Pharma News

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Virus-derived particles target blood cancer

Ottawa researchers have developed unique virus-derived particles that can kill human blood cancer cells in the laboratory and eradicate the disease in mice with few side effects. The study is published in Blood Cancer Journal by co-senior authors Drs. David Conrad and John Bell of the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa (uOttawa).

While Dr. Bell and his colleagues have been investigating replicating viruses for the treatment of solid cancers for many years, with very promising results, this is the first major success they have had treating blood cancer (leukemia). It is also the first success they have had using a non-replicating virus-derived particle as opposed to a replicating virus.

"Our research indicated that a replicating virus might not be the safest or most effective approach for treating leukemia, so we decided to investigate whether we could make virus-derived particles that no longer replicate but still kill cancer," said Dr. Conrad, a hematologist conducting research in the Blood and Marrow Transplant Program at The Ottawa Hospital, and currently completing his PhD at OHRI and uOttawa in the Department of Cellular and Molecular Medicine. "We were delighted to see that this novel therapy was very safe at high doses, and worked extremely well in our laboratory leukemia models. We hope to test this in patients in the near future."

The researchers used a specific method and dose of UV light to transform regular replicating viruses into unique particles that could no longer replicate and spread, but could still enter cancer cells efficiently, kill them and stimulate a strong immune response against the cancer. These particles were able to kill multiple forms of leukemia in the laboratory, including samples taken from local patients who had failed all other therapies. Normal blood cells were not affected. This novel treatment was also successful in mouse models of leukemia. In fact, 80 per cent of the mice that received the therapy had markedly prolonged survival and 60 per cent were eventually cured, while all of the untreated mice died of their leukemia within 20 days.

"Leukemia is a devastating disease that can be very difficult to treat, and new therapies are urgently needed," said Dr. Conrad. "While we're still at the early stages of this research, I think this therapy holds a lot of promise because it appears to have a potent, long-lasting effect on leukemia without the debilitating side effects of many cancer therapies used in the clinic right now. We will likely see even better results once we optimize the dose in our preparations to advance this research into human clinical trials."

This research was funded by the Ontario Institute for Cancer Research, the Terry Fox Foundation, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, Ottawa's Department of Medicine and The Ottawa Hospital Foundation.

Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunity. Batenchuk C, Le Boeuf F, Stubbert L, Falls T, Atkins HL, Bell JC, and Conrad DP. Blood Cancer J. 2013 Jul 12;3:e123. doi: 10.1038/bcj.2013.23. Corresponding author: Dr. David P Conrad.

[GodFather]

Targeting aggressive prostate cancer


A team of researchers from UC Davis, UC San Diego and other institutions has identified a key mechanism behind aggressive prostate cancer. Published on August 14, 2013 in Nature, the study shows that two long non-coding RNAs (PRNCR1 and PCGEM1) activate androgen receptors, circumventing androgen-deprivation therapy. In their active state, these receptors turn on genes that spur growth and metastasis, making these cancers highly treatment-resistant. The study illustrates how prostate cancer can thrive, even when deprived of hormones, and provides tempting targets for new therapies.

"Androgen-deprivation therapy will often put cancer in remission, but tumors come back, even without testosterone," said contributor Christopher Evans, professor and chair of the Department of Urology at the UC Davis School of Medicine. "We found that these long non-coding RNAs were activating the androgen receptor. When we knocked them out, cancer growth decreased in both cell lines and tumors in animals."

Evans' UC Davis group was part of a larger team, led by Michael Geoff Rosenfeld, professor at the Howard Hughes Medical Institute in the School of Medicine at UC San Diego, which has been eager to determine how androgen-dependent cancers become androgen-independent (also called castration-resistant). These prostate cancers are very aggressive and usually fatal, but their continued growth, despite being deprived of hormones, is just now being better understood. It's not unlike removing the key from a car ignition, only to have the vehicle re-start on its own.

