contains forward-looking statements that reflect the Company's current expectation regarding future events. The forward-looking statements involve risks and uncertainties. Actual events could differ materially from those projected herein and depend on a number of factors including, but not limited to, changing market conditions, successful and timely completion of clinical studies, uncertainties related to the regulatory approval process, establishment of corporate alliances and other risks detailed from time to time in the Company's filings. Such statements are also based on various assumptions, including the successful and timely completion of clinical studies on Ambrilia's products demonstrating efficacy and safety for human use, their successful commercialization within the forecasted timelines and the attainment of the forecasted milestone payments and other revenues. While Ambrilia anticipates that subsequent events and developments may cause Ambrilia's views to change, Ambrilia specifically disclaims any obligation to update these forward-looking statements.
ABOUT MERCK & CO., INC
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit: www.merck.com
Merck Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.
Contact:
Contacts:
Ambrilia Biopharma Inc.
Julie M. Thibodeau, Director, Communications
514-751-2003 ext 235
jthibodeau@ambrilia.com
ir@ambrilia.com
http://www.ambrilia.com
Merck & Co., Inc.
Media: Janet Skidmore
Director, Media Relations
267-305-7715
janet_skidmore@merck.com
Merck & Co., Inc.
Investors: Graeme Bell
Senior Director, Investor Relations
908-423-5185
graeme_bell@merck.com
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conjuchem is that randy or blade
it has really gotten cheap. Their long acting seemed to do very will.
Most of the value people are putting on Amlyn is not because of the current byetta 2 times a day dosing but because of the assumption that the LAR will get approved
I don't think that conjuchem is that far behind. I also think the human version of glp-1 that conjuchem is using would be superior to the Gila monster version that Amlyn is using
david says it doesn't work but the data seems to say it works at least as well as provenge, made by his favorite stock dendreon. the people in the brain cancer trial seem to be lasting a lot longer than they would be if the drug didn't work.
it is down today because they raised money a while ago from pipe investors and the stock became effective today.
That is the reason it came down.
it is funny how he made that comment about this company. when the stocks he likes go down it isn't because the drug doesn't work, it is because of manipulation.
I normally don't take issue with him because I think he is an asset to the board but his comment today added nothing and made me mad
accounting is a wonderful thing
Mike King:
DNA – Market Outperform: Note out post call: Takeaways =
1) Colorectal (Avastin) not ramping as well as expected
2) TnF Refractory oppty is smaller than some had thought
3) Quality of earnings light but top line growth should rebound (according to Mike) in Q4
4) PDUFA today for Avastin in NSCLC should help the stock (80% chance of approval)
5) Modifying #s going forward but nothing dramatic….
Partner Impact:
Avastin light = PDLI (Negative)
Rituxan very light = BIIB (Negative)
Tarceva light = OSIP (Negative)
Herceptin very light = PDLI
Xolair barely light = TNOX/NVS/PDLI (Flat)
Raptiva just missed = XOMA/PDLI (Flat)
Lucentis crushed it = XOMA/NVS (positive)
Pipeline – CRIS’s Hedgehog Inhibitor also mentioned
Every quarter Genentech beat expectations. without lucentis this quarter would have been a disaster. It is great to be able, to let us say, adjust internally some prior exuberance, if it can be offset by a new product
Sleeping pill that doesn't leave you feeling groggy
By ROGER DOBSON
I own Evotec. They have a services business which is profitable and they have a couple of drugs in the CNS space that they in-licences from Roche. Their head of R and D used to be the head of Roche's CNS R and D department so I think he knew which drugs to take with him
Last updated at 11:02am on 10th October 2006
http://www.dailymail.co.uk/pages/live/articles/health/healthmain.html?in_article_id=409568&in_pa....
In tests people who took EVT 201 felt no bad effects in the morning
People who suffer insomnia could soon be helped with a drug that gets them to sleep - and keeps them that way for up to eight hours.
In a study conducted by Surrey University, people who took the drug EVT 201 were able to get to sleep despite having a box under their beds playing 52 decibels of recorded traffic noise all night.
Those on the drug went to sleep more quickly, stayed asleep longer and woke up less frequently. They felt no bad effects the next morning. In many cases, those who had the drug felt even better.
In pre-clinical studies, the drug showed no tolerance or dependence problems, and no interaction with alcohol.
It is estimated that around half of the adult population have symptoms of insomnia on a regular basis. The causes range from stress or anxiety to too much coffee or alcohol before bed.
