FDA Advisory Panel Back Roche's Avastin for Brain Cancer

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Tuesday, 31 March 2009 18:15

By Susan Heavey. WASHINGTON (Reuters) - Early data for Roche Holding AG's drug Avastin shows enough promise in treating patients with a certain brain cancer to be considered for quick approval, a U.S. advisory panel said on Tuesday.

The drugmaker is seeking accelerated approval to market the drug for patients diagnosed with a recurrence of the particularly deadly disease after trying other therapies first. The drug, made by its recently acquired Genentech unit, is already used to treat lung, colon and breast cancers.

Data from two early studies showed enough of a response in patients whose disease did not advance and some whose tumors decreased in size to warrant faster approval before the company finishes a larger trial to confirm the benefit, the panel said in a 10-0 vote.

"I think these results are dramatic," said panel member Jay Loeffler, head of radiation oncology at Massachusetts General Hospital in Boston.

Many panelists also said they were optimistic that the company's larger, long-term trial would confirm Avastin's benefits for patients with glioblastoma multiforme, an especially fatal tumor.

Company officials said the trial, which would target newly diagnosed patients, would begin enrolling patients soon and would have full results in 2014. Meanwhile, earlier data looked promising enough to help patients now, especially with few other treatments available.

"We're confident that we have met the criteria for accelerated approval," said David Schenkein, senior vice president for cancer products at Genentech, which saw U.S. net sales of $2.7 billion from Avastin in 2008.

Glioblastoma has seen renewed public attention since Senator Edward Kennedy was diagnosed with the malignant tumor last year. It is one of the deadliest types of cancer, with patients surviving six to 12 months after diagnosis on average, or six months without treatment.

About 10,000 patients are diagnosed with the disease each year, Genentech said citing the American Cancer Society.

At the meeting, cancer advocates cheered the panel's vote after more than a dozen testified in support of approval.

Avastin patient Gail McWilliams, who lived several years after her diagnosis, said the injectable drug "was a blessing to me ... I feel like the luckiest person on earth."

While the FDA does not weigh costs when approving products, many insurers decide whether to pay for certain uses of medication based on FDA clearance.

Genentech spokeswoman Kristina Becker said the estimated cost for a course of Avastin for brain cancer would be $39,600, adding that programs are available to help with costs.

FDA staff reviewers expressed some concern about whether the magnetic resonance images used to measure patients' tumors was reliable. They also questioned whether Avastin was causing patient's response or whether some other factor was at play.

Several panelists also said they wanted to see more safety data. The most common side effects were fatigue, headache and hypertension, according to the FDA's analysis.

Still, the FDA's advisers overall said the data was positive for patients who relapse after chemotherapy and radiation.

"I think the totality of evidence suggests there's a benefit here," said panel chairman Wyndham Wilson of the National Cancer Institute.

The FDA will weigh the panel's recommendation when it rules on the new use for Avastin, also known as bevacizumab. A decision is expected by May 5.

 

Caraco Pharma Recalls Heart Drug

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Tuesday, 31 March 2009 18:00

March 31 (Reuters) - Caraco Pharmaceutical Laboratories Ltd (CPD.A) said it was recalling batches of the heart drug Digoxin distributed prior to March 31, saying these tablets could vary in size and thus dosage levels.

While a lower than labeled dosage may pose a risk of lack of efficacy resulting in cardiac instability, excessive intake of the drug could lead to death, the company said.

* Recalls generic heart drug Digoxin

* Says tablets may have more or less of active ingredient

Shares of the company closed down about 23 percent at $3.52 Tuesday on the American Stock Exchange.

Digoxin is a generic version of GlaxoSmithKline Plc's (GSK.L) drug Lanoxin to treat heart failure and abnormal heart rhythms.

The company said it was voluntarily recalling 0.125 mg and 0.25 mg tablets of the drug to the consumer level.

Digoxin toxicity can cause nausea, vomiting, dizziness, low blood pressure, cardiac instability, and bradycardia, the company said.

 

FDA Refuses to File Acorda MS Drug

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Tuesday, 31 March 2009 13:01

By Anuradha Ramanathan. BANGALORE, March 31 (Reuters) - Acorda Therapeutics Inc (ACOR.O) said U.S. health regulators refused to accept a new drug application filing for its multiple sclerosis treatment due to certain "format issues", delaying the drug's possible approval by a few months.

* FDA refuses to accept NDA filing for MS drug

* FDA asks co to reformat certain data

* FDA not recommending additional clinical studies

The company's shares tumbled 23 percent to touch $19.10 Tuesday on Nasdaq.

The biotech company, which is developing Fampridine-SR to improve walking ability in people with multiple sclerosis, said the Food and Drug Administration (FDA) asked it to reformat some of the data in the electronic submission of the application in a refuse-to-file letter.

"The issue here is uncertainty. Investors don't like uncertainty and that is why the reaction has been significant," Hapoalim Securities' analyst Raghuram Selvaraju said.

A lack of visibility on the seriousness of the issues related to the filing and the speed with which they can be addressed has led to Tuesday's sell-off, he said.

