Biovail stumbles on Phase III testing for Parkinson's drug

The risks of Biovail Corp.'s expansion into drugs for the central nervous system became apparent yesterday when a trial of a new treatment for Parkinson's disease failed.

The Toronto-based pharmaceutical giant, and its U.S. partner, Acadia Pharmaceuticals Inc., said a Phase III trial of the drug pimavanserin, which is supposed to treat hallucinations and delusions that often come with Parkinson's disease, did not meet its goals. In the trial with almost 300 patients, those treated with a placebo fared better than those getting one of the two trial dosages.

This is a disappointment, given Biovail's new focus on developing and marketing drugs for disorders of the central nervous system (CNS), but is not a significant setback, said chief executive officer Bill Wells.

"This sort of thing is to be expected in the drug development business," he said in an interview. "Phase III failures are quite normal."

Biovail's CNS strategy is unchanged, he said. "This game is all about shots on goal, which is why we wanted to build a portfolio of opportunities, understanding that the majority of those would fail, but the one or two which are successful will pay for all the rest."

Acadia and Biovail said they will examine the trial data in more detail before deciding whether to abandon the drug altogether. Pimavanserin also has potential to treat other diseases, such as Alzheimer's, and there is "a reasonable possibility we might have some other directions to go," Mr. Wells said.

For Acadia, a San Diego-based company that has only a small number of drugs in its pipeline, the failure is much more serious than for Biovail, which has a large portfolio of products. The response from investors underlined this, as Acadia shares plunged 66 per cent on the Nasdaq Stock Market yesterday, while Biovail's fell just 3 per cent on the Toronto Stock Exchange.

Biovail was not expecting any revenue from pimavanserin until at least 2012, so there is no short-term impact on the company, said Claude Camiré, an analyst at Paradigm Capital Inc. in Toronto.

While the new drug would have been helpful if it had been successful, the setback will push Biovail to make other acquisitions and diversify its risk, he said. Biovail is still one of the fastest-growing drug companies in the world, Mr. Camiré said, and he is maintaining his "buy" recommendation on the stock.

Biovail signed its deal with Acadia in May, paying an upfront fee of $30-million (U.S.) for the right to develop, manufacture and commercialize pimavanserin in Canada and the United States. Biovail agreed to make further payments in the hundreds of millions, if the drug were to meet specific milestones leading to commercialization. So far, no more payments have been made.

Acadia's CEO Uli Hacksell told analysts on a conference call that his company will go ahead with another Phase III trial of pimavanserin for Parkinson's, set to be complete in about a year. If the drug completely fails for Parkinson's, it might be useful for other diseases, Mr. Hacksell said.

"While we are obviously disappointed in the data we announced today, we still believe in the potential of pimavanserin as a product candidate, based on our clinical experience to date with this compound and its attractive safety profile," he said. "We haven't given up on pimavanserin."
Source : www.theglobeandmail.com

read more» Read more...

Depomed's new Parkinson's drug shows promise

Depomed , a specialty pharmaceutical company, reported positive updates in it's most recent 10Q regarding it's phase 1 clinical trial for the treatment of Parkinson's disease with DM-1992, a novel sustained-release formulation of LevoDopa/Carbidopa.

According to the company's 10Q, Depomed completed the study in early August of 2009. "In the study, DM-1992 extended coverage above Levodopa's efficacous threshold and extended the time to peak Levodopa concentration relative to Sinemet CR, the currently available sustained release Levodopa/Carbidopa formulation. One of Depomed's formulation was able to extend the therapeutic duration to nine hours, compared to Sinemet CR's seven hours. Furthermore, the time to peak blood levels was extended to four hours with Depomed's formulation compared to 2 hours for Sinemet CR. The Phase I trial in DM-1992 was a randomized, open-label crossover study that enrolled 18 patients with stable Parkinson's disease." The clinical results of this trial should be released fairly soon.

Depomed's new drug applies it's patented AcuForm technology to a commonly used Parkinson's drug, Sinemet. Despite being the current gold standard, Sinemet is known for it's debilitating side effects. "Waking up in the morning can be a real drawback for Parkinson's patients on Sinemet or Sinemet CR" said our industry expert. "They wake up and the blood levels of Sinemet have dropped so low that it becomes difficult for patients to even get up and take another pill. On the other hand, just after taking Sinemet, patients experience nausea or hallucinations because the tablet dumps the medicine over a narrow period of time." Sinemet CR is usually dosed three times a day and patients often experience nausea or hallucinations shortly after taking their treatment. Furthermore, as the effects of Sinemet wear-off, patients experience severe dyskinesia, especially late at night or in the early morning, when the blood levels of the drug have dropped significantly. Depomed hopes to capitalize on Sinemet's drawbacks, by improving the efficacy and eliminating some of these horrible side effects.

