FDA Advisory Committee Recommendation on Seroquel XR Supplemental New Drug Applications

WILMINGTON, Del., April 08, 2009 /PRNewswire-FirstCall/ -- Today, the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) conducted a review of the safety and efficacy of supplemental new drug applications (sNDA) for SEROQUEL XR (quetiapine fumarate) extended-release tablets proposed for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).

The Advisory Committee concluded:

Howard Hutchinson, M.D., Chief Medical Officer of AstraZeneca, said: "We are pleased that the committee found SEROQUEL XR to be effective and acceptably safe for use as adjunctive therapy for the treatment of MDD. Although the committee recognized the effectiveness of SEROQUEL XR as monotherapy for MDD and GAD, they had concerns around the long-term safety profile in these new populations. We look forward to having further discussions with the FDA regarding both sNDAs."

The FDA frequently convenes advisory committee meetings to obtain independent expert guidance and recommendations on clinical matters. While the FDA is not required to follow this guidance, the agency usually takes the advice into consideration when rendering its final decisions on pending applications and other public health matters.

SEROQUEL XR is not approved for the treatment of MDD and GAD.

SEROQUEL XR, a once-daily, extended-release tablet formulation of SEROQUEL(R) (quetiapine fumarate) tablets, was approved in the U.S. in 2007 for the acute and maintenance treatment of schizophrenia in adult patients and in October 2008 for the acute treatment of the depressive episodes associated with bipolar disorder, the manic and mixed episodes associated with bipolar I disorder, and the maintenance treatment of bipolar I disorder as adjunctive therapy to lithium or divalproex.

SEROQUEL XR is indicated for the treatment of acute depressive episodes associated with bipolar disorder, acute manic or mixed episodes associated with bipolar I disorder as monotherapy and as an adjunct to lithium or divalproex; maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex, and acute and maintenance treatment of schizophrenia. SEROQUEL is indicated for the treatment of depressive episodes in bipolar disorder; acute manic episodes in bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex; and schizophrenia. Patients should be periodically reassessed to determine the need for continued treatment and the appropriate dose.

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. The relationship of atypical use and glucose abnormalities is complicated by the possibility of increased risk of diabetes in the schizophrenic population and the increasing incidence of diabetes in the general population. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics. Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.

In long-term clinical trials of quetiapine, hyperglycemia (fasting glucose Greater Than or Equal To 126 mg/dL) was observed in 10.7% of patients receiving quetiapine (mean exposure 213 days) vs. 4.6% in patients receiving placebo (mean exposure 152 days).

Clinically significant increases in cholesterol (7%-16% for quetiapine vs. 3%-9% for placebo) and triglycerides (8%-23% for quetiapine vs. 5%-16% for placebo) have been observed in clinical trials.

The proportion of patients in clinical trials meeting a weight gain criterion of Greater Than or Equal To 7% of body weight was 5%-23% for quetiapine vs. 0%-7% for placebo.

A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include immediate discontinuation of antipsychotic drugs.

Leukopenia, neutropenia, and agranulocytosis (including fatal cases), have been reported temporally related to atypical antipsychotics, including quetiapine. Patients with a pre-existing low white blood cell (WBC) count or a history of drug induced leukopenia/neutropenia should have their complete blood count monitored frequently during the first few months of therapy. In these patients, SEROQUEL XR and SEROQUEL should be discontinued at the first sign of a decline in WBC absent other causative factors. Patients with neutropenia should be carefully monitored, and SEROQUEL XR and SEROQUEL should be discontinued in any patient if the absolute neutrophil count is <>

Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of TD.

Warnings and Precautions also include the risk of orthostatic hypotension, cataracts, seizures, hyperprolactinemia, and possibility of suicide attempts. Examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment. The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high risk patients should accompany drug therapy.

The most commonly reported adverse reactions associated with the use of SEROQUEL vs. placebo in clinical trials for schizophrenia and bipolar disorder were somnolence (18%-57% vs. 8%-15%), dry mouth (9%-44% vs. 3%-13%), dizziness (9%-18% vs. 5%-7%), constipation (8%-10% vs. 3%-5%), asthenia (5%-10% vs. 3%-4%), abdominal pain (4%-7% vs. 1%-3%), postural hypotension (4%-7% vs. 1%-2%), pharyngitis (4%-6% vs. 3%), weight gain (5%-6% vs. 1%-3%), lethargy (5% vs. 2%), nasal congestion (5% vs. 3%), SGPT increased (5% vs. 1%), and dyspepsia (5%-7% vs. 1%-4%).

