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link to Wall street reporter interview
http://www.wallstreetreporter.com/profiles/Genaera.html
Excellent interview. I shake my head at the prospects of this company. The only thing that Roy should have presented in more detail when explaining the advantages of squalamine to the vegf inhibitors was was the method of action as opposed to just the delivery features.
Keep up the good work Roy and others.
views from another poster that agrees with me about oxgn's hype
http://messages.yahoo.com/bbs?.mm=GN&action=m&board=7077012&tid=magn&sid=7077012&....
another excellent post by mark z which roy should emphasize more.
It makes squalamine the definite standout among the vegf inhibitors.
http://finance.messages.yahoo.com/bbs?.mm=FN&action=m&board=7077012&tid=magn&sid=707...
I believe genentech released some data at the aao meeting which referred to a subset of patients that had a 40 improvement at 6 months
It is good news for genaera, because it shows what squalamine will be capable of doing without a shot in the eye every 4 weeks.
can you imagine what must happen to an eye if it has been injected once a month for 3 years (36 shots).
Look at the inhaled insulins. It has been shown to be effective for the length of the trial but the fda was concerned about the fact that lung function decreased about 2 percent after one year. The fda became concerned. They said if you lose 2 percent in 1 year do you lose another 2 percent in the second year or does it geometrically progress and you lose 4 percent the following year, and so on.
How can anyone really know the damage to the eyeball in a 1 year trial. The fda might become concerned about how many injections the eye can actually take, and ask for longer safety information.
that is my guess.
As far as oxgn, it appears to work and I would consider it for an investment, but in my opinion they appear to hype more than they should.
That last press release was an example. They found a person that improved with the drug and went into a whole diatribe about changing their opthamalic focus. What did they really say?
But that doesn't mean the drug won't work. I am just a little put off by them
I think you feel that way about avn. I am not as confident about the management at avn as I am in genr, but at avn the drug, neurodex, is in the second pivotal trial, which had great results in the first pivotal trial. So the drug works or it doesn't, but I won't have to wait long to find out.
With oxgn the drug is still very early in the development process to be worrying about management.
isolation
actually, I believe lucentis has shown in their 6 month data an improvement in over 40 percent of their subjects.
You are saying the vefg trap will show side effects because of systemic administration. Why don't you feel squalamine will?
Red, they won't invest in more anthrax trials with higher animals unless they get a government grant for it. After all the only ones who will pay for the anthrax vaccine is the government.
That was the reason for this article
http://www.washingtonpost.com/wp-dyn/articles/A43948-2003Dec7.html
washingtonpost.com
The High Cost Of Making an Anthrax Drug
Human Genome Sciences Needs Commitment From Government to Proceed With Treatment
By Michael Barbaro
Washington Post Staff Writer
Monday, December 8, 2003; Page E01
A year ago, Gil H. Choi stood in the Rockville laboratories of Human Genome Sciences Inc., nervously watching a group of white rats. Injected with synthetic anthrax spores an hour and a half earlier, the rats should have been dead. But there they were, scurrying around in a sealed glass case.
The 46-year-old scientist picked up the phone. "The rats are alive!" he yelled into the receiver to a colleague. The other scientists in the room were already jumping up and down.
A little more than a year after the October 2001 anthrax attacks that killed five people and temporarily emptied the halls of Congress, Human Genome Sciences had created a treatment that seemed to protect against anthrax -- for rats, at least. The timing was fortunate. A month later, in his January 2003 State of the Union address, President Bush announced Project BioShield, a $6 billion plan for a medical arsenal against bioterrorism. Human Genome Science's anthrax treatment, which it calls Abthrax, seemed to be a perfect candidate. "There was tremendous enthusiasm to get this product moved forward as quickly as possible," said David C. Stump, senior vice president for research and development.
A year later, the scientists have moved the drug forward quickly through tests on rabbits, monkeys and human volunteers. But the mood in the lab is no longer enthusiastic. Project BioShield is bogged down in Congress and the company has yet to get the government to purchase the drug. Executives say they are considering shelving it and putting the money and manpower back into inventing treatments for which there is a definite market, for common diseases such as cancer, rheumatoid arthritis and hepatitis C.
Human Genome Sciences' experience shows how uncertain the new business of biodefense is. In the weeks after the Sept. 11, 2001, terrorist attacks, the Bush administration pleaded with drug companies to develop medicines against such diseases as anthrax, smallpox and botulism. To lure the companies away from developing drugs for cancer and heart disease, the government did something unprecedented: It promised to buy the medicines. But dozens of firms that rushed into the business say they have found that not even the president has the power to turn an almost unbearably risky market into a going business.
After moving swiftly through the House of Representatives this summer, the Project BioShield legislation stalled in the Senate. Resistance came from senators such as Carl M. Levin (D-Mich.), who said he worries that soldiers might be compelled to use experimental treatments and that the law would permit noncompetitive bidding on some contracts.
The approach to treating anthrax infections that Human Genome Sciences is taking is fraught with uncertainty. The drugs are expensive to make; terrorists may be able to engineer anthrax that is immune to the treatment; and, because it requires an injection, the drug could be impractical after a widespread attack. "It's not clear they are the best investment for the country right now," said Tara O'Toole, director of the Center for Biosecurity at the University of Pittsburgh Medical Center.
The industry had expected the Project BioShield bill to pass in August. Congressional aides say that if the bill passes, it won't be until early next year.
"It is totally turning the companies off," said Asha M. George, managing director of the Anser Institute for Homeland Security, an Arlington think tank. "They cannot develop things in the hope that someday soon the government will get around to funding them."
Human Genome Sciences executives say the legislation's six-month delay has begun to disrupt their long-term drug development plans. The 11-year-old company, founded by former Harvard researcher and genetics pioneer William A. Haseltine, is testing nearly a dozen other drugs in human volunteers -- drugs that company executives say would enter more predictable consumer markets . The company, which has yet to put out a commercial product, lost $220 million in 2002 on sales of $4 million.
For now, the company says it's going to stick with it at least until January.
Human Genome Sciences' case stands out because of the breakneck pace at which it developed its anthrax drug, industry executives said. But it's not the only company to consider ditching biodefense drugs. Two other companies working on anthrax treatments -- Avanir Pharmaceuticals of San Diego and Medarex Inc. of Princeton, N.J. -- say they are running out of money for their projects and need a federal commitment to buy their drugs. "Other than patriotism, there may not be a reason to continue to do this any longer," Avinar chief executive Gerald J. Yakatan said.
Sense of Urgency
Human Genome Sciences' biodefense venture began in the fall of 2001, when anthrax-bearing envelopes arrived in mailboxes across Washington, including in congressional offices. As scientists studied the highly refined anthrax from the letters, new information about the little-understood bacteria emerged. For years, scientists knew that anthrax produced toxins that, once released in the bloodstream, invaded and destroyed cells. But they did not understand precisely how.
In October of that year, researchers from Harvard University and the University of Wisconsin discovered the part of human-cell surfaces targeted by anthrax. That was just enough information to allow biologists to invent ways to neutralize the toxin. About the same time, Human Genome Sciences' top researchers, Craig A. Rosen, president of research and development, and Stump, began discussing what, if anything, they might have to offer in the race to treat anthrax infections. Given where they lived and worked, the idea took on unusual urgency. "We were going out to the mailbox every day wondering what would be in it," Stump said. Project BioShield had yet to be announced, but they thought the government might be interested in an anthrax drug.
The biotechnology company already possessed the technology required to manufacture human antibodies -- the immune-system proteins that attack and disarm invading organisms -- which it was using to develop more commercial drugs. In December 2001, Rosen assigned a microbiologist, Michael Laird to produce an antibody that would work against anthrax.
In tests on rabbits and monkeys, believed to be the best available stand-ins for people in such research, the drug protected the animals when administered either before or after exposure, Stump said. This June the federal Food and Drug Administration permitted Human Genome Sciences to test whether the drug makes people sick. The results could be ready by the end of the month. Medical ethics prohibit exposing people to anthrax, so it's not clear that the drug would work in humans.
Human Genome Sciences will not disclose how much it has spent on developing Abthrax. Alexander Hittle, a biotechnology analyst at brokerage A.G. Edwards & Sons Inc., estimated that the drug would earn Human Genome Sciences $50 million a year if the government purchased 500,000 doses at about $500 each. That is far smaller than the typical market for a biotechnology drug, which averages more than $100 million in annual sales.
The most expensive phase of the drug's development is ahead, when the company must manufacture the drug for hundreds of volunteers in a second and final safety test. To proceed, said James H. Davis, the company's general counsel, Human Genome Sciences needs a signed federal contract. "That is not a few millions of dollars," he said. "That is tens of millions of dollars."
© 2003 The Washington Post Company
chances of merck as a partner
Actually it may make sense that since merck doesn't have any products for amd they might be more willing to go into that area because there won't be any scientist with a vested interest of keeping their pet project going. There won't be anyone with anything to lose if a new project is picked up.
Il-9 and knock out mice
Knock out do not usually work the way things work in nature
here is an example of Il13 and il4 knockouts not working either
Clinical & Experimental Allergy
Volume 33 Issue 1 Page 119 - January 2003
doi:10.1046/j.1365-2222.2003.01560.x
Persistence of bronchopulmonary hyper-reactivity and eosinophilic lung inflammation after anti-IL-5 or -IL-13 treatment in allergic BALB/c and IL-4R knockout mice
B. Proust*, M. A. Nahori*, C. Ruffie*, J. Lefort* and B. B. Vargaftig*
Summary
BackgroundAntigen-induced bronchopulmonary hyper-reactivity (BHR) is generally associated with eosinophilia. It involves cytokines produced by Th2 lymphocytes, including IL-4, IL-5 and IL-13, which are implicated in IgE production, eosinophil differentiation and attraction, and related events relevant to allergic inflammation, whose mechanisms remain unclear.
ObjectiveTo investigate the mechanisms by which Th2 cytokines mediate eosinophilia and subsequent BHR using ovalbumin (OVA)-immunized and OVA-challenged IL-4R/ and IL-4/ mice, which fail to transduce and/or to produce IL-4 and IgE as compared with wild type (WT) mice, and specific neutralizing antibodies.
MethodsOn days 0 and 7, mice were immunized subcutaneously (s.c.) with OVA. At day 14, anti-IL-5 or anti-IL-13 antibodies were administered intranasally and/or intravenously before allergenic challenge. Different functional and cellular parameters were studied in vivo and cytokine production was followed with a newly described ex vivo procedure using lung explants.
ResultsIL-4R/ and IL-4/ mice developed BHR and pulmonary eosinophilia, even though eosinophil recruitment to the bronchoalveolar liquid lavage (BALF) was reduced. In vivo, IL-4/ and IL-4R/ mice produced, respectively, no or reduced amounts of IL-5 in the BALF/serum as compared with WT mice, whereas no IL-13 in the BALF was detected. By contrast, ex vivo, surviving lung explants from WT and IL-4/ or IL-4R/ mice produced IL-13 and large amounts of IL-5. The neutralization of IL-5 in vivo (BALF and serum) and ex vivo (from lung explant) in IL-4R/ and WT mice failed to suppress BHR and lung eosinophilia, and to modify IL-13 production ex vivo. In addition, neutralization of IL-13 in vivo from lung explant also failed to abrogate BHR and lung eosinophilia, whereas IL-5 was unchanged.
