Saturday, June 2, 2007

Pharma Sector: Few Newsmakers Of The Week - Biogen Idec, Exelixis, Pfizer, Rexahn Pharma, EntreMed, Wyeth, Roche, Bristol-Myers, GlaxoSmithKline, Coro

6/2/2007 7:00:55 AM The holiday shortened week due to Memorial Day holiday was a fairly busy one and there were a lot of interesting news related to our subject turf - the pharma sector.

Biogen Idec and Elan are working their way to restore the lost sparkle of multiple sclerosis drug Tysabri, by getting the drug approved for new indications. The sales potential of the drug, which was once touted as the next gold standard form of treatment for multiple sclerosis, has suffered a setback because of serious safety concerns and premium pricing. Prior to being withdrawn from the market in Feb.2005, for causing a deadly brain disease, sales forecasts for Tysabri, also called natalizumab were averaging over $1.5 billion by 2010.

Tysabri was allowed back on the market in July 2006, but with limited distribution. The drug, which was originally priced at $23,500 a year, per patient was relaunced at a new cost of $28,400 per patient per year. Last year, Tysabri garnered worldwide revenues of $36 million. It needs to be seen whether the sales of Tysabri will benefit if the drug gains approval for additional indications.

Bringing fourteen compounds into clinical testing in just over three years is no mean achievement for a company, which has just barely crested the $1 billion mark in market capitalization. The accomplisher of this unique achievement is Exelixis. Since the beginning of this year alone, Exelixis has brought four drug candidates into clinical development.

Exelixis, which means evolution in Greek, true to its name, has evolved from a genomic company, which was using model organisms - similar to humans at the genetic level -to learn more about the human genetic makeup and its role in disease, into a full-fledged drug company. This week, the company initiated mid-stage trials for its investigational lead cancer drug XL647.

The Lipitor patent challenge, regarded as the 'mother of all patent challenges' in the global pharmaceutical industry is back in the news. Pfizer's Lipitor patents were invalidated by a Norwegian Appeals Court this week, paving way for generic drug maker Ranbaxy to market a generic version of Lipitor in Norway. Though the ruling, which has no bearing on Lipitor patent challenges pending in other countries, including the United States, is unlikely to impact the sales of Lipitor, some experts believe that there might be leakage of low priced generic version of the drug across the borders into other markets.

More and more drug companies are now entering the arena of cancer drug business, once thought to be more of a niche market. Premium pricing of cancer drugs is one of the factors that have wooed a number of companies in cancer research. According to an article that appeared in New York Times on June 5, 2006, there are over 400 cancer drugs from 178 companies in clinical trials. Rexahn Pharma has initiated a phase II trial for its lead cancer compound Archexin in patients with renal cell carcinoma.

Few other newsmakers of the week include EntreMed, Wyeth, Roche, Bristol-Myers, GlaxoSmithKline and Coronado.


Brainy Matters - EntreMed Begins Phase II Trial Of Brain Cancer Drug

Tuesday, EntreMed, Inc. (ENMD) commenced a phase II clinical trial combining its investigational drug Panzem NCD and Schering-Plough Corp.'s Temodar in patients with recurrent glioblastoma multiforme, a form of brain cancer.

The purpose of the trial is to evaluate progression free survival, metabolism and action of drug, and safety in brain cancer patients receiving orally- administered Panzem NCD in combination with the current standard of care, Temodar. (Progression free survival refers to the length of time during and after treatment that the cancer does not grow).

Panzem NCD is an orally-administered anticancer agent that attacks tumor cells through apoptosis or programmed cell death, tumor cell cycle inhibition and disruption of angiogenesis. The drug is currently being evaluated in multiple Phase 2 studies in patients with a variety of cancers including brain cancer, prostate cancer, ovarian cancer, carcinoid tumors, and renal cell carcinoma.

Pre-clinical data have demonstrated that combination treatment with Panzem and Temodar resulted in tumor regression compared to either agent alone in a glioblastoma model.

A Slow But Steady Progress - Rexahn Pharma Initiates Mid-stage Trial With Kidney Cancer Drug

Following the FDA approval, U.S. biopharmaceutical company Rexahn Pharmaceuticals, Inc. (RXHN.OB) on Tuesday said that it would initiate a phase II trial for its lead oncology compound Archexin in patients with renal cell carcinoma, the most common form of kidney cancer. Enrollment in the trial is expected to begin in the third quarter of 2007.

Renal cell carcinoma is one of the most difficult cancers to treat, as most often it becomes resistant to both radiation therapy and chemotherapy.

