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

Soy Supplements Can Cool Hot Flashes

In continuation of my update on Soy...

Taking soy to relieve hot flashes has received mixed reviews over the years. Now, researchers who took another look at 19 published studies find that soy supplements may help, at least over time. Soy has been touted as an alternative treatment to hormone replacement therapy after HRT was linked to an increased risk of breast cancer.

“For many women with symptoms and especially with concerns about hormone replacement therapy, trying soy for six to 12 weeks to see if it relieves their symptoms could be a first line of treatment,” says Melissa Melby, PhD, a professor of medical anthropology at the University of Delaware.

Researchers conclude that, Soy isoflavone supplements, derived by extraction or chemical synthesis, are significantly more effective than placebo in reducing the frequency and severity of hot flashes. Additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone form, baseline hot flash frequency, and treatment duration.


Ref : http://journals.lww.com/menopausejournal/Abstract/publishahead/Extracted_or_synthesized_soybean_isoflavones.98844.aspx

Lorcaserin Receives Positive Vote From FDA Advisory Committee

In continuation of my update on Lorcaserin

Lorcaserin Receives Positive Vote From FDA Advisory Committee:  

(FDA) Endocrinologic and Metabolic Drugs Advisory Committee voted 18 to 4, with one abstention, that the available data demonstrate that the potential benefits of lorcaserin outweigh the potential risks when used long-term in a population of overweight and obese individuals. Lorcaserin is an investigational drug candidate intended for weight management, including weight loss and maintenance of weight loss, in patients who are obese (BMI greater than or equal to 30) or patients who are overweight (BMI greater than or equal to 27) and have at least one weight-related co-morbid condition.

"The advisory committee's positive vote supports our belief in lorcaserin as a potential new treatment option for the medical management of overweight and obesity," said Jack Lief, Arena's President and Chief Executive Officer. "We will continue to work with the FDA as the agency completes its review of the lorcaserin new drug application."

In continuation of my update on curcumin,,,,

Curcumin, an active component of the Indian curry spice turmeric, may help slow down tumor growth in castration-resistant prostate cancer patients on androgen deprivation therapy (ADT), a study from researchers at Jefferson's Kimmel Cancer Center suggests. More

 Curry spice component may help slow prostate tumor growth

2 Drugs Better Than 1 to Treat Youth With Type 2 Diabetes

2 Drugs Better Than 1 to Treat Youth With Type 2 Diabetes: A combination of two diabetes drugs, metformin and rosiglitazone, was more effective in treating youth with recent-onset type 2 diabetes than metformin alone, a study funded by the National Institutes of Health (NIH) has found. Adding an intensive lifestyle intervention to metformin provided no more benefit than metformin therapy alone.

The study also found that metformin therapy alone was not an effective treatment for many of these youth. In fact, metformin had a much higher failure rate in study participants than has been reported in studies of adults treated with metformin alone.

The study found that treatment with metformin alone was inadequate for maintaining acceptable, long-term, blood glucose control in 51.7 percent of youth over an average follow-up of 46 months. The failure rate was 38.6 percent in the metformin and rosiglitazone group, a 25.3 percent reduction from metformin alone. In the metformin plus lifestyle group the failure rate was 46.6 percent.

A trial looking at curcumin and FOLFOX for advanced bowel cancer (CUFOX)

In continuation of  my update on curcumin

An upcoming clinical trial conducted by the Cancer Research UK and National Institute for Health Research Experimental Cancer Medicine Centre (ECMC) in Leicester, England will evaluate the effectiveness of curcumin, a compound that occurs in turmeric, as a means of improving the results of standard chemotherapy for metastatic colon cancer. The compound has been found to enhance chemotherapy's ability to kill colon cancer cells in previous research involving cell cultures. 

Doctors often treat bowel cancer that has spread with chemotherapy. The combination of chemotherapy they usually use is called FOLFOX. It is made up of the drugs folinic acid (leucovorin), fluorouracil (5FU) and oxaliplatin. But this doesn’t always work very well.  And it often causes side-effects such as numbness and tingling in hands and feet (peripheral neuropathy). This means the doctors sometimes need to lower the dose or even stop chemotherapy, so they are keen to improve treatment.

Curcumin is a plant extract found in the spice turmeric and is found in many everyday foods. We know from research that curcumin can help shrink tumours in the laboratory. It has also been used in several studies involving patients with a range of conditions, including cancer.

FDA AAC recommends approval of Pfizer’s tofacitinib for RA

In continuation of my update on  Tofacitinib...

