Drug Firms Advance Rapidly After Long Drought, but Treatments Are Pricey

Drug companies have scored a string of recent successes against advanced prostate cancer, ending a long drought during which there seemed to be few weapons to combat the disease.

In the latest evidence of progress, researchers reported Tuesday that an experimental drug from San Francisco-based Medivation Inc. extended survival by nearly five months in a 1,199-patient study. A second drug, a radiation-emitter being developed by Bayer AG and Algeta ASA of Norway, targeting prostate cancer that has spread to the bone, improved survival by nearly three months in a 922-patient study.

Results of both trials were released ahead of their presentation at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium being held this week in San Francisco.

If the drugs win approval soon from the Food and Drug Administration, it would mean that after decades of frustration, the pharmaceutical industry will have turned out five new treatments for advanced prostate cancer within just three years.

Those already approved within the past two years include Dendreon Inc.’s Provenge, Jevtana from Sanofi SA, and Zytiga from Johnson & Johnson.

The pharmaceutical industry is increasingly looking for ways to speed development of new drugs—including the realization that closer ties to academic researchers can aid in discovery. Medivation’s compound, called MDV3100, is notable for how it was developed—largely in the research laboratory of Charles Sawyers, a scientist at Memorial Sloan-Kettering Cancer Center with a track record in drug discovery.

Medivation expects to file its application with the FDA this year. Assuming all goes well, the drug could be on a track to win approval about five years after it was first tested in people. “By any standard, that would be considered very, very quick,” said David Hung, Medivation’s chief executive officer.

Also helping progress is a growing understanding of the biology of prostate cancer, a disease fueled largely by the male hormone testosterone.

The new treatments aren’t cures and individually their impact on survival is modest—in clinical trials each added a median of roughly three to five months to patients’ lives. Their high cost is likely to complicate adoption for many patients. Provenge, for instance, costs $93,000 for a course of three treatments while Zytiga’s price is about $5,000 for a monthly supply of pills.

But some researchers believe that the options will lead to new strategies where the drugs are used either sequentially or in combination to significantly extend survival. The new treatments are expected to cause the world-wide market for prostate cancer therapies to surge to $4 billion by 2015, according to Morningstar Inc., up from about $1 billion currently.

“The whole equation for prostate cancer is completely different,” said Christopher J. Logothetis, chief of genitourinary medical oncology at M.D. Anderson Cancer Center, Houston. “It is [now] among the solid tumors that should be considered highly treatable.”

All of this stands in contrast to just a decade or so ago when the disease was considered resistent to almost any treatment. Drug companies would say “nothing has worked in 35 years. Why are we going to throw our [new] drug at that?” said Bruce Roth, professor of medicine and an oncologist at Washington University, St. Louis. “Now we’re starting to see a payoff in the investment in research about the biology of prostate cancer.”

MDV3100 is a case in point. Dr. Sawyers, a Howard Hughes Medical Institute investigator, played important roles in the development of Novartis AG’s breakthrough leukemia drug Gleevec and a second-generation version called Sprycel from Bristol-Myers Squibb Co.

In the mid-1990s, while at University of California at Los Angeles, Dr. Sawyers became interested in why men with prostate cancer relapsed on hormone therapy—the standard treatments, which starve prostate tumors of testosterone, the primary fuel that makes them grow.

Conventional wisdom was that once a patient relapsed, the so-called androgen receptors—structures that protrude from tumor cells like a lock to attract the testosterone “key” that activates them and promotes tumor growth—were no longer driving the disease. Dr. Sawyers was skeptical. In a series of experiments with mice, he and his colleagues found that drug-resistant patients actually had elevated (not lower) levels of androgen receptors. Drugs were now activating them instead of blocking out the testosterone.

“It wasn’t destroying dogma, but it wasn’t what people expected,” Dr. Sawyers said. “It put a spotlight on the androgen receptor as a drug target.”

But he said he wasn’t able to persuade any drug companies to pursue the lead. So he teamed up with a chemist, Michael Jung, at UCLA to design a drug themselves.

Scouring patent databases, Dr. Jung discovered a compound made by the former French drug maker Roussel Uclaf that locked onto the androgen receptor about 100 times more strongly than the commonly used prostate-cancer drug, Casodex.

