Experimental cholesterol drug, REGN727 (PCSK9 inhibitor) results called ‘game changing

In continuation on my update on drug discovery in the class of  Monoclonal antibodies

Researchers have known for some time that when the protein PCSK9, (below structure) which stands for proprotein convertase subtilisin/kexin 9, binds to LDL receptors on the liver, it compromises the organ’s ability to filter the bad cholesterol from the blood.

Too much LDL cholesterol circulating in the blood can lead to the thickening of artery walls, making them less flexible and therefore impairing their function and increasing the risk of heart disease.

In a phase one clinical trial, which is designed to determine if a drug is safe, researchers found that using a monoclonal antibody (lab-produced protein) called REGN727, was not only safe, but effectively blocked PCSK9 and therefore signficantly reduced bad cholesterol in healthy patients as well as those also taking the popular cholesterol-lowering drug Lipitor.

“Wars for PCSK9 are far bigger than the statin wars,” said Dr. Evan A Stein, lead author of the study and researcher at the Metabolic and Atherosclerosis Research Center in Cincinnati, Ohio. “This is a hot research area and everybody is so close together.”

The REGN727 study included three trial arms. Two arms used 72 healthy volunteers who were either injected with a single dose of the drug in increasing amounts to test for side effects, which is the purpose of a phase one clinical trial.  A third arm included 21 people with a family history of high cholesterol, and 30 people with nonfamilial high cholesterol. All of those subjects were also receiving treatment with the statin Lipitor.

A control group of subjects with nonfamilial high cholesterol was treated only with a special diet.  None of the subjects who received REGN727 discontinued the study because of adverse effects, and the subjects who received REGN727 had a striking reduction of 60 to 65%  in LDL cholesterol, according to Stein.

A PCSK9 inhibitor, Stein said, differs from statins “because it’s unlike any other drug. With statins you get toxicity – with these drugs we don’t see any side effects with the antibody.”

In an accompanying editorial, authors Dr. Stephen G. Young, and Loren G. Fong, Ph.D. write: “At this point, the status of PCSK9 therapeutics appears to be full speed ahead. Soon, we can expect more human trials in which investigators will dissect the properties of different PCSK9 antibodies and assess the effect of these agents.”

However, without long-term safety data and evidence that PCSK9 inhibitors truly help prevent heart disease, Young and Fong caution that it will remain unclear how important this class of drugs will be.

The cost of this drug will also play a role in determining which patients might use it, Fong and Young say.  But they also note that “patients who cannot tolerate statins could benefit greatly.”

Researchers also claim that,  the study methodology was thorough because it included people with high cholesterol as well as people with genetic familial high cholesterol, which is proven to be a result of impaired PCSK9 genetic function.

Researchers have known for some time that when the protein PCSK9, which stands for proprotein convertase subtilisin/kexin 9, binds to LDL receptors on the liver, it compromises the organ’s ability to filter the bad cholesterol from the blood.

Researchers conclude that, In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia.

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1105803

Endothelial Function Improvement With Dietary (Cocoa) Flavanols in Patients With Coronary Artery Disease....

A new study by UCSF cardiologists and researchers lead by Dr. Yerem Yeghiazarians found that high concentrations of cocoa flavanols decrease blood pressure, improve the health of blood vessels and increase the number of circulating blood-vessel-forming cells in patients with heart disease. The findings indicate that foods rich in flavanols  such as cocoa products, tea, wine, and various fruits and vegetables have a cardio-protective benefit for heart disease patients.

Flavanols are phytonutrient compounds that are found naturally in apples, grapes, tea, cocoa and cherries, which account for the antioxidant effect provided by red wine and green tea. The study found a protective effect from a cocoa drink with 375 mg of flavanols, but according to researchers, a standard or recommended dosage has not yet been defined to achieve optimal health benefit.

The UCSF team has shown for the first time that one of the possible mechanisms of flavanol's benefit is an increase in the circulation of so-called angiogenic cells in the blood. These cells, also known as early endothelial progenitor cells, are critical for the repair process after vascular injury, and perform function and maintenance roles in the endothelium. Endothelium is the thin layer of cells that line the interior wall of blood vessels.

In the current study, the benefit seen from the two-fold increase in circulating angiogenic cells was similar to that achieved by therapy with statins and with lifestyle changes such as exercise and smoking cessation. The benefit demonstrated with cocoa flavanol therapy occurred in addition to the medical regimen already being taken by study participants.

