Stabilizing artheosclerosis - alternatives

[dylan99]

I am a quad bypass patient (3 yrs ago) and just had an angioplasty and stent for a new 80% blockage which developed since I had my bypass. I'm on statins and have been told that my bypasses are clear and my cholestrol is under control, so it appears the statins are working to stabilize artheoclerosis in my bypasses. However, my doctor doesn't like the look of my arteries which haven't been worked on yet, and the statins don't appear to be doing enough here, given my recent blockage.

Has anyone heard of any new viable alternatives for slowing down or reversing artheosclerosis? I've heard there's some new "apo a milano" drugs being worked on that may hold promise, but haven't heard if they're available yet. What else should I consider?

[KShortie]

Pfizer is working on a new drug that is suppose to work miracles on plaque in the arteries, but it is still in clinical trials and isn't available yet for public use. I read in Newsweek I think about some treatment for patients with blockage that involved blood pressure cuffs placed on extremities forcing blood in alternative blood vessels around the blockages and it was working pretty good for some patients--though not all insurances were paying for this. It was $5000.00 per treatment vs. about $80,000 for bypass so you think they would like you to use that instead. Go figure. I had quad bypass last summer. My cholesterol, triglycerides and BP are good, but they were good before the bypass! I'm on Zocor with nyacin and magnesium, also very small dose of a beta-blocker because that is suppose to be good for your heart and keep you vessels dilated, even if you don't have high BP. I guess besides all you are already doing keeping up an exercise program and trying to eat a good diet is about all you can do. I try to think positive and not worry about it--doesn't do you any good anyway Try to hang in there. Something great could be just around the corner!

[Tony1]

December 24, 2003

Pfizer to buy Ann Arbor drug firm

ANN ARBOR, Mich. - Pfizer Inc., the world's biggest drugmaker, is paying $1.3 billion for a small Ann Arbor-based research firm with the potential to produce the next blockbuster cholesterol drug.


Pfizer said Sunday it will purchase Esperion Therapeutics Inc., a 5-year-old, 70-employee company that recently published promising results of early-stage trials of its experimental treatments.


While Esperion's drugs may take several years to reach the market, they have the potential to help millions of patients who suffer heart disease.


Esperion's potential drugs act by enhancing the body's high-density lipoprotein or HDL, the so-called good cholesterol, so that it reduces the level of plaque that forms in arteries.


The current leading cholesterol drug, Pfizer's product Lipitor, works by reducing low-density lipoprotein or LDL, the so-called bad cholesterol, too much of which can lead to plaque buildup.


John LaMattina, president of Pfizer Global Research and Development, called HDL research "the next Holy Grail" of research into cardiovascular disease. He said Pfizer would commit hundreds of millions of dollars to turning Esperion's research into marketable products.


Esperion's products are especially exciting, LaMattina said, because early trials show they are effective at reducing plaque in short-term acute care settings in a hospital, such as after a patient has had a heart attack. Current cholesterol drugs are prescribed on a chronic or long-term basis.


Pfizer's cash purchase translates into $35 per share for Esperion's stock. That represents a 54-percent premium over Esperion's average closing share price during the last 20 trading days. Esperion closed at $22.70 per share Friday.


New York-based Pfizer is a $32-billion-a-year pharmaceutical giant that produces such prescription medicines as erectile dysfunction therapy Viagra, antidepressant Zoloft and pain drug Celebrex. The company also sells over-the-counter remedies including Rolaids, Sudafed and Visine.


Sunday's purchase announcement caps a stunning success story for Esperion. Founded in 1998, Esperion is led by Roger Newton, the company's president and chief executive, who while working at Warner-Lambert/Parke-Davis (now part of Pfizer) codiscovered atorvastatin, the highly successful multibillion-dollar drug marketed by Pfizer as Lipitor.


In addition to its Ann Arbor headquarters, the company also operates a research center at Western Michigan University in Kalamazoo.


Newton said Sunday that Esperion had been looking for a way to build up its financial muscle to pursue research and development of cholesterol drugs.


"The acquisition will enable us to utilize Pfizer's skills and apply the resources necessary to develop our pipeline of compounds to benefit patients with atherosclerosis," he said. "We are pleased to have the opportunity to work with the world leader in cardiovascular medicines to develop HDL-focused therapies."


Esperion will continue to operate in Ann Arbor as a division of Pfizer.


"We don't envision any changes to that organization," LaMattina said. "They're doing some great work. They're good people. It's a natural fit for us."


Even before Sunday's announcement, Michigan played a big role in Pfizer. Michigan has more Pfizer employees - about 9,000 - than any other state, including people working in research and development, manufacturing, sales and other areas. Pfizer's largest manufacturing site in the world is in Kalamazoo.


The announcement signals a major step forward for Michigan's hopes to become a center of life-sciences research. Already the state is promoting its Life Sciences Corridor, a wide-ranging effort that includes research by scientists at the University of Michigan, Michigan State University, Wayne State University and the Van Andel Institute in Grand Rapids.


The state has committed $1 billion over 20 years from its share of the national tobacco settlement to fund life science initiatives. That places Michigan among the national leaders in funding such research.


Just this fall, researchers began moving into U-M's new Life Sciences Institute in Ann Arbor. When other efforts are completed and operational in 2008, U-M's commitment to integrated life sciences research will total more than $900 million in buildings and programs.


"There's the potential for the biotech industry to grow and thrive here," Newton said.


The success of Esperion, he added, "serves as a wonderful example of how if you have a dream and a vision of how you can take basic science and find the application to treat human disease, you can indeed see that into a reality."