It is possible to treat insomnia without resorting to medication. Psychotherapy and relaxation techniques can help, for instance. Some people, however, need sleeping pills.
But while these drugs can relieve the symptoms, they do not tackle the underlying problems, such as grief or stress, and they can have a number of side-effects.
One of the main problems is that users can become tolerant to their effects, resulting in a dependence on the drug which can lead to anxiety and panic attacks. They can also change the pattern of sleep and cause a significant hangover effect the following morning.
EVT 201 works differently from the other drugs on the market. It acts on the GABA receptors in the brain, which are involved in the regulation of alertness and relaxation. We become more relaxed - 'sedated' - as the GABA receptors responses are boosted.
But it is important not to over-stimulate these, because that can affect quality of sleep and result in a hangover effect.
The drug's unique way of working means it only partially boosts the chemical, triggering the release of just enough to get the insomniac to sleep and to keep them that way.
By not boosting the chemical too much, it does not cause meaningful side-effects.
"There is nothing with this mechanism of action on the market or at this stage of development," says Anne Hennecke, spokesman for the manufacturer, Evotec.
The drug is undergoing extensive trials in patients with primary insomnia at a number of centres in America. If all goes well, it is hoped it could be available within four years.
But Professor Jim Horne, director of sleep research at Loughborough University, is sceptical about the new drug.
"I'm afraid the perfect sleeping drug - one that works immediately, allows you to wake the next day feeling invigorated and refreshed, has no side-effects and that you can take night after night without becoming dependent on it - simply does not exist," he says.
"Various claims are made, but all new drugs tend to have some sort of side-effect. The best sleeping tablet is the one you put by the bedside so it is there if you need it - but, with a bit of luck, just sits there gathering dust. But drug companies are not really in favour of that idea."
Meanwhile, a number of other drugs are in development, including two which are designed to trigger a greater release of the sleep-inducing hormone melatonin.
Although the number of drugs is increasing, in most cases they tackle the symptoms rather than the cause - and a solution that addresses the underlying problem is the preferred option for most.
For many insomniacs, cognitive behavioural therapy is proving successful.
MY0G buyout.
and gilead doesn't have rights in Europe. already licensed out
gd2aussie you are added
Randy
why not mention ymi possible Nimo vs. Erbitux head to head trial
dvax NEJM
actually it is worse than I thought. companies can't put out data from the articles until wednesday night but people are mailed their copies as early as tuesday.
so everyone in the financing knew about the article. the company also knew about the article and underpriced the deal.
dvax
it certainly was nice of them to price a deal earlier this week before the data so the funds could make a 50 percent profit
cytk
the trial was so early I don't think it was anyone's radar as a competitor in head and neck cancer.
the reason to be in the stock is for the heart failure program
INNOVIVE Pharmaceuticals Discontinues Development of INNO-105
Friday September 29, 7:45 pm ET
I met the management of this company about 6 months ago. They had 3 drugs in development and they were looking to raise money. They were raising money at about a 20 million dollar valuation. I asked them how much did the company pay to get the 3 drugs and it basically came to about 1.5 million. This is the typical Lindsey Rosenwald business plan. Pay under 2 million dollars for some drugs with little or no human data hire some executives, and within 3 to six months raise about 6 to 10 million dollars for 50 percent of the company. In the meantime he gets his money out and still owns 40 percent of the company. I thought the same thing would happen when I met with Hana but those drugs may be a little better than his typical startup. Great business plan for him. I just wonder how he keeps getting funds to invest in these things to take him out. they were telling me that this drug was going to be the greatest thing since sliced bread
NEW YORK--(BUSINESS WIRE)--INNOVIVE Pharmaceuticals, Inc. today announced that, based on results of a Phase 1 clinical trial, it will discontinue development of INNO-105.
"After careful review of trial results, we have decided to concentrate our resources on the rest of our oncology pipeline and to seek more promising compounds," said Steven Kelly, President and Chief Executive Officer, INNOVIVE.
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Trial results showed that INNO-105 appears unlikely to achieve desired plasma levels without demonstrating adverse side effects. The compound is a naturally occurring peptide that inhibits cell growth and division by interacting with OGFr, a unique receptor found on the nuclear membrane of a wide range of malignant cells.
About INNOVIVE Pharmaceuticals
INNOVIVE Pharmaceuticals, Inc. is a public biopharmaceutical company headquartered in New York, N.Y. The company's mission is to acquire, develop and commercialize novel therapeutics addressing significant unmet medical needs in the fields of oncology and hematology. For additional information visit www.innovivepharma.com.
