Archive for the ‘New drugs’ Category

New Anti-AIDS pill under development

Saturday, January 3rd, 2009

New anti-aids pillScientists are developing an anti-AIDS pill that can be taken before sex and prevent transmission of the deadly disease.

The successful development of such a treatment would be controversial because it raises ethical questions about the circumstances in which the pill should be taken.

Experts in the disease, which claimed two million lives last year, are involved in scientific trials on antiretroviral drugs that already used to prevent transmission of AIDS from infected mothers to their babies during birth.

Scientists are hopeful that similar protection can be offered during sex.

Three trials of antiretroviral drugs are underway around the world. A report published in the Lancet claims they are “showing great promise” as experts meet in Mexico City for the International Conference on AIDS.

More research has to be done on the side-effects of the pill and the development of resistant strains of HIV before it is made available.

Controversy is bound to arise over who should take the pill and for what reasons. Globally, use would probably have to be restricted to those at greatest risk from AIDS such as sex workers or injecting drug users.

The pill could also have a major impact on the lifestyles at a time when experts have observed that promiscuity is on the rise.

“The party scene involving multiple sexual partners is definitely back in London and probably in most European cities,” said Sheena MCormack, a specialist in HIV prevention and reader in clinical epidemiology at Imperial College London, said.

“There is metrosexual mixing involving gay, bisexual and some heterosexual cases. We estimate new HIV infections in gay men are running at three per cent a year.”

She added: “People could pop a pill on a Friday night and be covered for a whole weekend.”

The trials involve 2,400 drug injectors in Thailand, 1,200 heterosexual men and women in Botswana and 3,000 homosexual men in America, Africa and Asia.

Experiments on primates suggest that the drugs are effective and can prevent the disease being passed. But their success in humans has yet to be proved, the Lancet report by Nancy Padian of Women’s Global Heath Imperative, San Francisco, said.

The trials use tenofovir, a drug currently used to treat AIDS, with a combination of other drugs.

Tenofovir (Trade name Viread) is an anti-HIV drug approved by the FDA (In October of 2001) to be used in combination with other HIV fighting medications. Viread belongs to a new class of drugs called Nucleotide Reverse Transcriptase Inhibitors (NtRTI). These are related to Nucleoside Reverse Transcriptase Inhibitors (NRTI) like zidovudine (AZT, Retrovir). The body converts Viread into a chemical that prevent HIV from reproducing in uninfected cells, but it does not help cells that have already been infected with the virus. As people with HIV lose CD4 cells - one of the immune system’s main defenses - they become more likely to get infections and illnesses.

(more…)

Posted in Drugs and Medications, HIV/AIDS medicines, New drugs, Research | 1 Comment »

Levoleucovorin is the first new oncology drug approved by the FDA in 2008

Sunday, March 9th, 2008

LevoleucovorinSpectrum Pharmaceuticals, Inc. today announced that it has received marketing approval from the U.S. Food and Drug Administration (FDA) for Levoleucovorin for Injection. It is indicated after high-dose methotrexate therapy in patients with osteosarcoma, and to diminish the toxicity and counteract the effects of impaired methotrexate elimination or inadvertent overdose of folic acid antagonists. LEVOleucovorin is the only commercially available formulation comprised only of the pharmacologically active enantiomer of leucovorin (Levoleucovorin or (6S)-leucovorin). The Company currently expects its commercial launch by June 2008.

LEVOleucovorin was reviewed under a full NDA, and included an Oncologic Drug Advisory Committee (ODAC) review. Spectrum anticipates that the drug will be listed without any therapeutically equivalent product in the FDA Orange Book. Drugs without therapeutic equivalents are considered ’single source drugs’ which under section 1847A of the Social Security Act generally qualify for a separate reimbursement code with CMS.

“LEVOleucovorin is the first new oncology drug approved by the FDA in 2008, and is the first of what we hope will be many approvals from our pipeline,” said Rajesh C. Shrotriya, M.D., Chairman, President and Chief Executive Officer of Spectrum Pharmaceuticals. “Only four of the 17 drugs approved by the FDA in 2007 were new oncology drugs. This approval is the result of dedicated efforts by our experienced team and serves as a validation of our business model. We are focused on building a diversified portfolio of promising late stage drugs, and advancing them through clinical development, regulatory process and commercialization.”

In preparation for the commercial launch, last year the Company appointed George Uy, an experienced oncology marketing veteran, as its Vice President of Sales and Marketing. George brings more than 20 years of hands on experience, including the launches of ABRAXANE® at Abraxis Bioscience, Inc., and XELODA® at Hoffmann-La Roche Inc. In addition, the Company recently appointed Lynne Murphy as Executive Director of Sales. Ms. Murphy has more than 20 years of sales and marketing experience, which include many sales leadership positions with responsibility for the launch of more than 10 products during her tenure at Bayer Healthcare. Ms. Murphy also led a specialty sales force for Amgen, Inc., and launched Aranesp® Singleject. Ms. Murphy will be responsible for building and assembling a launch team of experienced oncology sales specialists.

“LEVOleucovorin provides physicians and patients with an important treatment alternative to leucovorin,” said Richard A. Bender, M.D., F.A.C.P., Chief Medical Officer of Spectrum Pharmaceuticals. “With this drug, patients undergoing cytotoxic chemotherapy are spared the administration of the pharmacologically inactive dextro-isomer. Preclinical studies have shown that the dextro-isomer may compete with the active levo-isomer for transport into cells.”

The Company plans to file for a supplemental New Drug Application with the FDA for use in colorectal cancer in 5-fluorouracil containing regimens and an NDA amendment for an oral tablet formulation by mid-year 2008.

(more…)

Posted in Cancer drugs, Drugs and Medications, New drugs | No Comments »

New drug can help alcoholics

Saturday, February 16th, 2008

New DrugA new drug can help alcoholics overcome their addiction by reducing stress-induced cravings, a study has found.

There is already a drug on the market, Revia, which treats alcoholism by reducing the body’s ability to enjoy its effects.

This new drug cuts cravings by taking the edge off of stressful situations which might push recovering alcoholics to pick up the bottle again.

Behavioral stress is a major factor in extending the “vicious cycle” of alcoholism, said lead author Markus Heilig, clinical director of the National Institute on Alcohol Abuse and Alcoholism.

That’s because alcohol deprivation causes depression and increased sensitivity to stressful situations such as an argument with a spouse or tension at work.

“Alcohol is a particularly nasty drug because it actually makes you feel better, but it pushes you to feel worse once you’re without alcohol,” he told AFP.

The drug Heilig and his team tested targets an area of the brain, the neurokinin 1 receptor, which mediates responses to behavioral stress. It had previously been shown to reduce social anxiety but did not enter the market because results were inconsistent.

Helig and his team first tested its effectiveness on mice and then on a group of 50 alcoholics with anxiety problems who had been through detox and remained hospitalized for the four weeks of the trial.