ConclusionAntigen-induced BHR can develop independently from IL-4, IL-5 or IL-13 and from the IL-4 receptor chain, suggesting a possible novel IL-4, IL-5 and IL-13-independent pathway for the development of BHR in allergic BALB/c mice. The failure of IL-5 or IL-13 antibodies to prevent BHR in IL-4R/ mice suggests that neither is indispensable for BHR but does not exclude a role for lung tissue eosinophilia.
forbes article on macular degeneration mentions genaera
favorably
http://www.forbes.com/forbes/2003/1222/232_print.html
forbes article.
Zina the author of the article mentions the wet and dry form of amd and that the dry form can turn to the wet form.
She didn't make the connection that since squalamine works systemically it may either prevent the second eye from ever becoming the wet form or even if the eye does progress it may take care of the problem before the disease progresses and causes too much damage to the eye so that it can't be repaired.
is anyone working on il-13
regeneron regn Il-4/il-13 trap
They did a deal with aventis for 125 million up front with a 50/50 share of profits.
You are not the first one to warn me. I also saw the emanualascensio stuff.
I am willing to listen. If heb is a sham would these guys join the scientific advisory board
http://www.biospace.com/news_story.cfm?StoryID=14067920&full=1
discoverer of aids and hiv
http://www.biospace.com/news_story.cfm?StoryID=14200320&full=1
I know the story has hair on it, and the trial has taken forever but the data should be out by March or April.
Aside from the innuendo's being thrown around do you know anything.
I keep comming back to the ceo of regeneron. He was the ceo at merck but since joining regeneron he has been great at making deals but none of his drugs have worked. Why doesn't he lose credibility.
I haven't gotten in heavy,but to me the story looks good.
heb another taste
http://www.cfids-me.org/aacfs/ampligen.html
phase 3 will be announce next march or april
anyone know about hemispherx (heb)
here is a taste
http://members.aol.com/rgm1/private/wendall.htm
hey red re: avn
I believe they use the animals to see efficacy and use the vaccine on healthy volunteers to make sure there are no safety issues. I don't know if it can be approved at that point or they compare efficacy to other animals studies and pick the best.
The antibodies are the gravy, neurodex is the meal.
link to the article about macular degeneration
http://philadelphia.bizjournals.com/philadelphia/stories/2003/12/01/story2.html?t=printable
article on macular degeneration
Progress in search for cures
Encouraging news in the quest to treat blindness
John George
Staff Writer
Three local biopharmaceutical companies have cleared important hurdles in their race to find a more effective treatment for age-related macular degeneration, the leading cause of blindness in adults.
The disease, also known as AMD, afflicts an estimated 21 million people in the United States -- including 230,000 who are now blind.
Wanda Hamilton, executive director of the Toronto-based AMD Alliance International, said drug developers are paying more attention to AMD because of "changing demographics and the direct correlation between aging and the disease. The need is compelling."
The AMD Alliance is a nonprofit coalition of senior adult organizations and vision specialists working to raise awareness of the disease.
"There are a number of treatments in the pipeline that we are quite excited about," Hamilton said. "There are maybe a dozen in clinical trials at varying stages."
During the past two weeks, Philadelphia-based Acuity Pharmaceuticals Inc. and RetinaPharma Technologies Inc. of Jenkintown reported positive preclinical study results related to their experimental AMD treatments.
Last month, Genaera Corp. of Plymouth Meeting disclosed the findings from a study that found its new drug candidate Squalamine improved vision in all 39 AMD patients participating in the phase-II clinical trial.
AMD occurs in two forms: dry and wet.
Dry AMD, according to the AMD Alliance, is the more common and milder form of the disease, accounting for 85 percent to 90 percent of all cases. It develops gradually over time and usually causes mild loss of vision.
Wet AMD is caused by the growth of abnormal blood vessels under the central part of the retina. The abnormal vessels leak fluid and blood, causing a blister to form in the retina. The disease's progression leads to scar tissue, distortion and a loss of central vision.
Dry AMD has no proven treatment. The wet form of the disease is typically treated with laser surgery or photodynamic therapy, which have only limited success rates.
Acuity Pharmaceuticals is developing a new wet AMD treatment called Cand5, developed by and licensed from researchers at the University of Pennsylvania's Scheie Eye Institute. Cand5 treats the disease using a new technology in the biotechnology industry known as RNA interference or RNAi.
The RNAi technology works by disrupting the process by which genes make certain proteins responsible for human disease.
Cand5 is designed to block the production of vascular endothelial growth factor, or VEGF, a molecule identified as a key player in the development and leakage of blood vessels responsible for wet AMD.
The drug is also being studied as a potential treatment for diabetic retinopathy.
Based on the results of a study of Cand5 in primates, which found the drug was safe and effective, Acuity is getting ready to meet with the Food and Drug Administration next month and then file plans to begin testing the therapy in humans.
Dale Pfost, the company's president and CEO, said Acuity expects to begin human clinical trials during the second half of next year.
"The results we got [from the primate study] were the most robust and complete set of data we are aware of for a drug addressing AMD," he said.
Pfost said while other compounds now under development to treat the disease bind to harmful molecules in order to slow the progress of the disease, Cand5 completely shuts down the production of the molecules.
Acuity is closing a round of seed financing that will bring the company between $3 million and $4 million. Pfost said Acuity hopes to raise between $10 million and $15 million in a second round planned for next year.
Last week, RetinaPharma Technologies announced positive preclinical study results for its experimental drug desmethyldeprenyl, which the company said has the potential to help repair damaged nerve cells.
Desmethyldeprenyl is derived from the drug deprenyl, which is used to treat Parkinson's disease.
Among the first diseases RetinaPharma has targeted for desmethyldeprenyl is wet and dry AMD and glaucoma.
Terry A. Fuller, RetinaPharma's president and CEO, said desmethyldeprenyl works by interrupting cellular signaling involved in programmed cell death. By targeting a key enzyme called GADPH, desmethyldeprenyl can block the programmed cell death process and preserve the beneficial effects associated with GADPH.
"What we consider so exciting about the results of this new study is that it demonstrates that under laboratory conditions, [desmethyldeprenyl] not only increases the capacity of damaged cells to re-grow axons, but the resulting axons have the critical ability to connect with other cells," Fuller said. "What that means [for AMD patients] is that [desmethyldeprenyl] has the potential to not only prevent loss of vision, it also has the potential to restore vision."
An axon is the "arm" of a nerve cell that transmits electrical impulses away from a cell body to other parts of the body.
Fuller said RetinaPharma, which has raised $5 million from investors since its inception in 1998, plans to begin human testing in the second or third quarter of next year, providing FDA approval is secured.
In October, Genaera said the results of its 39-patient phase-I/II test of Squalamine, as a potential treatment of AMD, showed 10 patients demonstrated improved vision and 29 patients had preserved vision after taking the drug for four months.
Squalamine, derived from a substance found in the liver of the dogfish shark, is also being tested by Genaera as a potential treatment for a variety of different types of cancer.
Dr. Roy C. Levitt, president and CEO of Genaera, said the company is pursuing funding to help accelerate the development of Squalamine as a treatment for AMD.
"We've been very active in due diligence with potential partners," he said. "There's been a lot of sincere interest."
John George can be reached at jgeorge@bizjournals.com.
I spoke to someone that attended the AAO meeting
He took a poll of doctors and none of them had ever heard of squalamine. That is good and bad. The bad is that no one knows about it. The good news is that when they present at a eye meeting the news will make a big sqlash.
The other comment was that none of the doctors he spoke to were too enthused about injecting a needle in a patient's eye every six weeks. They didn't see any way to avoid retinal damage after a while.
Anyone ever hear of swiss cheese.
New Crop of Blindness Disease Drugs Show Promise.
--------------------------------------------------------------------------------
August 6, 2003.
By Bill Berkrot.
Reuters Health.
NEW YORK.
Genaera Corp. is betting its experimental treatment for the most common cause of age-related blindness is more fun than a needle in the eye.
The tiny Pennsylvania biotechnology company this week released promising results from a small, early-stage trial of its drug, squalamine, for treating the more severe wet form of age-related macular degeneration (AMD).
And while Genaera still has a long regulatory road ahead, company executives believe they have a very strong selling point compared to potential competition from industry giants in a market that could be worth billions of dollars.
About 500,000 new cases of wet AMD are diagnosed annually worldwide and that number is expected to soar as the baby-boom generation ages.
Squalamine, which demonstrated improvement or no deterioration of vision in 97 percent of the 40 patients in the recent study, is administered intravenously.
AMD drugs in later stages of development by Pfizer Inc. and another by Genentech are delivered by injection directly into the eye.
"We feel strongly that this will be a huge advantage," Genaera Chief Executive Roy Levitt told Reuters.
"We're very excited about differentiating the product we have in development from those in development that require an injection into the eye on a regular basis," Levitt said.
All three are anti-angiogenesis drugs that work by cutting off nutrients to the abnormal blood vessels that grow beneath the retina, causing the loss of eyesight.
Experts say there is dire need for new drugs because current treatments for wet AMD are very limited in effectiveness. While they can slow progression of the disease, they do not reverse it and it often returns with a vengeance.
"The early data from squalamine is remarkable because it shows that anti-angiogenesis can not only preserve vision in patients with AMD, but it can also restore vision as well," said Dr. William Li, president and medical director of the Angiogenesis Foundation.
"All these drugs show incredible promise," said Li, including Macugen, being developed by Pfizer and Eyetech Pharmaceuticals Inc., and Genentech's Lucentis.
AMD is the leading cause of blindness among adults over age 50 with about 25-30 million people affected globally.
"In an aging society this is literally an epidemic that is heading toward us," Li said.
Jason Kantor, an analyst for WR Hambrecht, called the new class of drugs "a $2 billion market opportunity."
Clearly, Pfizer is betting on a big money maker. The world's largest drug maker paid privately held Eyetech $100 million up front to acquire the Macugen marketing rights with another $645 million in potential milestone payments.
Genentech has a deal with Swiss drug maker Novartis, and Genaera is in talks with major drug companies with the resources that could help it compete with Pfizer's sales clout and likely earlier entry into the market.
Hambrecht's Kantor believes Genaera's intravenous (IV) treatment should have some competitive advantage. "But I don't think it's a foregone conclusion that weekly IV will dominate the market," he said, citing the inconvenience of regular doctor visits.
"There will be a continual race to develop oral drugs or eye drops," Kantor predicted.
Li agreed that finding a more convenient option that can prevent or reverse age-related blindness is the goal.
"The holy Grail of the whole ophthalmology field will be to ultimately develop an anti-angiogenic treatment that is safe and effective and can be delivered as an eye drop to prevent blindness," he said.
New Crop of Blindness Disease Drugs Show Promise.
August 6, 2003.
By Bill Berkrot.
Reuters Health.
NEW YORK.
Genaera Corp. is betting its experimental treatment for the most common cause of age-related blindness is more fun than a needle in the eye.
The tiny Pennsylvania biotechnology company this week released promising results from a small, early-stage trial of its drug, squalamine, for treating the more severe wet form of age-related macular degeneration (AMD).
And while Genaera still has a long regulatory road ahead, company executives believe they have a very strong selling point compared to potential competition from industry giants in a market that could be worth billions of dollars.
About 500,000 new cases of wet AMD are diagnosed annually worldwide and that number is expected to soar as the baby-boom generation ages.
Squalamine, which demonstrated improvement or no deterioration of vision in 97 percent of the 40 patients in the recent study, is administered intravenously.
AMD drugs in later stages of development by Pfizer Inc. and another by Genentech are delivered by injection directly into the eye.
"We feel strongly that this will be a huge advantage," Genaera Chief Executive Roy Levitt told Reuters.