Using that drug as a template, and taking on a task normally performed by drug-industry scientists, Dr. Jung fashioned some 200 slightly different molecules, which the researchers tested against tumor samples in their own version of the drug industry’s high-volume screening technology. They came up with a promising candidate, tweaked it so it would be absorbed in the blood as a pill and then performed the key experiment—testing it in mice to see if it would shrink tumors.

“It did, very dramatically,” Dr. Sawyers said. But academic scientists aren’t positioned to take the drug across the “valley of death”—the chasm between a promising compound discovered in the lab and the work required to test it in humans, said Dr. Sawyers, who as an inventor of MDV3100 is entitled to royalties on any sales.

In 2005, Medivation agreed to license the drug. The company confirmed the researchers’ findings, tested the molecule and altered its formulation to make it suitable for humans, and filed an application with the FDA to start human studies.

Howard Scher, a veteran of prostate-cancer studies and chief of the genitourinary oncology service at Memorial Sloan-Kettering Cancer, agreed to run the research, which began in 2007. Aided by a 13-center research consortium group funded by the Defense Department and the Prostate Cancer Foundation and intended to speed development of medicines for the disease, researchers ultimately and rapidly enrolled 140 patients, with promising results.

In 2009, Medivation, in collaboration with Astellas Pharmaceuticals Inc. of Japan, launched a late-stage trial, the results of which Dr. Scher reported Tuesday.

Dr. Scher reported that the 800 patients treated with the drug had a median survival of 18.4 months compared with 13.6 months for those given a placebo. In addition, 54% of MDV3100 patients—compared to 1.5% of those on placebo—had a greater than 50% reduction in a marker called prostate specific antigen—an indicator of a positive response to the drug. Side effects included fatigue.

During a news conference to announce the findings, Nicholas J. Vogelzang, chairman and medical director of the developmental therapeutics committee of US Oncology, a cancer treatment company, called the results “unprecedented.” He added: “This is definitely going to change the way we take care of patients every day in the office.”

Dr. Scher said the first patient he treated four and a half years ago is still alive and on the drug. “That’s the beauty of a targeted agent,” he said.

For Medivation, the successful study contrasts with news two weeks ago that, along with partner Pfizer Inc., it was pulling the plug on development of an Alzheimer’s drug called dimebon after it failed to show benefit in a late stage, 1003-patient study.

http://online.wsj.com/article/SB10001424052970203920204577195372964538152.html

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Medivation, Inc. (NASDAQ: MDVN) and Pfizer Inc. (NYSE: PFE) today announced results from the CONCERT trial, which is a Phase 3 trial that evaluated dimebon (latrepirdine) when added to ongoing treatment with donepezil HCL tablets in patients with mild-to-moderate Alzheimer’s disease. Dimebon did not achieve statistically significant results for either of the two co-primary endpoints, the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog), which measures cognitive ability, or the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL), which measures self care and daily function.

“We are disappointed in the CONCERT results and the implications for Alzheimer’s disease patients and their caregivers,” said David Hung, M.D., president and CEO of Medivation. “I would like to extend my sincere thanks to the patients, their physicians and study teams involved in this trial.”

Dimebon was generally well tolerated in the study. A full analysis of the results from CONCERT will be conducted and submitted for presentation at an upcoming scientific congress.

Medivation and Pfizer will discontinue development of dimebon for all indications and will terminate the ongoing open label extension study in Alzheimer’s disease. The companies also announce that they will terminate their collaboration to co-develop and market dimebon pursuant to the terms of their Collaboration Agreement.

“We recognize Alzheimer’s is a very complex disease,” said Steven J. Romano, M.D., senior vice president, head, Medicines Development Group, Global Primary Care Business Unit, Pfizer Inc. “Despite this disappointing result, Pfizer remains committed to advancing the science of Alzheimer’s disease, with the ultimate goal of delivering innovative and meaningful new treatment options to patients.”

The Phase 3 CONCERT trial was a 12-month global randomized, double-blind, placebo-controlled trial that enrolled 1,003 patients with Alzheimer’s disease. Patients on a stable dose of donepezil for at least four months were randomized to one of three treatment groups: dimebon 20 mg three times per day, dimebon 5 mg three times per day or placebo.

About Medivation

Medivation, Inc. is a biopharmaceutical company focused on the rapid development of novel small molecule drugs to treat serious diseases for which there are limited treatment options. Medivation aims to transform the treatment of these diseases and offer hope to critically ill patients and their caregivers. Together with its corporate partner Astellas, Medivation currently has its investigational drug MDV3100 in Phase 3 development to treat advanced prostate cancer.

http://www.vadvert.co.uk/health/20918-medivation-and-pfizer-announce-results-from-phase-3-concert-trial-of-dimebon-in-alzheimers-disease.html

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Pfizer and Medivation ended their collaboration on the experimental drug Dimebon for Alzheimer’s disease after the medicine failed in another late-stage clinical trial.