In accordance with agency regulations, he expects discussions with the FDA to take 30 days and that the company would require about one or two months to address the issues associated with the FDA action.

The FDA also requested for certain additional supporting information to be included in the filing but has not recommended further clinical studies to be conducted, the company said.

"Some of (the data) has to be reformatted, certainly not all," Acorda's Chief Executive Ron Cohen said in a conference call.

The company plans to request a meeting with the FDA to discuss its comments on the filing.

RBC Capital Markets analyst Michael Yee, who has an "out perform" rating on the stock, said FDA's refusal to accept Fampridine's filing was a non-clinical administrative problem and he does not expect the "slip-up" to delay any business development deals in the near-term.

If approved, Fampridine-SR would be the first multiple sclerosis drug to reverse a symptom of the disease. People affected by multiple sclerosis have problems with body movement and balance, among other symptoms.

 

Genzyme, Bayer Announce Strategic Pact

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Tuesday, 31 March 2009 07:20

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Genzyme Corporation (Nasdaq: GENZ - News) announced today that it has entered into an agreement to acquire the worldwide rights to Campath® (alemtuzumab) from Bayer HealthCare, giving Genzyme primary responsibility for the development and commercialization of this potential break-though treatment for multiple sclerosis (MS).

Bayer will continue to fund a portion of alemtuzumab’s development in MS and will retain an option to co-promote the product in MS upon approval. In addition, Genzyme will assume sole responsibility for worldwide sales and marketing for Campath in B-cell chronic lymphocytic leukemia (CLL), where it is indicated for use as a single agent in first-line and previously-treated patients with this disease. Bayer will retain the right to develop and commercialize alemtuzumab in solid organ transplant indications.

The agreement further expands Genzyme’s hematologic oncology commercial presence beyond Campath through the addition of Fludara® (fludarabine) and Leukine® (sargramostim), and provides an opportunity to integrate members of Bayer’s experienced commercial team for all three drugs into Genzyme’s global operations. Genzyme will acquire a new, Seattle-area Leukine manufacturing facility for $75 to $100 million and hire the plant’s operating personnel following FDA plant approval, which is expected in 2010.

The transaction is accretive and already reflected in Genzyme’s 2009 revenue and non-GAAP earnings per share guidance. The deal is structured as an earn-out arrangement. Bayer will receive payments based on revenues (subject to an aggregate cap) and potential milestone payments if cumulative revenue targets are achieved. There are no upfront payments for the rights of these three drugs. The transaction would provide Genzyme approximately $185 million in oncology revenue in 2009 and up to $700 million in revenue over the next three years. Genzyme’s Oncology segment revenues in 2008 were $117 million. Today’s announcement supports the company’s goal of 20 percent compound average non-GAAP earnings growth from 2006 to 2011.

Alemtuzumab in MS

“Alemtuzumab is a potentially transformative therapy for the treatment of multiple sclerosis, and an important part of our future. This strategic transaction clarifies the responsibilities of each company and gives Genzyme control over the execution of this program,” said Henri A. Termeer, chairman and chief executive officer of Genzyme Corporation. “We will continue to collaborate with Bayer in a more streamlined and focused way.”

Genzyme is now conducting two Phase 3 studies of alemtuzumab in MS. The first trial, for which enrollment is complete, treats early, active relapsing-remitting patients who have received no prior therapy. The second study, which is expected to complete enrollment before the end of this year, is studying relapsing-remitting patients who had active disease while on other MS therapies. “We are very pleased with the accelerated patient enrollment in our Phase 3 alemtuzumab multiple sclerosis clinical trials, an outgrowth of the positive Phase 2 data published last October,” said Mark Enyedy, president of Genzyme Oncology and Multiple Sclerosis. Data from the trials are expected to be available in 2011, and approval is anticipated in 2012.

The Phase 2 study published in the New England Journal of Medicine showed that patients with early, active relapsing-remitting MS experienced significant reductions in the risk of sustained accumulation of disability and annualized relapses after two annual cycles of alemtuzumab when compared with the active comparator Rebif® (interferon beta-1a), a currently approved therapy.

Oncology Expansion

Campath and Fludara are important therapy options for patients with B-cell chronic lymphocytic leukemia. Both drugs are approved in the United States and Europe as well as in other countries around the world. Leukine, which is marketed in the United States, reduces the incidence of severe and life-threatening infections in appropriate patients with acute myelogenous leukemia (AML) following chemotherapy. Fludara and Leukine complement Genzyme’s hematologic oncology product portfolio.

“Through the acquisition of these hematologic oncology assets, we enhance our commercial presence in the oncology market with a comprehensive product portfolio,” said Enyedy. “Genzyme is committed to this important disease area and to deepening our relationship with the specialist providers in this field around the world.”

The long-term growth of Genzyme Oncology will be driven by regulatory approvals for Mozobil™ (plerixafor injection) in new markets and new indications for Clolar® (clofarabine injection). The addition of members of Bayer’s global commercial team will support the introduction of Mozobil and Clolar for adult AML.