Half were given a placebo and the other half were given the drug.

Cravings declined over time for all patients in the protected inpatient environment and were minimal in the majority of patients by the end of the study period.

However, those who had been drug showed a more marked improvement in the severity of their cravings when measured by self-reporting questionnaires, the assessment of their clinicians, and tests where they were exposed to socially stressful situations and then told to touch a bottle and smell their favorite alcohol.

Interestingly, there was no impact on anxious or depressive psychopathology which suggests that “the improvements observed might be specific for brain processes related to alcoholism,” the study published online in Science Express concluded.

The drug also led to increased brain responses to positive imagery and lessened responses to negative imagery, something which a recent study showed predicts less alcohol consumption over the next six months, tests using MRI mapping showed.

The next step is larger clinical trials to see if the drug can be of assistance to alcoholics who do not suffer from anxiety problems.

New Drug Suspected Capable of Treating Alcoholism

A study revealed that an existing pill might in aid in the curbing of a person’s appetite for alcohol, simply by reducing the cravings caused by stress.

The new drug reportedly worked by controlling the results of stress, as behavioral stress was a major contributor to the “vicious cycle” of alcoholism.

Study author Markus Heilig of the National Institute on Alcohol Abuse explained that depriving a person of alcohol would lead to depression and increased chances of succumbing to stress.

“Alcohol is a particularly nasty drug because it actually makes you feel better,” Heilig explained, as quoted by AFP, “but it pushes you to feel worse once you’re without alcohol.”

He continued that the drug would control a person’s responses to these effects of stress by targeting a particular part of the brain responsible for the reactions to stressful situations.

Pooling together a total of 50 recovering alcoholics, scientists gave the drug to 25 of them, and placebo pills to the other half.

Their experiment resulted in a 50 percent cut in the craving for alcohol for those who had been given the drug.

Heilig, a director at the National Institute on Alcohol Abuse and Alcoholism, noted that while other studies regarding alcoholism aimed to reduce the pleasure derived from alcohol, their study attempted to reduce the effects of the actual causes of alcoholism.

“It’s a fairly new approach to treating alcoholism treatment,” Heilig said, as quoted by ABC News. “We’re really trying to open up a new category of treatments that would help most people.”

The study received commendations from other scientists, calling it a significant discovery.

“This is a potentially important finding which indicates a novel mechanism for reducing craving in individuals who drink to reduce high anxiety,” said Boris Tabakoff, a professor and director at the University of Colorado and Denver.

Stress-Related Drug May Cut Alcoholics’ Cravings

New Research May Pave Way for New Alcoholism Treatment Therapies

A drug known to inhibit the stress response in the brain may also be a potential weapon against alcohol addiction.

So suggests a small study on recovering alcoholics published in the journal Science.

Researchers with the National Institutes of Health already knew that the drug in question neutralizes the action of a protein called NK1R (short for neurokinin-1 receptor), which is involved in the stress response in the brain. The first hint that the drug might be useful in cutting alcohol cravings surfaced when the investigators noticed that mice who didn’t have NK1R seemed to have less desire to consume alcohol.

To test their suspicions, the scientists gave the NK1R-blocking drug to 25 recovering alcoholics, while giving 25 others an ineffective placebo treatment. They found that those who received the drug reported about 50 percent fewer alcohol cravings.

Lead study investigator Dr. Markus Heilig, clinical director of the NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA), says standard drug treatments to help curb drinking urges worked by reducing the pleasure that alcoholics get from drinking. This drug takes a different approach — reducing the anxiety that leads many alcoholics to reach for the bottle in the first place.

“It’s a fairly new approach to treating alcoholism treatment,” Heilig says. “We’re really trying to open up a new category of treatments that would help most people.”

Alcoholism experts not directly involved with the study say the finding offers tantalizing clues for new treatment — as well as hints to the connection between anxiety and drinking urges.

“This is a potentially important finding which indicates a novel mechanism for reducing craving in individuals who drink to reduce high anxiety,” says Boris Tabakoff, professor and chairman of pharmacology at the University of Colorado at Denver.

But even if the findings eventually lead to an effective drug treatment option for alcoholism, some experts say, there is no therapy yet that provides a sure-fire, one-size-fits-all solution to alcohol cravings.

“It may be that this medication would help alcoholics who drink when stressed,” says Dr. Charles O’Brien, vice chair of psychiatry and director of the Treatment Research Center for the University of Pennsylvania Health System. “It is wrong to think of all alcoholics as alike.”

A New Hope for Alcoholics?

Current drug treatments for alcoholism include naltrexone and disulfiram. And it has been shown that these medications offer help for some alcoholics. But Tabakoff says more options are needed.

“The current treatments, although producing statistically significant benefit, are still of modest utility,” Tabakoff says. “New approaches need to be introduced and tested. This represents one such novel treatment that seems to be particularly effective in reducing various measurements of craving.”

The need for another option in drug-based alcoholism treatment is underscored by the fact that the drug treatments that currently exist are each most effective for the relatively small subset of alcoholics who seem to be genetically predisposed to get an extra addictive kick from alcohol.

“Generally, these sorts of new drugs may help 20 percent of alcoholics or addicts initially quit drug use, though I am not sure they would work that well on maintaining abstinence,” says Steve Sussman, professor of preventive medicine and psychology at the University of Southern California.

“While this drug may be of assistance to the extreme users, I wonder about how well it would help the majority.”

Further Study Needed

Despite the apparent success in the human part of the trial, more research will be needed before such a treatment can be considered reliable and safe. For example, the possible interaction effects of the drug with alcohol, just in case users fall off the wagon, must be determined.

And since the new study involved only patients who were under hospital care, it remains to be seen how effective the drug could be in a real-world setting, where temptations for alcoholics abound.

Heilig says additional, broader trials are currently in the works. But even at this early stage, alcoholism experts say it’s possible that the most recent findings may be a sign that, at least for some alcoholics, more help could be on the way.

“The more types of treatment modalities available, the more people with addiction problems can be helped,” Sussman says.

Tabakoff agrees. “All of medicine is moving more and more towards personalized treatments that target subgroups of patients, and I believe this report is one example of that trend,” he says. “This may be an excellent option for a sub-group of alcoholics who also suffer symptoms of anxiety. Neither naltrexone nor disulfiram are focused on these subjects.”

Posted in Drugs and Medications, New drugs, Research | 1 Comment »

Cocain vaccine is coming soon

Friday, January 4th, 2008

cocaineTwo Baylor College of Medicine researchers in Houston are working on a cocaine vaccine they hope will become the first-ever medication to treat people hooked on the drug. “For people who have a desire to stop using, the vaccine should be very useful,” said Dr. Tom Kosten, a psychiatry professor who is being assisted in the research by his wife, Therese, a psychologist and neuroscientist. “At some point, most users will give in to temptation and relapse, but those for whom the vaccine is effective won’t get high and will lose interest.”