Dimebon was one of two drugs Pfizer had in its late-stage pipeline to treat the neurodegenerative disease. The other is bapineuzumab, which Pfizer is developing with Johnson & Johnson. The treatments have different mechanisms of action.

Dimebon didn’t show statistically significant results in a study that evaluated the compound when added to a standard treatment in patients with mild to moderate forms of the disease, the companies said Tuesday. The companies will end development of the drug for all uses, and will stop a current study.

San Francisco’s Medivation dropped 3.3 percent to $53.90 at the close in New York. Pfizer, the world’s biggest drugmaker, gained less than 1 percent to $21.94.

Dimebon also failed in a late-stage trial in 2010, sending Medivation shares down 67 percent in one day.

The federal Centers for Disease Control and Prevention in Atlanta estimates that at least 5 million Americans have Alzheimer’s. The disease usually begins affecting people around age 60. There is no known cure.

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Ending Dimebon Development: Pfizer and Medivation are ceasing development of Dimebon, an experimental Alzheimer’s treatment, the WSJ reports. It was the second phase 3 trial of the drug to fail. In 2008 Pfizer agreed to pay Medivation $225 million upfront plus up to an additional $500 million if milestones were met for development rights to Dimebon, the paper says.

Polio Setback: The number of polio cases in Afghanistan tripled to 76 in 2011, alarming public-health experts, the New York Times reports. The Taliban has historically permitted volunteers and workers to move freely and vaccinate people to prevent the disease’s spread; health workers say that has not changed, the paper says. Cases may have spread by travelers from Pakistan, where the disease is also endemic.

Marketing Confusion?: Branding experts aren’t particularly keen on celebrity chef Paula Deen’s partnership with pharma company Novo Nordisk, which makes drugs for type 2 diabetes, the WSJ reports. Deen revealed yesterday that she has had the disease for about three years. Her brand is all about “rich, tasty and decadent eating” but now she is supposed to be about “eating healthy and low fat,” Allen Adamson, managing director of Landor New York, a branding firm owned by WPP, told the WSJ. “It’s a big change to expect consumers to buy into,” he said.

Condom Requirement: The Los Angeles City Council voted 9-1 to approve an ordinance mandating condom use by actors in the pornography industry, the Los Angeles Times reports. The measure was supported by groups including the AIDS Healthcare Foundation but opposed by the porn industry.

http://blogs.wsj.com/health/2012/01/18/a-m-vitals-pfizer-medivation-end-dimebon-development/

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Latrepirdine attracted renewed interest in 2009 after being shown in small preclinical trials to have positive effects on persons suffering from Alzheimer’s disease. Animal studies showing potential beneficial effects on Alzheimer’s disease models were shown in Russian research in 2000. Preliminary results from human trials have also been promising. In an initial six-month phase II trial, results have shown that at 12 months there was significant improvement over placebo. Latrepirdine showed promising results in a Phase III equivalent double blind trial in Russia with mild–moderate stage patients. In April 2009, Pfizer and Medivation initiate a phase III trial (CONCERT study) aiming for FDA approval. In March 2010, Pfizer announced that this clinical trial failed to show any benefit for the treatment of Alzheimer’s disease patients.

Numerous phase III trials for AD were recruiting in 2009.

In July 2009 Pfizer and Medivation announced that latrepirdine will be the proposed international nonproprietary name for latrepirdine for the treatment of Alzheimer’s.

In March 2010 the results of a clinical trial phase III were released. It was announced that the investigational Alzheimer’s disease drug dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease.

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Latrepirdine ( also known as dimebolin and sold as Dimebon), is an antihistamine drug which has been used clinically in Russia since 1983.

Research is continuing in both Russia and western nations into potential applications as a neuroprotective drug to combat Alzheimer’s disease and, possibly, as a nootropic as well.However, a Phase III clinical trial for Alzheimer’s disease (AD) treatment failed to show any benefit. Three other AD trials continue. Dimebon failed in the phase III trial for Huntington disease.