Pfizer's pursuit of Esperion began last month, when the smaller company published its results of clinical trials in the Journal of the American Medical Association. The results of the Esperion compound known as ETC-216 were so stunning that a number of firms began to pursue Esperion.


Newton said he and his aides had promised their board of directors to find a major new source of research funding by the end of the year. The talks with Pfizer intensified over the past 10 days.


Newton said he will be staying with the company under Pfizer, adding, "I like to finish what I start."

[Tony1]

Esperion's products are especially exciting, LaMattina said, because early trials show they are effective at reducing plaque in short-term acute care settings in a hospital, such as after a patient has had a heart attack. Current cholesterol drugs are prescribed on a chronic or long-term basis.

[Tony1]

Apo A-1 Milano
In the late 70s and early 80s, University of Milan researchers found that a male inhabitant (Valerio Dagnoli) of the lakeside town Limone sul Garda in Northern Italy had a very low level of HDL cholesterol (the good cholesterol that tends to protect arteries from cholesterol-plaque buildup) and high levels of triglycerides (a bad form of fat in blood that can lead to cholesterol-plaque deposit in the arteries). Despite this highly abnormal lipid profile, the middle-aged man had no evidence of cardiovascular disease, and his parents had enjoyed longevity.

When blood tests were done on the entire 1,000 inhabitants of Limone, about 40 individuals had a similar lipid abnormality. Using birth records maintained in the local church going back several hundred years, it was found that these 40 individuals were all traceable to common ancestors from 1780 (Giovanni Pomaroli and Rosa Giovaneli). This then led to the discovery that these 40 individuals had a genetic mutation in the gene that makes a protein called apo A-1, which becomes a part of the HDL cholesterol particle.

In the normal apo A-1 there is arginine at position 173, whereas in the mutant form of apo A-1 (now called apo A-1 Milano) from these 40 individuals, instead of arginine there is cysteine. It was speculated that this mutant form of apo A-1 may be protecting its carriers from cardiovascular disease. However, there was no evidence to support this until 1994, when Dr. P.K. Shah and his colleagues at Cedars-Sinai Medical Center showed for the first time that intravenous injection of a genetically engineered form of apo A-1 Milano complexed to phospholipid (creating a synthetic form of HDL or HDL mimetic agent) and markedly reduced arterial plaque buildup in rabbits fed a high cholesterol diet (published in Circulation in October 1994 and also discussed in a 60 Minutes television segment in October 1994).

Over the past eight years, Dr. Shah's laboratory provided further evidence, based on experimental studies done in genetically altered mice with high cholesterol levels, that repeated intravenous injections of apo A-1 Milano would halt the progression of plaque buildup and induce reversal (regression) of preexisting plaque within five weeks (published in Circulation in 1998). Furthermore, Dr. Shah's laboratory also reported that a single large intravenous dose of apo A-1 Milano could remove cholesterol and inflammation out of arterial plaque within 48 hours, creating a more stable form of plaque (published in Circulation in 2001). Dr. Sanjay Kaul from Dr. Shah's laboratory also showed that local injection of a tiny amount of recombinant apo A-1 Milano directly at the site of coronary stent implantation in pig coronary arteries dramatically reduced the buildup of scar tissue inside the stent, raising the interesting possibility that local delivery of apo A-1 Milano could be useful in preventing re-clogging of coronary stents (published in Circulation in 2003).

Based on the body of evidence provided by these various studies from Cedars-Sinai and additional confirmatory studies from Dr. Cesare Sirtori's laboratory in Milan, Esperion Therapeutics initiated human trials of recombinant apo A-1 Milano. In the small Phase 2 study (reported in the November 5, 2003 issue of JAMA), investigators showed that as in animal studies reported from Dr. Shah's lab, once-a-week intravenous administration of recombinant apo A-1 Milano (ETC-216) for five weeks led to a significant and measurable shrinkage of human coronary artery plaques as measured by intravascular ultrasound technique. These findings are unprecedented in that reversal of plaque size has been shown in five short weeks. Among the currently available agents (e.g., statins), reversal of plaque is rare, and even when it occurs it takes many months to years to see regression. Although this human trial of recombinant apo A-1 Milano (ETC-216) is a small study and did not have clinical endpoints, results are extremely provocative and provide proof of concept that HDL mimetic based therapy has the potential to rapidly and favorably change human atherosclerotic plaques. Larger and more definitive trials will be needed to confirm the exciting results reported. Pfizer Pharmaceuticals has recently acquired Esperion Therapeutics and will be designing and launching more definitive human trials over the next two to three years before seeking FDA approval.

Potential limitations include the fact that producing the drug is quite expensive and laborious, the drug has to be given intravenously and repeated intravenous use may be needed to sustain the benefits. Alternatively, initial benefits from short-term intravenous use may be sustained by oral agents currently available (such as statins and niacin) and newer orally effective HDL boosting agents currently in development (such as CETP inhibitors, apo A mimetic peptides, etc.). No serious side effects were noted in this study.

Another approach in the future could be the gene transfer or gene therapy approach in which the actual DNA (gene) that codes for apo A-1 Milano protein is transferred into the body, where it stimulates the production of apo A-1 Milano by the host without need for exogenous repeated supply. Dr. Shah's laboratory is currently using this approach in animals models with the support of a grant from the NIH and in collaboration with researchers from the City of Hope Medical Center. In this project, Dr. Shah and his colleagues have successfully used a virus called the adeno-associated virus (AAV) to ferry the apo A-1 Milano gene into the body of genetically altered mice and shown that such gene transfer is feasible and reduces atherosclerotic plaque buildup after a single injection of the gene carried by the viral vector. Dr. Shah and his colleagues hope to be able to test this approach in humans sometime in the future.