"We're very excited about differentiating the product we have in development from those in development that require an injection into the eye on a regular basis," Levitt said.
All three are anti-angiogenesis drugs that work by cutting off nutrients to the abnormal blood vessels that grow beneath the retina, causing the loss of eyesight.
Experts say there is dire need for new drugs because current treatments for wet AMD are very limited in effectiveness. While they can slow progression of the disease, they do not reverse it and it often returns with a vengeance.
"The early data from squalamine is remarkable because it shows that anti-angiogenesis can not only preserve vision in patients with AMD, but it can also restore vision as well," said Dr. William Li, president and medical director of the Angiogenesis Foundation.
"All these drugs show incredible promise," said Li, including Macugen, being developed by Pfizer and Eyetech Pharmaceuticals Inc., and Genentech's Lucentis.
AMD is the leading cause of blindness among adults over age 50 with about 25-30 million people affected globally.
"In an aging society this is literally an epidemic that is heading toward us," Li said.
Jason Kantor, an analyst for WR Hambrecht, called the new class of drugs "a $2 billion market opportunity."
Clearly, Pfizer is betting on a big money maker. The world's largest drug maker paid privately held Eyetech $100 million up front to acquire the Macugen marketing rights with another $645 million in potential milestone payments.
Genentech has a deal with Swiss drug maker Novartis, and Genaera is in talks with major drug companies with the resources that could help it compete with Pfizer's sales clout and likely earlier entry into the market.
Hambrecht's Kantor believes Genaera's intravenous (IV) treatment should have some competitive advantage. "But I don't think it's a foregone conclusion that weekly IV will dominate the market," he said, citing the inconvenience of regular doctor visits.
"There will be a continual race to develop oral drugs or eye drops," Kantor predicted.
Li agreed that finding a more convenient option that can prevent or reverse age-related blindness is the goal.
"The holy Grail of the whole ophthalmology field will be to ultimately develop an anti-angiogenic treatment that is safe and effective and can be delivered as an eye drop to prevent blindness," he said.
Antiangiogenic Drugs May Stop Neovascularization in Wet Macular Degeneration
by Dan Roberts
Updated November, 2003
Research is currently underway to study the injection of antiangiogenic drugs as a means of stopping new blood vessel leakage (neovascularization). This is a report on nine of the drugs: rhufab V2 (aka lucentis), EYE001, tryptophanyl-tRNA synthetase (TrpRS), squalamine, Retaane 15 mg, Combretastatin A4 Prodrug (CA4P), VEGF-TRAP, and Macugen.
Rhufab V2 and EYE001
Two companies are conducting clinical trials on two separate drugs which evidence shows can prevent the growth of new vessels in the retina. The names of the drugs are rhufab V2 (also known as lucentis) and EYE001. Genentech, a pharmaceutical company, is conducting a phase I-II multi-center clinical trial to examine the safety and efficacy of rhufab V2, and Eyetech Pharmaceuticals is now in Phase III of a multi-center, randomized clinical trial. As of the date of this article, participating doctors estimate that from one-quarter to one-third of people with newly diagnosed wet macular degeneration have had significant improvement in their eyesight. In the remaining group, loss of sight has been stopped, at least temporarily.
A substance in the body called Vascular Endothelial Growth Factor (VEGF) is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. Evidence shows that when the retinal pigment epithelial (RPE) cells begin to wither from lack of nutrition (a condition called "ischemia"), the VEGF goes into action to create new vessels. This process is called "neovascularization," and it acts as a restorative function in other parts of the body. In the retina, however, the vessels do not form properly, and leaking results. This leakage causes scarring in the macula and eventual loss of central vision.
Rhufab V2 and EYE001 both prevent the VEGF from binding with the receptors on the surface of the endothelial cells. The drugs are injected into the vitreous of the eyeball, then pass into the subretinal space, where the vessels proliferate. Researchers are hoping that neovascularization will then be blocked, preventing bleeding into the retina.
In a presentation to the 2002 ARVO convention ("Anti-VEGF Therapy for Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration: Phase IB Results"), researchers reported that VEGF therapy is showing promise in the treatment of wet macular degeneration. To determine if multiple injections might be harmful to the patient, a Phase IB study was set up using 21 patients with subfoveal chroidal neovascularization (CNV) secondary to AMD. Conclusions were that multiple injections were "well tolerated, and visual results were very encouraging. Further clinical trials are required, and a Phase III study to evaluate the efficacy and long-term safety of this treatment is currently underway at 115 centers in the USA and abroad."
For more detailed information on the methods and results of this study, see the ARVO web site at http://www.arvo.org/index.htm.
Tryptophanyl-tRNA synthetase (TrpRS)
Another potentially potent inhibitor of angiogenesis has been found by two scientists from The Scripps Research Institute (TSRI). As reported by Paul Schimmel, Ph.D., Ernest and Jean Hahnin, and Martin Friedlander, M.D., Ph.D. in the January 2002 issue of the journal Proceedings of the National Academy of Sciences, the antiangiogenesis activity of a fragment of the human protein tryptophanyl-tRNA synthetase (TrpRS) has many potential applications ranging from macular degeneration to cancer. In pre-clinical trials, the researchers have found that angiogenesis is completely stopped in 70% of cases. Also, since TrpRS is a naturally-occurring protein in the body, it may be more effective, because it would not bring toxicity and immune system problems into the treatment. Once the cells have been "taught" how to make the substance, the molecules could be delivered directly to the eye through gene- and cell-based vectors.
For more information and further updates about the TrpRS research, go to the Scripps Research Institute web site at www.scripps.edu.
Squalamine
In August, 2002, Genaera Corporation announced commencement of a Phase 1-2 clinical trial designed to test squalamine, an angiogenesis inhibitor that has shown good results in primate models of ocular angiogenesis, including abnormal vessel regression. The study is now being performed with leading ophthalmologists in Mexico, in consultation with Dr. Charles Garcia, Professor of Ophthalmology, University of Texas, and Dr. Gholam Peyman, Professor of Ophthalmology, Tulane University. Genaera currently anticipates completing this study in the first half of 2003.
In the company's press release, Roy C. Levitt, President and Chief Executive Officer of Genaera, was quoted as saying, "squalamine has a striking ability to treat abnormal ocular angiogenesis in numerous animal models. Successful treatment of AMD with squalamine (which is injected systemically, rather than into or around the eye) also provides an excellent opportunity to demonstrate single agent action for this potent anti-angiogenic drug. These results could support not only our efforts to develop this drug for the enormous additional potential clinical indication of AMD, but successful data will also support our ongoing oncology development efforts."
In May 2003, Genaera Corporation announced that early results in the trials were promising, with patients showing either stabilization or shrinkage of the size of the choroidal neovascularization lesions, and improvement in acuity of up to 3 lines on the chart.
As of August 2003, researchers reported that 97% of patients treated with squalamine had preserved or improved vision two months after initiation of therapy. 33% had three lines or greater improvement in visual acuity, and 64% had preserved vision. The greatest degree of improvement was eight lines, from 20/125 to 20/20 vision. In addition, multiple lesions were notably smaller, and blood vessel leakage was significantly less.
Retaane 15 mg (anecortave acetate for depot suspension)
On Sep 28, 2002, Alcon, Inc. announced that Retaane 15 mg (anecortave acetate for depot suspension) continues to "demonstrate effectiveness in reducing vision loss in patients with the wet form of age-related macular degeneration."
According to Dr. Jason Slakter (retinal specialist at Vitreous-Retina-Macula Consultants of New York and Clinical Professor of Ophthalmology at the New York University School of Medicine), the 12-month data from Alcon's ongoing study demonstrated that Retaane 15 mg (anecortave acetate for depot suspension) was significantly better at preserving vision, preventing severe vision loss and inhibiting lesion growth in the retina than a placebo. Statistics showed that, after one year, 79% of experimental subjects lost fewer than three lines of vision from baseline, compared to 53% of people in the placebo group. In the sub-group of subjects with predominantly classic lesions, 84% of treated patients maintained vision within three lines compared to 50% of the placebo group.
After 24 months (reported in September 2003), 73% of the patients treated with Retaane 15 mg showed stable or improved vision. This compared significantly to only 47% of patients in the placebo group. Treated patients also showed no increase in choroidal neovascularization.
The drug is different (and less invasive) than the others described in this article, in that it is injected around and behind the eye, rather than into the vitreous. To date, there have been no clinically relevent safety issues.
Alcon has enrolled approximately 500 subjects for Phase III of the clinical trials at more than 50 sites in the United States, Europe, Australia and Canada. This phase of the study will compare the effectiveness of Retaane 15 mg (anecortave acetate for depot suspension) with photodynamic therapy (PDT) using Visudyne. For more information, go to the company's web site at www.alconinc.com. Click on "USA," then "clinical studies."
Combretastatin A4 Prodrug (CA4P)
OXiGENE, Inc., a biopharmaceutical company based in Watertown, Massachusetts, has been conducting a clinical trial of its lead vascular targeting compound, Combretastatin A4 Prodrug (CA4P), in patients with advanced anaplastic carcinoma of the thyroid. The trial is being conducted at the Ireland Cancer Center at University Hospitals of Cleveland. Recently, the Foundation Fighting Blindness (FFB) chose to make CA4P the focus of its first-ever physician-sponsored human clinical trial. The organization agreed to fund a Phase I/II study to assess the safety and effectiveness of CA4P as a treatment for wet age-related macular degeneration (ARMD).
The studies are being conducted at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine with a research team led by Peter A. Campochiaro, M.D., and Quan Dong Nguyen, M.D. The human trials are based upon successful results in recent animal studies, which showed the ability of CA4P to suppress the development of chroidal neovascularization leading to retinal degenerative diseases such as AMD. These results were published in the July 2003 issue of Investigative Ophthalmology and Visual Science,
VEGF-TRAP
An injectable protein that blocks growth of abnormal blood vessels associated with diabetic retinopathy may also be useful as a treatment for age-related macular degeneration.
VEGF-TRAP is a molecule which has been shown to block choroidal neovascularization in the retinas of mice. It was developed by researchers at the Johns Hopkins Wilmer Eye Institute and reported on in the June 2003 issue of the Journal of Cellular Physiology.
Macugen
Macugen, made by EyeTech Pharmaceuticals, is one of the newest anti-angiogenic drugs to be tested. It is a chemically synthesized strand of genetic material that bonds with VEGF cells to block replication. Early tests on the drug were promising, with significant percentages of patients either stabilizing or showing improvement in vision. A large trial of Macugen on 1,196 patients at 117 centers around the world was recently completed, and results should be published soon.
Squalamine certainly looks like a winner. genr is cheap
Red,
Did you ever buy avanir? It did a financing and has gone down. I can't look at the price. The story is great and have been buying more down here.
after posting this I looked at the avanir board, are you little red ridin hood. I think so.
I feel the same way about buying it as I did when I was buying genr at 20 to 80 cents when no one wanted that either.
I found out their drug may actually stop morphine addiction when given concurrently.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Nov;368(5):386-92. Epub 2003 Oct
15. Related Articles, Links
Co-administration of dextromethorphan with morphine attenuates morphine
rewarding effect and related dopamine releases at the nucleus accumbens.
Huang EY, Liu TC, Tao PL.
Department of Pharmacology, National Defense Medical Center, P.O. Box
90048-504, Nei-Hu, Taipei, Taiwan.