In this case, the aberrant starting mechanisms are long non-coding RNAs, a class of genetic material that regulates gene expression but does not code for proteins. Using patient samples from UC Davis, the group determined that both PRNCR1 and PCGEM1 are highly expressed in aggressive tumors. These RNAs bind to androgen receptors and activate them in the absence of testosterone, turning on as many as 617 genes.

Further investigation determined that one of these long non-coding RNAs is turning on androgen receptors by an alternate switching mechanism, like a car with a second ignition. This is critically important because many prostate cancer treatments work by blocking a part of the androgen receptor called the C-terminus. However, PCGEM1 activates another part of the receptor, called the N-terminus, which also turns on genes - with bad results.

"The androgen receptor is unique, if you knock out the C-terminus, that remaining part still has the ability to transcribe genes," said Evans.

In addition, about 25 percent of these cancers have a mutated version of the androgen receptor that has no C-terminus. These receptors are locked in the "on" position, activating genes associated with tumor aggression.

Regardless of the receptor's status, PRNCR1 and PCGEM1 are crucial to prostate cancer growth. In turn, knocking out these RNAs has a profound impact on gene expression, both in cell lines and animal models. The team used complementary genetic material, called antisense, to knock out the RNAs and observe how the tumors and cells responded. In each case, there was a direct relationship between RNA activity, gene expression and cancer growth.

"These long non-coding RNAs are a required component for these castration-resistant cancers to keep growing," said Evans. "Now we have preclinical proof of principle that if we knock them out, we decrease cancer growth."

The research team's next step is developing treatments that specifically target these long non-coding RNAs. That process has already begun.

"Most treatments for castration-resistant prostate cancer will get us around two to three years of survival," said Evans. "We rarely cure these patients. The tumor will continue to evolve resistance mechanisms. But now that we have additional insight into what's activating these receptors, we can begin developing new types of therapies to prevent it."

Other researchers included Liuqing Yang and Chunru Lin, Department of Medicine, UC San Diego and MD Anderson Cancer Center; Joy C. Yang, Department of Urology, School of Medicine, UC Davis; Chunyu Jin, Wenbo Li, Kenneth A. Ohgi and Jie Zhang, Department of Medicine, UC San Diego; Bogdan Tanasa, Department of Medicine, UC San Diego and The Scripps Research Institute; Daria Merkurjev, Department of Medicine and Department of Bioengineering, UC San Diego; and Da Meng, Department of Biological Sciences, UC San Diego.

Funding to outside researchers for this work came from the National Institutes of Health (DK039949, DK18477, NS034934, 1K99DK094981-01, CA173903 and 4R00CA166527-02) and the Department of Defense (W81XWH-08-1-0554) to outside researchers. Dr. Evans' team was funded by grants from the Department of (PC111467 and SU2C-AACR-DT0812)

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FDA approves new drug to treat HIV infection

The U.S. Food and Drug Administration has approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection. Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. It is a pill taken daily in combination with other antiretroviral drugs.

Tivicay is approved for use in a broad population of HIV-infected patients. It can be used to treat HIV-infected adults who have never taken HIV therapy (treatment-naïve) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced), including those who have been treated with other integrase strand transfer inhibitors. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naïve or treatment-experienced but have not previously taken other integrase strand transfer inhibitors.

"HIV-infected individuals require treatment regimens personalized to fit their condition and their needs," said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA's Center for Drug Evaluation and Research. "The approval of new drugs like Tivicay that add to the existing options remains a priority for the FDA."

About 50,000 Americans become infected with HIV each year and about 15,500 died from the disease in 2010, according to the Centers for Disease Control and Prevention.

Tivicay's safety and efficacy in adults was evaluated in 2,539 participants enrolled in four clinical trials. Depending on the trial, participants were randomly assigned to receive Tivicay or Isentress (raltegravir), each in combination with other antiretroviral drugs, or Atripla, a fixed-dose combination of efavirenz, emtricitabine and tenofovir. Results showed Tivicay-containing regimens were effective in reducing viral loads.