Archexin, which demonstrated effectiveness at inhibiting the proliferation of various cancer cells in very low levels and regulating the growth of tumors in both preclinical and phase I trial was granted “orphan drug designation" for kidney, stomach, ovarian, pancreas and brain cancers in December 2004. The only dose limiting toxicity was fatigue at a dosage of 315mg/m2.

Renal cell carcinoma, diagnosed in about 51,000 people annually in the U.S., accounts for about 85% of all U.S. adult kidney cancer, according to the FDA.

In the past, standard treatment for renal cell carcinoma that had not spread outside the kidney and nearby tissue was surgical removal of all or part of the kidney, while drugs like Proleukin were used to treat metastatic renal cell carcinoma that has spread outside the kidney.

Nexavar developed by Bayer and Onyx is the first drug in 12 years to be approved by the FDA in Dec.2005, for kidney cancer. Pfizer's Sutent won regulatory approval to treat advanced kidney cancer known as renal cell carcinoma in Jan. 2006. As recently as May 30, the drug Torisel, made by Wyeth was granted approval by the FDA in the treatment of renal cell carcinoma. The drug is expected to be available in July.

No Stopping It - Exelixis Commences Mid-stage Trial Of XL647 In Non-small Cell Lung Cancer Patients

Wednesday, Exelixis Inc. (EXEL) initiated a phase II clinical trial of XL647 in patients with non-small cell lung cancer who previously benefited from other lung cancer drugs like Genentech's Tarceva or AstraZeneca's Iressa or have a T790M mutation of the epidermal growth factor receptor or EGFR.

The T790M mutation of the epidermal growth factor receptor means the cells are resistant to the inhibitory effects of Tarceva or Iressa. Preclinical data have shown that XL647 has the potential to inhibit this mutation and other mutant forms of EGFR. A Phase II trial evaluating XL647 as a first-line therapy is currently underway.

Exelixis has inked multimillion dollar development deals with major pharmaceutical and biotechnology companies, including GlaxoSmithKline, Bristol-Myers Squibb Co., Genentech, Wyeth Pharma and Japan-based Sankyo.

An agreement signed with the British drug giant Glaxo in 2002, calls for Exelixis to discover drugs and advance them to Phase II stage of clinical development. Glaxo will then have the right to take over the clinical testing and to manufacture and sell the drugs. Under that agreement, Glaxo has three months to review the data and decide whether to exercise its option to select the compound for further development. If XL647 is selected, Exelixis will receive milestone payments and royalties from Glaxo, as well as the right to co-promote the drug in North America, under certain circumstances.


Oncology Partner - Burnham Institute Licenses Cancer Drug To Coronado Biosciences

Tuesday, Burnham Institute for Medical Research agreed to license cancer drug Apogossypol to Coronado Biosciences, a privately-held, clinical stage biopharmaceutical company.

In pre-clinical studies, Apogossypol is known to inhibit certain proteins found in a wide variety of solid tumors.

Under the terms of the agreement, San Diego, California-based Coronado will pay Burnham an upfront payment and potential future milestones in excess of $15 million if Apogossypol is successfully developed and commercialized. In addition, Burnham will receive royalties on worldwide sales of Apogossypol. Coronado plans to file Independent New Drug Application to the FDA for Apogossypol and commence clinical trials in mid-2008.


Exploring New Horizons - FDA Panels To Review Multiple Sclerosis Drug Tysabri For Crohn's Disease

Biogen Idec (BIIB) and Elan Corp. (ELN) on Tuesday revealed that two of the FDA's advisory committees, Gastrointestinal Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee will review multiple sclerosis drug Tysabri for the treatment of Crohn's disease at a July 31 joint advisory meeting.

Tysabri is made by Biogen-Idec and distributed by Dublin, Ireland-based Elan Corp. The companies submitted the supplemental biologics license application for Tysabri as a treatment of moderately to severely active Crohn's disease, a painful bowel disorder, to the FDA on December 15, 2006. The filing was based on the results of three randomized, double-blind, placebo-controlled, multi-center trials of Tysabri, which assessed the safety and efficacy of the drug in the treatment of Crohn's disease.

Tysabri, which was given the FDA approval for multiple sclerosis in November 2004, was voluntarily withdrawn from the market in February 2005, after it was found that three patients taking the drug developed a rare but potentially fatal brain disease, progressive multifocal leukoencephalopathy or PML. The drug proved fatal in two cases.