Morphine is one of the most effective analgesics in clinic to treat
postoperative pain or cancer pain. A major drawback of its continuous use is
the development of tolerance and dependence. In our previous study we found
that a widely used antitussive agent in clinics, dextromethorphan [(DM);
also known as a non-competitive N-methyl- d-aspartate (NMDA) antagonist],
could prevent the development of morphine tolerance. In the present study,
we further investigated its effect on morphine addiction. Conditioned place
preference (CPP) test and behavioral sensitization of locomotor activity
were used to investigate the drug-seeking related behaviors, which were in
correlation with psychological dependence. Our results showed that
co-administered DM was able to abolish completely the CPP effect induced by
morphine, but had no effect on morphine-induced behavioral sensitization. By
employing the microdialysis technique in free-moving animals, we also
determined the extracellular level of dopamine and serotonin metabolites in
the shell region of the nucleus accumbens (NAc) in its response to morphine
with/without DM. A significant increase in dopamine metabolites following
morphine administration was demonstrated in the NAc. This increase by
morphine could be attenuated by co-administered DM, whereas DM itself did
not show any effect. Based on our results, it is speculated that DM may
effectively attenuate morphine-induced psychological dependence.
Neurochemical analysis revealed that the effect of DM could be through its
action on the dopaminergic mesolimbic pathway, which could be activated by
morphine and attributed to the cause of rewarding.
Columbia University just received a grant for using neurodex as an anti addiction drug for morphine.
It can be HHHHHHUUUUUUUGGGGGGGGEEEEEEE
Have a nice holiday
Squalamine mentioned pretty prominently
I hadn't seen this
Antiangiogenic Drugs May Stop Neovascularization in Wet Macular Degeneration
by Dan Roberts
Updated November, 2003
Research is currently underway to study the injection of antiangiogenic drugs as a means of stopping new blood vessel leakage (neovascularization). This is a report on nine of the drugs: rhufab V2 (aka lucentis), EYE001, tryptophanyl-tRNA synthetase (TrpRS), squalamine, Retaane 15 mg, Combretastatin A4 Prodrug (CA4P), VEGF-TRAP, and Macugen.
Rhufab V2 and EYE001
Two companies are conducting clinical trials on two separate drugs which evidence shows can prevent the growth of new vessels in the retina. The names of the drugs are rhufab V2 (also known as lucentis) and EYE001. Genentech, a pharmaceutical company, is conducting a phase I-II multi-center clinical trial to examine the safety and efficacy of rhufab V2, and Eyetech Pharmaceuticals is now in Phase III of a multi-center, randomized clinical trial. As of the date of this article, participating doctors estimate that from one-quarter to one-third of people with newly diagnosed wet macular degeneration have had significant improvement in their eyesight. In the remaining group, loss of sight has been stopped, at least temporarily.
A substance in the body called Vascular Endothelial Growth Factor (VEGF) is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. Evidence shows that when the retinal pigment epithelial (RPE) cells begin to wither from lack of nutrition (a condition called "ischemia"), the VEGF goes into action to create new vessels. This process is called "neovascularization," and it acts as a restorative function in other parts of the body. In the retina, however, the vessels do not form properly, and leaking results. This leakage causes scarring in the macula and eventual loss of central vision.
Rhufab V2 and EYE001 both prevent the VEGF from binding with the receptors on the surface of the endothelial cells. The drugs are injected into the vitreous of the eyeball, then pass into the subretinal space, where the vessels proliferate. Researchers are hoping that neovascularization will then be blocked, preventing bleeding into the retina.
In a presentation to the 2002 ARVO convention ("Anti-VEGF Therapy for Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration: Phase IB Results"), researchers reported that VEGF therapy is showing promise in the treatment of wet macular degeneration. To determine if multiple injections might be harmful to the patient, a Phase IB study was set up using 21 patients with subfoveal chroidal neovascularization (CNV) secondary to AMD. Conclusions were that multiple injections were "well tolerated, and visual results were very encouraging. Further clinical trials are required, and a Phase III study to evaluate the efficacy and long-term safety of this treatment is currently underway at 115 centers in the USA and abroad."
For more detailed information on the methods and results of this study, see the ARVO web site at http://www.arvo.org/index.htm.
Tryptophanyl-tRNA synthetase (TrpRS)
Another potentially potent inhibitor of angiogenesis has been found by two scientists from The Scripps Research Institute (TSRI). As reported by Paul Schimmel, Ph.D., Ernest and Jean Hahnin, and Martin Friedlander, M.D., Ph.D. in the January 2002 issue of the journal Proceedings of the National Academy of Sciences, the antiangiogenesis activity of a fragment of the human protein tryptophanyl-tRNA synthetase (TrpRS) has many potential applications ranging from macular degeneration to cancer. In pre-clinical trials, the researchers have found that angiogenesis is completely stopped in 70% of cases. Also, since TrpRS is a naturally-occurring protein in the body, it may be more effective, because it would not bring toxicity and immune system problems into the treatment. Once the cells have been "taught" how to make the substance, the molecules could be delivered directly to the eye through gene- and cell-based vectors.
For more information and further updates about the TrpRS research, go to the Scripps Research Institute web site at www.scripps.edu.
Squalamine
In August, 2002, Genaera Corporation announced commencement of a Phase 1-2 clinical trial designed to test squalamine, an angiogenesis inhibitor that has shown good results in primate models of ocular angiogenesis, including abnormal vessel regression. The study is now being performed with leading ophthalmologists in Mexico, in consultation with Dr. Charles Garcia, Professor of Ophthalmology, University of Texas, and Dr. Gholam Peyman, Professor of Ophthalmology, Tulane University. Genaera currently anticipates completing this study in the first half of 2003.
In the company's press release, Roy C. Levitt, President and Chief Executive Officer of Genaera, was quoted as saying, "squalamine has a striking ability to treat abnormal ocular angiogenesis in numerous animal models. Successful treatment of AMD with squalamine (which is injected systemically, rather than into or around the eye) also provides an excellent opportunity to demonstrate single agent action for this potent anti-angiogenic drug. These results could support not only our efforts to develop this drug for the enormous additional potential clinical indication of AMD, but successful data will also support our ongoing oncology development efforts."
In May 2003, Genaera Corporation announced that early results in the trials were promising, with patients showing either stabilization or shrinkage of the size of the choroidal neovascularization lesions, and improvement in acuity of up to 3 lines on the chart.
As of August 2003, researchers reported that 97% of patients treated with squalamine had preserved or improved vision two months after initiation of therapy. 33% had three lines or greater improvement in visual acuity, and 64% had preserved vision. The greatest degree of improvement was eight lines, from 20/125 to 20/20 vision. In addition, multiple lesions were notably smaller, and blood vessel leakage was significantly less.
Retaane 15 mg (anecortave acetate for depot suspension)
On Sep 28, 2002, Alcon, Inc. announced that Retaane 15 mg (anecortave acetate for depot suspension) continues to "demonstrate effectiveness in reducing vision loss in patients with the wet form of age-related macular degeneration."
According to Dr. Jason Slakter (retinal specialist at Vitreous-Retina-Macula Consultants of New York and Clinical Professor of Ophthalmology at the New York University School of Medicine), the 12-month data from Alcon's ongoing study demonstrated that Retaane 15 mg (anecortave acetate for depot suspension) was significantly better at preserving vision, preventing severe vision loss and inhibiting lesion growth in the retina than a placebo. Statistics showed that, after one year, 79% of experimental subjects lost fewer than three lines of vision from baseline, compared to 53% of people in the placebo group. In the sub-group of subjects with predominantly classic lesions, 84% of treated patients maintained vision within three lines compared to 50% of the placebo group.
After 24 months (reported in September 2003), 73% of the patients treated with Retaane 15 mg showed stable or improved vision. This compared significantly to only 47% of patients in the placebo group. Treated patients also showed no increase in choroidal neovascularization.
The drug is different (and less invasive) than the others described in this article, in that it is injected around and behind the eye, rather than into the vitreous. To date, there have been no clinically relevent safety issues.
Alcon has enrolled approximately 500 subjects for Phase III of the clinical trials at more than 50 sites in the United States, Europe, Australia and Canada. This phase of the study will compare the effectiveness of Retaane 15 mg (anecortave acetate for depot suspension) with photodynamic therapy (PDT) using Visudyne. For more information, go to the company's web site at www.alconinc.com. Click on "USA," then "clinical studies."
Combretastatin A4 Prodrug (CA4P)
OXiGENE, Inc., a biopharmaceutical company based in Watertown, Massachusetts, has been conducting a clinical trial of its lead vascular targeting compound, Combretastatin A4 Prodrug (CA4P), in patients with advanced anaplastic carcinoma of the thyroid. The trial is being conducted at the Ireland Cancer Center at University Hospitals of Cleveland. Recently, the Foundation Fighting Blindness (FFB) chose to make CA4P the focus of its first-ever physician-sponsored human clinical trial. The organization agreed to fund a Phase I/II study to assess the safety and effectiveness of CA4P as a treatment for wet age-related macular degeneration (ARMD).
The studies are being conducted at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine with a research team led by Peter A. Campochiaro, M.D., and Quan Dong Nguyen, M.D. The human trials are based upon successful results in recent animal studies, which showed the ability of CA4P to suppress the development of chroidal neovascularization leading to retinal degenerative diseases such as AMD. These results were published in the July 2003 issue of Investigative Ophthalmology and Visual Science,
VEGF-TRAP
An injectable protein that blocks growth of abnormal blood vessels associated with diabetic retinopathy may also be useful as a treatment for age-related macular degeneration.
VEGF-TRAP is a molecule which has been shown to block choroidal neovascularization in the retinas of mice. It was developed by researchers at the Johns Hopkins Wilmer Eye Institute and reported on in the June 2003 issue of the Journal of Cellular Physiology.
Macugen
Macugen, made by EyeTech Pharmaceuticals, is one of the newest anti-angiogenic drugs to be tested. It is a chemically synthesized strand of genetic material that bonds with VEGF cells to block replication. Early tests on the drug were promising, with significant percentages of patients either stabilizing or showing improvement in vision. A large trial of Macugen on 1,196 patients at 117 centers around the world was recently completed, and results should be published soon.
For more information on clinical studies related to macular degeneration, see Clinical Trial Watch
For further explanation of the terms used in this article, see the MD Support Glossary and Eye Anatomy
more positive comments from Jason kantor on squalamine
http://www.openipo.com/sector/biotech/notes/gild20031117.pdf
merck doesn't have a drug for AMD do they?
UPDATE - Reuters Summit-Merck CEO sees no change of top brass
Friday November 21, 7:12 pm ET
By Jed Seltzer and Toni Clarke
(Recasts throughout, adds details)
NEW YORK, Nov 21 (Reuters) - Merck & Co. Inc. Chief Executive Raymond Gilmartin said on Friday investors should give him time to make the company grow again and there was no need for him to resign.
"Management changes are not at all under consideration," Gilmartin told reporters at the Reuters Health Summit a day after Merck reported yet another drug disappointment that sent its shares down 6.5 percent.
Merck had no earnings growth in 2002 and is expected to have flat profit this year, leading some investors and analysts to question Gilmartin's leadership.
When asked if he might resign, Gilmartin said, "In a word: No."
In the past two weeks, Merck (NYSE:MRK - News) has canceled drugs in advanced stages of development for diabetes and depression, two of the few potential big-sellers it has in the late stages of its pipeline. The diabetes drug blow came on Thursday night.
"This is the nature of the business that we're in," Gilmartin said, shrugging off the disappointment and noting that not all drugs in development work out.
The company is facing perhaps the biggest patent expiration in its history in 2006, when cholesterol drug Zocor, with more than $5 billion in annual sales, loses its U.S. patent protection.