A fifth trial established the pharmacokinetics, safety and activity of Tivicay as part of treatment regimens for HIV-infected children ages 12 years and older weighing at least 40 kg who have not previously taken integrase strand transfer inhibitors.

Common side effects observed during clinical studies include difficulty sleeping (insomnia) and headache. Serious side effects include hypersensitivity reactions and abnormal liver function in participants co-infected with hepatitis B and/or C. The Tivicay label gives advice on how to monitor patients for the serious side effects.

Tivicay is marketed by ViiV Healthcare and manufactured by GlaxoSmithKline, both based in Research Triangle Park, N.C. Isentress is marketed by Whitehouse Station, N.J.-based Merck, and Atripla is marketed by San Francisco, Calif.-based Gilead.

About FDA
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

[GodFather]

Flavonoids as an antioxidant

Celery, artichokes, and herbs, especially Mexican oregano, all contain apigenin and luteolin, flavonoids that kill human pancreatic cancer cells in the lab by inhibiting an important enzyme, according to two new University of Illinois studies.
"Apigenin alone induced cell death in two aggressive human pancreatic cancer cell lines. But we received the best results when we pre-treated cancer cells with apigenin for 24 hours, then applied the chemotherapeutic drug gemcitabine for 36 hours," said Elvira de Mejia, a U of I professor of food chemistry and food toxicology.
The trick seemed to be using the flavonoids as a pre-treatment instead of applying them and the chemotherapeutic drug simultaneously, said Jodee Johnson, a doctoral student in de Mejia's lab who has since graduated.
"Even though the topic is still controversial, our study indicated that taking antioxidant supplements on the same day as chemotherapeutic drugs may negate the effect of those drugs," she said.
"That happens because flavonoids can act as antioxidants. One of the ways that chemotherapeutic drugs kill cells is based on their pro-oxidant activity, meaning that flavonoids and chemotherapeutic drugs may compete with each other when they're introduced at the same time," she explained.
Pancreatic cancer is a very aggressive cancer, and there are few early symptoms, meaning that the disease is often not found before it has spread. Ultimately the goal is to develop a cure, but prolonging the lives of patients would be a significant development, Johnson added.
It is the fourth leading cause of cancer-related deaths, with a five-year survival rate of only 6 percent, she said.
The scientists found that apigenin inhibited an enzyme called glycogen synthase kinase-3β (GSK-3β), which led to a decrease in the production of anti-apoptotic genes in the pancreatic cancer cells. Apoptosis means that the cancer cell self-destructs because its DNA has been damaged.
In one of the cancer cell lines, the percentage of cells undergoing apoptosis went from 8.4 percent in cells that had not been treated with the flavonoid to 43.8 percent in cells that had been treated with a 50-micromolar dose. In this case, no chemotherapy drug had been added.
Treatment with the flavonoid also modified gene expression. "Certain genes associated with pro-inflammatory cytokines were highly upregulated," de Mejia said.
According to Johnson, the scientists' in vitro study in Molecular Nutrition and Food Research is the first to show that apigenin treatment can lead to an increase in interleukin 17s in pancreatic cells, showing its potential relevance in anti-pancreatic cancer activity.
Pancreatic cancer patients would probably not be able to eat enough flavonoid-rich foods to raise blood plasma levels of the flavonoid to an effective level. But scientists could design drugs that would achieve those concentrations, de Mejia said.
And prevention of this frightening disease is another story. "If you eat a lot of fruits and vegetables throughout your life, you'll have chronic exposure to these bioactive flavonoids, which would certainly help to reduce the risk of cancer," she noted.