The drug was allowed back on the U.S. market by the FDA in July 2006, and launched in several European countries, but with certain restrictions and enhanced safety warnings. The FDA has also recommended that Tysabri should be used as a stand-alone treatment and not combined with other drugs, which suppress the immune system. Previously, Tysabri was prescribed along with Biogen Idec's other multiple sclerosis treatment Avonex.

Crohn's disease afflicts 1 million people worldwide. The disease can strike people of any age but it most often affects people in their teens or 20s and there is currently no cure for it. The common symptoms of Crohn's disease include abdominal pain, diarrhea, vomiting, fever, and weight loss. In 1998, the FDA approved the use of Remicade as a treatment of moderately-to-severely active Crohn's disease in patients who have an inadequate response to conventional therapies. Remicade is manufactured and marketed by Centocor, Inc., a wholly owned subsidiary of Johnson and Johnson, Inc.

One's Loss, Another's Gain? - GlaxoSmithKline's Cervical Cancer Vaccine Denied Priority Review

British drug giant GlaxoSmithKline plc's (GSK) cervical cancer vaccine Cervarix has been denied a priority review, the company announced on Thursday. A priority review would have seen the launch of the vaccine on the U.S. market in six months.

Touted as a rival to Merck's Gardasil, analysts have an annual sales estimate of $1.5 billion for Cervarix. Merck's Gardasil, approved by the FDA in July 2006, is the first vaccine for the treatment of cervical cancer.

Glaxo's failure to get priority review for Cervarix is a gain for rival Merck. The FDA ruling means that Merck & Co.'s rival product Gardasil, which is already available in the U.S., will remain unchallenged until 2008.

According to reports, Gardasil, which costs $360 for three doses given over six months, is the most expensive vaccine on Centers for Disease Control and Prevention or CDC's list of recommended childhood vaccines. Gardasil pitched in sales of $365 million in the recently completed first quarter and since its launch, the vaccine has notched up sales of $600 million. Sanford Bernstein analyst, Gbola Amusa has an annual sales estimate of $2.5 billion for Gardasil.

Cervical cancer is the second most frequently occurring cancer in women between the ages of 20 to 39 in the United States, next to breast cancer. The main cause of cervical cancer is continuous infection with human papilloma viruses, especially HPV 16 and 18, which are spread by sexual contact. The American Cancer Society estimates that in 2007 more than 11,000 women will be diagnosed with cervical cancer and nearly 4,000 will succumb to this disease in the United States.

Gardasil is designed to protect against human papilloma viruses 6, 11, 16 and 18, while Cervarix offers protection against human papilloma viruses 16 and 18. Cervarix is delivered with a proprietary adjuvant system called AS04, containing aluminum hydroxide and monophosphoryl lipid A. The addition of adjuvant in a vaccine enhances the immune response, thereby making the action of the vaccine more effective.

With Cervarix, now having to go through a standard 10-month review, Glaxo expects to launch the drug in the U.S., sometime in 2008. However, the vaccine has already been approved in Australia, and the company is expecting to launch the vaccine in Europe during the second half of 2007. Glaxo applied for U.S. marketing approval in March and was hoping to get a priority review for Cervarix. A priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists.


Verdict Reversed - Philadelphia Court Overturns Prempro Verdict In Favor Of Wyeth

Thursday, drug giant Wyeth (WYE) announced that the Philadelphia Court of Common Pleas has overturned the verdict related to the hormone therapy drug, Prempro in favor of the company in the case of Jennie Nelson v. Wyeth.

The Jennie Nelson case, which was a “reverse bifurcation” phased trial, was first tried in October of 2006. Jennie Nelson of Dayton, Ohio had taken Wyeth's hormone replacement therapy drug, Prempro for five years before being diagnosed with breast cancer in 2001.

In the first phase of the trial, in which the jury determined causation and compensatory damages, the Pennsylvania state court jury on Oct.4, 2006 found that Wyeth's hormone replacement therapy was a cause of the plaintiff's breast cancer and determined that the amount of compensatory damages would be $1 million for Jennie Nelson and $500,000 for her husband. The second phase, in which the jury was to determine liability and punitive damages, was scheduled to begin on Oct. 14.

Following a motion filed by Wyeth, the judge threw out the verdict of the first phase of the trial and declared a mistrial. The judge did not give a reason for declaring the mistrial. Since a mistrial was declared, the case did not proceed to the second phase and the couple was not awarded any of the compensatory damages.

The retrial of Jennie Nelson case began on January 11, 2007 in the Philadelphia Court of Common Pleas. The jury on Feb.20, 2007 found Wyeth liable for failing to provide adequate warnings about breast-cancer risks of Prempro and this time, awarded Jennie Nelson $2.4 million in damages and an additional $600,000 to her husband.