Uses

Latrepirdine is an orally-active small molecule compound that has been shown to inhibit brain cell death in animal models of Alzheimer’s disease and Huntington’s disease. Research suggests that it may also have cognition-enhancing effects in healthy individuals, in the absence of neurodegenerative disease pathology.  However, because of negative results in human clinical trials, the drug remains unlicensed for any neurodegenerative condition.

http://en.wikipedia.org/wiki/Latrepirdine

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Dimebon clinical trials are currently being conducted in both the treatment of Alzheimer’s disease and the treatment of Huntington’s disease. Dimebon clinical trials are in phase III for Alzheimer’s and are phase II for Huntington’s disease.

Phase I clinical trials are the first phase of testing of a drug in humans. In most cases a small group of healthy volunteer subjects (20 – 80) are used in this phase of clinical trials. This phase includes trials designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug.

Phase II clinical trials are performed on larger groups of volunteers (20 – 300). This phase of clinical trials helps to determine the effectiveness of the drug as well as continues the assessment of the safety of the drug from Phase I.

Phase III clinical trials are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current ‘gold standard’ treatment. While not always a requirement, it is common that there be at least two successful Phase III trials, demonstrating a drug’s safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as the FDA (USA), TGA (Australia), EMEA (European Union), and Health Canada.

The phase III Dimebon clinical trial for Alzheimer’s treatment is as of October 20, 2008 in the recruiting phase according to ClinicalTrials.gov. The official title of the Dimebon clinical trial for Alzheimer’s is “A Global Phase 3, Double-Blind, Placebo-Controlled Safety and Efficacy Study of Oral Dimebon in Patients With Mild-to-Moderate Alzheimer’s Disease (CONNECTION)”. This clinical trial study is a randomized, placebo-controlled 6-month study designed as an adequate and well-controlled trial to demonstrate the safety and efficacy of Dimebon in the treatment of patients with mild-to-moderate AD. Dimebon is an investigational drug for Alzheimer’s disease. The target of Dimebon’s mechanism of action are the mitochondria (a cell’s primary source of energy). The Connection Study is the second of two pivotal studies evaluating the effect of Dimebon. It is a 6-month study enrolling 525 patients in the United States, Europe, and South America. All patients completing the 6-month study will be eligible to receive Dimebon in an open-label extension trial.

The primary outcome measures for this Dimebon clinical trial are to determine the effect of Dimebon as compared to placebo on the primary measure of cognition and memory, the ADAS-cog; and to determine the effect of Dimebon as compared to placebo on the primary measure of global function, the CIBIC-plus.

The secondary outcome measures for this Dimebon clinical trial are to determine the effect of Dimebon as compared to placebo on a measure of self care and daily function, the ADCS-ADL; • To determine the effect of Dimebon as compared to placebo on a measure of behavior, the NPI;

There are three arms to this Dimebon clinical trial. The first arm will receive Dimebon 5mg three times daily. The second arm will receive Dimebon 20mg three times daily. And the third arm of the clinical trial will receive placebo three times daily.

The previous Dimebon clinical trials in the treatment of Alzheimer’s have produced great results. We can only hope that this current clinical trial will further confirm the usefulness of Dimebon in the treatment of Alzheimer’s.

http://www.buydimebon.com/Dimebon/Clinical_trials.php

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Binary events, FDA decisions, and clinical trial results, are the lifeblood — and death wish — of the biotech industry. They’re a necessary part of the drug development process. They don’t always fall your way, but they’re always fun to watch, even if you’re sitting on the sidelines, which is often the most appropriate place to be for many binary events.

Since drugs have FDA review times of six or 10 months and the approximate end of clinical trials is known after the last patient is enrolled, investors get forewarning that the binary events are going to happen. There are a lot of drugs that will face binary events in 2012, and I’ve already reviewed three — but here are three more I think you should watch.

Party like its 2010
On April 17 and sometime in the middle of the year, VIVUS (Nasdaq: VVUS  ) and Arena Pharmaceuticals (Nasdaq: ARNA  ) , respectively, should both get decisions about their obesity drugs that were turned down in 2010. The companies have been working diligently throughout 2011, attempting to satisfy the FDA’s requests for additional information about the safety of their drugs.

VIVUS has already resubmitted its application, avoiding women who could become pregnant to eliminate the risk of a potential birth-defect issue, and should hear back from the FDA on April 17. Arena has guided for a resubmission around the end of the year, which would put a decision in the middle of next year.