"This is a serious problem. Most Parkinson's patient dread not being able to move in the mornings when the drug wears off or the nausea that occurs just after taking the drug. The problem is so severe that some patients elect to surgically implant a pump so that they can get continuous delivery of Levodopa/Carbidopa." Our analyst was referring to treatments like Duodopa, a patient-operated portable pump that is currently marketed by Solvay Pharmaceuticals

It seems that Depomed's new drug may change all of that.

Depomed uses a technology that capitalizes the expansile properties of certain polymers. These polymers have long been used in the food industry to "fluff" ice cream and are safe. Upon entering the stomach an AcuForm coated pill expands and is retained in the stomach for up to 8 hours. This helps to deliver a drug like Levadopa/Carbidopa over a longer period of time. In this case, Depomed's technology could decrease the daily dosage of Levadopa/Carbidopa and prevent the narrow peaks and sudden drops in plasma levels that leads to side effects like nausea and morning dyskinesia.

"When a Parkinson's patient takes a pill coated with Depomed's technology, they may not experience the same morning dyskinesia as patient on Sinemet or Sinemet CR. Depomed's drug candidate, DM-1992, seems to be well-differentiated and looks to be an improvement over Sinemet." Although the preliminary data from the 10-Q looks promising, no conclusions can be made until Depomed releases the results of the trial, which should be within the coming weeks.

In July 2008, the Michael J. Fox Foundation awarded Depomed a modest preclinical grant under the foundation’s Therapeutics Development Initiative. This grant helped in the development of DM-1992 under the hypothesis that Levodopa/Carbidopa’s window of absorption in the upper gastrointestinal tract can be optimized using Depomed’s AcuForm technology.

Earlier this month, Merck announced that it had licensed Depomed's AcuForm technology for a combination product with Januvia. Depomed is set to report three phase III trials in October of this year.

Source : www.threebrothershealth.com

read more» Read more...

Novel Drug Discovery Tool Could Identify Promising New Therapies For Parkinson's Disease

Researchers have turned simple baker's yeast into a virtual army of medicinal chemists capable of rapidly searching for drugs to treat Parkinson's disease.

In a study published online July 13 in Nature Chemical Biology, the researchers showed that they can rescue yeast cells from toxic levels of a protein implicated in Parkinson's disease by stimulating the cells to make very small proteins called cyclic peptides. Two of the cyclic peptides had a protective effect on the yeast cells and on neurons in an animal model of Parkinson's disease.

"This biological approach to compound development opens up an entirely new direction for drug discovery, not only for Parkinson's disease, but theoretically for any disease where key aspects of the pathology can be reproduced in yeast," says Margaret Sutherland, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS). "A key step for the future will be to identify the cellular pathways that are affected by these cyclic peptides." This research was funded by the National Institutes of Health.

The research emerged from the lab of Susan Lindquist, Ph.D., a professor of biology at the Massachusetts Institute of Technology (MIT), a member of the Whitehead Institute for Biomedical Research, and a Howard Hughes Medical Institute investigator. Dr. Lindquist is also an investigator at the Massachusetts General Hospital (MGH)/MIT Morris K. Udall Center for Excellence in Parkinson's Research, one of 14 such centers funded by NINDS to develop treatment breakthroughs for Parkinson's disease. The study received additional funding from NIH's National Institute of Environmental Health Sciences, and from the Michael J. Fox Foundation and the American Parkinson's Disease Association.

Parkinson's disease attacks cells in a part of the brain responsible for motor control and coordination. As those neurons degenerate, the disease leads to progressive deterioration of motor function including involuntary shaking, slowed movement, stiffened muscles, and impaired balance. The neurons normally produce a chemical called dopamine. A synthetic precursor of dopamine called L-DOPA or drugs that mimic dopamine's action can provide symptomatic relief from Parkinson's disease. Unfortunately, these drugs lose much of their effectiveness in later stages of the disease, and there is currently no means to slow the disease's progressive course.

In most cases, the cause of Parkinson's disease is unknown, but there are recent, tantalizing clues. Investigators have discovered that vulnerable brain cells in patients with Parkinson's disease accumulate a protein called alpha-synuclein. Moreover, genetic abnormalities in alpha-synuclein cause a rare familial form of the disease. Dr. Lindquist and her team previously showed that when yeast cells are engineered to produce large amounts of human alpha-synuclein, they die.

