Dutch biopharmaceutical company Crucell N.V. (Euronext, Nasdaq: CRXL) (SWISS: CRX) today announced the results of a second phase II clinical study of its investigational rabies monoclonal antibody combination, which started in May 2008 in the Philippines.

Crucell has a collaboration and commercialization agreement with sanofi pasteur, the vaccines division of sanofi-aventis Group, for Crucell’s rabies monoclonal antibodies to be used in association with a rabies vaccine for post-exposure prophylaxis against the fatal disease of rabies.

This phase II trial was set up as a randomized, single-blind, controlled study in 48 healthy children and adolescents in a high endemic area of Metro Manila, Philippines. The trial was set up to test the safety and tolerability of the antibody product in association with sanofi pasteur’s Verorab® rabies vaccine in a direct comparison with the marketed human rabies immune globulin (HRIG) product. It was performed at the Research Institute for Tropical Medicine under the leadership of Dr Beatriz P. Quiambao. The antibody product in association with the rabies vaccine was administered to 16 adolescents as well as 16 children. Its safety and neutralizing activity was compared to HRIG associated with the same rabies vaccine in 8 adolescents and 8 children. The results of the Philippines study showed Crucell’s rabies monoclonal antibody combination was safe and well tolerated. Neutralizing activity levels were similar in the subjects administered with the antibody product or with HRIG and all study participants reached adequate immunity levels. This study in children further broadens the population in which Crucell’s rabies monoclonal antibody combination could potentially be used. Earlier trials in adult populations have already shown safety and neutralizing activity. Detailed results of this study will be presented at the XX Rabies in the Americas RITA conference in Quebec, Canada on 18-23 October 2009.

“Our children are at high risk of getting rabies. The results of this study bring closer the moment that all-in-need get an adequate treatment against rabies.” said Dr Beatriz P Quiambao, Chief Clinical Research Division and Head, Rabies Research Group, Research Institute for Tropical Medicine, Muntiinlupa, Philippines.

“We are very pleased with our continued and rapid progress with this next generation rabies treatment and these results help us towards our ambition of reducing the global burden of this deadly disease” said Ronald Brus, Crucell’s Chief Executive Officer.

On February 12th, 2008 Crucell announced that its rabies monoclonal antibody combination was granted Fast Track status by the US Food and Drug Administration (FDA).

About rabies

Rabies is a viral disease of mammals most often transmitted through the bite of a rabid animal. The virus infects the central nervous system, causing encephalitis (inflammation of the brain) and ultimately death if medical intervention is not sought promptly after exposure. There is no proven treatment for rabies once symptoms of this fatal disease have appeared. Rabies is prevented by post-exposure prophylaxis (PEP) with the combined administration of a rabies vaccine and rabies immunoglobulin (RIG). Rabies is prevalent in Europe, Asia, Africa, North America and South America. Every year approximately 10 million people are vaccinated against the disease worldwide. An estimated 40,000 to 70,000 people die from rabies each year, mainly in Asia.

About Crucell’s rabies monoclonal antibody program

Crucell’s rabies monoclonal antibody product is a combination of two human monoclonal antibodies, generated using Crucell’s MAbstract® technology and produced using Crucell’s PER.C6® technology. Crucell’s rabies monoclonal antibody combination offers the potential to replace the traditional serum-derived products that are currently used for rabies post-exposure prophylaxis. Phase I clinical trials data conducted in the United States and India supported further clinical development. The program has been granted a Fast Track designation by the Food and Drug Administration ’s (FDA) Department of Health and Human Services. The Fast Track program facilitates the development and expedites the review of new drugs that are intended to treat serious or life-threatening diseases and that demonstrate the potential to address unmet medical needs.

In December 2007, Crucell and sanofi pasteur signed an exclusive collaboration and commercialization agreement for Crucell’s rabies monoclonal antibodies, next-generation rabies biologicals, to be used with rabies vaccine for post-exposure prophylaxis against this fatal disease. Under the terms of the agreement, Crucell will continue to perform the development activities. Crucell will be responsible for the manufacturing of the final product and will retain exclusive distribution rights in Europe, co-exclusive distribution rights in China and the rights to sell to supranational organizations such as UNICEF. Crucell received an initial payment of EUR 10 million following the execution of the agreement and will be eligible for milestone payments of up to EUR 66.5 million.

