Scientists Discover Drug Candidate for Alzheimer’s, Huntington’s

Scientists at the Gladstone Institutes have identified a drug candidate that diminishes the effects of both Alzheimer's disease and Huntington's disease in animal models, offering new hope for patients who currently lack any medications to halt the progression of these two debilitating illnesses.

Gladstone Investigator Paul Muchowski, PhD, has identified a new compound called JM6 in experiments done in collaboration with an international team of researchers, and which are being published today in an online article in Cell. In laboratory tests involving mice genetically engineered to model one or the other of the two diseases, Dr. Muchowski's team found that JM6 blocks kynurenine 3-monooxygenase (KMO), an enzyme that has long been speculated to play a role in neurodegenerative diseases.

In mice modeling Alzheimer's disease, the novel compound prevented memory deficits and the loss of synaptic connections between brain cells—both of which are key features of the human disease. In mice modeling Huntington's disease, JM6 prevented brain inflammation and the loss of synaptic connections between brain cells, while also extending lifespan.

“This discovery has significant implications for two devastating diseases and suggests that the KMO enzyme is a good protein for us to target with medications in diverse neurodegenerative disorders,” said Lennart Mucke, MD, who oversees all neurological research at Gladstone and who won the prestigious Potamkin Prize last year for developing experimental strategies to make the brain more resistant to Alzheimer's. “With any luck, Dr. Muchowski and his colleagues could begin testing this drug in patients within the next two years.”

Remarkably, JM6 (see structure) does not penetrate into the brain, but works by inhibiting KMO in the blood. The blood cells then send a protective signal to the brain, to stabilize brain-cell function and prevent neurodegeneration. The fact that the compound does not pass the so-called blood-brain barrier will facilitate testing in patients, as JM6's potential impact could be confirmed with a simple blood test.

JM6 was named for Dr. Muchowski's father, Dr. Joseph Muchowski, PhD, a retired medicinal chemist who helped his son devise the novel KMO inhibitor. The study was carried out in collaboration with the laboratories of Dr. Robert Schwarcz, a University of Maryland School of Medicine professor who pioneered studies linking KMO and metabolically related enzymes to nerve-cell loss, and Professor Eliezer Masliah at the University of California, San Diego, an expert in neuropathology.

 Ref : www.cell.com/abstract/S0092-8674(11)00581-2

Positive Results of Diltiazem from Fissure Trial

Ventrus Biosciences Inc. reported positive results from its Phase 3, randomized, double-blind, placebo-controlled clinical trial of diltiazem hydrochloride cream (VEN 307) in patients with anal fissures.

Ventrus' development partner, S.L.A. Pharma, has completed most of the outputs for the statistical analysis plan of the Phase 3 trial, and Ventrus is pleased to communicate the data that they have generated.

The Phase 3 study randomized 465 subjects to diltiazem hydrochloride 4% or 2% w/w cream, or placebo, applied topically three times daily (TID) for 8 weeks, followed by a 4 week blinded observation period. Both 4% and 2% diltiazem treatment arms demonstrated significant improvements compared to placebo in the primary endpoint of average of worst anal pain associated with or following defecation (pain score improvement 0.44, p=0.0108, 4%; 0.43, p=0.0134, 2%) and in the secondary endpoints of overall anal-fissure-related pain (pain score 0.36, p=0.030, 4%; 0.40, p=0.0183, 2%) and anal fissure healing (32.7%, p=0.0181, 4%; 31.2%, p=0.0359, 2%). Pain endpoints were assessed using an 11-point numerical pain rating scale (Likert-like scale).

Adverse events (AEs) were similar for the three treatment arms. Gastrointestinal Disorders were the most common. Reports of headaches were similar in the three arms (14.7% of 4% diltiazem, 12.3% of 2% diltiazem, and 14.2% of placebo). There was one serious adverse event of surgery for hemorrhoid reported in this trial. The study was conducted in 31 centers in Europe by S.L.A. Pharma, the product candidate's licensor. Ventrus holds rights to diltiazem hydrochloride cream in North America.

Based on these results, Ventrus will request a meeting with the U.S. Food and Drug Administration (FDA) to discuss the Phase 3 diltiazem study, as well as steps to move forward toward a New Drug Application (NDA). Because diltiazem is approved in oral formulations for the treatment of angina and high blood pressure, it is eligible for the FDA's 505(b)2 registration pathway. The Company is also preparing to initiate a second pivotal Phase 3 study of VEN 307 in anal fissures in the second half of 2012.

Ref : http://investor.ventrusbio.com/releasedetail.cfm?ReleaseID=672924

Trial will evaluate resveratrol in Alzheimer's dementia

In continuation of my update on Resveratrol

Researchers at Georgetown University and 25 other U.S. academic institutions affiliated with the Alzheimer's Disease Cooperative Study will be conducting a phase II double-blinded, placebo-controlled trial that will test the effects of resveratrol in Alzheimer's disease patients. "This is the gold-standard for conducting a clinical study because it allows us to objectively determine if resveratrol is offering any benefits," stated Brigid Reynolds, NP, who is the lead researcher for the study's center at Georgetown.