"What matters is what the growth will be when it resumes," Gilmartin said, asserting that Merck can fill the gap when Zocor sales are slashed by generic competition, in part with new vaccines currently in development.
Sam Isaly, managing partner at investment fund OrbiMed Advisors LLC, said Gilmartin's personal appearance in the company's last earnings conference call shows the CEO is nervous.
"He's either fearful for the independence of Merck or for his job," Isaly said.
Gilmartin, at the Merck helm since 1994, has steadfastly sworn against a big merger for Merck, the world's third-largest drugmaker, to catch up with Pfizer Inc. (NYSE:PFE - News) and GlaxoSmithKline Plc (London:GSK.L - News). He reiterated that view on Friday.
Merck investors are accustomed to double-digit percentage earnings growth, but recent patent expirations, a dearth of new drugs and a slowdown in sales of arthritis drug Vioxx have significantly hurt the company.
Merck's stock closed at $42.23, down $2.93, after sinking as low as $41.75, its lowest point since July 2002, when it hit a six-year low.
"We might not see something as dramatic as the 4,400 we announced, but we're continually looking for ways to reduce the cost structure and that may lead to additional reductions," Gilmartin said at the summit.
Gilmartin also said Merck is turning a "friendlier" face to the biotechnology industry as it seeks to acquire new products to fill the gaping pipeline.
Having turned a cold shoulder to biotech companies for years, Merck is now eager to form partnerships and alliances that could give it access to new science or new experimental drugs.
Merck is becoming more "friendly," Gilmartin said, because biotechnology companies have embraced chemistry in a way that is allowing them to bring their products further along the development path. That presents drug companies looking to acquire products with more choice.
"We haven't lost confidence in our own internal research," he said, but the company wants to take advantage of as much good science as is available, inside or outside Merck's laboratories.
Gilmartin said that this year the company closed deals with 40 research institutions such as biotech companies, compared to just 10 in 1999. The company currently has 70 possible transactions on its radar.
Yahoo poster's thought about laf-237. Dew I saw you on the nvs board and thought you would be interested.
I have caught this poster not being 100 percent accurate on another occasion, wears rose colored glasses in reference to Amlyn, but he makes good points here
Within the last few days, Novartis released some basic information about its diabetes drug candidate LAF237. LAF237 is an orally administered medication currently in Phase 2 testing on non-insulin dependent type 2 diabetics. LAF237 works by inhibiting the natural destruction of GLP-1. GLP-1 is naturally produced in humans. GLP-1 is very helpful in controlling blood sugar levels because it slows postprandial gastric emptying, inhibits glucagons release (which reduces the rate of glycogen breakdown to glucose in the liver), and tells the pancreas to manufacture insulin when blood sugar levels begin to rise. GLP-1 has been long studied by Lilly and others as a possible therapy for type 2 diabetics. GLP-1, if administered in its pure form is safe and effective at lowering blood sugar. However, GLP-1 has such short half-life that at least to date GLP-1 therapies have been impractical. After decades of trying, Lilly eventually abandoned its GLP-1 therapy route in favor of becoming Amylin's partner with Amylin's drug candidate exenatide. Exenatide hits the same receptors in the human body as does GLP-1, but has the substantial advantage of having a much much longer half-life. As a result, two already completed phase 3 placebo controlled studies have proven that exenatide is a powerful and practical therapy for type 2 diabetics. It not only results in a substantial lowering of blood sugar above the levels obtainable from oral medications, but results in statistically significant weight loss among overweight diabetics. Mild to moderate transient nausea was reported in some patients during the initial introduction of exenatide. This has been shown to be a manageable problem because drop-out rates have been very modest.
Type 2 diabetes is a disease that tends to get worse over time. At the initial outset, type 2 diabetes is treated with diet and exercise. When that approach is no longer successful, patients are placed on oral medications - typically metformin (Glucophage) and/or sulfonylurea. When these medications are no longer sufficient, a patient typically must begin insulin therapy. Insulin therapy, although often necessary to protect the lives of the more advanced type 2 diabetics, comes with numerous problems. First, it requires injections. Second, since an overdose of insulin can be extremely dangerous, proper administration of insulin requires frequent testing of blood sugar levels through the finger
pin prick method. Insulin therapy often causes weight gain and makes patients not feel as good as they do absent insulin therapy.
Exenatide has the disadvantage of requiring injections, but has the advantage of not requiring finger pin pricks because it does not contain the dose dangers associated with insulin. Exenatide also has the advantages of weight loss instead of weight gain. Since oral medications are often initially effective, Amylin and Lilly have perceived that the role for exenatide is after type 2 diabetes has progressed to the point where the oral medications are not adequate by themselves. Rather than moving to insulin, patients will move to exenatide. Thus, at least for now, because of the need to inject exenatide, it is is competition for insulin and in most cases is not likely to be competition for metformin and/or sulfonylurea. The long acting, or LAR version of exenatide which is still in phase 2 testing, might eventually become a practical alternative to oral medications for many patients.
The question of concern to Amylin investors is whether or not LAF237 is competition for exenatide. Based upon the data that Novartis has released, the answer appears to be no. Here's why. First, Novartis presented its slide #25 which is entitled "LAF237 Leads to Dose-Dependent Reductions in HbA1c in Mild Diabetics". Note the word "Mild". Mild diabetics are type 2 diabetics that have not yet begun taking any oral medication. These patients did show a dose-dependent reduction in HbA1c when taking LAF237. A the higher doses, i.e. 50 mg and 100 mg, LAF237 showed a statistically significant reduction in HbA1c after 12 weeks. Specifically, for patients that began therapy with an average HbA1c level of 7.8%, LAF 237 showed an ability to lower HbA1c by 0.36% versus placebo at the 50 mg dose and by 0.48% at the 100 mg dose. For patients with a baseline HbA1c of 8.5%, a study involving 24 patients at an undisclosed dose of LAF237 achieved an HbA1c lowering of 1.2% versus baseline and something more than 1.2% versus placebo (again undisclosed). Are these reductions helpful? Absolutely. However, since these are patients that would otherwise be candidates for metformin, a comparison to metformin is important. Metformin is sold by Bristol-Myers Squibb. The Bristol-Myers Squibb website shows that metformin results in an average lowering of HbA1c by 1.4% versus baseline, or 1.8% versus placebo when measured against patients with a baseline HbA1c level of 8.4%. Whether or not the 1.2% + placebo power of LAF237 is achievable in the real world depends on whether or not the "undisclosed" LAF237 dose is or is not a dose that patients can tolerate. Remember, all of the above data applies to patients not previously on medication. It is much more difficult, but becomes critically important to achieve, decreases in HbA1c in patients already on one or more medications.
Probably what has caused the most stir in the investment community is Novartis' slide #26 that is entitled "LAF237 Monotherapy Suggested to Be As Effetive As Exenatide in Combination with Metformin". A review of the data on the associated table shows that the title of this slide is substantively, if not literally, a lie. Why? The data for exenatide was taken from Amylin's study conducted by adding exenatide to people who were already on Metformin. The Novartis slide correctly shows that the effect of adding exenatide to people already on Metformin was to lower HbA1c an ADDITIONAL 0.9%. The key omission by Novartis is any consideration of the "additional" lowering. Any of the HbA1c lowering that had already been achieved by metformin is not included in the 0.9% reduction. Therefore, Novartis's comparision is a lie because the true HbA1c lowering of the combination of metformin and exenatide should include the HbA1c lowering effect of BOTH metformin and exenatide. For example, if we were to add the known HbA1c lowering of metformin to the additional HbA1c lowering effect of exenatide, the total effect of the combination therapy is more in the range of 2.7% than 0.9%. This critical omission on the part of Novartis means that the proper comparison is that metformin + exenatide combination therapy is 2.5 to 3 times more powerful than LAF237 monothreapy.
AND WE'RE NOT DONE YET. Novartis Slide #26, the one slide showing LAF237 as an add-on to metformin, shows that the larger benefits of LAR237 that are often quoted do not occur until the 100 mg dose. Fine, except, one has to ask the question if there may be some tolerability issues with the larger dose. Study drop-out data is not specifically given, but isn't it curious that in the reported study, data was provided for 50 patients on placebo, 53 patients on the 50 mg dose, and the number of patients who
completed the 12 week therapy drops to only 12 patients at the 100 mg dose. Did Novartis intentionally conduct a study with a key arm containing many fewer patients than the other arms? Or, were there tolerability problems at 100 mg?
ANOTHER KEY POINT. LAF237 works by reducing the decay rate of natural GLP-1. Fine. However, as type 2 diabetes progresses, the amount of GLP-1 produced declines. This means, the sicker the patient, the more difficult a time LAF237 should be expected to have in accomplishing its task. In other words, right at the time type 2 patients are sick enough to be faced with the decision of adding either exenatide or insulin, is also the time that LAF237's potential effectiveness might be diminished.
For the above reasons, current data shows the true competition for LAF237 is metformin and sulfonylurea. As oral monotherapy, although metformin is more powerful than LAF237, there could be a place for LAF237. Metformin has a 41.5% higher incidence of diarrhea than placebo, has a 17.2% higher incidence of Nausea/vomiting, and some other problems. For this, and other reasons, it is plausible that LAF237 could be an oral medication that is chosen for some patients prior to the time that their type 2 diabetes progresses to the point where metformin and/or sulfonylurea therapy is required. However, there are still significant risks ahead. Unlike new drugs such as symlin and exenatide, LAF237 is introducing a mechanism that is totally foreign to the body. It is inhibiting an enzyme. It has not been through any phase 3 testing. What problems, if any, might develop over time are not yet know. Assuming phase 3 testing is successful, based upon both the test data that has been presented and what we know of the mechanism of LAF237, it appears that LAF237 is not a potential competitor to exenatide in its Amigo trial patient intent to treat group. However, exenatide LAR and LAF237 have a similar target population. Given how powerful exenatide is in improving HbA1c while in its more challenging role in combination therapy, it is reasonable to expect that LAR exenatide will be considerably more powerful as monotherapy than is suggested in the early data on LAF237.
[he is assuming that the Lar Exenatide will ever make it out of phase 1. AMLN started the trial in March and have not released any data. On their last conference call the flat out told the analysts they will not accept any questions about the trial because they have nothing to say.]
The last paragraph about the stock, conjuchem being cheap, and them doing a huge deal like the one I am expecting from genaera is mine.
Sorry for the confusion.
Actually my thinking with conjuchem is similar to my thoughts about genaera. Genaera does a large deal and gets to use the proceeds to work on their vast pipeline. Same goes for conjuchem. They make a huge deal and they get the cash to use their dac system on other proteins and peptides.
Conjuchem
Ron Garren's comments
CJC is traded on the Toronto exchange and is currently at $4.07 Canadian. CJC's market cap. is about $142 million Ca.. In my mind this makes it a very cheap company considering that the target and therapy have been validated by Amylin's (AMLN) studies with exenatide. Both of these companies are using a peptide hormone either similar to or identical to human GLP-1 to treat type 2 diabetes. The remarkable feature of these molecules is that they sense the level of blood sugar and only act when it is too high. Their side effect profile does not include hypoglycemia, which is the case with to much insulin or some of the oral agents. Another remarkable property is that GLP-1 causes weight loss which is a big plus for type 2 diabetics. Novo is another competitor in the GLP-1 field.
CJC has a remarkable technology that puts a linker on small molecules and peptides with an activated group at the free end. The concept is that when the drug plus linker is injected IV or SC the activated group binds covalently with serum albumin and creates and active product with the same half -life (19 days) and volume of distribution as albumin, which is not excreted by the kidneys. This technology turns drugs that have a short half-life into ones with a long- half life. The end result is that you have a much longer acting drug with less frequent dosing. CJC tried using this technology with a few other molecules over the last two years but for one reason or another these projects were unsuccessful. However the GLP-1 program was always the jewel in their crown. Now that promise seems to be materializing.