The vaccine, currently in clinical trials, stimulates the immune system to attack the real thing when it’s taken.

The immune system — unable to recognize cocaine and other drug molecules because they are so small — can’t make antibodies to attack them.

To help the immune system distinguish the drug, Kosten attached inactivated cocaine to the outside of inactivated cholera proteins.

In response, the immune system not only makes antibodies to the combination, which is harmless, but also recognizes the potent naked drug when it’s ingested. The antibodies bind to the cocaine and prevent it from reaching the brain, where it normally would generate the highs that are so addictive.

“It’s a very clever idea,” says David Eagleman, a Baylor neuroscientist. “Scientists have spent the last few decades figuring out reward pathways in the brain and how drugs like cocaine hijack the system. It turns out those pathways are difficult to rewire once they’ve seen the drug. But the vaccine just circumvents all that.”

Kosten asked the Food and Drug Administration in December to green-light a multi-institutional trial to begin in the spring and is awaiting a response.

Approval would mark a breakthrough in the treatment of cocaine addiction, which now mostly involves psychiatric counseling and 12-step programs. It presumably would be the final clinical hurdle before the vaccine — more than a decade in the making — might be approved for treatment. But one expert warns against expecting too much.

“Addiction vaccines are a promising advance, but it’s unlikely any treatment in this field will work for everyone,” said Dr. David Gorelick, a senior investigator at the National Institute on Drug Abuse. “Still, if they prove successful, they will give those working in drug addiction an important option.”

Scientists testing vaccine for cocaine users

Nothing says drug addiction more than a needle and syringe. But that’s exactly what a team of U.S. researchers believes can help cocaine users kick their menacing habit.

Two Baylor College of Medicine scientists based in Houston have developed a cocaine vaccine that creates antibodies that bind to the drug and prevent it from travelling from the bloodstream to the brain.

Unable to penetrate the brain, the drug can produce no high.

If the vaccine makes it through regulatory hurdles, it would be the first medication approved to treat cocaine addiction.

“It certainly is a way of combining immunology that had not been used before,” Tom Kosten, a professor of psychiatry and neuroscience at Baylor, said in a telephone interview yesterday. “We had always thought of altering the brain as a way to prevent drug abuse. This way, the drug never gets into the brain to begin with.”

Drug addiction treatment has largely been psychiatric counselling and 12-step programs. Dr. Kosten said that won’t go away – any approved vaccine would be complementary to behavioural therapy.

“If it’s approved in the U.S., then getting approval in Canada won’t be that difficult,” he said, adding that, if all goes well, a cocaine vaccine could be available in the United States in four years.

About 50 pharmaceutical options have previously been explored for cocaine addiction.

Dr. Kosten, who has been assisted in his decade-long research by his spouse, Therese Kosten, also a psychologist and neuroscientist at Baylor, asked the U.S. Food and Drug Administration last month to allow a Phase 3 clinical trial to begin this spring, involving 300 patients at six U.S. sites. Other trials are expected in Spain and Italy.

“Because there are no treatments for cocaine addiction, it’s been one of their fast-tracked programs at the FDA,” Dr. Kosten said. He is also at work on vaccines for heroin, nicotine and methamphetamine.

Yesterday, Evan Wood, co-principal investigator of the supervised injection facility evaluation in Vancouver, called the cocaine vaccine “new and provocative.”

“From a societal perspective, cocaine is one of the drugs that continue to be overlooked as one of the big problem drugs in our society,” said Dr. Wood, a physician epidemiologist at the British Columbia Centre for Excellence in HIV/AIDS.

“Crack cocaine is what is driving many of the social problems and public order problems and crime problems, particularly in the Downtown Eastside [of Vancouver].”

Dr. Wood said the “explosive HIV outbreak” in Vancouver’s east side is largely attributed to heroin users switching to cocaine, which leads to “more frequent injections, more chaotic behaviour and more syringe sharing.”

Learning about the immune system is opening all sorts of “avenues and possibilities,” said Dr. Wood. “But whether this is a useful tool remains to be seen.”

Certainly, the science is intriguing.

Since cocaine molecules are so small, the immune system does not recognize them and cannot make antibodies to attack them.

To fix that problem, Dr. Kosten attached inactivated cocaine to the outside of inactivated cholera proteins.

The immune system made harmless antibodies to the combination, but also recognized the drug when it was ingested. The antibodies bound to the cocaine, preventing it from reaching the brain, where the addictive highs are generated.

In Canada, there are no hard figures on how many are currently addicted to cocaine. Studies such as the Canadian Addiction Survey, published in 2004, found that more than 14 per cent of males, and 10.6 per cent of the total population, reported having tried cocaine.

Gerald Sidel, director of Addington Addiction Treatment Centre in Montreal, said yesterday that everybody is looking for the “magic bullet” to treat addictions.

He compared using modified cocaine to treat cocaine addicts to allowing alcoholics to engage in controlled drinking.

“Certainly if there is a way of helping people, I am not adverse to that,” Mr. Sidel said in a telephone interview yesterday. “But don’t treat drug addicts with drugs.”

Posted in Drugs and Medications, New drugs, Research, Vaccines | No Comments »

Amrubicin shows great in treatment of small cell lung cancer

Saturday, November 10th, 2007

AmrubicinPharmion Corporation (Nasdaq: PHRM) released interim findings from its Phase 2 trial of Amrubicin in second-line chemo-sensitive small cell lung cancer (SCLC). Amrubicin, the company’s third-generation synthetic anthracycline, is a potent topoisomerase II inhibitor currently in development for the treatment of SCLC. These findings indicate favorable interim results in terms of response rate and survival for Amrubicin in second-line treatment of small-cell lung cancer patients with extensive disease (ED) SCLC. The early results of this study were presented at the 2007 Chemotherapy Foundation Symposium in New York City.

“Treatment options for second-line SCLC are limited and preliminary data from the US-based Phase 2 sensitive SCLC trial indicate that Amrubicin may provide a new option for SCLC patients who desperately need more treatment choices,” said principal investigator Robert M. Jotte, MD, PhD, Medical Director of the Lung Cancer Clinic of the Rockies, Developmental Co-Chair USON Lung Committee. “As we near completion of the Phase 2 trial, we hope that accrual to the Phase 3 trial will be rapid and confirm the results of the US Phase 2 trial and similar trials in Japan.”

The trial presented today compares Amrubicin and topotecan in patients with ED-SCLC that initially responded to first-line platinum-based therapy but whose disease recurred or progressed at least 90 days after completion of first-line treatment (sensitive SCLC). Study participants are randomized in a 2:1 ratio to receive either IV Amrubicin (40mg/m2 daily for 3 days) or topotecan (1.5 mg/m2 daily for 5 days), both starting on Day 1 of a 21-day cycle.