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[GodFather]

International partnership receives funding to develop a drug product to fight schistosomiasis (bilharzia) in children

An international public-private partnership (PPP) was launched in July last year to develop a new pediatric formulation to combat schistosomiasis - commonly known as bilharzia - in preschool children. The Bill & Melinda Gates Foundation grants $1.15 million to support some research & development activities before Phase I clinical trials. The current partners in this consortium, coordinated by TI Pharma, are Merck KGaA, Astellas Pharma Inc. and the Swiss Tropical and Public Health Institute ("Swiss TPH").

Schistosomiasis is a severe chronic inflammatory disease caused by parasitic worms and is endemic in 78 developing countries, infecting more than 243 million people globally every year. Schistosomiasis is the second most prevalent tropical disease in the world after malaria, and occurs primarily in developing countries with limited access to safe drinking water and adequate sanitation. If not treated properly, the disease can lead to anemia, stunting and reduced learning ability, and can be fatal.

The consortium's goal is to develop a suitable pediatric drug for preschool children, a high-risk group for schistosome infections counting for 10-20 million of the global prevalence. The standard recommended praziquantel treatment is available in oral tablets for adults and children from the age of six. Younger children cannot always swallow these tablets because of their size and bitter taste. An appropriate treatment with praziquantel for preschool children is non-existent and highly needed.

The amount from the Gates Foundation was granted to Merck, one of the consortium partners, and will be used to finance some important R&D activities needed to bring the product up to the first clinical studies in man. It will also allow the involvement of disease experts, including from countries affected. Altogether, this will ensure that the product to be developed fits the needs of the pediatric population best.

Annalisa Jenkins, Chair of the Consortium Board and Head of Global Drug Development and Medical at Merck Serono, the biopharmaceutical division of Merck: "There is an urgent need for the treatment of schistosomiasis in very young children, for whom there is currently no approved therapy. The support of the Gates Foundation is a key step in moving forward with new options for this highly vulnerable population with the ultimate goal of elimination."

About Astellas Pharma Inc.
Astellas Pharma Inc., based in Tokyo, Japan, is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. Astellas Pharma Inc. has approximately 17,000 employees worldwide. The organization is committed to becoming a global category leader in Urology, Immunology (including Transplantation) and Infectious Diseases, Oncology, Neuroscience, and DM Complications and Kidney Diseases. Astellas Pharma Inc. is committed to increasing access to health in developing countries through its partnership initiatives. Astellas Pharma Inc.'s pharmaceutical research and technology labs have contributed to improving convenience for use and the functionality of treatments by developing novel formulations and bringing additional value based on its excellent pharmaceutical technologies (e.g. solubilization, controlled release, oral disintegration tablet and drug delivery technologies).

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EMA and US FDA release first conclusions of parallel assessment of quality-by-design applications

The European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) have published a joint question-and-answer document that outlines the conclusions of their first parallel assessment of quality-by-design (QbD) elements of marketing-authorisation applications.

Quality-by-design is a science- and risk-based approach to pharmaceutical development and manufacturing that was introduced a few years ago in international guidelines intended for the pharmaceutical industry. QbD involves the use of statistical, analytical and risk-assessment methods to design and develop pharmaceutical compounds and manufacturing processes to ensure the quality of the manufactured product.

In March 2011, the EMA and the US FDA launched a three-year pilot programme for the parallel assessment of certain quality or chemistry, manufacturing and control (CMC) sections of applications that are relevant to QbD.

The objective of this parallel assessment is to share knowledge, facilitate a consistent implementation of the international guidelines on the implementation of the QbD concept (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines Q8, Q9, Q10 and Q11) and promote the availability of pharmaceutical products of consistent quality throughout the European Union and the US.

The programme is open to selected procedures, including applications for initial marketing authorisations, type-II variations and scientific advice. Participation in the pilot is voluntary. Interested applicants and sponsors should notify both agencies three months prior to submission of an application.