This press release contains forward-looking statements that involve risks and uncertainties that could cause INNOVIVE's actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are based on current expectations, forecasts and assumptions that are subject to risks and uncertainties which could cause actual outcomes and results to differ materially from these statements. Among other things, there can be no assurances that any of INNOVIVE's development efforts relating to its product candidates will be successful. Other risks that may affect forward-looking information contained in this press release include the risk that the results of clinical trials may not support INNOVIVE's claims, the possibility of being unable to obtain regulatory approval of INNOVIVE's product candidates, INNOVIVE's reliance on third-party researchers to develop its product candidates and its lack of experience in developing pharmaceutical products. These and other risks are discussed in INNOVIVE'S Registration Statement on Form 10 filed with the SEC. INNOVIVE assumes no obligation to update these forward-looking statements, except as required by law.
Contact:
For INNOVIVE Pharmaceuticals
Jon Weisberg, 801-359-9977
Fax: 801-359-9980
Cell: 801-860-9977
E-mail: jonweisberg@inkandair.com
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ceo emisphere
michael goldberg
emisphere ceo
blade Would you buy more SPPI here, especially in light of BRS-David's theories? I'm certainly tempted, evn though I own a ton already[/]
I am tempted on valuation but haven't done so yet
acor
I had the stock on my screen but I didn't think it was going to work
that is my honest answer
Spectrum Pharmaceuticals Announces Positive Results of Satraplatin Pivotal Phase 3 Trial in Patients with Hormone-Refractory Prostate Cancer
I bought some last week but now that this data is out it isn't enough
Sunday September 24, 7:14 pm ET
- Highly statistically significant (p< 0.00001) results seen for PFS (progression free survival) endpoint in favor of satraplatin
- US Regulatory Submission (NDA) expected by year-end 2006, European filing in H1 2007
Conference call to be held Monday, September 25 at 12:00 PM ET (9:00 AM PT) (Tel: 1 866 578 5801 code: 62669828) or www.spectrumpharm.com
IRVINE, Calif., Sept. 24 /PRNewswire-FirstCall/ -- Spectrum Pharmaceuticals, Inc. (Nasdaq: SPPI - News) today announced positive results from the Phase 3 satraplatin pivotal registrational trial known as SPARC (Satraplatin and Prednisone Against Refractory Cancer). The trial is evaluating satraplatin, the first orally available platinum-based chemotherapy in advanced clinical development, plus prednisone versus placebo plus prednisone as a second-line treatment in 950 patients with hormone-refractory prostate cancer (HRPC). The study data show that the results for progression-free survival (PFS) are highly statistically significant (p<0.00001) using the protocol-specified log-rank test. PFS is the primary endpoint for submission for accelerated approval in the U.S. and will also serve as the primary basis for a Marketing Authorization Application (MAA) in Europe.
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"We are excited about the positive outcome of this pivotal Phase 3 trial of satraplatin as it validates our team's ability to identify promising drugs and select the most efficient method of moving these drugs through development and toward commercialization," stated Raj Shrotriya, M.D., President and CEO of Spectrum Pharmaceuticals. "This news is the first of what we expect will be a number of near-term announcements as we continue to advance our rich pipeline of ten drug candidates."
The milestone payments due to Spectrum, on acceptance and approval of regulatory applications in the U.S. and Europe, are approximately $20 million. Further payments are due on achieving certain sales targets. In addition to milestones, Spectrum will receive royalties on worldwide sales of satraplatin. The company also has co-promotion rights in the U.S., if the partner markets the drug in the U.S.
Patients in the SPARC trial who received satraplatin plus prednisone had a 40% reduction in the risk of progression (hazard ratio of 0.6; 95% Confidence Interval: 0.5-0.7) compared with patients who received prednisone plus placebo.
The improvement in PFS in the satraplatin arm was not affected by the type of prior chemotherapy; in particular, the improvement was seen equally for patients who had received prior Taxotere® (docetaxel), as well as those who received other types of chemotherapy treatments. All disease progression events were adjudicated by an independent expert review committee of medical oncologists and radiologists. The majority of progression events were based on radiological progressions and pain progressions.
As anticipated, the most common adverse reactions consisted of myelosuppression (bone marrow functions, such as lowered platelet count or lowered white blood cell count) and gastrointestinal events, such as nausea, vomiting and diarrhea. These adverse reactions were mostly mild to moderate in severity.