Response data from 42 patients have been analyzed, 28 treated with Amrubicin and 14 with topotecan. Eleven of 28 (39 percent) patients who received one or more cycles of Amrubicin have demonstrated a response, including two complete responses (CR) and nine partial responses (PR). Eight of the responses are confirmed and three are pending follow-up scans. Two of 14 (14 percent) patients who received one or more cycles of topotecan had a response (both PRs). One is confirmed and one is pending a follow-up scan.

Survival times are not yet mature, however, at this time preliminary data already show an observed difference of 2.4 months in overall survival, which translates to a hazard ratio of 0.67, favoring Amrubicin.

The most common adverse events were hematological and were generally equal between the two arms. No classical anthracycline cardiotoxicity has been observed to date, supporting data from earlier Japanese studies that suggest Amrubicin may be devoid of this anthracycline-associated adverse event.

A second Amrubicin Phase 2 trial is also underway evaluating single-agent Amrubicin in patients with ED SCLC that are chemo-refractory or progressive within 90 days of completion of first-line platinum-based chemotherapy (refractory SCLC). Study participants receive Amrubicin (40 mg/m2 via 5-minute infusion daily for 3 days) on Day 1 of a 21-day cycle.

Enrollment in both second-line Phase 2 studies of Amrubicin is expected to complete by the end of 2007.

Pharmion has an additional ongoing Phase 2 study of Amrubicin in first line SCLC patients in association with the European Organization for the Research and Treatment of Cancer (EORTC). This study evaluates Amrubicin as single-agent or combination therapy with cisplatin versus cisplatin plus etoposide in previously untreated ED-SCLC patients. Preliminary data from this study are expected in the second half of 2008.

Pharmion recently initiated an international pivotal Phase 3 trial of Amrubicin versus topotecan as second-line treatment of small cell lung cancer (sensitive or refractory and limited or extensive disease). The randomized, controlled, multi-center study will compare Amrubicin to topotecan, the only approved chemotherapy for second-line treatment of SCLC in the US and EU. The primary endpoint of the study is overall survival. Enrollment in the study of 480 patients is underway. Pharmion has completed the Scientific Advice (SA) process with the European Medicines Agency (EMEA) and has reached Special Protocol Assessment (SPA) agreement with the US Food and Drug Administration (FDA) for the Amrubicin Phase 3 SCLC study.

New Synthetic Anthracycline, Amrubicin, Shows Promise for the Treatment of Small Cell Lung Cancer

Researchers from Japan have determined that a new synthetic anthracycline in combination with cisplatin (Platinol®) has significant activity in newly diagnosed extensive small cell lung cancer (SCLC). The details of this phase I/II study appeared in the March 2005 issue of the Annals of Oncology .

Small cell lung cancer is very sensitive to a variety of chemotherapy agents, including anthracyclines such as doxorubicin (Adriamycin®). However, anthracyclines are associated with early and late cardiac damage, limiting their use. Amrubicin is a totally synthetic anthracycline developed by the Japanese and is currently in phase I testing. In animal testing, this synthetic agent has few, if any, heart toxicities.

In this phase I/II study, the goal was to determine the maximum tolerated doses of the drug combination amrubicin and cisplatin and to ensure the safety of the recommended doses. Study participants were diagnosed with extensive SCLC and had not been previously treated with any type of chemotherapy. All patients received their amrubicin doses on days 1-3 and cisplatin on day 1 only, every 3 weeks. Results of the study defined safe and potentially effective doses. The overall response rate was 87.8% among both groups. The average survival time was 13.6 months and the 1-year survival rate was 56.1%. The most common side effects that were observed included a drop in the white blood count. Researchers concluded that the combination of amrubicin and cisplatin demonstrated a promising response rate and survival period for patients who were previously untreated for extensive SCLC.

Comments: This is an important study, as it shows significant activity for a totally synthetic drug that was engineered to eliminate cardiac. Unfortunately, this drug will not be on the market for quite some time. However, when there is concern about cardiac toxicity, there are currently FDA-approved drugs such as Doxil®, that are less cardio-toxic than doxorubicin.

About Amrubicin

Pharmion acquired the rights to Amrubicin in November 2006 through its acquisition of Cabrellis Pharmaceuticals. In 2002, Amrubicin was approved and launched for sale in Japan based on Phase 2 efficacy data in both SCLC and NSCLC. Since January 2005, Amrubicin has been marketed by Nippon Kayaku, a Japanese pharmaceutical firm focused on oncology, which licensed Japanese marketing rights from Dainippon Sumitomo, the original developer of Amrubicin.

(more…)

Posted in Cancer drugs, Drugs and Medications, New drugs, Pharmion, Research | No Comments »

Cordaptive to replace Zokor?

Wednesday, November 7th, 2007

CordaptiveMerck announced that the extended-release niacin/laropiprant (cordaptive) co administered with simvastatin had significant additive effects on reducing LDL-cholesterol (LDL-C), increasing HDL-cholesterol (HDL-C) and reducing triglyceride levels in a phase III study with patients with primary hypercholesterolemia or mixed dyslipidemia. The results were presented by Merck & Co, Inc. at the American Heart Association 2007 Scientific Sessions in Orlando, Fla.

In the study, 2 g (two 1-gram tablets) of Cordaptive co administered with simvastatin (pooled across 20 mg or 40 mg doses) reduced LDL-C by 48 per cent, increased HDL-C by 28 per cent, and reduced triglyceride levels by 33 per cent following 12 weeks of treatment. The primary study endpoint was LDL-C reduction; secondary endpoints included increased HDL-C, triglyceride reduction and effects on other lipoproteins. A 1 g tablet of cordaptive contains 1 g of Merck-developed extended-release niacin and 20 mg of laropiprant - a novel flushing pathway inhibitor that is designed to reduce the flushing associated with niacin. All of the comparative lipid efficacy results were measured as mean per cent change from baseline and were statistically significant, p < 0.001.

“The results in this study suggest that, if approved, cordaptive used with a statin could offer another approach to treat patients with dyslipidemia,” said Christie M. Ballantyne, associate chief and professor of medicine, Baylor College of Medicine, and co-author of the study.

The double-blind, parallel, 12-week study with seven treatment arms in almost 1400 patients evaluated 1 g of cordaptive (1 g extended-release niacin/20 mg laropiprant) coadministered with simvastatin 10 mg to 40 mg in weeks one through four and 2 g of cordaptive (two 1-gram tablets each containing 1 g extended-release niacin/20 mg of laropiprant) co administered with simvastatin 20 mg to 40 mg in weeks five through 12 (n = 590). Tolerability and the safety profile of Cordaptive co administered with simvastatin were also evaluated.

Reported lipid results in other treatment arms included a 17 per cent decrease in LDL-C, 23 per cent increase in HDL-C, and 22 per cent decrease in triglycerides with Cordaptive alone (n = 192); and a 37 per cent reduction in LDL-C, six per cent increase in HDL-C and 15 per cent reduction in triglycerides with simvastatin alone (pooled) (n = 585).