"Our data support the concept that dietary flavanols at the levels provided -- in tandem with current medical therapy -- are safe, improve cardiovascular function, and increase circulating angiogenic cells, which have previously been shown to correlate positively with long-term cardiovascular outcomes" said Yeghiazarians.

Though long-term trials examining the effects of high-flavanol diets on cardiovascular health and function are warranted, but these early findings help us understand how these compounds impact the function of damaged blood vessels...

Ref : Yerem Yeghiazarians et.al., J. Am. Coll. Cardiol., July 13, 2010; 56: A20. 

Lovastatin: A New Weapon Against Plague?

We know that, Lovastatin is a member of the drug class of statins,  used for lowering  cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms  and red yeast rice.

Now scientists at the Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (CNRS/Université Aix-Marseille 2), have found that Lovastatin protects animals against the deadly effects of plague.

After inoculating small rodents with the Yersinia pestis bacterium, the team led by Didier Raoult and Michel Drancourt at the URMITE (CNRS/Université Aix-Marseille 2) showed that animals treated with lovastatin presented fewer and less severe infections. Lovastatin therefore has preventive properties against plague mortality in an animal model. This experimental study also reveals that this statin has no direct antibiotic effect against Yersinia pestis but that it prevents the development of septicemia.  

Researchers conclude that Lovastatin had no in-vitro antibiotic effect against Y. pestis. The difference in the mortality between control mice (11/15; 73.5%) and lovastatin-treated mice (3/15; 20%) was significant (P<0.004; Mantel-Haenszel test). Dead mice exhibited Y. pestis septicemia and inflammatory destruction of lung and spleen tissues not seen in lovastatin-treated surviving mice. These data suggest that lovastatin may help prevent the deadly effects of plague, with a caution that field observations are warranted to assess the role of lovastatin in the prophylaxis of human plague....

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010928

Synthetic peptide may regenerate brain tissue in stroke victims

A synthetic version of a naturally occurring peptide promoted the   creation of new blood vessels and repaired damaged nerve cells in lab animals, according to researchers lead by Dr. Daniel Morris Sr.Staff Physician at Henry Ford Hospital in Detroit.

"Neurorestorative therapy is the next frontier in the treatment of stroke." claims Dr. Daniel Morris...

As per the claim by the researchers,  addition of  the synthetic peptide Thymosin beta 4 (structure : acetate of Thymosin beta 4 : courtesy : ChemBlink) to a group of drug treatments including statins (used for neurorestorative therapy to activate repair mechanisms) repaired and regenerated stroke-injured brain tissue.

Interestingly, this  research follows an earlier study reported by the same team in March, which found that Thymosin beta 4 improved neurological function after stroke in adult rats by increasing the formation of protective myelin around nerve fibers in brain cells.

In the latest study, adult rats were dosed with Thymosin beta 4 one day after they were subjected to a blockage in the cerebral artery, then given four more doses, once every three days. Rats treated only with saline were used as a control group. After eight weeks, the Thymosin beta 4 group showed significant overall improvement compared to the control group.

The researchers concluded that the peptide improved blood vessel density as well as promoted a certain type of immature brain cells called oligodendrocyte progenitor cells to differentiate into mature oligodendrocytes, which produces myelin to protect axons in nerve cells.

These experiments conclude that the peptide repairs and regenerates stroke-injured brain tissue. and as per the claim by the researchers,  the results of the first study also were similar to other research using the peptide to regenerate damaged heart, corneal tissue and wound repair...

Ref : http://www.henryfordhealth.org/body.cfm?id=46335&action=detail&ref=1107

Eprotirome a promising addition to statin therapy ?

People with bad cholesterol have  risk of  future heart disease,  despite  cholesterol-lowering statin therapy. Now researchers from  Johns Hopkins have come up with interesting finding i.e.,  a drug that mimics the action of thyroid hormone [Eprotirome (new generic name for KB2115) structure source : chemBlink)  lowered cholesterol up to 32 percent in those already on statins, an effect equal to that expected from doubling the statin drug doses, without harmful side effects. 

Interestingly, the researchers caution that the results don't suggest that eprotirome will or should replace statins, which are the current gold standard for treating high LDL cholesterol.

However, the results of their small trial on 168 patients do suggest that eprotirome may eventually be a promising addition to statin therapy, a substitute for statins in people who can't tolerate their side effects, or a novel treatment for mixed dyslipidemia, a condition in which people have high levels of lipids other than cholesterol such as triglycerides or apolipoprotein B (apo B).