Mozobil, launched in the United States earlier this year, mobilizes hematopoietic stem cells in patients with non-Hodgkin’s lymphoma and multiple myeloma for subsequent autologous stem-cell transplants. Because of the clinical benefits Mozobil offers patients, and the potential economic benefits to transplant centers, the U.S. product launch is proceeding well. European Union approval of Mozobil is expected in the second half of 2009, and additional applications in up to 60 countries are planned.

Clolar is in several clinical trials to secure new therapeutic indications. The U.S. Food and Drug Administration will review Genzyme’s supplemental New Drug Application for Clolar to treat adult AML at its September Oncologic Drugs Advisory Committee meeting. European authorities have asked Genzyme to include in its submission for Clolar in adult AML data from a randomized clinical trial, several of which are ongoing. Clofarabine is currently approved in the United States and Europe (where it is marketed under the tradename Evoltra®) for the treatment of acute lymphoblastic leukemia in relapsed and refractory pediatric patients, and has become a standard of care in this setting. Additional approvals are expected in Latin America and Canada this year.

Key Terms of the Agreement

The agreement creates efficiencies for the alemtuzumab MS development program, and expands the Genzyme Oncology business unit revenues. The new agreement contains the following key terms:

Alemtuzumab in MS

 

  • Genzyme will lead the development program. Bayer, which has been co-developing alemtuzumab in MS with Genzyme, will continue to fund development at current levels until the investigational compound is approved for this indication.
  • After approval, Bayer will receive payments contingent on annual revenue until $1.25 billion in payments is realized. The agreement includes a ten-year time cap on payments. Bayer may also receive future milestone payments as a percentage of worldwide sales beginning in 2021 if Genzyme does not exercise a buyout option in 2020 for up to $900 million.
  • Genzyme will assume primary responsibility for the commercialization. Bayer, which currently markets Betaseron® (interferon beta-1b) for MS, retains an option to co-promote alemtuzumab in MS.

 

Oncology Drugs

 

  • For the oncology drugs Fludara, Leukine, and Campath/MabCampath, Bayer will receive payments contingent on annual revenue, capped at $500 million or eight years.
  • In addition, Bayer could receive $150 million in total milestone payments beginning in 2011 if certain annual revenues are met across a three-year time period.
  • Bayer will supply Fludara and Leukine. Genzyme will take over the production of Leukine following FDA approval of a new, Seattle-area Leukine plant.

 

The transaction is expected to close in the second quarter, pending Federal Trade Commission review and international regulatory clearances. Genzyme and Bayer will work closely to allow for an orderly transition of drug sales and distribution. This process is expected to take place over a period of months following the close of the transaction, during which Bayer will provide transition services.

Prior to this agreement, Genzyme received two-thirds of Campath net profits on U.S. sales and a significant royalty on foreign sales from Bayer. Genzyme acquired Campath in the 2004 acquisition of Ilex Oncology, while Bayer obtained the marketing and distribution rights to Campath in its 2006 acquisition of Schering, which had been the exclusive distributor of Campath for Ilex. As a precondition to FTC clearance of the Ilex acquisition, Genzyme agreed to divest to Schering the right to develop and commercialize alemtuzumab in solid organ transplant. Bayer will retain such right under this agreement.

About Campath® (alemtuzumab)

Alemtuzumab is a humanized monoclonal antibody that binds to a specific target, CD52, on cell surfaces and directs the body’s immune system to destroy those cells. It is the first and only monoclonal antibody approved by the FDA for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL).

Safety Data from the alemtuzumab in MS Phase 2 Trial

A total of six alemtuzumab-treated patients, and one Rebif-treated patient, in this study developed a serious adverse event, immune thrombocytopenic purpura (ITP). ITP is a disorder characterized by a low platelet count and corresponding increased risk of uncontrolled bleeding. A patient monitoring program was instituted in the trial. Common non-serious adverse events in the trial included infusion-associated reactions in the alemtuzumab patients and flu-like symptoms in patients using Rebif. Alemtuzumab-treated patients were more likely than Rebif patients to experience infections, particularly of the upper respiratory tract; infections were predominantly mild to moderate in severity and there were no life-threatening or fatal infections. Though alemtuzumab transiently lowers white blood cell counts, the trial did not show an increased risk of opportunistic infections. Serious infections were infrequent in the alemtuzumab-treated patients. Some alemtuzumab-treated patients developed autoimmune thyroid-related adverse events, including Graves’ disease, and were managed using conventional therapies. Alemtuzumab is an investigational drug for the treatment of MS and must not be used in MS patients outside of a formal, regulated clinical trial setting in which appropriate patient monitoring measures are in place.

About Leukine® (sargramostim)

Leukine® (sargramostim) is a growth factor that helps fight infection and disease in appropriate patients by enhancing immune cell function. Leukine was approved in the United States in 1991. Leukine is the only growth factor approved in the U.S. for use following induction chemotherapy in older adults with acute myelogenous leukemia (AML) to shorten the time to neutrophil recovery and reduce the incidence of severe and life-threatening infections and infections resulting in death. Leukine also has been approved in the U.S. for use in four additional indications: myeloid reconstitution following allogeneic and autologous bone marrow transplantation (BMT), peripheral blood stem cell (PBSC) mobilization and subsequent myeloid reconstitution in patients undergoing PBSC transplantation, and bone marrow transplantation failure or engraftment delay.

