Avandia Continues to Face Scrutiny: Biotech's Latest Mishaps

GlaxoSmithKline’s (GSK) diabetes drug Avandia is once again under regulatory scrutiny—this time it’s in Europe where the European Medicines Agency met to discuss whether Avandia should continue to be marketed. The agency in a press statement said that no final decision has been made about the drug.

It said it has further questions for GSK before deciding whether and what action needs to be taken. A final decision is expected by September 23. The meeting took place as a controversy erupted in the United Kingdom over a recommendation made at the end of July by the UK Commission on Human Medicines, according to TheHeart.Org. The commission unanimously voted that Avandia should be withdrawn. Though it informed the Medicines and Healthcare Products Regulatory Agency, the agency responsible for licensing drugs in the United Kingdom, its decision was not made public. Instead the agency sent letters to doctors restating safety information about the drug and suggesting they consider alternatives. Because the drug was approved by the European Medicines Agency, only it can revoke the license for the drug.

Roche said it halted dosing of patients in a late-stage trial of its experimental diabetes drug taspoglutide because side effects including nausea and vomiting resulted in many participants in the study to drop out of it, Bloomberg reported. The company is trying to determine what caused the side effects and see if it can reformulate the medication to reduce the risk, a spokeswoman told Bloomberg. Because a large number of patients dropped out of the study, the company said it would be difficult to determine whether the drug is effective.

Genzyme is laying off an undisclosed number of staff as part of a restructuring first announced in May, Reuters reported. The company said the move was unrelated to Sanofi-Aventis’ efforts to acquire the company. Genzyme has 12,800 employees. It offered no estimates on how much it expects to save through the restructuring.

Shares of Idenix Pharmaceuticals (IDIX) plummeted after the U.S. Food and Drug Administration ordered the company to halt a mid-stage study of two experimental hepatitis C drugs. Three healthy volunteers testing a combination of the drugs IDX184 and IDX320 showed elevated liver enzyme levels in a routine post-study safety test, the Cambridge, Massachusetts company says. Although liver function returned to nearly normal levels in all three subjects, the FDA placed a clinical hold on the study until it can discuss the results and other relevant data with Idenix. Idenix shares fell to $3.18 from $5.99 on the day it was announced. On top of that punishment, the hold will also likely make Idenix's ongoing search for an outside partner to advance its hepatitis C program more difficult. [see story].

U.S.-based Valeant Pharmaceuticals International and Canada’s Biovail plan to eliminate about 25 percent of their combined workforce once a merger is completed between the two companies, Reuters reported. The company’s said they expect to save more than $300 million through cost synergies with more than $200 million being realized in 2011. The companies have a combined workforce of about 4,400.

Marc Tessier-Lavigne, Genentech’s (DNA) executive vice president of research and chief scientific officer, is leaving the biotech to become president of Rockefeller University in New York, Reuters reported. The departure of Tessier-Lavigne, the second highest executive in research at Genentech, is one of the most significant executive changes since Roche acquired Genentech last year. He takes on his new post in early 2011.

U.S. Food and Drug Administration is requiring that certain contrast agents used in magnetic resonance imaging carry new warnings on their labels about the risk of a rare and potentially fatal condition known as nephrogenic systemic fibrosis, if the drug is administered to certain patients with kidney disease.

Nephrogenic systemic fibrosis or NSF is a condition involving the formation of excess fibrous connective tissue in the skin, joints, eyes, and internal organs. Symptoms of NSF can include scaling, hardening and tightening of the skin, red or dark patches on the skin, and stiffness. NSF may lead to death, especially if it involves body organs. The order pertains to gadolinium-based contrast agents or GBCAs.

The agency said three of the GBCAs—Magnevist, Omniscan, and Optimark— will be described as inappropriate for use among patients with acute kidney injury or chronic severe kidney disease. All GBCA labels will emphasize the need to screen patients to detect these types of kidney dysfunction before administration.

GBCAs are intravenous drugs used to help detect abnormalities of body organs, blood vessels, and other tissues through MRI. Magnevist is marketed by Bayer Healthcare, Omniscan by GE Healthcare, and Optimark by Covidien (COV).

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Study sharpens focus on Glaxo's heart drug hope

A scientific study provided support on Friday for a way of fighting heart disease being pioneered by GlaxoSmithKline, likely to boost interest in drugs that target an enzyme involved in clogging arteries.

A study published in The Lancet medical journal suggests that the enzyme, known as lipoprotein-associated phospholipase A2, or Lp-PLA2, plays as much of a role in the risk of heart disease as high blood pressure and bad cholesterol.

Alex Thompson and John Danesh of Cambridge University, who conducted the research, said their findings would sharpen focus on an experimental drug called darapladib being developed by Glaxo and currently being studied in two large-scale clinical trials involving 27,000 patients worldwide.

"This reinforces interest in this enzyme, and reinforces the need to see the results from these clinical trials," Thompson said in a telephone interview.

Results of the trials are expected between 2012 and 2014.

Coronary heart disease is the leading cause of death worldwide, responsible for around 7 million deaths a year.