Reported side effects of interest included: liver enzyme elevations >3x ULN in ALT and/or AST (0.3 per cent with cordaptive co administered with simvastatin, 0.5 per cent with Cordaptive alone, and 1.0 per cent with simvastatin alone), and increased median fasting plasma glucose values (4.0 mg/dL with Cordaptive plus simvastatin, 4.0 mg/dL with Cordaptive alone, and 1.0 mg/dL with simvastatin alone). There were no cases of creatine kinase (CK) levels >10x ULN in the group treated with Cordaptive coadministered with simvastatin, which was not significantly different than that of the group treated with Cordaptive or simvastatin alone (0.5 per cent and 0.3 per cent, respectively). All elevations were asymptomatic and resolved with discontinuation of treatment. There were no cases of myopathy, rhabdomyolysis or drug-related hepatitis.

Discontinuations due to flushing were 4.8 per cent in the group treated with cordaptive co administered with simvastatin, 8.7 per cent with Cordaptive alone and 0.3 per cent with simvastatin alone.

Niacin-induced flushing is primarily caused by a prostaglandin, PGD2, a chemical that causes vasodilatation in the skin and flushing symptoms, acting through the DP1 flushing pathway. Laropiprant selectively blocks the binding of PGD2 to its receptor, DP1. Research has shown blocking DP1 reduces flushing associated with niacin.

“It has been shown that niacin-based therapies reduce the risk of cardiovascular events. But even though niacin has broad lipid effects, the flushing side effect has been a barrier to many patients reaching the maximum 2 g dose,” said John Paolini, MD, Clinical Research, Cardiovascular Disease, Merck Research Laboratories.

Cordaptive is in development by Merck for the treatment of elevated LDL-C, low HDL-C and elevated triglycerides. Merck has previously announced that the NDA for cordaptive has been accepted by the US FDA and the regulatory action is anticipated in the second quarter of 2008. Merck is also on track to file an NDA in 2008 for the company’s investigational compound MK 0524B.

Dyslipidemia is the elevation of LDL-C and/or triglycerides or a low HDL-C level that contributes to the development of atherosclerosis, the number one cause of death among men and women and the primary reason for loss of quality of life in Western countries. Major modifiable risk factors for atherosclerotic disease include hypertension, diabetes, obesity, smoking and high levels of total cholesterol or LDL-C. Low levels of HDL-C also increase a person’s chances of developing atherosclerosis. In fact, epidemiologic studies have shown that for every 1 mg/dL rise in HDL-C, the risk of developing cardiovascular disease decreases by two per cent to three per cent.

Simvastatin, a cholesterol-modifying medicine from Merck, and marketed under the brand name Zocor, is used in addition to diet to modify cholesterol levels after diet and other non-drug measures have failed to achieve target levels.

Researchers have said that patients were able to safely use Merck & Co.’s experimental Cordaptive drug to raise good HDL cholesterol alongside the company’s older Zocor cholesterol medicine.

Results of the Phase III trial involved about 1,400 patients and lasted 12 weeks. Cordaptive is a combination of an extended release form of niacin, a nutrient that raises heart-protective HDL, and an experimental drug called laropiprant that reduces the uncomfortable facial flushing which is a side effect of niacin.

Merck aims to seek approval next year for a separate product called MK-524B. It would combine Cordaptive in the same tablet with simvastatin, the active ingredient of Zocor which works by cutting the body’s production of LDL.

In the trial, levels of LDL fell 48 percent among patients receiving simvastatin as well as Cordaptive containing the full recommended two gram dose of niacin. That effectiveness against LDL, the primary goal of the trial, was deemed highly statistically significant.

Patients taking Cordaptive by itself in the trial experienced favorable, but less-impressive results: a 17 percent decrease in LDL, a 23 percent boost in HDL and a 22 percent drop in triglycerides.

Cordaptive is now awaiting U.S. marketing approval.

Posted in Cholesterol-modifying medicines, Drugs and Medications, Merck, New drugs, Research | No Comments »

New blood thinner Prasugrel proved better than Plavix!

Sunday, November 4th, 2007

PrasugrelA new blood thinner proved better than Plavix, one of the world’s top-selling drugs, at preventing heart problems after procedures to open clogged arteries, doctors reported Sunday. But the new drug also raised the risk of serious bleeding.

People given the experimental drug, prasugrel, were nearly 20 percent less likely to suffer one of the problems in a combined measure — heart attack, stroke or heart-related death — than those given Plavix, a drug that millions of Americans take to prevent blood clots that cause these events.

However, for each heart-related death that prasugrel (PRASS-uh-grell) prevented, compared to Plavix, almost one additional bleeding death occurred.

“There is a price to pay” for greater effectiveness, Dr. Deepak Bhatt, a Cleveland Clinic cardiologist, wrote in an editorial accompanying the results, which were published online by The New England Journal of Medicine and presented at an American Heart Association conference in Florida.

Still, many doctors said that on balance, the new drug comes out ahead, and offers great promise as a more potent alternative to Plavix, which costs $4 a day and does not work for many patients.

“I’m encouraged by the results” and think prasugrel should win Food and Drug Administration approval because it so dramatically cuts non-fatal heart attacks, said the Cleveland Clinic’s Dr. Steven Nissen, a frequent government adviser.

Doctors can sort out who might most benefit from it, such as diabetics, and who might face too much bleeding risk to use it, like the elderly, people who previously had strokes and those with kidney problems, he said. (The Cleveland doctors give to charity or the clinic the consulting and research fees they earn from drugmakers.)

Doctors also were waiting for prasugrel’s makers to clarify why they stopped two small studies of it a week ago. They said it was due to dosing problems but did not explain.

Prasugrel is being developed by Indianapolis-based Eli Lilly and Co. and a Japanese firm, Daiichi Sankyo Co. It could be a hugely important drug, and the study has been one of the most-watched tests of a novel heart medication in recent years.

Like Plavix, prasugrel prevents blood components called platelets from sticking together and forming a clot. Anti-platelet drugs are advised for most people with stents — tiny mesh tubes that keep arteries open after balloon angioplasty, an artery-clearing procedure that more than a million Americans have each year.

Plavix, sold by Sanofi-Aventis SA and Bristol-Myers Squibb Co., has been the most effective drug of this type. More than 70 million people have taken it since it went on sale a decade ago.

Plavix had 18.6 million prescriptions and nearly $3 billion in U.S. sales last year, according to IMS Health, a healthcare information firm. Worldwide sales were nearly $6 billion.

The study comparing it to prasugrel involved 13,608 patients from 30 countries and was led by Dr. Elliott Antman at Harvard Medical School and Brigham and Women’s Hospital in Boston. Prasugrel’s makers paid for the study; many of the researchers work or consult for them.

Study participants were having angioplasty due to heart attacks or blockages causing sudden or worsening chest pain, and were randomly assigned to one drug or the other for six to 15 months.