About Fludara® (fludarabine phosphate for injection)

Unlike alkylating cytotoxic chemotherapies, Fludara®, a purine nucleotide analog, inhibits the synthesis of new DNA, thus preventing leukemia cells from multiplying. The intravenous (i.v.) formulation of Fludara was first approved in 1991 and is available in 98 countries worldwide as a second-line therapy for B-CLL patients who have failed previous treatment with alkylating agents. In addition, Fludara i.v. has been approved as a first-line therapy of B-CLL in 62 countries. In 29 countries, Fludara i.v. is also approved for the second-line treatment of low grade non-Hodgkin’s Lymphoma (lg-NHL). The oral formulation has the same effect as the i.v. formulation and was approved in Europe in 2001.

About Mozobil™ (plerixafor injection)

Mozobil, a novel small molecule CXCR4 chemokine receptor antagonist, has been shown in multiple earlier studies to rapidly and effectively increase the number of stem cells in circulation in the blood in patients with non-Hodgkin’s lymphoma and multiple myeloma. Once circulating in the blood, stem cells can be collected for use in an autologous stem cell transplant. For full prescribing information, please visit www.genzyme.com.

About Clolar® (clofarabine injection)

Clolar is indicated in the U.S. for the treatment of pediatric patients one to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. In the European Union, clofarabine is marketed as Evoltra® and Clolar is indicated in ALL pediatric patients who have relapsed or are refractory after receiving at least two prior regimes and where there is no other treatment option anticipated to result in durable response. Clolar received FDA approval in 2004, and EMEA approval in 2006. Clolar has Orphan Drug designation for adult and pediatric ALL, and seven years of market exclusivity in the United States for relapsed/refractory pediatric ALL. The FDA also granted six months of extended market exclusivity to Clolar under the Best Pharmaceuticals for Children Act. For more information about Clolar, please call 1-800-RX CLOLAR or visit www.clolar.com.

About Genzyme

One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 11,000 employees in locations spanning the globe and 2008 revenues of $4.6 billion. In 2007, Genzyme was chosen to receive the National Medal of Technology, the highest honor awarded by the President of the United States for technological innovation.

With many established products and services helping patients in approximately 100 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune disease, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.

 

FDA Approves Novartis Kidney Cancer Drug

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Monday, 30 March 2009 16:59

WASHINGTON (AP) -- A drug from Novartis has won U.S. approval as a treatment for patients with kidney cancer that has returned after treatment with older drugs.

The Food and Drug Administration approved the pill on Monday to treat renal cell cancer, the most common form of kidney cancer.

The agency said patients tested with Novartis' Afinitor (everolimus) lived more than twice as long without tumor growth as those who didn't receive the drug. The study by the Swiss drugmaker showed Afinitor delayed tumor growth nearly 5 months, compared with less than two months for patients not taking the drug.

Afinitor works by blocking a protein that helps cancer cells divide and grow. The drug was approved for patients who have already taken Pfizer Inc.'s Sutent and Bayer's Nexavar.

Kidney cancer is resistant to chemotherapy and radiation therapy, and the most effective remedy is usually to surgically remove the kidney. When the cancer is isolated to the kidney, a majority of patients will survive at least five years. If the cancer has spread to other parts of the body, the survival rate is much shorter.

About 13,000 patients died from the disease last year, according to the American Cancer Society.

Basel, Switzerland-based Novartis has submitted the drug for approval in the European Union, Japan and elsewhere.

Shares of Novartis fell 47 cents to close at $36.55 Monday.

 

Glaxo Finalizes FDA Filing for Cervical Cancer Vaccine

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Monday, 30 March 2009 16:43

PHILADELPHIA and LONDON, March 30 /PRNewswire-FirstCall/ -- GlaxoSmithKline (NYSE: GSK - News) today provided the following update regarding its application to the U.S. Food and Drug Administration (FDA) for approval of CERVARIX®, its vaccine to prevent cervical cancer and cervical pre-cancer related to human papillomavirus types 16 and 18.

GSK has submitted final data from its Phase III pivotal efficacy study, HPV-008, to the FDA. The FDA has previously reviewed interim data from the same trial. FDA review of this type of Biologics License Application (BLA) submission is expected to take six months, according to agency regulations.

"We are pleased to have reached this significant milestone for CERVARIX®. The data submitted to the FDA reaffirm our confidence in the vaccine's safety and efficacy profile," said Barbara Howe, M.D., Vice President and Director, North American Vaccine Development, GlaxoSmithKline. "We will continue working closely with the FDA in order to make this vaccine available to help protect the cervical health of girls and women in the U.S."

HPV-008 is a Phase III clinical study of more than 18,600 women between 15-25 years of age, from 14 countries across Europe, Asia-Pacific and Latin and North America. The primary objective was to assess vaccine efficacy in the prevention of high-grade pre-cancerous cervical lesions (CIN2+) caused by human papillomavirus types 16 or 18. Secondary objectives included evaluation of vaccine efficacy in the prevention of pre-cancerous cervical lesions (CIN1+) and infections caused by virus types 16 or 18 or other cancer-causing virus types, as well as immune response and safety. GSK will submit the data to a peer-reviewed journal in the coming months.