Peak sales for Crucell’s rabies antibody combination are expected to exceed $ 300 million.

About PER.C6® technology

Crucell’s PER.C6® technology is a cell line developed for the large-scale manufacture of biopharmaceutical products such as recombinant proteins including monoclonal antibodies. The strengths of the PER.C6® technology lie in its safety profile, scalability and productivity under serum-free culture conditions.

About MAbstract® technology

Crucell’s proprietary MAbstract® technology can be used to discover drug targets, such as cancer markers or proteins from infectious agents including bacteria and viruses, and identify human antibodies against those drug targets.

Source
Crucell

Depression in older adults too often goes unrecognized and untreated, resulting in untold misery, worsening of medical illness, and early death. A new study has identified one important remedy: Adding a trained depression care manager to primary care practices can increase the number of patients receiving treatment, lead to a higher remission rate of depression, and reduce suicidal thoughts.

The two-year outcomes of the multicenter Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study are published online in the American Journal of Psychiatry.

Lead author of the study is Dr. George S. Alexopoulos, director of the Institute of Geriatric Psychiatry at NewYork-Presbyterian Hospital/Westchester Division and professor of psychiatry at Weill Cornell Medical College.

“Almost one in 10 older adults in the United States has some form of depression, and one-fifth among them contemplates suicide. Two-thirds of these patients are treated by primary care physicians. Sadly, their depression is often inadequately treated due to the primary care physician’s time constraints and the patient’s reluctance to discuss their symptoms and adhere to treatment,” says Dr. Alexopoulos. “The critical finding of the PROSPECT study is that adding a trained care manager to primary care practices increases the number of depressed older patients who receive treatment and improves their outcomes, not only in the short term, but over two years.

“This is important because depression can either become chronic or relapse after an initial improvement,” adds Dr. Alexopoulos. “Most diseases have worse outcomes when an old person becomes depressed. Depression almost doubles the risk for death. It follows that treating depression effectively can reduce sickness, disability and death.”

The study, conduced by NewYork Presbyterian/Weill Cornell, the University of Pittsburgh, and the University of Pennsylvania, followed 599 patients aged 60 years and older with depression at 20 primary care practices of varying sizes in New York and Pennsylvania. Participants were randomized to receive either the PROSPECT intervention or usual care. Those in the PROSPECT group were assigned a care manager — a trained social worker, nurse or psychologist — who helped the physician offer treatment according to accepted practice guidelines, monitored treatment response and provided follow-up over two years. Practice guidelines included the antidepressant citalopram (Celexa), with the option of other drugs or psychotherapy.

After two years, nearly 90 percent of patients in the PROSPECT care management group had received treatment for depression, compared with 62 percent of those receiving usual care by their physicians. The decline in suicidal ideation (thinking about and/or planning suicide) was 2.2 times greater in the PROSPECT group.

Remission of depression happened faster in the PROSPECT intervention group and remission rates continued to increase between months 18 and 24, while no appreciable increase occurred in the usual care group during the same period.

The PROSPECT intervention worked especially well for a subgroup of patients with major depression, the more severe form of the disease, with a greater number achieving remission, or the near absence of symptoms. Patients with minor depression had favorable outcomes regardless of their study group.

Various forms of care management are being used successfully for cardiovascular patients needing anticoagulation medication and for diabetes patients needing insulin monitoring, says Dr. Alexopoulos. “The PROSPECT study has demonstrated that care management is highly successful for older adults with major depression.”

“At this time, our nation is focused on disease prevention as a way to improve the health of Americans and to reduce health care cost. Reducing depression over long periods of time can be one of the ways to achieve this objective,” continues Dr. Alexopoulos. “Care management, like that of the PROSPECT study, is relatively inexpensive. Finding ways to reimburse it can make it broadly available and have a major impact on the overall heath care.”

Dr. Alexopoulos serves as a paid member of the speaker’s bureau and a paid member of the Scientific Advisory Board for Forest Laboratories Inc., the maker of the antidepressant drug citalopram (Celexa). Forest offered free citalopram and a small stipend to support the study.

Co-authors include Drs. Martha L. Bruce and Patrick J. Raue of NewYork-Presbyterian/Westchester and Weill Cornell Medical College; Dr. Charles F. Reynolds III of the University of Pittsburg; Drs. Ira R. Katz, David W. Oslin and Thomas Ten Have of the University of Pennsylvania; and Dr. Benoit H. Mulsant of the University of Toronto.