"Based on my almost forty years of experience in developing oncology drugs, I believe satraplatin, with the data demonstrated in this trial, and its oral formulation, could have great potential in several oncology indications. It is the most advanced compound in development for second-line chemotherapy for hormone-refractory prostate cancer, an area for which there are currently no approved therapies," stated Luigi Lenaz, M.D., Chief Scientific Officer of Spectrum Pharmaceuticals, who has been involved with the development of oncology drugs, especially platinum-based chemotherapies, since the 1970s. "If satraplatin is approved, we believe it could improve the lives of thousands of cancer patients each year who currently have no other options."
It is expected that a complete New Drug Application (NDA) will be submitted to the U.S. Food and Drug Administration (FDA) by year-end, and that the European marketing application will be filed in the first half of 2007. Satraplatin has been granted fast track designation from the FDA. If approved, it could be on the market in the U.S. in the second half of 2007.
Spectrum has partnered with GPC Biotech AG (Frankfurt Stock Exchange: GPC; TecDAX Index; Nasdaq: GPCB) for the development and commercialization of satraplatin. A joint development committee, which included Spectrum and GPC Biotech scientists, followed the progress of the study but GPC Biotech was responsible for funding and overseeing the study. GPC Biotech issued a press release today in which the company provided additional details about the results.
Conference Call Information
Spectrum will host a conference call on Monday, September 25, 2006 at 12:00 PM Eastern Time (9:00 AM Pacific Time). Domestic callers can access the call by dialing 866.578.5801 and international callers can access the call by dialing 617.213.8058. The passcode for the call is 62669828. Subsequently, the call will also be webcast live over the company's website at www.spectrumpharm.com and will be archived there for 30 days following the call. Please log onto the company's website several minutes prior to the start of the call to ensure adequate time for any software download that may be necessary.
About Prostate Cancer
Prostate cancer is the most common cancer among men in the U.S. and Europe. Approximately 234,000 men in the U.S. are expected to be diagnosed with the disease in 2006 and more than 27,000 men are expected to die from the disease. In the European Union, over 200,000 new cases are expected to be diagnosed, and more than 60,000 patients are expected to die each year. Since the incidence of prostate cancer increases with age, the aging of the overall population is expected to further increase the number of prostate cancer patients.
Most patients diagnosed with prostate cancer initially receive surgery or radiation therapy, and some of these patients are cured. For many others, though, the disease recurs. Recurrent disease is treated with hormone therapy, and most patients initially respond well to this treatment. Eventually, however, the tumor cells become resistant to the hormones - or "hormone-refractory" - and the tumor again progresses. Increasingly, chemotherapy is being used as an effective first-line treatment for HRPC. However, it is not a cure. Consequently, there is a growing need for effective therapeutic options, such as second-line chemotherapy treatments, for patients once they have progressed.
About Satraplatin
Satraplatin, a fourth-generation, oral investigational drug, is a member of the platinum family of compounds. Over the past three decades, platinum- based drugs have become a critical part of modern chemotherapy treatments and are used to treat a wide variety of cancers. Unlike the platinum drugs currently on the market, all of which require intravenous administration, satraplatin is an oral compound and is given as capsules that patients can take at home.
In addition to HRPC, satraplatin has been studied in clinical trials involving a range of tumors, and Phase 2 trials have been completed in ovarian cancer and small cell lung cancer. Other trials evaluating the effects of satraplatin in combination with radiation therapy, in combination with other cancer therapies and in various other cancers are underway or planned.
About Spectrum Pharmaceuticals
Spectrum Pharmaceuticals is opportunistically acquiring and advancing a diversified portfolio of oncology drug candidates that meet critical health challenges for which there are few other treatment options. Spectrum's expertise lies in identifying undervalued drugs with demonstrated safety and efficacy, and adding value through further clinical development and selection of the most viable and low-risk methods of commercialization. The company's pipeline includes promising early and late-stage drug candidates with unique formulations and mechanisms of action that address the needs of seriously ill patients, such as at-home chemotherapy and new treatment regimens for refractory disease. For more information, please visit our website at www.spectrumpharm.com.
genr evison
I haven't been involved in genr in a while. Do you know if they have ever done studies with evison and lucentis.
one of their problems is even though evison may be a good drug you can't get anyone to take a placebo because lucentis is on the market
maybe genr can start a trial evison and lucentis vs. lucentis plus placebo.
since it works by a different mechanism of action it may the combination may make one plus one equals 3
I may call the company and see if this has been thought of