The BLA for the vaccine includes safety, efficacy and immune response data from clinical trials in nearly 30,000 females and reflects an ethnically diverse population.

To date, GSK's vaccine has been approved in more than 90 countries around the world including the 27 member countries of the European Union, Mexico, Australia, Singapore and the Philippines. Licensing applications have been submitted in more than 20 additional countries including Japan. GSK also submitted the vaccine to the World Health Organization (WHO) for prequalification in September 2007.

Notes to Editors

Cervical Health Facts - Worldwide, every two minutes a woman dies of cervical cancer; each year more than 500,000 women will be newly diagnosed and more than 280,000 women will die. In the U.S., after breast cancer, cervical cancer is the leading cause of cancer-related death in women between the ages of 20 to 39 in the United States. Also, in the U.S. each year there are an estimated 3.5 million abnormal Pap smears, and more than 1.5 million precancerous lesions are diagnosed.

GlaxoSmithKline Biologicals - GSK's vaccines business is one of the world's leading vaccine companies and a leader in innovation. The company is active in the fields of vaccine research, development and production with over 30 vaccines approved for marketing and 20 more in development. Headquartered in Belgium, GSK Biologicals has 13 manufacturing sites strategically positioned around the globe. In 2008 GSK Biologicals distributed 1.1 billion doses of vaccines to 176 countries in both the developed and the developing world - an average of 3 million doses a day. Through its accomplished and dedicated workforce, GSK Biologicals applies its expertise to discover innovative vaccines that contribute to the health and well-being of people of all generations around the world.

GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer.

 

Arena Announces Phase 3 Results for Weight Loss Drug

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Monday, 30 March 2009 06:50
SAN DIEGO, March 30, 2009 /PRNewswire-FirstCall/ -- Arena Pharmaceuticals, Inc. (Nasdaq: ARNA) announced today positive top-line results from BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), the first of two pivotal trials evaluating the safety and efficacy of lorcaserin for weight management. Statistical significance (p<0.0001) was achieved on all three of the hierarchically ordered co-primary endpoints for patients treated with lorcaserin versus placebo. Treatment with lorcaserin was generally very well tolerated. An assessment of echocardiograms indicates no apparent drug-related effect on the development of US Food and Drug Administration (FDA)-defined valvulopathy over the two-year treatment period.

The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months:

  • 47.5% of lorcaserin patients lost greater than or equal to 5% of their body weight from baseline compared to 20.3% in the placebo group. This result satisfies the efficacy benchmark in the most recent FDA draft guidance.
  • Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds, in the placebo group. Statistical separation from placebo was observed by Week 2, the first post-baseline measurement.
  • 22.6% of lorcaserin patients lost greater than or equal to 10% of their body weight from baseline, compared to 7.7% in the placebo group.

Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2% of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in the placebo group (p<0.0001).

"The BLOOM results, demonstrating lorcaserin's medically important weight loss coupled with the tolerability and safety profile displayed in this trial, differentiate lorcaserin from approved drugs or other agents in clinical trials," commented Steven R. Smith, M.D., Co-Principal Investigator and Professor and Assistant Director for Clinical Research at the Pennington Biomedical Research Center. "Obesity is a widespread disease; having a well tolerated and effective therapy that can be used by the majority of patients who need weight reduction could also have beneficial effects on co-morbid conditions, such as diabetes, lipid disorders, and cardiovascular disease."

Lorcaserin was generally very well tolerated. The most frequent adverse events reported in Year 1 and their rates for lorcaserin and placebo patients, respectively, were as follows: headache (18.0% vs. 11.0%), upper respiratory tract infection (14.8% vs. 11.9%), nasopharyngitis (13.4% vs. 12.0%), sinusitis (7.2% vs. 8.2%) and nausea (7.5% vs. 5.4%). The most frequent adverse events reported in Year 2 and their rates for lorcaserin and placebo patients, respectively, were as follows: upper respiratory tract infection (14.5% vs. 16.1%), nasopharyngitis (16.4% vs. 12.6%), sinusitis (8.6% vs. 6.9%), arthralgia (6.6% vs. 6.2%) and influenza (6.6% vs. 6.0%). In patients crossing over from lorcaserin to placebo after Year 1, the rates of these Year 2 adverse events were: 11.0%, 13.8%, 10.6%, 6.0% and 4.9%, respectively.

Adverse events of depression, anxiety and suicidal ideation were infrequent and reported at a similar rate in each treatment group, and no seizures were reported. Serious adverse events occurred with similar frequency in each group throughout the trial without apparent relationship to lorcaserin. One death occurred during the trial, which was a patient in the placebo arm.