CJC recently reported a fourth cohort of patients in a Phase I/II study in type II diabetics. These patients were off all other antidiabetic drugs. They showed tolerability and efficacy with good control of the main side effects, nausea and vomiting. Nausea decreased during the slow titration protocol and patients were able to get off anti-emetics quickly. They showed amazing efficacy for a short 20 day trial with significant reductions in fasting glucose, mean glucose, and body weight. HbA1c was not reported since this usually is a three month marker. Efficacy was also evident 7 days after the last dose. The implication is that after a brief titration their drug could be injected on a weekly SC schedule. As a comparison Amylin just released further data from a 24 week Phase III study showing good HbA1c (a measure of long-term blood sugar levels) control in type II diabetes using a twice-a-day SC injection of their GLP1 like product, exenatide. Weight loss, some nausea, and a lack of hypoglycemia are generic properties of all the GLP-1 like products. However exenatide, which is a synthetic copy of exendin 4 isolated from the saliva of the Gila Monster, causes a significant incidence of antibody formation. However the drug remained effective so the antibodies were not neutralizing antibodies. AMLN is currently working with Alkermes to develop a long-acting formulation (an IND was filed in March of '03). AMLN's market cap is 2.6 billion US and they are partnered with Lilly. So far CJC is not partnered with DAC:GLP-1, the formulation is already long-acting (most probably) and they have a market cap of only about $100 million US. Granted they are in very early trials and only reported on a small group of patients but their drug looks promising. One downside is that CJC is a Canadian company with little visibility in the US. I placed a bet on them because I like that they are using human GLP-1, their technology produces a long half-life product and early trials show a profile consistent with that of Amylin's exenatide which must be injected twice daily. So far there is no evidence of antibody formation. I think a major pharma will make them an attractive deal and if CJC keeps control through Phase II trials the rewards could be very rich. I will probably add to my personal position.
My opinion is that the stock is very cheap. They will be able to do a deal with their glp-1 formulation after they release their phase 2 data in May on about the same scale I am expecting for genr to make with squalamine.
from the FOUNDATION FOR FIGHTING BLINDNESS webstie.
Experimental Drug Squalamine for Patients with Wet AMD - CLOSED
Earlier this fall, the manufacturer of a study drug to treat wet age-related macular degeneration (AMD) announced positive findings in patients. The drug, called squalamine, is an anti-angiogenic drug being tested in a Phase I/II clinical trial. Phase I and Phase II are the early stages in the drug testing process in humans and assess the safety and dosing level of a drug in a small number of patients. This part of Genaera’s study is now closed for further enrollment.
The drug was tested in 39 patients who received the drug intravenously once a week for 4 weeks. When researchers tested vision 4 months after the study began, they found that every participant had better vision than when they started, or vision that had not decreased. Ten patients had three lines or greater improvement in visual acuity. Twenty-nine patients had preserved vision.
Wet AMD is caused by a growth of abnormal blood vessels under the macula. An anti-angiogenic drug like squalamine halts the growth of new blood vessels. Researchers hope this will help them manage AMD. Age-related macular degeneration (AMD) represents the most common cause of blindness in patients over the age of 60. Age-related macular degeneration is of two types, dry and wet. Dry AMD accounts for 85-90% of cases. Although wet AMD is less common, it causes 90% of the severe vision loss associated with AMD. Squalamine is one of several anti-angiogenic drugs being tested for treating AMD.
Future Phase II clinical studies will probably include testing of the therapy to maintain the positive outcome, testing of various drug dosages, and testing of squalamine in combination with photodynamic therapy. Enrollment is likely to start by June 2004 or earlier. If successful, phase III studies will include larger numbers of patients for obtaining data on visual acuity that can be used to support application to bring squalamine to market. Dr. Hugo Quiroz-Mercado of Hospital Luis Sanchez Bulnes in Coyoacan, Mexico conducted the research.
For more information, go to www.genaera.com, the web site of the manufacturer of squalamine, Genaera Corporation of Plymouth Meeting, Pennsylvania.
When I use the lowered bar it is not for the purpose of approval of squalamine.
The lowered bar refers to the efficacy of the drugs on the market. If macugen had the great results in the phase 3 you saw in the phase 2 then even though it is a shot in the eye, doctors would not be so fast to start squalamine treatments when it would get approved because they would say, I am not going to take you off this drug which is improving your vision, just to avoid the shot in the eye.
If squalamine can now get approved with better data and a better delivery system it is a no brainer to switch, and I believe the big pharma that Roy is speaking with right now, will see that also.
The predominantly classic received visudyne
What about completely classic?
I wasn't aware of that. Where did you see that? Good catch, that would explain some of it.
Remember in macugen's 24 person trial they had 6 people that acutually improved. That is a placebo effect that had nothing to do with visudyne.
It is posible that macugen had a greater effect after 3 months than after a year. The fact that the drug only targets vegf may be the culprit. The leaky vessels figure out a way around it.
squalamine has multiple targets.
The high placebo effect makes me believe that genaera had quite a few placebo effects in their trial. I still think it will be better than any results until now but not anywhere near 100 percent. I would be curious to find out whether the people on placebo in the macugen trial that had stabilization had stabilization in their angiograms or whether the eyes deteriorated, even though they were able to keep their sight.
The people in the placebo group had a sham injection. A needle wasn't actually inserted into their eye,an empty syringe was pressed against their eye.
Why wouldn't you believe it is approvable.
It slowed progression in 70 percent of the patients, which included occult patients. In that respect it is better than visudyne. I don't think it will be an enormous drug though, because people won't want a shot in the eye to get mediocre results.
Did you see the elation on the qlti board except for the basher that think the data is great. those bashers are as dumb as the ones genr has.
Genaera has a very low hurdle to climb over now
Qlti may do well on Monday because they are reading too much into the fact that the writer wrote that the results aren't too different from the visudyne results. The difference is that visudyne results didn't include the occult version, which has more patients.
FROM THE TIMES ARTICLE
About 30 percent of those getting Macugen suffered a vision loss of three lines or more on the eye chart after one year, less than the 45 percent of the control group that suffered such a vision loss. There were 21 cases of infection, cataracts or retinal detachments in people who got the injections, which Dr. Puliafito called an acceptable risk.
The results were not too different from those of Visudyne, the drug already on the market. In its Phase III trial, about 39 percent of those taking the drug lost three or more lines of vision, compared with 54 percent for the comparison group.
MY COMMENTS
What the scientific community must be made aware of is that Squalamine is not just a vegf inhibitor but also targets fbf and other growth factors, the cycoskeleton and integrin expression, so it should work better and non-invasively
I don't believe this IL-9 patent is part of the Partnership with Medimune. Genaera would have all the rights to it from the wording of the press release
http://biz.yahoo.com/prnews/031113/nyth052_1.html
I made the same I point when I posted to yahoo but the folks on that board are too interested in mindless trading messages.
what a waste
I listened to the conference call
They certainly aren't going to hype macugen but I don't really think they bashed it much.
What I did notice is that 50 minutes into the call Mathew Geller asked the ceo how the macugen phase to result compared to Visudyne's phase 2. The ceo said visudyne's phase 2 showed that 44 percent of subjects had an increase in vision versus macugen's 27 percent.
He lied, the trial as a whole showed a deterioration, he picked a cohort of 8 people with a 50 percent drop out rate where they had multiple treatments in a short time. The fda would never approve that many treatments.
Hasting as far as I am concerned lost all credibilty but it seemed to make the hyping analysts happy.
Dew, did you hear that part?
conjuchem abstract of long acting glp-1
Diabetes
March, 2003
Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. (Islet Studies).
Author/s: Jung-Guk Kim
Glucagon-like peptide 1 (GLP-1) is a proglucagon-derived peptide secreted from intestinal L-cells in response to nutrient ingestion (1,2). GLP-1 acts as an incretin to lower postprandial glycemic excursion via stimulation of insulin secretion and inhibition of glucagon secretion. GLP-1 also exerts actions independent of islet hormone secretion, including inhibition of both gastric emptying and food intake (3,4), and stimulation of [beta]-cell proliferation (5,6).
Although the structurally related gut hormone glucose-dependent insulinotropic peptide (GIP) also potentiates glucose-dependent insulin secretion (7), unlike GLP-1, the insulinotropic actions of GIP are diminished in diabetic rodents or in human subjects with type 2 diabetes (8,9). In contrast, GLP-1 administration rapidly lowers glucose in both normal and diabetic subjects (9-11), and 6 weeks of continuous subcutaneous infusion of native GLP-1 significantly decreased blood glucose and Hb[A.sub.1c] in human patients with type 2 diabetes (12). Hence there is considerable enthusiasm for the development of GLP-1-based pharmaceutical agents for the treatment of type 2 diabetes (2,13).
Although native GLP-1 effectively lowers blood glucose following acute peptide administration (14,15), both endogenous and exogenously administered GLP-1 exhibit a short [t.sub.1/2] in vivo due primarily to N[H.sub.2]-terminal cleavage and inactivation by the enzyme dipeptidyl peptidase (DPP-IV) (16,17). The physiological importance of DPP-IV for GLP-1 degradation and glucose homeostasis is exemplified by studies of mice or rats with inactivating mutations in the DPP-IV gene. These rodents exhibit enhanced glucose clearance following glucose challenge and increased circulating levels of intact GLP-1 in vivo (18,19). Similarly, administration of DPP-IV enzyme inhibitors is associated with reduced glycemic excursion, enhanced insulin secretion, and reduced degradation of GLP-1 in normal and diabetic rodents (20-22) and in human subjects (23).
Accordingly, there is considerable interest in complementary strategies for circumventing the rapid cleavage of GLP-1, including the development of GLP-1-based analogs with enhanced resistance to degradation and increased biological potency in vivo (13,24). The majority of these analogs exhibit one or more amino acid substitutions that reduce the affinity of the peptide for DPP-IV and subsequent cleavage both in vitro and in vivo. Similarly, the naturally occurring lizard peptide exendin-4 is a potent GLP-1R agonist that exhibits reduced DPP-IV mediated cleavage and a longer duration of action in both rodents and human subjects (25,26). We have recently initiated studies of GLP-1 derivatives that are resistant to DPP-IV and are synthesized with a short covalent reactive chemical linker that interacts with a specific cysteine residue in the albumin molecule following parenteral administration of the modified GLP-1 peptide. The resultant GLP-1-albumin drug affinity complex (DAC) is predicted to retain the actions of GLP-1, yet exhibit a more prolonged duration of action due to a combination of DPP-IV resistance and the longer [t.sub.1/2] conferred by serum albumin in vivo. To test the hypothesis that albumin-bound DAC-GLP-1 derivatives retain the biological properties of native GLP-1, we studied the activity of a DAC-GLP-1 compound, CJC-1131, using cells and in normal GLP-1R-/- and diabetic rodents.