Merck & Co., Inc. and Cardiome Sign License Agreement for Vernakalant, an Investigational Drug for Treatment of Atrial Fibrillation

WHITEHOUSE STATION, N.J. & VANCOUVER--(BUSINESS WIRE)--Apr 8, 2009 - Merck & Co., Inc. and Cardiome Pharma Corp. (NASDAQ: CRME / TSX: COM) today announced a collaboration and license agreement for the development and commercialization of vernakalant, an investigational candidate for the treatment of atrial fibrillation. The agreement provides Merck with exclusive global rights to the oral formulation of vernakalant (vernakalant [oral]) for the maintenance of normal heart rhythm in patients with atrial fibrillation, and provides a Merck affiliate, Merck Sharp & Dohme (Switzerland) GmbH, with exclusive rights outside of the United States, Canada and Mexico to the intravenous (IV) formulation of vernakalant (vernakalant [IV]) for rapid conversion of acute atrial fibrillation to normal heart rhythm.

"This agreement underscores Merck's ongoing commitment to the research and development of new cardiovascular drugs," said Luciano Rossetti M.D., senior vice president and franchise head, Atherosclerosis and Cardiovascular, Merck Research Laboratories. "Vernakalant is an important addition to our broad portfolio of products and candidates that target multiple aspects of heart disease."

“Given Merck's long-established leadership in the cardiovascular space, we believe there is no company better suited to advance vernakalant,” said Bob Rieder, chairman and chief executive officer of Cardiome. “This collaboration places Cardiome in a strong financial position as we conclude our strategic review, and moves the Company closer to providing doctors with an important tool to address this critical unmet medical need.”

Under terms of the agreement, Merck will pay Cardiome an initial fee of US$60 million. In addition, Cardiome is eligible to receive up to US$200 million in payments based on achievement of certain milestones associated with the development and approval of vernakalant products (including a total of US$35 million for initiation of a planned Phase III program for vernakalant [oral] and submission for regulatory approval in Europe of vernakalant [IV]), and up to US$100 million for milestones associated with approvals in other subsequent indications of both the intravenous and oral formulations. Also, Cardiome will receive tiered royalty payments on sales of any approved products and has the potential to receive up to US$340 million in milestone payments based on achievement of significant sales thresholds.

Cardiome has retained an option to co-promote vernakalant (oral) with Merck through a hospital-based sales force in the United States. Merck will be responsible for all future costs associated with the development, manufacturing and commercialization of these candidates. Merck has granted Cardiome a secured, interest-bearing credit facility of up to US$100 million that Cardiome may access in tranches over several years commencing in 2010.

Vernakalant (IV) is an investigational candidate being evaluated for its ability to terminate an atrial fibrillation episode and return the heart to normal rhythm. Cardiome's co-development partner in North America, Astellas Pharma U.S., Inc., submitted a New Drug Application with the U.S. Food and Drug Administration (FDA) for KYNAPID™ (vernakalant hydrochloride) Injection in December 2006 that included results from two pivotal Phase III clinical trials. In December 2007, the Cardiovascular and Renal Drugs Advisory Committee recommended that the FDA approve vernakalant (IV) for rapid conversion of atrial fibrillation. In August 2008, the FDA issued an Approvable action letter requesting additional information.

Vernakalant (oral) is being evaluated as an oral maintenance therapy for the long-term prevention of atrial fibrillation recurrence. A Phase IIb double-blind, placebo-controlled, randomized, dose-ranging clinical trial in patients at risk of recurrent atrial fibrillation showed that at the 500 mg dose, vernakalant (oral) significantly reduced the rate of atrial fibrillation relapse as compared to placebo.

The effectiveness of the collaboration agreement is subject to the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act, if applicable, as well as other customary closing conditions. The agreement between Cardiome and Astellas Pharma U.S., Inc. for vernakalant (IV) in the United States, Canada and Mexico is unaffected by this agreement.

Research could lead to new non-antibiotic drugs to counter hospital infections

Lack of an adequate amount of the mineral phosphate can turn a common bacterium into a killer, according to research to be published in the April 14, 2009, issue of the Proceedings of the National Academies of Science. The findings could lead to new drugs that would disarm the increasingly antibiotic-resistant pathogen rather than attempting to kill it.