The results: about 12 percent of people taking Plavix but only 10 percent on prasugrel suffered heart attacks, strokes or heart-related deaths — a 20 percent reduction in risk. Only 1.1 percent on the new drug developed blood clots in stents versus 2.4 percent on Plavix — a 52 percent lower risk. Prasugrel also worked faster than Plavix and showed more effectiveness at the first checkpoint — three days.

However, major bleeding occurred in 2.4 percent of those on prasugrel versus 1.8 percent of those on Plavix. This included brain or gastrointestinal bleeding, or after falls. Fatal bleeding was uncommon, but four times more frequent with the new drug.

Results hinted that some people might be in greater danger — those who had a previous stroke, were elderly, or weighed less than 132 pounds.

These signs are why prasugrel’s makers suspended two small studies a week ago to see whether such patients should be included in the study or should get a lower dose, said Dr. Anthony Ware of Eli Lilly.

“It was a precaution … because of a risk of a safety problem rather than an actual one,” he said.

Lilly will conduct another big study of prasugrel in people not having angioplasty but on medications because they are at risk of having a heart attack, Ware said.

That 10,000-person study will be led by Dr. E. Magnus Ohman at Duke University Medical Center.

In the study reported on Sunday, “the benefit clearly outweighs the risk” for most patients, Ohman said.

Bhatt of Cleveland Clinic noted that even aspirin — which is widely recommended to prevent clots and was prescribed to all patients in this study — carries a risk of bleeding.

Dr. Spencer King, a heart specialist at Piedmont Hospital in Atlanta and spokesman for the American College of Cardiology, was on the safety monitoring committee for the study. He said prasugrel would be “a little bit of a tough sell” to doctors who are comfortable with using Plavix, but that competition could give patients drugs more closely matched to their needs.

“We’ve had one size fits all … now we’ll have two choices,” King said.

Dr. Harlan Krumholz, a Yale University cardiologist with no role in the study, noted that “in absolute numbers, for every 1,000 people you treat, you’d save a lot more heart events than you’d cause bleeds,” because heart problems are more common.

Cost also keeps many people from taking Plavix now. Prasugrel’s makers have not said what it would cost, but “if they start competing on price, it could be a boon for the health care system,” Krumholz said.

Lilly’s Prasugrel Reduces Heart Risks But Has Higher Bleeding Rate

An experimental Eli Lilly & Co. blooding-thinning drug, prasugrel, was effective at reducing the number heart attacks, strokes and cardiovascular deaths, but carries a risk of serious bleeding, according to a new study released Sunday.

The study compared prasugrel and a similar anti-clotting drug, Plavix, by Bristol-Myers Squibb Co. and Sanofi-Aventis SA in 13,608 patients set to undergo a procedure to open blocked coronary arteries. Most patients then received a stent to keep the arteries open.

Overall, the study showed prasugrel was better than Plavix at reducing the number of heart attacks, strokes and cardiovascular deaths, but prasugrel had a higher rate of bleeding including fatal bleeding.

One of the study’s researchers, Elliott Antman, the director of the Brigham and Women’s Hospital’s cardiac unit, said patients on Prasugrel were 19% less likely to have a stroke, heart attack or death from a cardiovascular cause compared with patients on Plavix, but were 32% more likely to suffer a serious bleeding event. Patients on prasugrel were 24% less likely to suffer a heart attack compared with those on Plavix, Dr. Antman said.

Both drugs are designed to keep blood platelets from sticking together to form dangerous blood clots that can cause heart attacks and strokes. But they also carry a risk of bleeding if the drugs go too far at inhibiting platelets. Aspirin is also an anti-clotting agent and is commonly prescribed with Plavix.

The study, known as Triton, was presented Sunday at the American Heart Association’s annual meeting in Orlando and is also being published online in the New England Journal of Medicine.

Researchers, led by Harvard Medical School and Brigham and Women’s Hospital in Boston, said the net clinical benefit, which takes into account the benefits and risks of a drug, favors prasugrel. Dr. Antman said that for every 1,000 patients treated with prasugrel compared with Plavix, prasugrel would prevent an additional 23 heart attacks, but would likely cause six additional cases of serious bleeding.

Lilly, which is developing prasugrel with Daiichi Sankyo Co. of Japan, said Oct. 24 it halted two smaller studies of prasugrel amid concerns about the dosage used in certain patient groups, rattling investors and in turn, putting an even greater focus on the Triton data. Both Lilly and Daiichi funded the study.

Specifically, the Triton study showed that 12.1% of patients on Plavix had a heart attack, stroke or death from a cardiovascular cause during the study, compared with 9.9% of patients receiving prasugrel, which translates into an overall difference of 19%. Patients in the study were either given a one-time “loading” dose of prasugrel at 60 milligrams and maintenance doses of 10 milligrams, or a 300 milligram loading dose of Plavix followed by 75 milligram maintenance doses. Patients were treated for six to 15 months.

The rate of major bleeding among patients receiving prasugrel was 2.4% compared with 1.8% receiving Plavix. The study showed the rate of life-threatening bleeding was 1.4% for patients on prasugrel and 0.9% for patients on Plavix. That included fatal bleeding, which occurred among 0.4% of patients receiving prasugrel and 0.1% of patients on Plavix, along with non-fatal bleeding, which was 1.1% in the prasugrel group and 0.9% in the Plavix group.

Lilly has said it plans to submit an application for Food and Drug Administration approval of prasugrel by the end of this year.

“We are very pleased with the trial’s outcome and are excited by the potential for these results to help us further tailor prasugrel therapy to assure the greatest benefit from this novel treatment,” said J. Anthony Ware, Lilly’s cardiovascular platform leader for prasugrel.

Researchers said there were “significant reductions” in stent thrombosis and repeat procedures to reopen clogged arteries among patients on prasugrel compared with those on Plavix. The stent thrombosis rate, or blood clots attributed to the stent, was 1.1% for those receiving prasugrel and 2.4% for the Plavix patients, or a 52% reduction in the stent thrombosis rate for patients on Plavix. Urgent target vessel revascularization among prasugrel patients was 2.5% compared with 3.7% for those on Plavix, a 34% reduction.

In an accompanying editorial in the New England Journal of Medicine, Dr. Deepak Bhatt of The Cleveland Clinic, said for each additional cardiovascular death prevented by the use of prasugrel compared with Plavix, “approximately one additional episode of fatal bleeding was caused by prasugrel.” He wrote that prasugrel would probably benefit patients who are at high risk of additional heart problems such as a heart attack and at low risk of bleeding, while patients with a high risk of bleeding and at lower risk for heart attacks or strokes “may be better served by” Plavix.

Indeed, researchers wrote that an analysis of subgroups of patients in the study suggested those with a history of smoking, stroke, those age 75 and older as well as those who weighed less than 60 kilograms (132 pounds) had “less clinical efficacy and greater absolute levels of bleeding than the overall cohort.”