RESEARCH DESIGN AND METHOD
Animals. All animal experiments were carried out in accordance with protocols approved by the Toronto General Hospital Animal Care Committee or the Comite Institutionnel de Protection des Animaux de I'UQAM C57BL/6 db/db mice (The Jackson Laboratory, Bar Harbor, ME) and age- and sex-matched C57BL/6 wild type mice from the same genetic background were used for chronic administration studies following a minimum 1-week acclimatization period in the animal facility. Wild-type CD-1 mice and GLP-IR-/- mice (27) in the CD-1 background were used for acute peptide administration experiments. Mice were allowed ad libitum access to food and water, except where noted. Animals were on a 12-h light, 12-h dark cycle (lights on 0700 h). For dose-response experiments shown in Fig. 2B, female CD-1 mice (Charles River Canada, St-Constant, QC), 7- to 10-weeks old, were studied, whereas for glycemic measurements shown in Figs. 2C and D, experiments were carded out with female db/db mice aged 7-10 weeks. CJC-1131 is a synthetic modification of GLP-1 (Fig. 1A) consisting of a single amino acid substitution of L-[Ala.sup.8] to D-[Ala.sup.8] at position 2, enabling some additional protection from DPP-IV and the addition of a lysine ([Lys.sup.37]) to the COOH-terminal of the peptide. The other modification involves the selective attachment of a [2-[2-[2-maleimidopropionamido(ethoxy)ethoxy]acetamide to the epsilon amino group of [Lys.sup.37].
In vitro experiments: binding affinity and cyclic AMP generation. Binding affinity was determined by incubating either native GLP-1 or CJC-1131 and 0.03 nmol/l [sup.125]-labeled GLP-1(7-36) amide with Chinese hamster ovary (CHO) cells stably transfected with the human GLP-1R cDNA using an incubation buffer of 20 mmol/l Tris-HCl, pH 7.4, 5 mmol/l Mg[Cl.sub.2], 20 mmol/l NaCl, 2% BSA for 90 min at 37[degrees]C. For analysis of cAMP generation, CHO-GLP-1R cells were incubated for 20 min with various peptide ligands in the presence of 100 mmol/l IBMX followed by analysis of cAMP as described (28).
Experimental protocol for db/db mouse studies. Baseline plasma glucose, oral and intraperitoneal glucose tolerance testing, and food intake were assessed before beginning CJC-1131 treatment. During the 4-week treatment period, wild-type and db/db mice were given an intraperitoneal injection of either 25 [micro]g of CJC-1131 or an equal volume of saline twice daily at 800 and 1600 h. Following the 4-week treatment period, a subset of mice from each group was sacrificed for analyses, whereas an additional set of mice continued to be monitored for another 3 weeks.
Glucose tolerance tests and measurement of plasma insulin. Oral and intraperitoneal glimpse tolerance tests were carried out following an overnight fast (16-18 h) as described (27,29). Glucose (1.5 mg/g body wt) was administered orally through a garage tube or via injection into the peritoneal cavity, and blood was drawn from a tail vein at 0, 10, 20, 30, 60, 90, and 120 min after glucose administration. Blood glucose levels were measured by the glucose oxidase method using a glucose meter (Glucometer Elite; Bayer, Toronto, Canada). For plasma insulin determinations, a blood sample was removed from the tail vein during the 10- to 20-min period following glucose administration, and plasma insulin was determined using a rat insulin enzyme-linked immunosorbent assay kit (Crystal Chem, Chicago, IL) with mouse insulin as a standard.
RNA isolation and Northern blot analysis. Mice were anesthetized with C[O.sub.2], and pancreata were removed immediately for RNA extraction by the acid-guanidinium isothiocyanate method. Total RNA (10 [micro]g) was electrophoresed in a 1% (wt/vol) formaldahyde-agarose gel and transferred to a nylon membrane (Nytran Plus; Schleicher & Schuell, Keene, NH). For Northern blot analysis, the blot was hybridized to [sup.32]P-labeled random-primed complementary DNA probes corresponding to rat proglucagon, rat insulin, or 18S RNA. Analysis of islet size and [beta]-cell proliferation. Mice were injected with 100 mg/kg 5 bromo-2'-deoxyuridine (BrdU, Sigma-Aldrich, St. Louis, MO) intraperitoneally 6 h before being sacrificed. The pancreas was removed, fixed overnight in either 10% buffered formalin or 4% paraformaldehyde, and embedded in paraffin. Sections were obtained and stabled with hematoxylin and eosin using standard protocols. Histological sections were immunostained for insulin using guinea-pig anti-insulin (Dako Diagnostics Canada, Mississauga, ON, Canada) as primary antibody (1:100 dilution) and rabbit anti-guinea-pig immunoglobulin (Dako Diagnostics Canada) as secondary antibody (1:50 dilution). Antibody binding was visualized by 3,3-diaminobenzidine, and sections were counterstained by Meyers hematoxylin. Islet histomorphometry was carried out according to the principles of Delesse (30). The sections were examined using a Leica (Leitz Labor Lux S; Leica Microsystem, Heerbrugg, Switzerland) microscope equipped with a video camera and connected to a computer with imaging software (Q500MC; Leica Microsystem). Estimates of islet area, islet number, number of BrdU immunopositive cells, and total pancreatic area were determined in a blinded maturer as described (29,31).
Statistics. Results are expressed as mean [+ or -] SD or mean [+ or -] SE. Statistical significance was calculated by Student's t test using SPSS windows version 10 (SPSS, Chicago, 1L). P < 0.05 was considered to be statistically significant.
RESULTS
To circumvent the short biological [t.sub.1/2] of native GLP-1 due principally to DPP-IV-mediated degradation, we designed a new DPP-IV-resistant GLP-1 derivative that would form a covalent bond with albumin in vivo, thereby conferring to covalently linked GLP-1 the longer circulating [t.sub.1/2] of albumin (32). A D-alanine residue at position 2 was substituted for the native alanine, and the COOH-terminal end of the GLP-1 molecule wins coupled to a reactive chemical linker capable of forming a 1:1 covalent bond to the Cys residue in serum albumin (Fig. 1A). The resultant GLP-1 derivative, designated CJC-1131, should retain the biological properties of native GLP-1 yet exhibit DPP-IV resistance and a prolonged [t.sub.1/2] consistent with the clearance of native serum albumin in vivo (33).
[FIGURE 1 OMITTED]
To assess the properties of a CJC-1131-human serum albumin (HSA) conjugate, we incubated HSA with CJC-1131 in vitro arm utilized the purified CJC-1131:HSA conjugate for studies of GLP-1R binding using CHO cells transfected with human recombinant GLP-1R (Fig. 1B). The displacement of [sup.125]1-labeled GLP-1 by native GLP-1 versus the CJC1131:HSA complex was highly similar over a range of CJC-1131 concentrations ([K.sub.i] = 5.16 nmol/l for native GLP-1 vs. 12 nmol/l for CJC-1131:HSA). To assess the bioactivity of CJC-1131, we measured cAMP accumulation using CHO cells transfected with human recombinant GLP-1R. These experiments demonstrated virtually identical dose-response relations for cAMP accumulation, with native GLP-1 exhibiting an E[C.sub.50] of 13 nmol/l, whereas the E[C.sub.50] for CJC-1131-HSA was 11-13 nmol/l (Fig. 1C).
We next assessed whether the route of CJC-1131 administration was an important determinant of bioactivity in C57BL/6 mice following glucose loading. CJC-1131 markedly reduced glycemic excursion following intraperitoneal or subcutaneous administration (Fig. 2A). Similarly, intravenous CJC-1131 administration produced a dose-dependent reduction in glycemic excursion following glucose loading (Fig. 2B). To ascertain whether a single injection of CJC-1131 would lower blood glucose in diabetic mice, we administered CJC-1131 by subcutaneous injection to db/db mice. Remarkably, basal random glycemia decreased rapidly and remained lower in db/db mice for up to 10 h following a single subcutaneous injection of CJC-1131 (Fig. 2C). Furthermore, the glucose-lowering effect of CJC-1131 was still evident during an oral glucose tolerance test performed 12 h after a single intravenous CJC-1131 injection (Fig. 2D). Although CJC-1131 consistently lowered glucose in wild-type mice, no effect was observed in GLP-1R-/- mice (Fig. 2E), demonstrating the critical importance of an intact GLP-1R for the biological activity of CJC-1131 in vivo.
[FIGURE 2 OMITTED]
These findings demonstrated that single injections of CJC-1131 exert glucose-lowering effects in normal and diabetic mice. We next assessed whether more prolonged repeated administration of CJC-1131 would lower glucose in mice with severe diabetes. Wild-type control C57BL/6 (C57 +/+) or db/db mice were treated with saline or CJC-1131 twice daily for 4 weeks. Before initiation of CJC-1131, mean fasting glucose was 4.3 [+ or -] 0.9 mmol/l in C57+/+ vs. 17.9 [+ or -] 6.7 mmol/l in db/db mice (Fig. 3A). After 2 weeks of twice daily saline or CJC-1131 administration, fasting blood glucose was significantly lower in both control C57+/+ and db/db mice treated with CJC-1131 (4.5 [+ or -] 0.7 vs. 3.3 [+ or -] 0.5 mmol/l and 19.2 [+ or -] 5.8 vs. 12.5 [+ or -] 3.7 mmol/l, saline vs. CJC-1131 in C57+/+ vs. db/db mice, respectively; P < 0.01, Fig. 3.4). Fasting glucose remained significantly lower in C57+/+ mice but not in db/db mice treated with CJC-1131 at the end of the 4-week treatment period (Fig. 3A). In contrast, fed blood glucose was significantly lower in CJC-1131-treated C57+/+ and db/db mice throughout the 4-week experiment (Fig. 3B; P < 0.01, saline versus CJC-1131). Furthermore, fed blood glucose remained significantly lower in db/db mice 1 week following the last injection of CJC-1131 (Fig. 3B, P < 0.05). Although CJC-1131 produced a small but significant decrease in body weight in C57+/+ mice, no differences in body weight were detected in db/db mice treated with saline versus CJC-1131 over the 4-week experiment (Fig. 3C).
[FIGURE 3 OMITTED]
To determine whether repeated administration of CJC-1131 was associated with improvement in glucose tolerance, we performed oral and intraperitoneal glucose tolerance testing in C57+/+ and db/db mice treated with saline or CJC-1131 for 2 weeks. Blood glucose excursion was significantly lower in CJC-1131-treated control C57+/+ mice following either oral or intraperitoneal glucose loading (Fig. 4A and B). Similarly, both fasting glucose and the glycemic excursion following glucose loading were modestly but significantly reduced in CJC-l131-treated db/db mice at multiple time points (Fig. 4A and B). Although plasma insulin levels were significantly greater in db/db mice compared with C57+/+ mice both in the fasting state and after glucose loading, plasma insulin levels were not further increased in db/db mice treated with CJC-1131 (data not shown).
[FIGURE 4 OMITTED]
GLP-1R agonists have been shown to increase proinsulin gene expression and promote islet neogenesis and [beta]-cell proliferation (5,6,34). To determine whether a larger CJC-1131:albumin conjugate exhibits comparable actions on the diabetic pancreas in vivo, we carried out Northern blot analysis using pancreatic RNA from C57+/+ and db/db mice. Levels of pancreatic insulin mRNA transcripts were comparable in normoglycemic wild-type C57+/+ mice treated with either saline or CJC-1131. In contrast, 4 weeks of CJC-1131 administration significantly increased the levels of proinsulin mRNA transcripts in db/db mice (Fig. 5A). Pancreatic insulin content was reduced in db/db compared with control C57+/+ mice, but was not significantly different in saline-vs. CJC-1131-treated C57+/+ or db/db mice (Fig. 5B).