Pseudomonas aeruginosa is one of the most serious hospital-acquired pathogens. A common cause of lung infections, it is also found in the intestinal tract of 20 percent of all Americans and 50 percent of hospitalized patients in the United States.

It is one of the hundreds of bacteria that colonize the human intestinal tract, usually causing no apparent harm. It might even be beneficial to its host. Once the host is weakened by an illness, surgical procedure or immunosuppressive drugs, however, P. aeruginosa can cause infection, inflammation, sepsis and death.

Why P. aeruginosa can suddenly turn on its host has eluded researchers—until now. Scientists have long known that after an operation or organ surgery, levels of inorganic phosphate fall. The authors of the PNAS paper, led by scientists at the University of Chicago, hypothesized that phosphate depletion in the stressed intestinal tract signals P. aeruginosa to become lethal.

To test this theory, they let worms (Caenorhabditis elegans) feed on "lawns" of P. aeruginosa and Escherichia coli grown in both low-phosphate and high-phosphate media. Only the worms that ate P. aeruginosa with low levels of phosphate died. The researchers dubbed the phenomenon "Red Death" since unexpected large red spots appeared on the worms before they died.

"These findings provide novel insight into the mechanisms by which P. aeruginosa is able to shift from indolent colonizer to a lethal pathogen when present in the intestinal tract of a stressed host," said Alexander Zaborin, lead author of the study and a research professional at the University of Chicago’s Department of Surgery.

"It's almost as if the bacterium sense when to strike," said John Alverdy, corresponding author of the study and professor of surgery at the University of Chicago Medical Center. "That should come as no surprise since the bacteria are smart, having been around for 2 billion years."

Bacteria seek phosphate as an important nutrient, Alverdy explained. And rather than try to look for it in the blood steam of critically ill patients, where they would encounter armies of antibiotics and disease-fighting white blood cells, they find it inside organ tissues. This process damages and sometimes even kills their host.

Experiments with mice showed that the harm caused when P. aeruginosa becomes activated to express lethal toxins inside the intestinal tract can be mitigated by providing excess phosphate.

The research findings could lead to a pharmaceutical product that would restore healthy phosphate levels in the intestines of such stressed and compromised patients, Alverdy said.

"Antibiotics attempt to kill harmful bacteria, but in the process they often kill beneficial bacteria," said Olga Zaborina, an associate professor at the University of Chicago’s Department of Surgery and another key researcher in this study. "A more sensible approach to fighting infectious diseases may be to try to understand the circumstances that provoke a microbe to cause harm in the first place and then find ways to pacify them without destroying them."

Containment on a case-by-case basis might be a more effective and longer-lasting strategy than a scorched earth policy, Alverdy said. Midway Pharmaceuticals, which Alverdy founded in 2005, is developing a pipeline of non-antibiotic compounds that contain or disarm specific bacteria.

Appreciation of the subtle mechanisms in pathogens that colonize the intestinal tract of critically ill patients has important implications for the design of phosphate-based compounds that might prevent P. aeruginosa and other pathogens from turning lethal, the researchers concluded.

Despite the use of powerful antibiotics, P. aeruginosa remains a leading cause of sickness and death among hospitalized patients who have undergone surgery or have reduced immunity. If the bacterium attacks critical body organs such as the lungs, urinary tract and kidneys, it is likely to be fatal. P. aeruginosa thrives on moist surfaces, so it is often found on catheters, causing cross-hospital infections. It is also implicated in a common form of dermatitis associated with poor hygiene and inadequate maintenance of hot tubs.

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Drug shows activity in men with advanced prostate cancer

A new multi-center study shows that an experimental drug lowers prostate specific antigen (PSA) levels – a marker for tumor growth – in men with advanced prostate cancer for whom traditional treatment options have failed. The study, led by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC), is published today in Science Express, the online version of the journal Science.

Most men with metastatic prostate cancer eventually build up resistance to the drugs that lower or block male hormones and develop a more aggressive form of the illness called castration-resistant prostate cancer (CRPC), or hormone-refractory disease. According to the study's findings, investigators studied two novel compounds, RD162 and MDV3100, and not only gained an understanding of their novel mechanism of action, but found that these agents showed activity in CRPC cells in culture and in mice.

The study also reports on a Phase 1/2 trial of MDV3100 in 30 patients with advanced CRPC and found that 22 out of 30 men showed declining PSA levels, and 13 out of 30 men (43 percent) had PSA levels fall by more than half.