Dr. Antman said most of the excess bleeding and fatal bleeding occurred in patients who’ve suffered a previous stroke and said if approved, the drug shouldn’t be used in that group.

Plavix, which generated almost $6 billion in global sales last year, is among the world’s top-selling drugs. Lilly is hoping prasugrel, which some researchers said might work more consistently than Plavix, could take market share away from Plavix if it’s approved later next year.

In a statement, Bristol-Myers said “with the wealth of safety and efficacy data on Plavix, this drug is well understood by phsyicians in a real-world setting. The bleeding rate observed with prasugrel in Triton raises important questions.”

Lilly’s best selling drug Zyprexa loses U.S. patent protection in 2011 and prasugrel is widely viewed as the company’s most promising drug in its pipeline. Zyprexa treats schizophrenia and bipolar disorder.

Other companies also are developing anti-clotting drugs, including AstraZeneca PLC and Schering-Plough Corp. along with Bayer AG and Johnson & Johnson, which are jointly working on a product.

Posted in Anti-platelet drugs, Blooding-thinning drugs, Eli Lilly, New drugs, Research | No Comments »

Rivaroxaban submitted for approval

Saturday, November 3rd, 2007

RivaroxabanBayer HealthCare AG announced today the submission of a Marketing Authorization Application to the European Agency for the Evaluation of Medicinal Products (EMEA) for approval to market rivaroxaban (Xarelto®) for the prevention of venous thromboembolism (VTE) after major orthopedic surgery of the lower limbs. Rivaroxaban is an investigational, oral, once-daily direct Factor Xa inhibitor. Data from one of the pivotal studies (RECORD3) was presented prior to the EMEA submission and revealed that rivaroxaban significantly reduces the risk of VTE in patients undergoing total knee replacement surgery compared with enoxaparin, the current standard of care therapy. Rivaroxaban is being jointly developed by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

“The submission of the data for VTE prevention to the EMEA is an important milestone in the development of this new treatment for the prevention of life-threatening blood clots,” said Dr. Kemal Malik, Head of Global Development and member of the Bayer HealthCare Executive Committee. “As an effective and convenient, once-daily oral treatment with a reassuring safety profile, we feel confident that rivaroxaban has the potential to set a new standard of care in the preventative treatment of thrombosis in patients undergoing major orthopedic surgery.”

VTE is a type of thromboembolic disease that is caused by the obstruction of a blood vessel by a blood clot. In the EU it is estimated that there are 543,000 deaths due to VTE each year. People undergoing major surgery, in particular total knee or hip replacement, are prone to developing VTE due to a combination of factors such as prolonged bed rest, damage to blood vessels and an increased tendency of the blood to clot. It is estimated that up to 50% of patients undergoing lower limb surgery develop VTE if they do not receive preventative care.

The Marketing Authorization Application is based on data from three Phase III studies of rivaroxaban involving nearly 10,000 patients in total, and an extensive Phase I and Phase II program. One of the Phase III studies was in patients undergoing total knee replacement surgery, the results of which were presented at the International Society on Thrombosis and Hemostasis (ISTH) in July 2007 (RECORD3). The results of the other two studies in patients undergoing hip replacement surgery (RECORD1 and RECORD2) will be presented at the upcoming 49th Annual Meeting of the American Society of Hematology (ASH) meeting, 8–11 December 2007.

About RECORD3
The results of this study in 2,531 patients undergoing knee replacement surgery revealed that once-daily oral rivaroxaban 10 mg was superior in preventing VTE to once-daily subcutaneous enoxaparin 40 mg, the current standard of care therapy. Specifically, patients in this RECORD3 study (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE) who were treated with rivaroxaban demonstrated a 49% relative risk reduction (p<0.001) in the composite primary endpoint of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality compared to those treated with enoxaparin. Patients treated with rivaroxaban also had a 62% reduced risk (p=0.01) of developing major VTE (the composite of proximal DVT, non-fatal PE and VTE-related death), the main secondary endpoint of the trial. Importantly, there was a similar low rate of major bleeding for patients being treated with rivaroxaban and enoxaparin (0.6% and 0.5%, respectively).

About Rivaroxaban (Xarelto®)
To date, rivaroxaban is the most studied oral direct Factor Xa inhibitor in development. More than 20,000 patients have been evaluated in the completed Phase II programs and enrolled thus far in the Phase III programs. More than 40,000 patients are expected to be evaluated in total.

Upon regulatory approval, rivaroxaban will be commercialized in Europe by Bayer Schering Pharma. A filing for rivaroxaban for a similar indication in the United States is planned in 2008, where if approved, it will be will commercialized by Scios Inc. and Ortho-McNeil, Inc., both of which are Johnson & Johnson companies.

The trade name of rivaroxaban is expected to be Xarelto®, pending health authority approval.

CLINICAL PHARMACOLOGY: Rivaroxaban directly inhibits factor Xa therefore prolonging clotting times and reducing the formation of thrombin, an essential component to the development of thrombus formation. The L-shaped structure of rivaroxaban allows it to be highly selective for factor Xa.1, 3 This high selectivity allows the drug to inhibit free factor Xa, prothrombinase activity, and clot-associated factor Xa, giving it the ability to not only prevent clots from forming, but to also possibly break down clots already present. This drug does not have significant direct effects on thrombin or antithrombin activity.1, 3, 8 The mechanism of action of rivaroxaban is beneficial in the prevention and treatment of thromboembolic diseases.

PHARMACOKINETICS:

Absorption:

Peak plasma concentrations are reached 2 to 4 hours after oral administration, and the bioavailability of rivaroxaban ranges from 60-80%. The presence of food increased maximum concentration, time to maximum concentration, and AUC. Prothrombin time was also affected depending on if a patient was in a fed or fasting state. Maximum PT was increased by 53% (10mg) and 83% (20mg) if patients were fed compared to 44% (10mg) and 53% (20mg) in the fasting state. Maximum inhibition of factor Xa occurred within 1 to 4 hours after administration and ranged from 20-61% for the 5-80mg doses.

Distribution:

After multiple doses of rivaroxaban, dose-proportional increases in AUC were observed. It was also noted that once the drug reached steady state, there were no significant accumulations of the drug.1 It appears that body weight influences the volume of distribution, but this change has not been found to be significant.

A study by Kubitza et al. looked at the effects of extreme body weights (>= 120 kg and <= 50 kg) and gender on the PK and PD of rivaroxaban 10mg. Results showed no effects on Cmax in subjects >= 120 kg and up to a 24% increase in Cmax in subjects <= 50 kg. This increase in Cmax caused a slight increase in prothrombin time, but the investigators concluded that this was not clinically significant. No significant differences were seen between males and females as well. These results suggest that dose adjustments are not needed in patients with extreme body weights or between the different genders.

Metabolism:

It is unknown whether rivaroxaban is metabolized hepatically or renally. Other direct factor Xa inhibitors are metabolized by the liver, so there is a high probability that rivaroxaban is also metabolized through this route.