The FDA has treated obesity treatments as lifestyle drugs that require a clean bill of health before approval. Thus far, meeting that high standard has proved difficult. From the agency’s perspective, there’s little motivation to approve the drugs and risk another fen-phen issue.

My prediction: Same result as 2010, with the caveat that the FDA can be schizophrenic and could shift gears and become more lenient — or bow to some outside pressure. Either way, stay away until it’s clear the agency has turned over a new leaf.

Don’t forget the binary event
Near the middle of next year, Elan (NYSE: ELN  ) , Johnson & Johnson (NYSE: JNJ  ) , and Pfizer (NYSE: PFE  ) will finally get results from the phase 3 trials testing their Alzheimer’s treatment bapineuzumab. Elan has only a 25% stake in the drug, but being considerably smaller than either of the pharmas, Elan has the most to gain from a positive result.

Predicting the results of the upcoming trial based on the phase 2 results is difficult, because, as you may recall, the earlier trial was marred with controversy. With little to go on, we’ll have to turn to history of previous Alzheimer’s treatment, which doesn’t bode well for bapineuzumab. There was Myriad Genetics‘ Flurizan, and Medivation (Nasdaq: MDVN  ) and Pfizer‘s (NYSE: PFE  ) Dimebon, and the list of failures in the Alzheimer’s disease space goes on. It’s a tough space to work in; even the drugs that have been approved don’t work all that well.

Fortunately for Elan, I think expectations for bapineuzumab are fairly low; I doubt a negative trial will crush the stock, but a positive one will surely cause Elan to skyrocket.

My prediction: I’m going with history on this one and predicting that one or more of the phase 3 trials fails.

Succeed indeed
In early June, the FDA should make a decision about Ariad Pharmaceuticals (Nasdaq ARIA) and Merck‘s (NYSE: MRK  ) sarcoma drug ridaforolimus. Nothing is a guarantee when the FDA is involved, but the drug looks like it has a very good chance at getting on the market next year. The companies’ phase 3 trial, SUCCEED, lived up to its name, improving the progression-free survival by 21% compared with placebo.

My prediction: I’ll go out on a limb of steel and predict an FDA approval.

http://www.fool.com/investing/general/2011/12/31/3-more-stock-moving-binary-events-to-watch-in-2012.aspx

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US biotech firm Medivation (Nasdaq: MDVN) says that patient enrollment was completed at end November in the CONCERT study, a 12-month, Phase III clinical trial in patients with mild-to-moderate Alzheimer’s disease evaluating the potential efficacy of Dimebon (latrepirdine) when added to ongoing treatment with donepezil.

Medivation is conducting this study under its collaboration agreement with drug behemoth Pfizer (NYSE: PFE) which acquired rights the product in 2008 in a deal worth a potential $725 million ($225 million upfront) to the former company.

Dimebon – an old Russian antihistamine approved in that market in 1983 – had once been touted as a blockbuster drug for AD, with potential for anything between $1.5 billion and $5 billion annual sales. However, earlier this year, the majority of observers wrote it off after – somewhat unexpectedly – it failed to meet co-primary or secondary efficacy endpoints compared to placebo in two Phase III trials (The Pharma Letter March 4). After the disastrous results, Medivation’s shares cratered and have yet to recover from the beating they received.

Has received FDA feedback

“Completing patient enrollment in CONCERT is an important step forward for our Dimebon development program in Alzheimer’s disease,” said Lynn Seely, chief medical officer of Medivation. “Now that enrollment is complete, we expect to report top-line results from the CONCERT trial in the first half of 2012. We have previously received feedback from the FDA [Food and Drug Administration] confirming that we can use our Phase III CONCERT trial to complete our registration package for mild-to-moderate Alzheimer’s disease, provided that the results are robustly positive,” she added.

The international, randomized, double-blind, placebo-controlled Phase III CONCERT trial  enrolled 1,003 patients with mild-to-moderate AD at approximately 100 sites in the USA, Australia, New Zealand and Western Europe. Patients on a stable dose of donepezil were randomized to one of three treatment groups: Dimebon 20mg three times per day, Dimebon 5mg three times per day or placebo. Patients were required to be on treatment with donepezil for at least six months and at a stable dose of 10mg daily for at least four months prior to enrollment in the study. The primary endpoints are the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) – a measure of self-care and daily function.

http://www.thepharmaletter.com/file/100475/medivation-persists-with-dimebon-research-in-alzheimers-despite-earlier-failures.html

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