"The BLOOM trial, having met all of its primary endpoints and the FDA categorical efficacy benchmark as stated in their guidance, suggests lorcaserin has the potential to become the first in a new class of effective and very well tolerated weight management therapeutics that selectively target the serotonin 2C receptor," said William R. Shanahan, M.D., Arena's Vice President and Chief Medical Officer. "We look forward to building on these positive top-line data with the BLOSSOM study results expected around the end of September leading to an NDA submission by the end of this year. We also look forward to working with the FDA during the approval process to bring this treatment to patients in need of new options."

Using an ITT-LOCF analysis, the assessment of echocardiograms performed at baseline and after patients completed 6, 12, 18 and 24 months of dosing indicated no apparent drug-related effect on the development of FDA-defined valvulopathy (moderate or greater mitral insufficiency and/or mild or greater aortic insufficiency).

Lorcaserin met the primary safety endpoint of no significant difference in rates of valvulopathy at 12 months. Rates of valvulopathy at 6, 12, 18 and 24 months for lorcaserin versus placebo were 2.1% vs. 1.9%, 2.7% vs. 2.3%, 2.9% vs. 3.1% and 2.6% vs. 2.7%. At 18 and 24 months, rates of valvulopathy for lorcaserin patients crossing over to placebo were 3.6% and 1.9%, respectively.

The FDA has requested that Arena rule out a 1.5-fold or greater risk of valvulopathy with 80% power. Assuming similar results in BLOSSOM (Behavioral modification and LOrcaserin Second Study for Obesity Management), the integrated data set from the two trials will be more than sufficiently large to meet this requirement.

"The echocardiographic safety data is very reassuring," commented Neil J. Weissman, M.D., Co-Principal Investigator, Director, Cardiac Ultrasound and Ultrasound Core Labs, President, MedStar Research Institute, and Professor of Medicine, Georgetown University. "In this double-blind, prospective study, there was no evidence of a difference in the development of valve disease in the large number of patients on lorcaserin versus control for up to two years of continuous use. No prospective valvulopathy trial has ever studied this many patients for this period of time, particularly under such well-controlled circumstances."

Treatment with lorcaserin was also associated with statistically significant improvements (ITT-LOCF) in a range of secondary endpoints compared to treatment with placebo, including:

  • Total cholesterol
  • LDL cholesterol
  • Triglycerides
  • Blood pressure

Changes in HDL cholesterol were similar in the two groups. Analysis of the above and additional endpoints, including glucose, insulin and waist circumference, is ongoing and will be announced at a later date.

During Year 2 of the trial, patients continuing on lorcaserin were better able to maintain more of the Week 52 weight loss than Year 1 lorcaserin patients re-randomized to placebo in Year 2.

Patient demographic characteristics at baseline were well balanced across the treatment groups. The Week 52 completion rate was higher for patients on lorcaserin (55.4%) compared to those on placebo (45.1%). The difference is primarily attributed to higher discontinuation rates for "Subject Decision" (19.2% lorcaserin vs. 27.7% placebo), which includes "Lack of Efficacy" (1.7% lorcaserin vs. 5.5% placebo). Discontinuations for adverse events (7.1% lorcaserin vs. 6.7% placebo) and other reasons were similar.

Completion rates for Year 2 were similar across the treatment groups: 74.3%, 72.7%, and 68.9% for patients continuing on lorcaserin for both years, patients taking placebo both years, and patients switching from lorcaserin to placebo in Year 2, respectively. Discontinuations for adverse events were also similar across the treatment groups.

"The positive outcome of the BLOOM trial serves as a very significant milestone for Arena, demonstrating lorcaserin's potential to provide a new treatment option for patients who need to lose weight and keep it off," stated Jack Lief, Arena's President and Chief Executive Officer. "Given lorcaserin's status as the only novel, single agent weight loss therapeutic in Phase 3 development, as well as data that continues to support our expectation for a well-tolerated and efficacious drug, I expect to have a range of commercialization options to consider."

BLOOM, the first of three lorcaserin Phase 3 trials, is a double-blind, randomized, placebo-controlled trial involving 3,182 patients in approximately 100 sites in the US. The trial evaluated 10 mg of lorcaserin dosed twice daily versus placebo over a two-year treatment period in obese patients (Body Mass Index, or BMI, 30 to 45) with or without co-morbid conditions and overweight patients (BMI 27 to less than 30) with at least one co-morbid condition. The trial did not include any dose titration or run-in period. Patients were randomized in a 1:1 ratio to lorcaserin or placebo at baseline. At Week 52, 856 patients taking lorcaserin were re-randomized in a 2:1 ratio to continue lorcaserin or to switch to placebo, and 697 patients on placebo were continued on placebo. Patients received echocardiograms at screening, and at 6, 12, 18 and 24 months after initiating dosing in the trial; patients with FDA-defined valvulopathy were excluded from enrolling in the trial.

The Phase 3 program consists of three trials, BLOOM, BLOSSOM and BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus), and is planned to enroll a total of approximately 7,800 patients. BLOOM and BLOSSOM comprise the Phase 3 pivotal registration program. BLOSSOM has enrolled 4,008 patients and is evaluating 10 mg of lorcaserin dosed once or twice daily versus placebo over a one-year treatment period in obese patients with or without co-morbid conditions and overweight patients with at least one co-morbid condition at about 100 sites in the US. Results are expected around the end of September 2009. BLOOM-DM is currently enrolling and is evaluating 10 mg of lorcaserin dosed once or twice daily versus placebo over a one-year treatment period in obese and overweight patients with type 2 diabetes at about 60 sites in the US. Approximately 600 patients are expected to be enrolled in BLOOM-DM, which is planned as a supplement to the lorcaserin NDA.