[FIGURE 5 OMITTED]
To determine whether CJC-1131 administration was associated with changes in the number or size of pancreatic islets, we carried out morphometric analysis of pancreata from C57+/+ and db/db mice following 4 weeks of treatment with either saline or CJC-1131 (Fig. 6). Total percent islet area was increased in C57+/+ mice and significantly increased in db/db mice following CJC-1131 administration (P < 0.01; Fig. 6B). We next assessed the proportion of small, medium, and large islets, as previously described (35). CJC-1131 treatment significantly increased the percent large islet area in db/db mice (Fig. 6C; P < 0.01). The percentage of large islets was also increased in control mice treated with CJC-1131, but this difference did not achieve statistical significance (Fig. 6C). In contrast, the number of small islets was significantly increased in both C57+/+ (212.2%, P < 0.05) and db/db mice (94.6%, P < 0.05) treated with CJC-1131 (Fig. 6D). Furthermore, CJC-1131 significantly increased the total number of islets in both C57+/+ and db/db mice (Fig. 6E).
[FIGURE 6 OMITTED]
To determine whether the observed differences in percent islet area and number of islets were attributable in part to increased rates of islet cell replication, we assessed the numbers of BrdU+ islet cells in saline- or CJC-1131-treated mice (Fig. 6F and G). CJC-1131 administration significantly increased the number of BrdU+ islet cells in db/db mice (413.1%, P < 0.01; Fig. 6G).
DISCUSSION
The observation that GLP-1 administration effectively reduces blood glucose in human subjects with type 2 diabetes has stimulated considerable effort toward the development of GLP-1-based agonists for pharmaceutical administration. Although infusion of native GLP-1 is highly effective in lowering blood glucose in diabetic patients (12,36), the native peptide is an excellent substrate for DPP-IV (16,17), and exhibits a very short [t.sub.1/2] in vivo. Hence, the requirement for constant GLP-1 infusion places potential constraints on the widespread use of native GLP-1 in the diabetes clinic. Accordingly, there remains ongoing interest in the development and characterization of peptidase-resistant GLP-1 analogs with longer durations of action suitable for subcutaneous administration in vivo (13).
Several approaches have been undertaken to develop stable long-acting GLP-1 analogs, with DPP-IV-resistant molecules such as NN2211 currently being tested in clinical trials for the treatment of type 2 diabetes (37). Exendin-4, a naturally occurring lizard salivary gland peptide (38) that exhibits potent GLP-1-like activity and exerts its actions through the GLP-1R, is also undergoing clinical evaluation for the treatment of type 2 diabetes (26,39). The data presented here describe the results of introducing two specific modifications of the native GLP-1 molecule, one to engineer DPP-W resistance, the second to achieve chemical coupling of the GLP-1 analog (CJC-1131) to serum albumin. Albumin is known to exhibit a longer [t.sub.1/2] in vivo, ~19 days in humans (40), which is much greater than the [t.sub.1/2] of short-lived regulatory peptides such as GLP-1. Accordingly, peptide binding to albumin has been used to improve the pharmacokinetie properties of several smaller proteins, including Fab antibody fragments (33), coagulation factor VIIa inhibitor 1a (41), and insulin (42). The present results indicate that a much larger albumin-GLP-1 covalently linked conjugate retains the biological properties of native GLP-1, including binding to and activation of the GLP-1R in vitro. Furthermore, the glucose-lowering effects of CJC-1131 were abolished in GLP-1R-/- mice, providing important complementary evidence that the actions of CJC-1131 in vivo are mediated by the known GLP-1R.
Several experimental results provide indirect evidence for a sustained duration of CJC-1131 action on glucose lowering in vivo. First, oral glucose tolerance remained significantly improved in mice even 12 h after a single CJC-1131 injection. Furthermore, fed glucose remained significantly lower in db/db mice treated with CJC-1131, even 1 week after the last CJC-1131 injection. These findings are consistent with data demonstrating sustained improvements in insulin secretion in Zucker diabetic fatty rats detectable even 1 week following a transient GLP-1 infusion (43). Similarly, blood glucose remained lower in exendin-4-treated partially pancreatectomized rats several weeks following discontinuation of exendin-4 administration (5). Although fed glucose and glucose tolerance were clearly improved in db/db mice treated with CJC-1131, significant hyperglycemia persisted even during repeated CJC-1131 administration. In contrast, daily administration of exendin-4 to younger, less severely diabetic db/db mice (starting fasting hyperglycemia of 5.1 mmol/l) prevented the progression to more severe hyperglycemia over the 2-week treatment period (44). However, a 2-week treatment of older, more severely diabetic db/db mice with twice dally administration of 200 [micro]g/kg NN221 or exendin-4 (100 [micro]g/kg) did not prevent ongoing deterioration in glucose tolerance, with mice remaining very hyperglycemic even after the 2-week treatment period (45). Hence the effects of chronic GLP-1 agonist administration in the db/db mouse appear dependent, in part, on the clinical severity of the diabetes and age of the mice at the onset of treatment.
Although treatment of rodents and human subjects with GLP-1R agonists has been associated with prevention of weight gain or modest weight loss (12,25,46), we did not observe a significant reduction in body weight in db/db mice treated with CJC-1131 over the 4-week treatment period. Similarly, body weight was not significantly reduced in db/db mice treated with NN2211 or exendin-4 over comparable 2- to 4-week treatment periods (45,47). At present, it remains unclear whether restricted transport of an albumin-GLP-1 conjugate across the blood-brain barrier might compromise the ability of molecules such as albumin-CJC-1131 to reduce food intake and weight gain in vivo. Nevertheless, significant weight loss was observed in control C57+/+ mice treated with CJC-1131 over the same time period. Furthermore, intravenous infusion of CJC-1131 rapidly induced c-fos immunoreactivity in several regions of the rat central nervous system (H. Yamamoto, J. Elmquist, and D.J.D., unpublished observations), providing complementary evidence suggesting that an albumin-GLP-1 conjugate is capable of activating central nervous system functions in vivo.
Despite the failure to observe normalization of glycemia in the older db/db mouse, CJC-1131 administration increased islet area, with a significant increase in both the number and the relative percentage of small and large islets detected following 4 weeks of CJC-1131 treatment. Furthermore, the number of BrdU+ islet cells was significantly increased in CJC-1131-treated mice, consistent with previous studies demonstrating that activation of the GLP-1R is coupled to expansion of islet mass in the db/db mouse (6,44,45). Hence, although fenestration of islet capillaries does restrict access and reduce permeability toward larger molecules in the islet microcirculation (48), the comparatively larger CJC-1131-albumin conjugate apparently retains the ability to promote islet growth and enhance insulin gene expression in the mouse in vivo.
Despite the increase in islet area and proinsulin mRNA transcripts in CJC-1131-treated mice, we did not observe a significant increase in insulin content in the db/db mice treated with CJC-1131. Indeed, pancreatic insulin content was modestly decreased in control and CJC-1131-treated db/db mice relative to C57+/+ mice consistent with the functional exhaustion of [beta]-cell insulin stores in db/db mice with blood glucose levels approaching 20 mmol/l.
Given the increasing interest in strategies based on enhancement of incretin action for the treatment of diabetes, there remains an unmet need for developing approaches that circumvent the requirement for dally or continuous administration of GLP-1 analogs. Accordingly, long-acting or slow-release forms of GLP-1 analogs that exhibit desirable therapeutic properties are awaited with interest. The administration of albumin-based GLP-1 derivatives should confer a longer circulating [t.sub.1/2] to the newly derived albumin-peptide conjugate, compared with the native GLP-1 peptide alone (32,33). The data presented here demonstrate that a prototype DPP-IV resistant GLP-1 analog that covalently couples to albumin, CJC-1131, retains the biological properties generally ascribed to GLP-1R agonists. The findings that CJC-1131 binds to and activates the GLP-1R, lowers blood glucose, increases proinsulin gene expression, and stimulates islet cell proliferation suggest that further assessment of the efficacy and mechanisms of action of albumin-based GLP-1 derivatives appears warranted.
ACKNOWLEDGMENTS
The work in the Drucker Lab was supported in part by an operating grant from the Juvenile Diabetes Research Foundation. Conjuchem, Inc., provided a travel grant to J.K. and L.B. to present this data in abstract form at the 2002 Annual Meeting of the American Diabetes Association. D.J.D. is a Senior Scientist of the Canadian Institutes of Health Research.
REFERENCES
(1.) Drucker DJ: The glucagon-like peptides. Diabetes 47:159-169, 1998
(2.) Holst JJ: Glucagon-like peptide 1 (GLP-1): an intestinal hormone, signalling nutritional abundance, with an unusual therapeutic potential. Trends Endocrinol Metab 10:229-235 1999
(3.) Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ: Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 38:665-673, 1993
(4.) Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CMB, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JPH, Smith DM, Ghatei MA, Herbert J, Bloom SR: A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379:69-72, 1996
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(6.) Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Egan JM, Bonner-Weir S, Habener JF: Insulinotropic glucagon-like peptide-1 agonists stimulate expression of homeodomain protein IDX-1 and increase [beta]-cell mass in mouse pancreas. Diabetes 49:741-748, 2000
(7.) Dupre J, Ross SA, Watson D, Brown JC: Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 37:826-828, 1973
(8.) Lynn FC, Pamir N, Ng EH, McIntosh CH, Kieffer TJ, Pederson RA: Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes 50:1004-1011, 2001
(9.) Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W: Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91:301-307, 1993
(10.) Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S: Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326:1316-1322, 1992
(11.) Nathan DM, Schreiber E, Fogel H, Mojsov S, Habener JF: Insulinotropic action of glucagon-like peptide-I-(7-37) in diabetic and non-diabetic subjects. Diabetes Care 15:270-276, 1992
(12.) Zander M, Madsbad S, Madsen JL, Holst JJ: Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359:824-830, 2002
(13.) Drucker DJ: Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes. Curr Pharm Des 7:1399-1412, 2001
genaera versus regeneron
http://www.investorshub.com/boards/read_msg.asp?message_id=1715755
regeneron vs genaera comparison
here is a press release about regeneron
http://biz.yahoo.com/bw/031029/295824_2.html
Regeneron has IL-4/IL-13 trap for asthma Genaera has IL-9
Regeneron has VEGF trap just starting human trials for cancer partnered with aventis for 125 cash upfront and 50/50 share of profits Genaera has squalamine a small molecule targeting VEGF and other growth factors with good 3 or 4 years worth of cancer data, and great macular degeneration data. Unpartnered
regeneron has axokine that failed in trials, they have never said what the mechanism of action is. Genaera has msi-1436 which targets NPY and AGRP, two very exciting targets. these cover obesity.
genaera has lomucin and the patent estate for HCLCA1 regn has nothing
Market cap regeneron 700 million Genaera 150 million
What am I missing?
Thanks Red,
I bought a little more avn today. how did you keep the virs message board open
Red,
Thanks for your post on avn. I can't understand how someone would not want to pay 1.60 but is willing to pay 1.50. I cannot price stocks that perfectly.
You may want to tell the fellow that the quinidine is given in such low doses that when a blood test is given the patient right after the injection, they cannot find it in the blood, so it shouldn't have any interaction with any other drug.
I believe the the drug will not only be effective for emotional lability, and diabetic neuropathy but also Alzheimer's and parkinson's. here is why in think it may be good for parkinson's
http://www.dextroverse.org/Archives/DXM_Protects_Dopaminergic_Neurons.pdf
I think it may be good for alzheimer's because it is a more potent nmda receptor antagonist than memantine and that has just been approved for alzheimer's
As far as the asthma drug, it is very early but if it does work it would not be for just extreme cases but for mild cases also because it is oral. The tanox drug is a shot, that is why it was approved for more severe cases.
thanks again, I think you should buy some
By the way it is good to have you on the board. I didn't like triagle but I always liked you