In their new study, Dr. Lindquist and her team tested whether yeast could make cyclic peptides that would save them from alpha-synuclein's toxicity. Cyclic peptides are fragments of protein that connect end-to-end to form a circle. Although cyclic peptides are synthetic, they resemble structures that are found in natural proteins and protein-based drugs, including pain killers, antibiotics and immunosuppressants. Cyclic peptides that suppress alpha-synuclein toxicity could be candidate drugs for Parkinson's disease, or they could help researchers identify new drug targets for the disease.

"Our technique, which capitalizes on a long line of investigation in my lab, will lead to a whole new way to obtain small molecule tools useful for improving our understanding of disease mechanisms and for developing new therapies," says Dr. Lindquist. She notes that her lab and others have modeled many human diseases in yeast and in other kinds of cells.

Joshua Kritzer, Ph.D., a chemist and postdoctoral fellow in Dr. Lindquist's lab, designed and executed the cyclic peptide strategy. His procedure involves exposing yeast cells to short snippets of DNA that the cells can absorb and use to make cyclic peptides. Then, he flips the genetic switch that causes the cells to produce toxic levels of alpha-synuclein. If the yeast make cyclic peptides that suppress alpha-synuclein toxicity, they live; if not, they die. This simple assay enables testing millions of cyclic peptides simultaneously in millions of yeast cells. The process is extremely rapid and much less expensive compared to other techniques used to screen large number of chemicals with an eye toward new drugs.

"We are making the yeast do a ton of work for us. They make the compounds and then they tell us which ones are functional," Dr. Kritzer says. Out of a library of 50 million cyclic peptides, only two saved the yeast from alpha-synuclein toxicity.

Dr. Lindquist's team collaborated with other researchers to test these two cyclic peptides in C. elegans, a millimeter-long worm with a small number of dopamine-producing neurons that are easy to examine and count. Those neurons are vulnerable to alpha-synuclein toxicity, but they were less vulnerable and more likely to survive in worms that were genetically modified to make either of the two cyclic peptides. Guy Caldwell, Ph.D., and Kim Caldwell, Ph.D., professors of biology at the University of Alabama in Tuscaloosa developed this C. elegans model, and performed the testing.

The researchers have not yet determined why the cyclic peptides are protective. They found that the cyclic peptides do not affect a system of transport inside cells known as vesicle trafficking – which was a surprise, since alpha-synuclein and other proteins that have been implicated in human Parkinson's disease are believed to play a role in vesicle trafficking. However, the researchers observed that the two peptides share a structure that may hold clues to their targets.

"This protein structure has important biological functions," says Dr. Kritzer. It is found in a class of antioxidant proteins known as thioredoxins, in proteins that shuttle metals around a cell, and in proteins that regulate gene activity. The connection to antioxidants and to metals ties into other lines of research. NINDS is currently supporting clinical trials in patients to test whether specific antioxidants slow the progression of Parkinson's disease. High doses of heavy metals such as lead, manganese, iron and mercury are known to be toxic to brain cells.

The researchers are conducting further experiments to explore how cyclic peptides prevent cell death. They are also adapting their system for making cyclic peptides so that it can be used in other cell types (including human cells) and other diseases.

Source : www.sciencedaily.com

read more» Read more...

Parkinson's medications may help treat extreme drug-resistant TB

Two drugs that are commonly used to treat Parkinson's disease have been found to be effective in treating extreme drug-resistant tuberculosis, say researchers at the University of California, San Diego.

They have discovered that the two commercially available drugs, entacapone and tolcapone, have the potential to treat multi-drug resistant and extensively drug resistant tuberculosis.

"We have computational, and experimental data to support this repositioning," said Dr Philip E. Bourne, professor of pharmacology at UCSD's Skaggs School of Pharmacy and Pharmaceutical Sciences and the principle investigator on the project.

"What is exciting about this finding is that the TB target, enzyme InhA, is already well known. But existing drugs are highly toxic and of completely different chemical structure than entacapone and tolcapone.

"Here we have drugs that are known to be safe and with suitable binding properties which can be further optimized to treat a completely different condition," he added.

While working with the TB bacterium itself, they found that the active component in Comtan tablets (entacapone) is effective at inhibiting M.tuberculosis in concentrations well below a level that is toxic to cells.

"Although we have demonstrated in the lab that Comtan is active against M.tuberculosis, additional studies are required in order to transform it into an anti-tubercular therapeutic," said Sarah L. Kinnings, a graduate student and lead author on the study.

"Given the continuing emergence of M.tuberculosis strains that are resistant to all existing, affordable drug treatments, the development of novel, effective and inexpensive drugs is an urgent priority," she added.

The study appears in PLoS Computional Biology.

Source : www.newkerala.com

read more» Read more...