The researchers found that among the patients taking the 25, 50 or 100 mg doses of eprotirome reduced their LDL cholesterol levels by 22 percent, 28 percent, and 32 percent respectively, compared to only 6.5 percent in those taking placebo. Remarkably, they also found similar dose-related reductions in triglycerides, apo B, and Lp(a). They also found modest reductions in HDL cholesterol of approximately 3 percent.

As per the claim by the lead researcher Dr. Paul W. Ladenson,   'this drug represents a new class of medications that might offer hope to those at risk of future cardiovascular disease whose lipid profiles are not effectively altered with statin therapy, and perhaps for about a quarter of those who have tried statins but cannot tolerate their side effects'. Dr. Ladenson is a consultant to Karo Bio, maker of eprotirome.......

Ref : http://content.nejm.org/cgi/content/short/362/10/906

Statins may protect against GVHD complications

Statins may protect against GVHD complications

Positive results from mipomersen- a new hope for FH sufferers...

About Familial hypercholesterolemia :

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a genetic disorder characterized by high cholesterol levels, specifically very high low-density lipoprotein (LDL, "bad cholesterol") levels, in the blood and early cardiovascular disease. Many patients have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.

Heterozygous (FH) is normally treated with statins, bile acid sequestrants or other hypolipidemic agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

Recently, Genzyme Corp. and Isis Pharmaceuticals Inc have come up with some intresting results from the drug mipomersen [mipomersen - is an antisense oligonucleotide, with phosphorothioate linkage at 5'- postion and 2'-O-methoxymethyl moety] ( phase 3). As per the claim by the companies, the study met its primary endpoint in an intent-to-treat analysis, with a 25 percent reduction in LDL-cholesterol after 26 weeks of treatment, vs. 3 percent for placebo (p<0.001)>.

The trial met all of its secondary and tertiary endpoints, suggesting that mipomersen may offer potential benefits to patients beyond LDL-C reduction. Patients treated with mipomersen experienced a 27 percent reduction in apolipoprotein B vs. 3 percent for placebo; a 21 percent reduction in total cholesterol vs. 2 percent for placebo; and a 25 percent reduction in non-HDL cholesterol vs. 3 percent for placebo (all p<0.001).>Mipomersen patients’ HDL-C levels increased 15 percent (p=0.035 vs. placebo), which combined with the LDL-C reductions observed, resulted in improved LDL/HDL ratios, a ratio considered an important measure of cardiovascular risk. Mipomersen patients’ LDL/HDL ratios decreased by 34% (p<0.001>Mipomersen a representative of Isis’ leadership in the field of RNA targeted therapeutics will bring a sigh of relief to the sufferers of FH, in the days to come.

I had an opportunity to work with ISIS (as contract R & D, Innovasynth Technologies Limited, Khopoli) and really excited to see the results..

Ref : http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1356364&highlight=

Statins as anticancer and anti diabetic agents ?

We know that statins are widely used as cholesterol lowering drugs. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. But researchers from University of Gothenburg, have found that statins might be useful as anticancer and antidiabetic too.

Statins lower cholesterol by blocking certain enzymes involved in our metabolism. However, they have also been shown to affect other important lipids in the body, such as the lipids that help proteins to attach to the cell membrane (known as lipid modification). Because many of the proteins that are lipid-modified cause cancer, there are now hopes that it will be possible to use statins in the treatment of cancer.

Studies show that statins can have a dramatic inhibitory effect on growth and development. As the researchers managed to identify the enzyme involved, they can also explain how the effect arises at molecular level. Not least that they can prevent the growth of cancer cells caused by lipid-modified proteins, but also that they can be effective in the treatment of diabetes and neurological disorders such as Parkinson's. In one of my earlier blog, I have mentioned about the simvastin (Simvastatin prevents progression of Parkinson's Disease ?).

So in the days to come statins may be useful as anticancer, anti diabetic and even to treat Parkinsons disaese....


Source : http://www.science.gu.se/english/News/News_detail/Cholesterol-lowering_medicines_may_be_effective_against_cancer.cid898016

Simvastatin prevents progression of Parkinson's Disease ?

About Simvastin :
Simvastatin, (marketed under the names Zocor, Simlup, Simcard, Simvacor) is a hypolipidemic drug belonging to the class of pharmaceuticals called "statins". It is used to control hypercholesterolemia and to prevent cardiovascular disease. Simvastatin is a synthetic derivate of a fermentation product of Aspergillus terreus. When I was working with Bangalore based company, the sister company was working on it and now its marketing too.