Both agencies found the first parallel assessment extremely useful and reached agreement on a wide range of QbD aspects, as reflected in the question-and-answer document. Experts from the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) participated as observers in this first parallel assessment, with the agreement of the applicant.

The EMA and the US FDA will publish further conclusions on other QbD-related topics as the pilot programme continues and more parallel assessments are conducted.

[GodFather]

First pre-clinical gene therapy study to reverse Rett symptoms

The concept behind gene therapy is simple: deliver a healthy gene to compensate for one that is mutated. New research published today in the Journal of Neuroscience suggests this approach may eventually be a feasible option to treat Rett Syndrome, the most disabling of the autism spectrum disorders. Gail Mandel, Ph.D., a Howard Hughes Investigator at Oregon Health and Sciences University, led the study. The Rett Syndrome Research Trust, with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation, funded this work through the MECP2 Consortium.

In 2007, co-author Adrian Bird, Ph.D., at the University of Edinburgh astonished the scientific community with proof-of-concept that Rett is curable, by reversing symptoms in adult mice. His unexpected results catalyzed labs around the world to pursue a multitude of strategies to extend the pre-clinical findings to people.

Today's study is the first to show reversal of symptoms in fully symptomatic mice using techniques of gene therapy that have potential for clinical application.

Rett Syndrome is an X-linked neurological disorder primarily affecting girls; in the US, about 1 in 10,000 children a year are born with Rett. In most cases symptoms begin to manifest between 6 and 18 months of age, as developmental milestones are missed or lost. The regression that follows is characterized by loss of speech, mobility, and functional hand use, which is often replaced by Rett's signature gesture: hand-wringing, sometimes so intense that it is a constant during every waking hour. Other symptoms include seizures, tremors, orthopedic and digestive problems, disordered breathing and other autonomic impairments, sensory issues and anxiety. Most children live into adulthood and require round-the-clock care.

The cause of Rett Syndrome's terrible constellation of symptoms lies in mutations of an X-linked gene called MECP2 (methyl CpG-binding protein). MECP2 is a master gene that regulates the activity of many other genes, switching them on or off.

"Gene therapy is well suited for this disorder," Dr. Mandel explains. "Because MECP2 binds to DNA throughout the genome, there is no single gene currently that we can point to and target with a drug. Therefore the best chance of having a major impact on the disorder is to correct the underlying defect in as many cells throughout the body as possible. Gene therapy allows us to do that."

Healthy genes can be delivered into cells aboard a virus, which acts as a Trojan horse. Many different types of these Trojan horses exist. Dr. Mandel used adeno-associated virus serotype 9 (AAV9), which has the unusual and attractive ability to cross the blood-brain barrier. This allows the virus and its cargo to be administered intravenously, instead of employing more invasive direct brain delivery systems that require drilling burr holes into the skull.

Because the virus has limited cargo space, it cannot carry the entire MECP2 gene. Co-author Brian Kaspar of Nationwide Children's Hospital collaborated with the Mandel lab to package only the gene's most critical segments. After being injected into the Rett mice, the virus made its way to cells throughout the body and brain, distributing the modified gene, which then started to produce the MeCP2 protein.

As in human females with Rett Syndrome, only approximately 50% of the mouse cells have a healthy copy of MECP2. After the gene therapy treatment 65% of cells now had a functioning MECP2 gene.

The treated mice showed profound improvements in motor function, tremors, seizures and hind limb clasping. At the cellular level the smaller body size of neurons seen in mutant cells was restored to normal. Biochemical experiments proved that the gene had found its way into the nuclei of cells and was functioning as expected, binding to DNA.

One Rett symptom that was not ameliorated was abnormal respiration. Researchers hypothesize that correcting this may require targeting a greater number of cells than the 15% that had been achieved in the brainstem.

"We learned a critical and encouraging point with these experiments - that we don't have to correct every cell in order to reverse symptoms. Going from 50% to 65% of the cells having a functioning gene resulted in significant improvements," said co-author Saurabh Garg.