Several years ago, the senior author of the study, Charles Sawyers, MD, and his colleagues at the University of California, Los Angeles (UCLA), uncovered a potential reason why metastatic prostate cancer patients eventually relapse with CRPC. This insight was used to discover RD162 and MDV3100.

"It's gratifying to know that our hypotheses about why men develop resistance to currently available treatments are confirmed and, most importantly, that there are already patients who are benefiting from our research," said Dr. Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a Howard Hughes Medical Institute investigator.

Current treatments for men who have advanced prostate cancers inhibit the activity of male hormones that help drive tumor growth. Many of these drugs disrupt the androgen (male hormone) receptor, which helps regulate cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the receptor. Preclinical studies by Dr. Sawyers and others have demonstrated that CRPC cells have increased expression of the androgen receptor and that overexpression of this receptor may contribute to the progression of disease.

Based on this information, Dr. Sawyers initiated a collaboration with Michael Jung, PhD, Professor of Chemistry at UCLA, that led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100, which has been shown to retain its anticancer activity, even when the receptor's expression is elevated.

"The discovery and initial development of this drug was a collaborative effort all done in the academic setting, without reliance on the engine of the pharmaceutical industry that typically drives drug development," said Dr. Sawyers. Dr. Jung's group synthesized the compounds, which Dr. Sawyers' team then evaluated using prostate cancer mouse models engineered to highly express the androgen receptor, mimic progression to castration-resistant disease, and reflect the biology of clinical drug resistance.

According to the new study, the team of researchers tested various compounds to block the androgen receptor in CRPC cells. They chose to further evaluate the drug RD162 and a closely related compound, MDV3100. According to their findings, both drugs inhibit the androgen receptor function by impairing the receptor's ability to enter a CRPC cell's nucleus (called nuclear translocation), blocking it from binding to the DNA of its target genes, and preventing the cell from growing. They found that both compounds worked well in cells in culture, shrank tumors in mice, maintained tumor shrinkage for months, and prevented the androgen receptor from activating additional genes later in the process, or "downstream." Other currently approved drugs cannot disable the receptor in such a way.

The biopharmaceutical company Medivation, Inc., licensed RD162 and MDV3100 from UCLA in 2006 and has already completed enrollment in the first human trial of oral MDV3100 – a Phase 1/2 clinical trial, which was led by investigators at MSKCC and conducted through the Prostate Cancer Clinical Trials Consortium. The Consortium is sponsored by the Department of Defense and the Prostate Cancer Foundation. The trial enrolled men with metastatic, castration-resistant prostate cancer who relapsed after treatment with conventional hormone therapy and demonstrated anti-prostate cancer effects beginning with the first patient treated with MDV3100 at the lowest dose. Further positive results from an additional 110 patients who received the drug at higher doses were recently reported at the ASCO Genitourinary Cancers Symposium in February 2009 (see abstract: http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=64&abstractID=20500).

"The declines in PSA levels observed thus far and the general tolerability of this treatment are encouraging," said Howard Scher, MD, a study co-author and Chief of the Genitourinary Oncology Service at MSKCC. "I am looking forward to continuing the study of this drug, which has the potential to be a powerful tool in a limited arsenal of treatments against this deadly form of the disease." A Phase 3 trial is planned to begin later this year.

Stem cell therapy makes cloudy corneas clear, according to Pitt researchers

PITTSBURGH, April 9 – Stem cells collected from human corneas restore transparency and don't trigger a rejection response when injected into eyes that are scarred and hazy, according to experiments conducted in mice by researchers at the University of Pittsburgh School of Medicine. Their study will be published in the journal Stem Cells and appears online today.

The findings suggest that cell-based therapies might be an effective way to treat human corneal blindness and vision impairment due to the scarring that occurs after infection, trauma and other common eye problems, said senior investigator James L. Funderburgh, Ph.D., associate professor, Department of Ophthalmology. The Pitt corneal stem cells were able to remodel scar-like tissue back to normal.

"Our experiments indicate that after stem cell treatment, mouse eyes that initially had corneal defects looked no different than mouse eyes that had never been damaged," Dr. Funderburgh said.

The ability to grow millions of the cells in the lab could make it possible to create an off-the-shelf product, which would be especially useful in countries that have limited medical and surgical resources but a great burden of eye disease due to infections and trauma.

"Corneal scars are permanent, so the best available solution is corneal transplant," Dr. Funderburgh said. "Transplants have a high success rate, but they don't last forever. The current popularity of LASIK corrective eye surgery is expected to substantially reduce the availability of donor tissue because the procedure alters the cornea in a way that makes it unsuitable for transplantation."