Wyeth had appealed the verdict and the company's attorneys, blamed Jennie Nelson's cancer on other factors, including her family history.

Wyeth's hormone replacement therapy drugs, Premarin and Prempro touted as "magic bullets" are indicated for the relief of hot flashes and night sweats, associated with menopause. After the U.S. government's Women's Health Initiative study found that healthy postmenopausal women enrolled in the study who were treated with the hormone replacement therapy drugs, Premarin and Prempro had increased risk of invasive breast cancer, stroke and blood clots, Wyeth came under fire. The eight-year study, which was to continue until 2005, came to an abrupt halt in early June 2002. However, the drugs continue to be in the market.

Wyeth won the first hormone therapy trial in September, 2006 in federal court in Little Rock, Arkansas. The company faces over 5,000 suits on behalf of over 8,400 women who claim that the drug maker, despite knowing the potential harmful side effects associated with the hormone replacement therapy drugs - Premarin and Prempro, downplayed them. Thus far, Wyeth has won three cases, including the mistrial that was turned in favor of the company and has lost two cases.

Premarin has been in use since 1942 while Prempro was approved by the FDA in 1994. In late 2002, Wyeth added a boldface warning on Prempro and on Premarin. In 2003, the drugs' label sported the FDA's strictest black box warning.

Premarin and Prempro had combined sales of $2 billion in 2001. Following the study results, the sales of Premarin and Prempro took a beating, dropping to $1.3 billion in 2003 and $880 million in 2004. The drugs generated $910 million in 2005. However, last year, Wyeth's hormone-replacement drugs generated sales of $1.05 billion, an increase of 16% over 2005.

A Clear Skin … But At What Cost? - Roche Loses First Product Liability Case Related To Acne Drug Accutane

Tuesday, Swiss drug giant Roche Holding AG was ordered by a New Jersey Superior Court jury to pay over $2.5 million to an Alabama man who claimed that the company's acne drug Accutane had caused his inflammatory bowel disease. The case is the first of the nearly 400 U.S. lawsuits involving Accutane.

The plaintiff Andrew McCarrell, 36, said he had undergone multiple surgeries, including having his colon removed, after taking the drug in 1995. The jury awarded McCarrell $2.5 million in damages and $119,000 to cover medical expenses. Roche, which believes that there is no scientific evidence to prove that its drug had caused inflammatory bowel disease, as claimed by the plaintiff intends to appeal the verdict.

Accutane was approved by the FDA in 1982 for severe, recalcitrant acne, a serious and debilitating condition that causes cysts, scarring and disfigurement. Since its approval, the drug's label carried a warning that it should not be used by pregnant women or women who might become pregnant. There were reports of birth defects associated with the use of Accutane as early as 1983. In order to reduce the risk of birth defects, the FDA in 2005, approved safety labeling revisions for Accutane to inform patients of a mandatory risk management program. The program involved mandatory registration of prescribers, patients, wholesalers, and pharmacies.

There have been reports linking the drug to depression, and suicides, in addition to inflammatory bowel disease. Reports reveal that from 1982 to May 2000 the FDA had determined that Accutane was associated with 147 suicides and hospitalizations for depression. By 2002, the FDA had confirmed 173 cases of suicide among persons taking Accutane, since its introduction in 1982.

Patent Palooza - Norway Supreme Court Allows Ranbaxy To Market Generic Lipitor In Norway

India-based generic drug maker Ranbaxy will soon be able to sell a generic version of Pfizer Inc.'s (PFE) cholesterol lowering blockbuster drug - Lipitor, in Norway. Tuesday, Norway's Supreme Court - Borgarting Court of Appeal in Oslo ruled that four of Pfizer's patents covering Lipitor, are either invalid or not infringed by Ranbaxy's proposed generic form of Lipitor. Pfizer intends to appeal the ruling immediately.

The Norwegian Court of Appeal ruled that three Pfizer patents covering intermediate compounds used to make atorvastatin, the active ingredient in Lipitor, would not be infringed by the sale of Ranbaxy's generic form of Lipitor in Norway. The Norwegian court also ruled that Pfizer's patent covering a process for converting crystalline atorvastatin calcium to amorphous atorvastatin calcium is invalid.

The patent on Lipitor, the world's best-selling medicine expires in 2010 in the U.S. and between February 2009 and July 2016 in Norway. Pfizer noted that the ruling has no bearing on Lipitor patent challenges pending in other countries, including the United States.