The twelve-month trial, funded by the National Institute on Aging, will enroll men and women age 50 and over with mild to moderate dementia diagnosed as probable Alzheimer's disease and will require one caregiver or friend for each patient. Participants will be initially assigned to 500 milligrams resveratrol or a placebo daily, with dosage to be increased at 13 week intervals to a maximum of 1,000 milligrams twice per day. Lumbar punctures, brain magnetic resonance imaging (MRI) scans, and blood and urine tests will monitor the subjects' progress over the course of ten visits. The researchers hope to determine whether supplementation with resveratrol is helpful in delaying or altering the deterioration of memory and daily function that occurs in Alzheimer's disease.

"Most resveratrol studies showing any health benefits have been conducted in animal models, such as mice, and with doses that far exceed intake from sipping wine or nibbling on chocolate," stated R. Scott Turner, MD, PhD, who is the director of Georgetown University Medical Center's Memory Disorders Program and the national study's lead investigator. "With this clinical trial, we'll find out if daily doses of pure resveratrol can delay or alter memory deterioration and daily functioning in people with mild to moderate dementia due to Alzheimer's."

"During this study, we will also test whether resveratrol improves glucose and insulin metabolism in older individuals -- although those who already have diabetes will not be included in this study," he added....

Ref : http://explore.georgetown.edu/news/?ID=64145

Ebola, Marburg Virus Treatments Safe in Phase 1 Studies

In continuation of my update on antisense drugs and RNAi

AVI BioPharma Inc. announced positive safety results from the first five cohorts of Phase 1 single ascending dose trials of AVI-6002 and AVI-6003, AVI's lead drug candidates being evaluated for the treatment of the Ebola virus and Marburg virus.

Data were evaluated by an independent Data and Safety Monitoring Board (DSMB), which issued recommendations for both studies to progress as planned to the next highest dosing level after no safety concerns were identified. The Phase 1 single ascending dose trials are designed to characterize the safety, tolerability, and pharmacokinetics of each therapeutic candidate in healthy adult volunteers.

"We are very encouraged that these two drugs, which use our advanced PMOplus chemistry, have demonstrated a favorable safety profile through five cohorts in our dose-escalation studies,”says Chris Garabedian, president and chief executive officer of AVI BioPharma...

Ref : http://phx.corporate-ir.net/phoenix.zhtml?c=64231&p=RssLanding&cat=news&id=1619940

To date, 25 healthy human subjects (five per group) have been enrolled into five sequential dose groups in each of the two studies. Within each group, four subjects received the indicated dose of the therapeutic and one subject received placebo. For each group, safety, clinical laboratory and renal biomarker results through five days after treatment were reviewed by a DSMB. Subjects enrolled in the sixth group for the drug studies will receive 9.0 mg/kg of the therapeutic or placebo. Final, un-blinded safety and pharmacokinetic results for all subjects will be available upon completion of the trial.

Both candidates employ AVI's patented PMOplus technology that selectively introduces positive charges to its phosphorodiamidate morpholino oligomer (PMO) backbone to improve interaction between the drug and its target.

Tivozanib Improves RCC (renal cell carinomas) Survival

Tivozanib (see structure, AV-951) is an oral VEGF receptor tyrosine kinase inhibitor. It is undergoing clinical trial investigation for the treatment of renal cell carinomas. An oral quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor.

The positive results of this Phase 2 trial informed the design and implementation of TIVO-1, a pivotal Phase 3 clinical study in advanced RCC demonstrating tivozanib superiority over sorafenib in the primary endpoint of PFS in the first-line setting, top-line data from which were reported in January 2012.

“Current RCC therapies are associated with toxicities that can interfere with patients’ treatment regimens and impact treatment efficacy and activities of daily living,” said Dmitry A. Nosov, M.D., Ph.D., senior clinical researcher at the Blokhin Oncology Research Center, Moscow, Russian Federation, lead author of the Phase 2 study and TIVO-1 investigator.

“Despite recent progress in treating patients with RCC, patients and physicians would benefit from a new RCC treatment option that delivers both improved efficacy and a more tolerable safety profile. The combined tivozanib efficacy and safety data demonstrated in this Phase 2 study supports tivozanib as a potential advancement in the RCC treatment landscape.”

Based on the positive Phase 2 data and success of the TIVO-1 trial, AVEO and its collaborator Astellas Pharma Inc. are moving forward with plans for submitting the tivozanib NDA in RCC in the third quarter of 2012, with the MAA submission to follow.

“We believe that the efficacy and safety profile consistently demonstrated by tivozanib and recently validated in our Phase 3 TIVO-1 trial represent an important step forward in the treatment of patients who have advanced RCC,” said William Slichenmyer, M.D., Sc.M., chief medical officer, AVEO. “We are pleased with the opportunity to collaborate with tivozanib study investigators on publishing these positive Phase 2 data in the Journal of Clinical Oncology, and look forward to advancing our work with our global partners at Astellas to bring tivozanib to patients who can benefit from this therapy.”....

http://jco.ascopubs.org/content/30/14/1678.abstract?sid=1fe73024-e1cc-481f-acc3-1dc09b596f7f

Dalcetrapib Testing Halted..