A few years ago, Dr. Funderburgh and other University of Pittsburgh researchers identified stem cells in a layer of the cornea called the stroma, and they recently showed that even after many rounds of expansion in the lab, these cells continued to produce the biochemical components, or matrix, of the cornea. One such protein is called lumican, which plays a critical role in giving the cornea the correct structure to make it transparent.

Mice that lack the ability to produce lumican develop opaque areas of their corneas comparable to the scar tissue that human eyes form in response to trauma and inflammation, Dr. Funderburgh said. But three months after the lumican-deficient mouse eyes were injected with human adult corneal stem cells, transparency was restored.

The cornea and its stromal stem cells themselves appear to be "immune privileged," meaning they don't trigger a significant immune response even when transplanted across species, as in the Pitt experiments.

"Several kinds of experiments indicated that the human cells were alive and making lumican, and that the tissue had rebuilt properly," Dr. Funderburgh noted.

In the next steps, the researchers intend to use the stem cells to treat lab animals that have corneal scars to see if they, too, can be repaired with stem cells. Under the auspices of UPMC Eye Center's recently established Center for Vision Restoration, they plan also to develop the necessary protocols to enable clinical testing of the cells.

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Rheumatoid Arthritis Therapeutics in China

JAKARTA, Indonesia, April 9 - Rheumatoid arthritis (RA) is a systemic disease or an autoimmune disorder in which the body's defense system attacks the joints through the thin layer of cells called the synovium that lines and lubricates the joints. The most visible symptoms of RA are swollen joints and crippling stiffness, particularly of the hands and feet. It can cause fatigue, fever, loss of appetite and also impedes mobility and quality of life.

In 2007, the prevalence of rheumatoid arthritis (RA) in China was 0.3 percent, and has remained stable. About three times as many women as men are afflicted with the disease. Earlier, NSAIDs were mainly used for treatment, and as the disease progressed to moderate and severe, DMARDs were introduced. However, with time, education, awareness, and treatment options, physicians have started to treat with a combination of NSAIDs and DMARDs in the early stages of treatment. Patients are also treated with traditional Chinese medicine (TCM) in combination with western medicine, or independently.

State health insurance funds the treatment cost for NSAIDs and some DMARDs such as Methotrexate (MTX). However, a majority of the population has no health insurance, putting pressure on out-of-pocket payment, or go without treatment.

Frost & Sullivan, Research Analyst Sushma Rajan says, "The diagnosis of RA is based on clinical examination of symptoms, patient history, as well as some blood tests. RA cannot be confirmed or excluded by any one test. The most common test is rheumatoid factor (RF). The other supporting tests are: anti-cyclic citrullinated peptide (Anti-CCP), erythrocyte sedimentation rate (ESR), and X-ray.

"Recent work productivity studies have confirmed that better disease awareness and availability of treatment options have resulted in fewer patients ceasing to work and more patients reporting lower impact of their disease on work as well as family and social activities," she further elaborates.

Methotrexate (MTX), a DMARD (disease-modifying anti-rheumatic drug) has been traditionally used to treat RA. It is also the most used form of treatment in rheumatoid arthritis, especially with generic forms available. Currently, combination therapies between DMARDs and NSAIDs (non-steroidal anti-inflammatory drugs) are commonly practiced.

DMARDs capture the majority of the RA therapeutics market owing to the availability of reimbursement for treatment with these drugs and their easy availability over the counter. DMARDs are expected to retain majority share in the forecast period as well.

According to Rajan, "Biologics are used in combination with DMARDs for moderate to severe RA patients. Some biologic drugs are currently reimbursed, if treated in government hospitals. Physicians opine that with more drugs brought into the hospital formularies, the usage of biologics would increase for treatment earlier in the disease."

Though there are new drugs available for treating RA, specialists in china are likely to continue using DMARDs as their first line therapy, as they have the most experience with this drug class, and it is seen as the most cost effective treatment option. Even though biologics are highly effective and recommended for treatment, they are likely to be the third line of treatment, due to their high cost. Physicians are willing to use biologics if they are listed in the hospital formulary and if they are affordable to their patients (current price range is seen to be out of reach of most patients). Physicians are of the opinion that more studies are required to make them feel confident in using biologics, but the cost of treatment is likely to restrain the high use of the drug class.