FDA AAC recommends approval of Pfizer’s tofacitinib for RA: Pfizer Inc. the Arthritis Advisory Committee to the U.S. Food and Drug Administration (FDA) voted 8-2 to recommend approval of the investigational agent tofacitinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). The Committee's recommendation will be considered by the FDA in its review of the New Drug Application (NDA) for tofacitinib. The FDA has provided an anticipated Prescription Drug User Fee Act (PDUFA) action date in August 2012. If approved by the FDA, tofacitinib would be the first new oral disease-modifying antirheumatic drug (or DMARD) for RA in more than 10 years and the first RA treatment in a new class of medicines known as Janus kinase (JAK) inhibitors..

Novartis Drug Pasireotide LAR Shows Superior Efficacy Compared to Sandostatin LAR in Phase III Trial of Patients With Acromegaly

Results of the largest Phase III study of acromegaly patients show the novel therapy pasireotide (SOM230 structure left below) long-acting release (LAR), was significantly more effective at inducing full biochemical control compared to the current standard medical therapy, Sandostatin® LAR® (octreotide/IM injection below right structure). 

Novartis Drug Pasireotide LAR Shows Superior Efficacy Compared to Sandostatin LAR in Phase III Trial of Patients With Acromegaly:  Patients on pasireotide (SOM230) LAR were 63% more likely to achieve full biochemical control than those on Sandostatin LAR, the current standard of care[1]  Acromegaly, a rare  endocrine disorder caused by excess growth hormone, can... 

Ref : http://www.novartis.com/newsroom/media-releases/en/2012/1609172.shtml

Positive Results from First of Two ATX-101 European Phase III Trials for Reduction of Submental Fat

KYTHERA,  announced the presentation of initial trial results from Study ATX-101-10-16, the first of two pivotal European Phase III clinical trials with ATX-101 (a first-in-class injectable drug being studied for the reduction of localized fat. ATX-101 is a proprietary formulation of deoxycholate (see below structure)  a well-studied endogenous compound that is present in the body), a facial injectable drug for the reduction of unwanted fat under the chin, or submental fat. V. Leroy Young, MD, FACS, presented the initial results at the American Society for Aesthetic Plastic Surgery (ASAPS) 45^th Annual Aesthetic Meeting in Vancouver, British Columbia, on May 4, 2012.

The ATX-101-10-16  trial met its pre-specified primary endpoints based on clinician and patient assessments. At the 2 mg/cm² dose, ATX-101 resulted in a statistically significant reduction of submental fat, relative to placebo, as measured using a 5-point Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) (mean of 0.90 vs. 0.22; p<0.001, week 24). Similarly, ATX-101 (2 mg/cm²) resulted in a statistically significant percentage of subjects, relative to placebo, achieving a pre-defined categorical change using a 7-point Subject Self Rating Scale (SSRS) (66.1 vs. 28.7; p<0.001, week 24).

Molecule Found That Inhibits Estrogen, Key Risk Factor for Endometrial and Breast Cancers

Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered a molecule, KLF15 (see structure) that inhibits the action of estrogen. This female hormone plays a key role in the growth, maintenance and repair of reproductive tissues and fuels the development of endometrial and breast cancers. The molecule, discovered in animal studies, could lead to new therapies for preventing and treating estrogen-related diseases in humans.

In studies involving rodents, Dr. Pollard discovered that a molecule called KLF15 (Kruppel-like transcription factor-15) controls the actions of estradiol and progesterone in the endometrium by inhibiting the production MCM2, a protein involved in DNA synthesis.

 

"Our findings raise the possibility that it may be possible to prevent or treat endometrial and breast cancer and other diseases related to estrogen by promoting the action of KLF15," said Dr. Pollard.

The paper, titled "KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing," is coauthored by Sanhita Ray, Ph.D., a postdoctoral fellow at Einstein.

More....

Molecule Found That Inhibits Estrogen, Key Risk Factor for Endometrial and Breast Cancers

Flavonoid Compound Found in Foods and Supplements May Prevent the Formation of Blood Clots, Study Suggests...

A compound called  rutin (see structure - a quercetin derivative), commonly found in fruits and vegetables and sold over the counter a dietary supplement, has been shown to inhibit the formation of blood clots in an animal model of thrombosis.

 As per the researchers claim,

"Approximately half of all morbidity and mortality in the United States can be attributed to heart attack or stroke."..

The study focused on protein disulfide isomerase (PDI) which is found in all cells. Investigators in BIDMC's Division of Hemostasis and Thrombosis had previously shown that PDI is rapidly secreted from both platelets and endothelial cells during thrombosis, when a clot forms in a blood vessel, and that inhibition of PDI could block thrombosis in a mouse model.

"This was a transformative and unanticipated finding because it identified, for the first time, that PDI is secreted from cells in a live animal and is a potential target for preventing thrombosis," says Flaumenhaft. However, because intracellular PDI is necessary for the proper synthesis of proteins, the scientists had to identify a specific compound that could block the thrombosis-causing extracellular PDI -- without inhibiting the intracellular PDI.