Smoking, diabetes, high blood pressure and high levels of "bad" cholesterol known as LDL are known to cause heart disease, but they do not entirely explain its incidence, so scientists and drug companies have been investigating other links.

Glaxo discovered darapladib through the use of gene technology from Human Genome Sciences, which has an agreement with Glaxo to receive clinical development milestone and royalty payments for such compounds.

It is the first in a new class of drugs targeting Lp-PLA2 and is designed to offer something beyond the hugely successful class of cholesterol-lowering statin drugs like Pfizer's Lipitor and AstraZeneca's Crestor.

Darapladib seeks to cut the risk of artery-clogging plaques rupturing, blocking blood vessels and triggering heart attacks. Thompson and Danesh looked at links between Lp-PLA2 and risk of heart disease, stroke and death in almost 80,000 people in 32 previous studies.

They found that higher blood levels of Lp-PLA2 were associated with increased risk. For heart disease, the size of the increased risk was similar to that from higher blood pressure or bad cholesterol, they said.

But they added that their analysis, which was mostly of data for people studied in North America and Europe, also showed weaker than expected links between heart disease and blood pressure and bad cholesterol.

"This enzyme in this study was as strongly associated with heart disease as blood pressure and cholesterol, but we need to be cautious in interpreting that because the associations of blood pressure and cholesterol were themselves substantially lower than we would have expected," Thompson said.

He said this may be because many patients in the studies were already taking heart medications that would alter their blood pressure or cholesterol levels.

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More data needed on Glaxo nausea drug

The U.S. Food and Drug Administration has rejected GlaxoSmithKline PLC's application to approve an experimental drug for nausea and vomiting, saying more data is needed.

The British drugmaker said Tuesday that it had received a "complete response letter" from the FDA regarding its application for casopitant. Glaxo applied to the FDA in May 2008 for approval to sell the drug for nausea and vomiting that occurs after surgery or is triggered by chemotherapy.

The FDA's Center for Drug Evaluation and Research issues complete response letters when staff have finished reviewing all the experimental and other data in a new drug application and there are outstanding questions or issues that bar approval of the product.

GlaxoSmithKline said in a statement that the company is reviewing the FDA's letter and will work with the agency to decide the next appropriate steps.

Company spokeswoman Lisa Behrens said the FDA is requiring specific, additional information in order to consider approval of casopitant.

Glaxo plans to sell the drug under the trade name Rezonic. It already sells a drug for nausea caused by chemotherapy and radiation therapy, Zofran, and tested Rezonic for its effectiveness in combination with both Zofran and a third drug, dexamethasone.

If approved, Rezonic would compete with a few similar drugs, including Whitehouse Station, Merck & Co.'s Emend, Tokyo-based Eisai Co. Ltd.'s Aloxi and New Jersey-based Par Pharmaceutical's Marinol.

Source : www.google.com

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Glaxo's GLP-1 diabetes drug beats Byetta in test

An experimental diabetes drug from GlaxoSmithKline was more effective than Eli Lilly and Amylin Pharmaceuticals' Byetta in controlling blood sugar, a mid-stage test unveiled on Sunday.

Glaxo's injectable Syncria belongs to the same class of medicines, called GLP-1s, as Byetta and Novo Nordisk's Victoza, which the Danish drugmaker expects to launch in Europe this summer.

Safety issues have recently clouded prospects for the GLP-1 drug class.

In a 356-patient Phase II clinical study, presented at the annual meeting of the American Diabetes Association, Glaxo's Syncria, given once weekly, reduced HbA1C -- a common measure of blood sugar -- by 0.9 percent compared to 0.5 percent for Byetta, which is injected twice daily.

Syncria also caused patients to lose 0.9-1.8 kilos in weight, depending on dose. Common side effects included nausea, vomiting and headache.

British-based Glaxo began a final-stage Phase III clinical programme for the new medicine at the beginning of 2009, which is expected to take two to three years to complete.

GLP-1s have been touted as potential multibillion-dollar sellers, given demand for new ways to fight a global epidemic of type two diabetes driven by rising obesity levels.

But recently doubts have grown about the drug class, after Novo's Victoza caused thyroid cancer in rats and there were cases of pancreas inflammation last year with Byetta.

In case of Syncria, Glaxo's vice president of clinical development Murray Stewart said the drug could not be tested on rats for technical reasons but ongoing studies using monkeys had shown no signs of thyroid problems.

He remains optimistic that GLP-1s will emerge as an important new treatment option for difficult-to-treat diabetics, since they are highly effective at controlling blood sugar levels and also help people lose weight.

Some analysts have predicted they will lose out to DPP-4 inhibitors, another novel type of treatment for diabetes.

"I think in four years time people will realise there is probably no risk with pancreatitis and the thyroid issue is more related to animals than it is to humans," Stewart said.

"There is scientific reason to believe these issues will not be real and the benefits of the GLPs compared to the DPP-4s will be demonstrated."

Source : www.reuters.com

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Avandia Study Spurs New Heart Risk Debate

A company-sponsored clinical trial shows that the diabetes drug Avandia causes no more heart deaths than standard treatment, but critics say the study is flawed.