A second experimental cholesterol medicine in a once-promising class of drugs meant to replace blockbusters such as Lipitor has failed in testing, casting doubt on whether any of the drugs will ever make it to pharmacies.

Swiss drugmaker Roche Holding AG said it has halted testing of its dalcetrapib (see structure), which the company had hoped would become a blockbuster, with eventual annual sales of more than $1 billion. The drug was in expensive late-stage patient testing as a treatment to raise HDL, or so-called good cholesterol, in heart disease patients.

Basel-based Roche said it decided to pull the plug on the recommendation of its independent data and safety monitoring board after an interim analysis, in a study called dal-OUTCOMES, found no "clinically meaningful" benefit.

Ref : http://www.roche.com/media/media_releases/med-cor-2012-05-07.htm

Positive Data from aripiprazole intramuscula for Schizophrenia Trial

Otsuka Pharmaceutical Co. Ltd. and H. Lundbeck A/S announced results from a Phase 3 clinical trial evaluating the efficacy, safety and tolerability of once-monthly aripiprazole (see structure) intramuscular (IM) depot formulation for the maintenance treatment of adults with schizophrenia. Trial results were presented in four poster presentations at the 2012 American Psychiatric Association (APA) Annual Meeting in Philadelphia. 

In a 52-week, double-blind, randomized, placebo-controlled study conducted by Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC), aripiprazole IM depot formulation significantly delayed time-to-impending relapse compared to placebo, the primary endpoint of the study (Hazard ratio = 5.03, p<0.0001). In addition, improvements in the symptoms [as measured by the Positive and Negative Syndrome Scale (PANSS) total score] were maintained throughout the study in patients treated with aripiprazole IM depot formulation, while patients who received placebo reported significantly worsening scores (mean change from baseline at week 52 was 1.4 for aripiprazole IM depot formulation compared to 11.6 for placebo; LOCF analysis, p<0.0001).

Canagliflozin Provided Substantial and Sustained Glycemic Improvements as Monotherapy and in Add-On Combinations in Adults with Type 2 Diabetes in Five Phase 3 Studies

Canagliflozin is an experimental drug being developed by Johnson & Johnson for the treatment of type 2 diabetes. It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine..

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Lilly, Boehringer Ingelheim announce results from linagliptin Phase III trial on T2D

 In continuation of my update on Linagliptin

Results of the one Phase III study presented (Poster No. 999-P) showed that linagliptin was effective as an add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone in reducing blood glucose levels in adult patients with T2D, when compared to placebo as an add-on to these background therapies. Linagliptin demonstrated a placebo-adjusted reduction in HbA1c of 0.65% (p<0.0001) from a baseline HbA1c of 8.3% at 24 weeks without weight gain or additional risk of hypoglycaemia.  HbA1c is measured in people with diabetes to provide an index of blood glucose control for the previous two to three months. 

A post-hoc analysis from a second Phase III trial (Poster No. 1044-P) found that in hyperglycaemic patients on a background of metformin randomised to add linagliptin or glimepiride, a greater proportion of patients taking linagliptin achieved target HbA1c <7% without weight gain and/or hypoglycaemia than those taking glimepiride after 104 weeks (linagliptin 54% versus glimepiride 23%) while comparably improving blood glucose levels.

Ref : http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2012/09_june_2012_linagliptin1.html

Drug kills cancer cells by restoring faulty tumor suppressor

A new study describes a compound that selectively kills cancer cells by restoring the structure and function of one of the most commonly mutated proteins in human cancer, the "tumor suppressor" p53. The research, published by Cell Press in the May 15th issue of the journal Cancer Cell, uses a novel, computer based strategy to identify potential anti-cancer drugs, including one that targets the third most common p53 mutation in human cancer, p53-R175H. 

Restoring the function of mutant p53 with a drug has long been recognized as an attractive cancer therapeutic strategy," explains senior study author, Dr. Darren R. Carpizo, from The Cancer Institute of New Jersey. "However, it has proven difficult to find compounds that restore the lost function of a defective tumor-suppressor."

Using the National Cancer Institute's anticancer drug screen data researchers identified two compounds from the thiosemicarbazone family that manifest increased growth inhibitory activity in mutant p53 cells, particularly for the p53^R175 mutant. Mechanistic studies reveal that NSC319726 (see structure) restores WT structure and function to the p53^R175 mutant. 

This compound kills p53^R172H knockin mice with extensive apoptosis and inhibits xenograft tumor growth in a 175-allele-specific mutant p53-dependent manner. This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53^R175 mutant reactivator and as a lead compound for p53-targeted drug development.

Drug kills cancer cells by restoring faulty tumor suppressor