One of the potential challenges of gene therapy in Rett is the possibility of delivering multiple copies of the gene to a cell. We know from the MECP2 Duplication Syndrome that too much of this protein is detrimental. "Our results show that after gene therapy treatment the correct amount of MeCP2 protein was being expressed. At least in our hands, with these methods, overexpression of MeCP2 was not an issue," said co-author Daniel Lioy.

Dr. Mandel cautioned that key steps remain before clinical trials can begin. "Our study is an important first step in highlighting the potential for AAV9 to treating the neurological symptoms in Rett. We are now working on improving the packaging of MeCP2 in the virus to see if we can target a larger percentage of cells and therefore improve symptoms even further," said Mandel. Collaborators Hélène Cheval and Adrian Bird see this as a promising follow up to the 2007 work showing symptom reversal in Rett mice. "That study used genetic tricks that could not be directly applicable to humans, but the AAV9 vector used here could in principle deliver a gene therapeutically. This is an important step forward, but there is a way to go yet."

"Gene therapy has had a tumultuous road in the past few decades but is undergoing a renaissance due to recent technological advances. Europe and Asia have gene therapy treatments already in the clinic and it's likely that the US will follow suit. Our goal now is to prioritize the next key experiments and facilitate their execution as quickly as possible. Gene therapy, especially to the brain, is a tricky undertaking but I'm cautiously optimistic that with the right team we can lay out a plan for clinical development. I congratulate the Mandel and Bird labs on today's publication, which is the third to be generated from the MECP2 Consortium in a short period of time," said Monica Coenraads, Executive Director of the Rett Syndrome Research Trust and mother of a teenaged daughter with the disorder.

[GodFather]

Single injection may revolutionize melanoma treatment

A new study at Moffitt Cancer Center could offer hope to people with melanoma, the deadliest form of skin cancer. Researchers are investigating whether an injectable known as PV-10 can shrink tumors and reduce the spread of cancer. PV-10 is a solution developed from Rose Bengal, a water-soluble dye commonly used to stain damaged cells in the eye. Early clinical trials show PV-10 can boost immune response in melanoma tumors, as well as the blood stream.

"Various injection therapies for melanoma have been examined over the past 40 years, but few have shown the promising results we are seeing with PV-10," said Shari Pilon-Thomas, Ph.D., assistant member of Moffitt's Immunology Program.

In the initial study, researchers injected a single dose of PV-10 into mice with melanoma. The result was a significant reduction in the skin cancer lesions, as well as a sizable reduction in melanoma tumors that had spread to the lungs. The researchers said the dye solution appeared to produce a robust anti-tumor immune response and may be safer than existing immunological agents.

"We are currently in the middle of our first human clinical trial of PV-10 for advanced melanoma patients. In addition to monitoring the response of injected melanoma tumors, we are also measuring the boost in the anti-tumor immune cells of patients after injection," explained Amod A. Sarnaik, M.D., assistant member of Moffitt's Cutaneous Oncology Program.

The initial study appears in PLOS ONE, an open-access, peer-reviewed online journal. It was supported by a sponsored research agreement with Provectus Pharmaceuticals, Inc., developer of PV-10.

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Nexavar® (sorafenib) granted priority review for differentiated thyroid cancer in the U.S.