Lipitor, garnered revenues of $12.89 billion in 2006, up 6% from $12.19 billion in 2005. Lipitor accounted for nearly 29% of Pfizer's total pharmaceutical revenues last year.

Ranbaxy is involved in a legal spat with Pfizer in more than 17 countries including the United States, over Lipitor's patent.

For Ranbaxy, which spent about $37 million during 2004-05, to fight the patent battle related to Pfizer's Lipitor, the launch of the atorvastatin - the generic version of Lipitor is vital in its plan to generate nearly $2 billion in sales over the next five years. Ranbaxy has about 20 first-to-file or FTF applications, which gives the company exclusive marketing rights on the generic version of the branded drugs for six months, pending in the U.S. Of the 10 FTF applications, which are facing legal hurdles, atorvastatin or generic Lipitor remains a big bet.

A Moral Issue - Bristol-Myers Pleads Guilty In Plavix Case

Wednesday, the Department of Justice announced that Bristol-Myers Squibb Co. (BMY), agreed to plead guilty to two counts of making false statements to the Federal Trade Commission, related to its botched Plavix settlement negotiations with a privately held Canadian firm, Apotex Inc. Bristol-Myers has also agreed to pay an aggregate statutory maximum fine of $1 million.

Earlier this month, Bristol-Myers reached an agreement in principle with the Department of Justice or DoJ to end the federal anti-trust investigation, related to the proposed Plavix settlement agreement.

The Department of Justice in a statement said that Bristol-Myers' actions had threatened to reduce competition for Plavix, one of the biggest prescription medications sold worldwide.

Plavix, a blood thinner is manufactured by Paris-based Sanofi-Aventis SA (SNY) and marketed by New York-based Bristol-Myers Squibb. A Canadian firm, Apotex challenged Plavix's patent, which expires in 2011 and confident of overturning Plavix patent, Apotex launched the generic version of the drug on August 8, 2006. The generic version had a list price of $124 for 30 tablets, compared to $148 for the brandname product. Following the entry of generic version, sales of Plavix took a beating.

On August 14, 2006 Bristol-Myers and its partner Sanofi-Aventis filed a suit seeking to immediately block the sale of Apotex's generic equivalent to Plavix, and requested a recall of the drug that had already been shipped. Fearing that his company might lose the suit, Bristol-Myers CEO Peter Dolan made a deal with Apotex agreeing to pay $40 million, in order to delay the entry of the generic version of Plavix. But the deal did not materialise. Bristol-Myers did not disclose the details of the deal to the FTC.

Bristol-Myers is required to have any patent-settlement agreement reviewed in advance by the FTC, as per a previous settlement reached with federal authorities over a separate investigation.

The Plavix deal came to light when the FBI agents searched Bristol-Myers' Park Avenue headquarters, following which, the Department of Justice opened a probe into it. Dolan was forced out from his executive position in September last year.

But the Plavix patent was not as vulnerable as Dolan had feared. On August 31, 2006 a preliminary injunction ordering Apotex to halt its sales of generic version of Plavix was issued by the United States District Court for the Southern District of New York. In early December 2006, the United States Court of Appeals for the Federal Circuit upheld the August 31, 2006 preliminary injunction, thus preventing Apotex from selling a generic version in the U.S., until the drug's patent expired.

Despite a favorable ruling for Bristol Myers, the damage was already done to Plavix because of the launch of the generic version of the drug. According to IMS Health, global plavix sales declined to $5.8 billion in 2006 from $5.9 billion in 2005. Plavix, which was the world's second best-selling branded prescription drug after Pfizer's Lipitor has now been pushed down in rank to the fourth place.

In 2003, Bristol-Myers was charged by the FTC for involving in a series of similar anticompetitive acts to obstruct the entry of low-price generic version of three of its products namely two anti-cancer drugs, Taxol and Platinol, and the anti-anxiety agent BuSpar.

In 2005, Bristol-Myers signed a deferred prosecution agreement and agreed to pay $300 million into a shareholder fund for conspiring to commit securities fraud by inflating the company's revenue by about $2.5 billion and profits by about $900 million between 1999 and 2002. The deferred-prosecution agreement will expire as scheduled on June 15.


According to reports, Researchers at the University of Cincinnati have found that a topical gel derived from a patient's own blood is capable of preventing infection, besides accelerating the healing process. The healing effect of the blood lies in its platelets - the irregularly-shaped, colorless bodies that gather at the site of the wound and attempt to block the blood flow.

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