A standardized program of moderate diet and exercise guidance is included in the Phase 3 program. The program's hierarchically ordered co-primary efficacy endpoints are: the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Arena is also studying several key secondary endpoints, including changes in serum lipids and HbA1c levels and, in the BLOOM-DM trial, other indicators of glycemic control. In BLOSSOM and BLOOM-DM all patients will receive echocardiograms at baseline, at month 6, and at the end of the study to assess heart valve function over time. In contrast to the BLOOM trial, however, there are no echocardiographic exclusion criteria for entry into these trials and there is no monitoring by an independent monitoring board.

 

New Diabetes Drugs to be Reviewed at FDA Advisory Panel Meetings

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Sunday, 29 March 2009 19:04

By Ben Hirschler. LONDON, March 26 (Reuters) - Two new diabetes drugs face tough appraisals from U.S. experts next week, promising a volatile ride for shares in Novo Nordisk (NVO), AstraZeneca (AZN) and Bristol-Myers Squibb (BMY).

Investors are nervous about prospects for Novo's Victoza, or liraglutide, and AstraZeneca and Bristol's Onglyza, or saxagliptin, both of which could face safety issues that delay their approval in the key U.S. market.

* FDA panel to review Onglyza April 1, Victoza April 2

* Focus on cardiovascular safety of both diabetes drugs

* Bristol, AstraZeneca, Novo Nordisk say confident of data

Worries have been heightened since March 6, when Takeda Pharmaceutical (TKPHY.PK) said the U.S. Food and Drug Administration (FDA) needed more data on its new diabetes drug alogliptin, sending the Japanese group's stock tumbling.

The FDA may not be in a rush to clear medicines that work the same way as other drugs on the market, Morningstar analyst Damien Conover said.

"You've got some headwinds going up against these drugs," Conover said.

Onglyza, which will be assessed by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee on April 1, belongs to the same DPP-4 drug class as alogliptin.

The only successful DPP-4 drug at present is Merck & Co's (MRK) Januvia, which had sales of $1.4 billion in 2007. Novartis (NVS) was also an early pioneer of DPP-4s but it has struggled to get rival medicine Galvus to market amid concerns about skin and kidney safety.

Both Onglyza and Galvus were linked to skin lesions when high doses were given to primates.

If successful, Onglyza could generate sales of more than $3 billion a year, some analysts believe. But most are forecasting just $200 million to $400 million, reflecting uncertainties about its chances in front of a cautious FDA.

Underlining that caution, the FDA in December told companies it wanted more evidence on cardiovascular risk, following a scare over heart risks with GlaxoSmithKline's (GSK) Avandia.

"IMPORTANT READ-THOUGH"

The panel meeting "is going to be a very important read-through on how the FDA is going to apply the guidelines for a lot of companies," Citigroup analyst John Boris said.

Bristol-Myers, in a statement with AstraZeneca, said it was "confident in the comprehensiveness of our development program for Onglyza" and has "not seen a cardiovascular safety signal throughout our clinical development program."

Doubts have also grown about Novo's Victoza, which will go in front of the same committee on April 2.

The Danish company is confident its drug has an excellent cardiovascular safety profile and says it has not been asked by the FDA to conduct any more clinical studies before approval.

"We believe that the data we have submitted to the FDA will satisfy the agency's requirements for an approval, perhaps with a commitment of a post-approval study of long-term cardiovascular risk," said Dr. Alan Moses, Novo's global chief medical officer.

But many investors still fear a delay is possible.

Confidence in Victoza -- the key driver for Novo in the years ahead -- has weakened in recent months because of worries about the FDA's stance and slowing sales of Amylin Pharmaceuticals' (AMLN) rival product Byetta.

Both Victoza and Byetta belong to the GLP-1 class of injectable drugs that stimulate insulin release only when glucose levels become too high. Byetta carries a warning about rare cases of pancreatitis, and the FDA may want a similar caution on Victoza, analysts said.

Consensus forecasts for Victoza have come down to around $1.3 billion to $1.5 billion, according to analysts at Citigroup, nearer the brokerage's own cautious prediction of $1.2 billion in 2015.

The FDA usually approves drugs that win panel recommendations, although it has rejected or delayed some drugs in the past year that were backed by advisory committees.

"It's very hard to handicap how much you need to appease them with the safety concerns," Conover said. (Additional reporting by Lisa Richwine and Susan Heavey in Washington; Editing by Sharon Lindores and Brian Moss)

 

Long-Term Data Favors Abbott's Heart Stent over Rival

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Sunday, 29 March 2009 18:36

By Bill Berkrot. NEW YORK, March 29 (Reuters) - Safety advantages of Abbott Laboratories' (ABT) Xience stent over Boston Scientific Corp's (BSX) rival Taxus stent increased between two and three years, according to long-term data presented on Sunday.