They began by conducting a high-throughput screen of a wide array of compounds to identify PDI inhibitors. Among the more than 5,000 compounds that were screened, quercetin-3-rutinoside (rutin) emerged as the most potent agent. "Rutin was essentially the champion compound," says Flaumenhaft.

A bioflavonoid that is naturally found in many fruits, vegetables and teas including onions, apples and citrus fruits, rutin is also sold as an herbal supplement, having received a special designation for safety from the U.S. Food and Drug Administration (FDA). Surprisingly, studies of the rutin molecule demonstrated that the same part of the molecule that provides rutin with its ability to inhibit PDI also prevents the compound from entering cells."That finding explained how this compound can be both a potent inhibitor of PDI and a safe food supplement," says Flaumenhaft. "Our next questions were, 'Is this compound anti-thrombotic? Can it prevent blood clots?'"

Soybeans Soaked in Warm Water Naturally Release Key Cancer-Fighting Substance

In continuation of my update on Soy...

Hari B. Krishnan and colleagues explain that the substance, Bowman-Birk Protease Inhibitor (BBI) 9see the below structure), has shown promise for preventing certain forms of cancer in clinical trials. Those human tests resulted from evidence of BBI's beneficial effects, including indications that BBI derived from the large amounts of soybeans in traditional Japanese diets might underpin low cancer mortality rates in Japan. However, the current method of extracting BBI from soybeans is time-consuming and involves harsh chemicals. The scientists set out to see if there might be a greener and more environmentally friendly way of obtaining BBI.

They found that soybean seeds incubated in water at 122 degrees Fahrenheit naturally release large amounts of BBI that can easily be harvested from the water. The protein appeared to be active, with tests showing that it stopped breast cancer cells from dividing in a laboratory dish.

Sunscreen ingredient may be linked to endometriosis

                          (Picture source: Paper published)
Researchers have come with an interesting findings,  some sunscreens and other personal care products contain benzophenone (BP)-type ingredients that are very effective in blocking potentially harmful ultraviolet rays from the sun. Small amounts of BPs can pass through the skin and be absorbed into the blood, where they mimic the effects of estrogen. Endometriosis, which affects up to 1-in-10 women of reproductive age, needs estrogen to develop. Despite those facts, scientists until now had not checked for a connection between the use of BP sunscreens and the likelihood of being diagnosed with endometriosis.

Sunscreen ingredient may be linked to endometriosis

Ref : http://pubs.acs.org/doi/abs/10.1021/es204415a

Lenalidomide Shows Significant Benefit for Myeloma Patients, Phase III Study Suggests

In continuation of my update on lenalidomide...

Data from the first large U.S. study assessing the effectiveness of long-term "maintenance" therapy with lenalidomide for patients with multiple myeloma show that the drug significantly improves the time to progression and overall survival for patients with this often-deadly hematologic cancer. 

Among 460 patients aged 18 to 70 (median age 59), 321 were randomly assigned to the lenalidomide arm, and 229 to the placebo group. All participants had received prior autologous hematopoietic stem-cell transplantation and had stable (non-progressing) disease. The participants' assignments and responses to date were unblinded in December 2009 when the primary endpoint of the study (time to disease progression) showed a statistically significant difference between the two study groups. After January 2010, 86 of 128 eligible patients crossed over from the placebo arm to the active arm.

The researchers found that the therapy extended the time to disease progression by 19 months overall, even with the majority of placebo patients without progression crossing over to lenalidomide. The treatment was fairly well-tolerated particularly as compared to other treatments for multiple myeloma, such as thalidomide. There was more hematologic toxicity, particularly neutropenia, in the lenalidomide group. When the study data was analyzed again in October 2011, at a median follow-up of 34 months, 37% of participants receiving lenalidomide had disease progression or had died, compared to 58% of those in the placebo group.

"These findings fill a gap that existed previously in terms of data on whether maintenance therapy with lenalidomide prolongs the time to disease progression after initial therapy. We now have evidence that it does, in this and the two other lenalidomide studies that are presented in this issue of the Journal," said Dr. McCarthy. "This shows that patients with multiple myeloma now have options for prolonging the response to initial therapy. The next steps will be trying to improve on these responses by adding new agents that may prove even more effective in combination with lenalidomide following transplant."

Rexahn submits Phase II protocol for Archexin clinical study for ovarian cancer

In continuation of my update on Archexin (Archexin(R) was fromerly named as RX-0201, is  an oligonucleotide with 20 mers..c ompound that  inhibits the expression of human Akt-1.)...

Rexahn submits Phase II protocol for Archexin clinical study for ovarian cancer: Rexahn Pharmaceuticals, Inc., a clinical stage pharmaceutical company developing and commercializing potential best in class oncology and CNS therapeutics, today announced that it has submitted a Phase II protocol for the clinical study of Archexin as a treatment of ovarian cancer to the U.S. Food and Drug Administration (FDA).