Elimination:

Rivaroxaban goes through both renal (66%) and biliary (28%) excretion, and 36% is excreted as unchanged drug in the urine. In young, healthy subjects, rivaroxaban has a half-life of around 9 hrs, but this number increases in elderly subjects (12 hrs) and patients with renal impairment. It has not been determined if dose-adjustments are needed in the elderly or renal impairment because of this increased half-life. In Phase III trials, patients with renal impairment received reduced doses of rivaroxaban. Most trials have excluded patients with creatinine clearances below 30 ml/min, but it has not been officially determined if this level of renal impairment required dosage adjustments.

PK parameters correlated closely with the inhibition of factor Xa activity and PT prolongation.

Because of its predictable pharmacokinetics, this drug does not require the routine monitoring like warfarin does.

DRUG INTERACTIONS: No significant drug interactions have been found with rivaroxaban, including with aspirin, NSAIDs, antacids, H2 antagonists and digoxin.

The interaction between rivaroxaban and aspirin was studied in a phase I trial to determine if aspirin influenced the effectiveness and safety of rivaroxaban. This combination was well tolerated in the healthy, male subjects studied. Aspirin did not affect the inhibition of factor Xa activity or prolongation of PT/aPTT by rivaroxaban. In addition, rivaroxaban did not interfere with the inhibitory effects of aspirin on platelet aggregation.

A phase II study in 2007 looked at the effects of the combination of naproxen and rivaroxaban on safety, tolerability, PK and PD. Patients were given naproxen alone, rivaroxaban alone, or a combination of the two drugs. This study showed no mechanistic interaction between rivaroxaban and naproxen, and the addition of naproxen did not effect the prothrombin time, pTT or platelet aggregation. There was a significant increase in bleeding seen with the combination group, however, this increase was less than that seen with naproxen alone. Further phase III studies are being conducted to confirm the safety of this combination.

DOSING: There have been several studies that have looked at various dosing ranges of rivaroxaban, from 2.5mg to 40mg, given either twice-daily or once-daily. Most strengths of rivaroxaban have proven to be effective, and no dose-efficacy response has been established. However, twice daily dosing has resulted in significantly more bleeding than once-daily dosing suggesting that dose frequency might influence bleeding risk independently of dose intensity.

Rivaroxaban 20mg once-daily is the strength that is being used in Phase III trials looking at treatment of VTE and prevention of stroke in A. fib. During the RECORD3 study, a phase III trial, it was determined that 10mg of rivaroxaban given once daily was the most effective and safest dose at preventing VTE after orthopedic surgery. This strength is currently being evaluated further in this population.

CONCLUSION: There is a need for a new anticoagulant that is just as effective as warfarin, but without the rigorous monitoring schedule. Once-daily dosing of rivaroxaban has been shown to produce 24 hours of inhibition of factor Xa and thrombin generation, allowing for convenient dosing. Rivaroxaban offers once-daily dosing, and there may be the potential for no monitoring with this drug. Unlike warfarin that has several different strengths and may need to be taken differently each day, rivaroxaban will be much easier to manage and may increase patient compliance as well.

Related drugs

Ximelagatran, a direct thrombin inhibitor, was not marketed further due to its potential side-effects; the related compound dabigatran is undergoing studies. Together with rivaroxaban, the related factor Xa-inhibitor apixaban (Bristol-Myers-Squibb) andLY517717 (Lilly) are under development as non-monitored antithrombotic drugs.

Posted in Antithrombotic drugs, Bayer, Drugs and Medications, New drugs | No Comments »

Axitinib: great results for the new cancer drug

Tuesday, October 30th, 2007

New cancer drugA phase II trial on axitinib, a new experimental drug for treating patients with cytokine-refractory, metastatic kidney cancer who have a poor response to more traditional drugs has shown promising results according to a new study published in the The Lancet Oncology.

Professor Olivier Rixe of the University of Paris, France, and colleagues assessed the activity and safety of axitinib in a group of patients with metastatic renal-cell cancer who had failed to respond to cytokine-based treatments.

The researchers enrolled 52 patients between October 2003 and April 2004. Each patient had at least one measurable lesion that could be targeted and was given an oral dose of axitinib starting at 5 mg twice a day.

Rixe and colleagues assessed the percentage of patients who responded either completely or partially using the Response Evaluation Criteria In Solid Tumors (RECIST) method, as well as how long they took to respond, the time to progression, overall survival, safety and other measures.

In an intention to treat analysis, the study produced the following results:

  • Of the 52 patients, 2 responded completely and 21 partially.
  • This equated to an objective response rate of 44.2 per cent.
  • The median response rate was 23.0 months (range 4.2 to 29.8 months).
  • But 12 of 23 initial responders progressed with response durations of 4.2 to 26.5 months.
  • Also, 22 patients showed stable disease for more than 8 weeks, with 13 of them for 24 weeks or more.
  • 4 patients had early disease progression, 3 had missing response data.
  • Median time to progression was 15.7 months (range 0.03 to 31.5 months).
  • Median overall survival was 29·9 months (range 2·4 to 35·8 months).
  • Adverse events linked to treatment included diarrhoea, hypertension, fatigue, nausea, and hoarseness.
  • High blood pressure was found in 30 patients.
  • Of these, all but 8 responded to blood pressure treatment. 7 of the 8 had a history of high blood pressure at enrollment.

The researchers concluded that:

“Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.”

Kidney cancer is the sixth leading cause of cancer deaths in the US, and thought to be responsible for nearly 13,000 deaths a year. Kidney cancer is actually a range of cancers, each with a different histology or tissue characteristics. Each type of kidney cancer also develops differently and needs different kinds of treatment.

The most common type of kidney cancer is clear-cell renal cancer, found in 75 per cent of kidney cancer patients.

There are few treatment options for kidney cancer and most patients die. Even with chemotherapy, hormone or biological therapy with the latest targeted drugs, the survival rate is rarely more than 10 per cent.

Axitinib is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. By selectively targeting a single growth factor receptor pathway, treatments with this drug could provide a way to adjust dosage and combine with other drugs aimed at specific parts of the pathway. This would potentially minimise toxicity as well as optimise therapeutic outcomes suggested the researchers.

Rixie said that although a randomized controlled trial was now needed:

“The objective response and time to progression in our study suggest that axitinib might be a promising drug in the treatment of patients with metastatic renal-cell cancer.”

In an accompanying article in the same issue of the journal, Dr W Marston Linehan of the US National Cancer Institute, said that these findings “suggest that a drug such as axitinib has promise as a second-line treatment in cytokine-refractory metastatic renal-cell carcinoma, and might have potential as first-line treatment or in combination with other agents targeting the Von Hippel-Lindau pathway (or both).”

(more…)

Posted in Cancer drugs, Drugs and Medications, New drugs, Research | No Comments »