Bayer HealthCare and Onyx Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has granted priority review designation to the Supplemental New Drug Application (sNDA) for Nexavar® (sorafenib) tablets, for the treatment of locally advanced or metastatic radioactive iodine (RAI)-refractory differentiated thyroid cancer.
"We welcome this priority review as it supports our ongoing effort to make more treatment options available for cancer patients who until now have only limited or no treatment options," said Kemal Malik, MD, Member of the Bayer HealthCare Executive Committee and Head of Global Development.
The FDA grants priority review to medicines that, if approved, would significantly improve the efficacy or safety of treatment for serious conditions. Under the Prescription Drug User Fee Act (PDUFA), the FDA aims to complete priority review within six months, rather than the standard ten-month review cycle.
The regulatory submission is based on data from the Phase III DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer) trial, an international, multicenter, placebo-controlled trial. In the trial, sorafenib significantly extended progression-free survival (PFS), the primary endpoint of the study, compared to placebo (HR=0.587 [95% CI, 0.454-0.758]; p<0.0001), which represents a 41 percent reduction in the risk of progression or death for patients who received sorafenib compared to placebo-treated patients. The median PFS was 10.8 months in patients treated with sorafenib, compared to 5.8 months in patients receiving placebo.
The safety and tolerability profile of sorafenib for patients in the trial was generally consistent with the known profile of sorafenib. The most common treatment-emergent adverse events in the sorafenib arm were hand-foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss and hypertension. Results from the trial were presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2013.
DECISION Trial Design
The DECISION trial was an international, multicenter, placebo-controlled study. A total of 417 patients with locally advanced or metastatic, RAI-refractory, differentiated thyroid cancer (papillary, follicular, Hürthle cell and poorly differentiated) who had received no prior chemotherapy, tyrosine kinase inhibitors, monoclonal antibodies that target VEGF or VEGF receptor, or other targeted agents for thyroid cancer were randomized to receive 400 mg of oral sorafenib twice daily (207 patients) or matching placebo (210 patients).
About Thyroid Cancer
Thyroid cancer has become the fastest-increasing cancer in the world in recent years and is the sixth most common cancer in women. There are more than 213,000 new cases of thyroid cancer annually and approximately 35,000 people die from thyroid cancer worldwide each year.
Papillary, follicular, Hürthle cell and poorly differentiated types of thyroid cancer are classified as "differentiated thyroid cancer" and account for approximately 94 percent of all thyroid cancers. While the majority of differentiated thyroid cancers are treatable with treatment options such as resection and/or radioactive iodine (RAI), RAI-refractory differentiated thyroid cancer is more difficult to treat and is associated with a lower patient survival rate.
About Nexavar® (sorafenib) Tablets
Nexavar®, an oral anti-cancer therapy for liver cancer and for the treatment of patients with advanced kidney cancer, is currently approved in more than 100 countries worldwide. In Europe, Nexavar is approved for the treatment of hepatocellular carcinoma (HCC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.
In preclinical studies, Nexavar has been shown to inhibit multiple kinases thought to be involved in both cell proliferation (growth) and angiogenesis (blood supply) - two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.
Nexavar is also being evaluated by Bayer and Onyx, international study groups, government agencies and individual investigators in a range of other cancers.
About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now includes three oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 55,300 employees (Dec 31, 2012) and is represented in more than 100 countries.

[GodFather]

The science of collaboration

It's a long, expensive, risky road to turn a scientific breakthrough into a treatment that can help patients. Fewer organizations are trying to tackle the challenges alone, says a new paper from MIT researchers published August 28 in the journal Science Translational Medicine.

An essential new way to move discoveries forward has emerged in the form of multi-stakeholder collaborations involving three or more different types of organizations, such as drug companies, government regulators and patient groups, write Magdalini Papadaki, a research associate, and Gigi Hirsch, a physician-entrepreneur and executive director of the MIT Center for Biomedical Innovation.

The authors are calling for a new "science of collaboration" to learn what works and doesn't work; to improve how leaders can design, manage and evaluate collaborations; and to help educate and train future leaders with the necessary organizational and managerial skills.

"Getting new, better, affordable drugs to the right patients faster involves a series of historically independent decisions made by different players or stakeholders," says Hirsch. The system is uncoordinated, takes too long, and costs too much. In some cases, the drug - such as new antibiotics for life-threatening resistant infections - may never become available.