Recently researchers from the Rush University, have found an interesting fact that Simvastin, may prevent Parkinson's disease from progressing further. The authors have shown that the activity of one protein called p21Ras is increased very early in the midbrain of mice with Parkinson's pathology. Simvastatin enters into the brain and blocks the activity of the p21Ras protein and other associated toxic molecules, and goes on to protect the neurons, normalize neurotransmitter levels, and improves the motor functions in the mice with Parkinson's.

If the researchers are able to replicate these results in Parkinson's patients in the clinical setting, it would be a remarkable advance in the treatment of this devastating neurodegenerative disease. Hope some relief to the sufferers of Parkinson disease....

Ref : http://www.rush.edu/webapps/MEDREL/servlet/NewsRelease?id=1304

Lovastatin-synthesizing enzyme successfully reconstituted...

Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms and red yeast rice. When I was working with a Banglore based company (Biocon), they did try this compound and I think the company is marketing this drug now. As for as my knowledge goes there were two ways to synthesise 'biosynthesis using Dield-Alder catalyzed cyclization' & 'biosyntheis using broadly specific acyltransferase'

Dield-Alder catalysed cyclisation : In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. The stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.

Biosynthesis using broadly specific acyltransferase : It has been found that a dedicated acyltransferase, LovD, is encoded in the lovastatin biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. The biosynthesis of lovastatin is coordinated by two iterative type I polyketide syntheses and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of lovastatin, is assembled by the upstream megasynthase LovB (also known as lovastatin nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases.

Recently more interesting out come from a group of UCLA researchers is that, for the first time thy have successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. As per the claim by the researchers, the lovastatin-synthesizing enzyme is one of the most interesting but least understood of the polyketide synthases, which are found in filamentous fungi and which play a crucial role in the synthesis of "small molecule natural products" — pharmacologically or biologically potent compounds produced by living organisms, many of which are the active ingredients in pharmaceuticals.

This finding is of great significance because commonly used antibiotics, such as tetracycline, are produced by polyketide synthases. Polyketides represent a class of 7,000 known structures, of which more than 20 are commercial drugs, including the immunosuppressant rapamycin, the antibiotic erythromycin and the anticancer drug doxorubicin. In their study studied the enzyme that makes a small-molecule precursor to lovastatin. The real difference about this enzyme, is its extraoridnarily large size in comparison to all other enzymes so for studied. As per the claim by the lead researcher Dr. Yi Tang, "It's one of the largest enzymes ever to be reconstituted in a test tube. It is 10 times the size of most enzymes people study & the enzyme has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Hope with this remarkable achievement, one can prepare many natural products in the lab in the days to come.

Ref : http://www.newsroom.ucla.edu/portal/ucla/ucla-engineering-researchers-have-111812.aspx

Lovastatin for the treatment of degenerative disc disease ?

We know that Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. But recentlyDr. Yang and his research group has come up with new innovative idea that Lovastatin, helps the differentiation of disc cells in vitro.

Degenerative disc disease is one of the leading sources of back and neck pain. Disc degeneration is part of the normal aging of the spine. In this condition, the spinal discs (the pillow-like pads between the bones) lose their cushioning. When this happens, it can cause persistent pain in the lower back, legs, neck or arms. Treatments for pain can include medications and physical therapy. Sometimes surgery is needed if the pain is severe and keeps a person from participating in everyday activities.

In their quest to discover ways to stop or reverse degenerative disc disease, orthopaedic researchers have been removing disc tissue from patients who are having spine surgery and extracting cells from that tissue for cultivation in vitro (a controlled environment outside of a living organism). They then transfer the cells back into the patient. Shu-Hua Yang, MD, PhD, is part of a Taiwanese research team that has discovered that Lovastatin, a cholesterol-lowering medication, helps the differentiation of disc cells in vitro.

The results are of great interest : 1. the number of nucleus pulposus cells had increased; 2. Lovastatin increased the synthesis of collagen II, a protein that makes up moveable joints, and decreased the synthesis of collagen I, a protein that is related to fibrosis and 3. Lovastatin had no cytotoxicity (the quality of being toxic) on nucleus pulposus cells..

I think if proven, one more addition to the list of serendipity.......

Though further studeis are essential to establish their claim, its a good beginning..