NewYork-Presbyterian Hospital/Westchester Division

NewYork-Presbyterian Hospital/Westchester Division, opened in 1894, is one of the world’s most advanced centers for psychiatric care. The Westchester Division serves children, adolescents, adults and the elderly with comprehensive outpatient, day treatment, partial hospitalization and inpatient services. In addition to clinical treatment, the Westchester Division is also a center for interdisciplinary medical research and education through its academic affiliate, Weill Cornell Medical College. NewYork-Presbyterian Hospital also comprises NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, NewYork-Presbyterian Morgan Stanley Children’s Hospital and NewYork-Presbyterian Hospital/The Allen Pavilion. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area and is consistently ranked among the best

A report in Cancer Research, a journal of the American Association for Cancer Research, highlights a new biomarker that may be useful in identifying patients with recurrent glioblastoma, or brain tumors, who would respond better to anti-vascular endothelial growth factor therapy, specifically cediranib.

Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases. It is an investigational, oral agent that is administered once daily. Using a form of magnetic resonance imaging (MRI) that looked at the mechanism of action of this agent, the researchers were able to determine, even as early as after a single dose of cediranib, those patients who benefited from the agent and those who did not.

“We found that results from an advanced MRI scan taken just a day after starting treatment correlated with survival. Combining MRI with blood biomarkers did an even better job of identifying patients who best responded to treatment,” said researcher A. Gregory Sorensen, M.D., associate professor of radiology and health sciences and technology at Harvard Medical School, Massachusetts General Hospital. “If this approach is validated in larger studies, we could use these tools to keep patients on therapies that their tumors respond to, and shift non-responders to other therapies much earlier.”

Sorensen and colleagues sought to find the potential biomarkers that could be used to predict those patients who would respond better from antiangiogenic therapy early in the course of treatment by use of MRI.

The researchers measured vascular normalization prior to and one day after patients’ received cediranib using an advanced MRI technique. They performed blood analysis and examined correlations between vascular parameters and treatment response after a single dose of cediranib in 31 patients with recurrent glioblastoma; all biomarkers were measured in 28 patients.

“Vascular normalization is an important mechanism of how these drugs work in cancer patients,” said Rakesh K. Jain, Ph.D., Andrew Werk Cook professor of tumor biology at Harvard Medical School and director of the Edwin L. Steele Laboratory for Tumor Biology in the department of radiation oncology at Massachusetts General Hospital Cancer Center, Boston. Jain is also a researcher on this study.

The correlative analysis in this single arm, phase II study showed that those patients whose extent of vascular normalization was greater, had a longer duration of overall survival as well as progression-free survival, according to Jain. Median overall survival rate was 227 days; some patients lived for about two years and some lived less than two months.

“I was intrigued by the findings from this innovative trial, especially the fact that you could use separate biomarkers in combination to potentially predict the outcomes of patients,” said Richard B. Gaynor, M.D., Ph.D., deputy editor of Cancer Research. Gaynor is the vice-president of cancer research at Eli Lilly and Company.

“This is really a severe disease and being able to determine response at such an early point is helpful to tailor treatment,” he said. “If we can predict those responding to antiangiogenic therapy early on, we may be able to define where the benefit would be.”

These findings need to be validated in larger, prospective studies. The researchers are currently conducting several studies based on these promising results in efforts to evaluate the benefits and prolonged survival of these patients.

One study is a phase III, randomized, multicenter, international trial that will compare patients treated with standard chemotherapy, those treated with cediranib, and those treated with a combination of the two to evaluate the effects and prolongation of life in all three cohorts. Approximately 300 patients are enrolled in this study, with enrollment halfway complete, according to Jain.

Another study, which just began enrollment, is a phase II, single-arm trial among patients who are newly diagnosed with glioblastoma. Researchers plan to evaluate treatment effects in patients treated with this agent combined with standard radiation and chemotherapy.

“We hope to develop biomarkers to help physicians and researchers know if a patient is responding; if they are not responding we can move them to a more effective therapy, if they are responding we can continue treatment, even if the treatment carries risks or side effects,” Sorensen said.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and nearly 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

Source: American Association for Cancer Research