"One of the interesting paradoxes of biomedical innovation is increasingly going to be that even though we have the scientific knowledge required to provide potentially better treatments for patients - or even to prevent disease in those who are at high risk - we may be unable to help patients benefit from them anytime soon," she says.

To help change this scenario, in the last decade, thousands of researchers, pharmaceutical and biotechnology companies, government regulators, payers, clinicians and patients have come together in more than 100 multi-stakeholder collaborations to solve some specific shared problem standing in the way of finding a cure or a better diagnostic approach.

"Multi-stakeholder collaborations provide the opportunity to create an environment that allows for new kinds of interactions among the players," Hirsch says. The largest multi-stakeholder effort, the European Union's Innovative Medicines Initiative (IMI) began in 2008 and has established more than 40 consortia with financial and in-kind investments totaling €2 billion. Some projects focus on specific health issues, such as Alzheimer's disease, chronic pain, diabetes and obesity. Others tackle bigger issues, such as drug and vaccine safety and the use of stem cells for drug discovery. The success has led to a proposal to extend the effort for 10 years and €3.5 billion. Last year, the U.S. President's Council of Advisors on Science and Technology (PCAST) recommended the U.S. form something similar.

"The prevalence of multi-stakeholder initiatives reflects a continued optimism about the value of this collaboration approach for addressing biomedical innovation bottlenecks," the authors write in the paper. "Although the need for collaboration is no longer in question, it is worth noting the importance of this development. A willingness to share proprietary data among industry competitors represents a dramatic shift in the culture of the historically highly competitive pharmaceutical industry."

The article reviews the history of collaborations beginning with HIV/AIDS. By the early 2000s, multi-stakeholder collaborations proliferated to address the need for important tools, such as biomarkers, that require preclinical data sharing. Since then, they have reached to encompass later stages in product development, including manufacturing, reimbursement and post-market monitoring.

Some people involved in multi-stakeholder consortia are concerned about redundancy, inefficiency and lack of productivity of some collaborative efforts, all contributing to a sense of "consortium fatigue," the researchers write.

In a newer trend, funders and participants are seeking a smaller number of strategically coordinated initiatives that will reliably address critical gaps, Hirsch and Papadaki write. They cite the example of TransCelerate BioPharma, a group of 10 major pharmaceutical companies that came together to share and direct resources toward selected priorities in order to improve the efficiency of drug development, such as clinical trial site qualification standards.

The authors propose a rigorous evidence-based approach (the science of collaboration) to figure out what works and doesn't work in collaborations. They recommend early steps in this new field and structuring the research to help learn from the past but also to evolve effectively as new innovation challenges emerge.

To launch their new discipline, the Robert Wood Johnson Foundation just awarded Hirsch and her colleagues a start-up grant to lay the foundation. Their research will begin with case studies in biomedical innovation to identify the organization design components, as well as systematic learning from a broad range of collaborative innovation models in other industries.

About the MIT Center for Biomedical Innovation
CBI's mission is to improve global health by overcoming obstacles to the development and implementation of biomedical innovation. CBI provides a safe and transparent environment for collaborative research among industry, academia, and government, and draws on the expertise of the Massachusetts Institute of Technology's (MIT) Schools of Engineering, Science, and Management, as well as the Harvard-MIT Division of Health Sciences and Technology (HST). In this unique setting, CBI is addressing profound challenges in the global biomedical industry by developing, testing, and disseminating new knowledge and tools designed for real world application through the following programs: the Biomanufacturing Research Program (BioMAN), the Consortium on Adventitious Agents in Biomanufacturing (CAACB), New Drug Development Paradigms (NEWDIGS), and the Sanofi Biomedical Innovation Award Program (saBIP). CBI was established in 2005 and in 2008, the Center merged with MIT's Program on the Pharmaceutical Industry (POPI). POPI was founded in 1991 with a major grant from the Alfred P. Sloan Foundation to promote research and educational activities on issues related to competitiveness, performance and productivity in the pharmaceutical field.