The data showed that patients treated with Xience experienced fewer heart attacks, deaths or need for repeat procedures at the stenting site by an increasing margin compared with patients treated with Taxus three years after the stents were initially placed, researchers said.

* Xience stent keeps low cardiac death rate at 2 to 3 yrs

* Taxus stent death rate rises to 4.2 pct from 1.3 pct

* MACE rate 57 pct lower with Xience at 3 years

The latest data from the 300-patient Spirit II trial, unveiled at the American College of Cardiology scientific meeting in Orlando, followed previous data comparing the two drug coated stents after six months, one year and two years.

Stents are tiny mesh tubes used to prop open arteries that have been cleared of plaque. The medicines coating the stents help to prevent reclogging.

Between two and three years, Xience maintained its low cardiac death rate of 0.5 percent, while the rate among Taxus patients rose from 1.3 percent at two years to 4.2 percent at three years, researchers said.

On the composite measure of major adverse cardiac events (MACE) -- cardiac death, heart attack and need for revascularization -- Xience maintained a rate of 6.4 percent between two and three years. The Taxus MACE rate increased about 40 percent from 10.5 percent at two years to 14.9 percent at three years.

Three years after stent placement there was a statistically significant 88 percent reduced risk of cardiac death with Xience compared to Taxus and a 57 percent MACE risk reduction, researchers said.

For Xience there was also a statistically significant lower risk of stent thrombosis, or formation of dangerous blood clots, with no incidence of stent thrombosis in the Xience patients between two and three years.

"It's positive to see the performance sustained, and with the curves continuing to favor Xience, it's a very strong result," said John Capek, Abbott's executive vice president for medical devices.

In addition to Taxus, Boston Scientific sells a version of Xience under a different name. Xience was originally developed by Guidant Corp, which was acquired by Boston Scientific in 2006. Boston sold Guidant's stent business to Abbott, but retained the right to sell Xience under the Promus brand name with 40 percent of the profit going to Abbott. (Additional reporting by Martinne Geller; Editing by Bernard Orr and Steve Orlofsky)

 

Combo Cholesterol Pill is Safe, Effective

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Sunday, 29 March 2009 18:04

By Lewis Krauskopf. ORLANDO, Fla, March 29 (Reuters) - A combination of Abbott Laboratories' (ABT) new TriLipix triglycerides medicine and a low dose of AstraZeneca's (AZN) Crestor cholesterol drug proved better than the individual pills in helping improve heart risk factors, researchers said.

The combination did significantly better at lowering bad LDL cholesterol and other blood fats called triglycerides, as well as raising levels of good HDL cholesterol in patients with complex lipid disorders.

The late-stage data presented on Sunday at the American College of Cardiology scientific meeting in Orlando will be part of the U.S. application for a fixed-dose combination pill of the two medicines, which the drugmakers expect to submit in the second half of 2009.

Statins such as Crestor that lower LDL cholesterol are among the most widely used prescription drugs in the world. But many of the patients with high cholesterol also have high triglycerides and low levels of good HDL cholesterol, raising heart risks.

"There is a significant benefit to combining the two treatments together," said Dr. Eli Roth, professor of clinical medicine at the University of Cincinnati College of Medicine and an investigator in the study. "You tend to correct the entire atherogenic profile."

The 760 subjects in the Phase III trial were randomized to the standard dose of TriLipix, also known as finofibric acid, 5 milligrams of Crestor, also called rosuvastatin, or a combination of both.

After 12 weeks of therapy, the combination lowered LDL by 28.7 percent compared with 4.1 percent with TriLipix alone. It cut triglycerides by 40.3 percent compared with 17.5 percent with just Crestor. The combination raised HDL by 23 percent compared with 12.4 percent with Crestor alone.

The results were considered highly statistically significant.

"The numbers are impressive," Roth said. "If you quizzed most physicians about what kind of changes they'd see, they would know the direction it would go but I don't think they would know the magnitude."

The combination also lowered levels of a key inflammation marker, known as C-reactive protein, by 28 percent, compared with 8.7 percent with only TriLipix, and 11.4 percent with Crestor alone.

There were no additional adverse events found in combining the two drugs than from the individual pills, Roth said.

"The combination is very safe," Roth said

The planned combination pill can make it easier for doctors to help patients stay on their medicines, where they otherwise might have to juggle multiple prescriptions.

"Having two medicines in a single pill tends to make compliance on the patient's part much better," Roth said.

Results of combination studies using higher doses of Crestor with TriLipix were presented last June. The combination involving 5 mg of Crestor will appeal to patients who have difficulty tolerating higher doses of statins, Roth said.

Approved by U.S. regulators in December, TriLipix is the successor to Abbott's blockbuster TriCor medicine. Both are in triglyceride lowering fibrate class of drugs, but unlike TriCor, TriLipix is approved for use with statins. Crestor is one of AstraZeneca's top-selling medicines. (Additional reporting by Bill Berkrot; Editing by Carol Bishopric)

 
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