Avandia, made by GlaxoSmithKline, is an oral drug that makes the body more sensitive to insulin.

But concerns that Avandia causes heart problems has led the American Diabetes Association's treatment guidelines committee to advise against prescribing Avandia in favor of Actos, another drug in the same class with fewer heart-safety concerns -- although both drugs increase a patient's risk of heart failure.

GlaxoSmithKline's RECORD study was supposed to answer these concerns. And according to study leader Philip D. Home, DPhil, of the U.K.'s Newcastle University, it did. Home presented the study findings at this week's meeting of the American Diabetes Association in New Orleans.

"The findings are essentially that in overall cardiovascular terms the drug is safe," Home said at a news conference. "There is no increased or decreased risk of death from heart disease, and that includes the heart failure data."

David Nathan, MD, chairman of the American Diabetes Association guideline committee, said the group would reconsider its recommendations in light of the study findings.

However, the study was unable to determine whether Avandia increases a patient's risk of heart attack. That concern was raised by several experts, including Steven Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic.

Nissen remains unconvinced by the final report from Home and colleagues.

"The RECORD trial is seriously flawed," Nissen tells WebMD. "The authors don't reveal the number of patients who were still taking Avandia by the end of the study, but I would estimate this number to approach 50%. Obviously, it is impossible to assess the safety of a drug when patients are not actually taking it."

Home says patients assigned to Avandia treatment took the drug for 88% of the study time. But Nissen says Home's own previously published interim findings do not support this calculation.

Indeed, Home agrees that the study does not answer the question of whether patients taking Avandia have an increased risk of heart attack.

"But what we do know is that this is not associated with cardiovascular death," he said. "There were actually fewer deaths in the [Avandia] group."

In the study, all patients received standard treatment with metformin and/or a sulfonylurea. Half added Avandia to this treatment. The study was not blinded, meaning that study investigators and patients knew which treatment they were getting.

Nissen doubts that this unblinded study will convince experts to change their minds about Avandia. That, he says, will happen only if a new study -- the just-started TIDE study -- shows Avandia is truly safe. The TIDE study is a double-blind trial. And even though it is sponsored by GlaxoSmithKline, there will be a direct comparison of Avandia to Actos, made by Takeda Pharmaceuticals.

Home disagrees, and expects the American Diabetes Association committee to give serious consideration to the new findings, which appear in the June 5 early online edition of The Lancet.

In an editorial accompanying the study, Ravi Retnakaran and Bernard Zinman of Toronto's Mt. Sinai Hospital agree with Nissen that the study's open-label design -- and it's much lower-than-expected rate of cardiovascular deaths -- are problematic.

"Definitive conclusions about the relation between [Avandia] and cardiovascular risk remain elusive, owing to study limitations," Retnakaran and Zinman write. "Furthermore, the findings are inconclusive for [heart attack], for which a non-statistically-significant increased risk was noted in the [Avandia] group."

Unfortunately, a definitive answer isn't soon forthcoming. The TIDE trial isn't scheduled to end until October 2015.

Meanwhile, Retnakaran and Zinman suggest that doctors consider prescribing half doses of Avandia, noting that a half dose offers more than half the benefit of a full dose -- and fewer risks.

Source : diabetes.webmd.com

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Glaxo drug delays kidney cancer progression

An experimental cancer pill from GlaxoSmithKline (GSK.L) reduced the risk of tumour progression or death by 54 percent in advanced kidney cancer patients compared to placebo, trial results showed on Monday.

In spite of this, however, some 4 percent of patients taking the drug died during the course of the study against 3 percent of those on placebo.

Pazopanib belongs to a growing class of anti-cancer drugs that prevent the growth of new blood vessels which feed tumours.

Data presented at the annual American Society for Clinical Oncology meeting in Orlando showed the median progression free survival (PFS) -- the time without tumour growth or death -- for patients on pazopanib was 9.2 months compared with 4.2 months for those on placebo.

"The study shows that pazopanib significantly improved PFS for patients regardless of whether or not they had prior therapy," said Dr. Cora Sternberg of the Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome.

"While there have been many treatment advances for patients with advanced kidney cancer, there is still a need for medicines that are effective and well-tolerated."

The pivotal Phase III trial involved 435 patients with advanced kidney cancer, or renal cell carcinoma, who had either received no prior drug therapy or had been given cytokine-based treatment.

Side effects associated with the new drug included diarrhoea, hypertension, hair colour change, nausea, anorexia, vomiting and raised liver enzymes, which can signal liver toxicity, as well as rarer cases of thrombosis and haemorrhage.

Investigators attributed death due to the drug in 1.4 percent of patients in the treatment arm.

Glaxo is looking to pazopanib to help boost its position in cancer medicine. The drug was filed for approved with regulators in the United States in December 2008 and was submitted in Europe early this year.

The British-based drugmaker is also currently conducting a head-to-head study comparing pazopanib with Pfizer's (PFE.N) rival kidney cancer treatment, Sutent.

Source : www.reuters.com

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