Pharma News

[GodFather]

Amino acid with promising anti-diabetic effects


New experiments conducted by researchers from the University of Copenhagen (Denmark) show that the amino acid arginine - found in a wide variety of foods such as salmon, eggs and nuts - greatly improves the body's ability to metabolise glucose. Arginine stimulates a hormone linked to the treatment of type 2 diabetes, and works just as well as several established drugs on the market. The research findings have just been published in the scientific journal Endocrinology.

More than 371 million people worldwide suffer from diabetes, of whom 90% are affected by lifestyle-related diabetes mellitus type 2 (type 2 diabetes). In new experiments, researchers from the University of Copenhagen working in collaboration with a research group at the University of Cincinnati, USA, have demonstrated that the amino acid arginine improves glucose metabolism significantly in both lean (insulin-sensitive) and obese (insulin-resistant) mice.

"In fact, the amino acid is just as effective as several well-established drugs for type 2 diabetics," says postdoc Christoffer Clemmensen. He has conducted the new experiments based at Faculty of Health and Medical Sciences, University of Copenhagen. He is currently conducting research at the Institute for Diabetes and Obesity at Helmholtz Zentrum München, the German Research Centre for Environmental Health in Munich.

To test the effect of the amino acid arginine, researchers subjected lean and obese animal models to a so-called glucose tolerance test, which measures the body’s ability to remove glucose from the blood over time.

"We have demonstrated that both lean and fat laboratory mice benefit considerably from arginine supplements. In fact, we improved glucose metabolism by as much as 40% in both groups. We can also see that arginine increases the body's production of glucagon-like peptide-1 (GLP-1), an intestinal hormone which plays an important role in regulating appetite and glucose metabolism, and which is therefore used in numerous drugs for treating type 2 diabetes," says Christoffer Clemmensen, and continues: "You cannot, of course, cure diabetes by eating unlimited quantities of arginine-rich almonds and hazelnuts. However, our findings indicate that diet-based interventions with arginine-containing foods can have a positive effect on how the body processes the food we eat."

The research findings were recently published in the American scientific journal Endocrinology under the heading Oral l-arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice.

Researchers have known for many years that the amino acid arginine is important for the body’s ability to secrete insulin. However, the latest findings show that it is an indirect process. The process is actually controlled by arginine’s ability to secrete the intestinal hormone GLP-1, which subsequently affects insulin secretion.

"Mice without GLP-1 receptors are not affected to the same extent by arginine. There is no perceptible improvement in glucose metabolism or insulin secretion, confirming our hypothesis of a close biological connection between GLP-1 and arginine," says Christoffer Clemmensen, who conducted the biological experiments in the USA using a special animal model where the receptor for GLP-1 is genetically inactivated.

The new findings provide optimism for better and more targeted drugs for treating type 2 diabetes; the outlook is long-term, but promising.

"This exciting result has raised several new questions which we want to investigate. Can other amino acids do what arginine does? Which intestinal mechanisms 'measure' arginine and lead to the release of GLP-1? Finally, there is the more long-term perspective - the question of whether the findings can be transferred from mice to humans and be used to design drugs that will benefit diabetes patients," says Professor Hans Bräuner-Osborne, who is continuing work on the project in the research group at the Department of Drug Design and Pharmacology at the University of Copenhagen.

[GodFather]

AstraZeneca and Merck enter licence agreement for investigational oral WEE1 kinase inhibitor therapy for cancer

AstraZeneca announced that MedImmune, its global biologics research and development arm, has entered into a definitive agreement to acquire Amplimmune, a privately-held, Maryland, US-based biologics company focused on developing novel therapeutics in cancer immunology.

WEE1 helps to regulate the cell-division cycle. The WEE1 inhibitor MK-1775 is designed to cause certain tumour cells to divide without undergoing the normal DNA repair processes, ultimately leading to cell death. Preclinical evidence suggests that the combination of MK-1775 and DNA damage-inducing chemotherapy agents can enhance anti-tumor properties, in comparison to chemotherapy alone.

Under the terms of the agreement, AstraZeneca will pay Merck a $50 million upfront fee. In addition Merck will be eligible to receive future payments tied to development and regulatory milestones plus sales-related payments and tiered royalties. AstraZeneca will be responsible for all future clinical development, manufacturing and marketing.

"MK-1775 is a strong addition to AstraZeneca's growing oncology pipeline, which already includes a number of inhibitors of the DNA damage response," said Susan Galbraith, Head of AstraZeneca's Oncology Innovative Medicines Unit. "The compound has demonstrated encouraging clinical efficacy data and we intend to study it in a range of cancer types where there is a high unmet medical need."

"Merck is committed to advancing potentially meaningful therapeutic options promptly for patients with cancer," said Iain D. Dukes, senior vice president and head of licensing and external scientific affairs at Merck. "We are pleased to enter this agreement with AstraZeneca to realise the potential of MK-1775 while we focus on advancing our later stage oncology programs, MK-3475 and vintafolide."

The agreement is contingent on expiration or termination of the waiting period under the Hart Scott-Rodino Antitrust Improvement Act.

About MK-1775
WEE1 is a cell cycle checkpoint protein regulator. Preclinical data indicate that disruption of WEE1 may enhance the cell killing effects of some anticancer agents. MK-1775 is an investigational orally available inhibitor of the cell cycle checkpoint protein WEE1. MK-1775 is being evaluated in Phase IIa clinical trials for the treatment of patients with P53-deficient ovarian cancer.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships.

About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

[GodFather]

New system uses nanodiamonds to deliver chemotherapy drugs

Researchers at UCLA's Jonsson Comprehensive Cancer Center have developed an innovative drug-delivery system in which tiny particles called nanodiamonds are used to carry chemotherapy drugs directly into brain tumors. The new method was found to result in greater cancer-killing efficiency and fewer harmful side effects than existing treatments.

The research, published in the advance online issue of the peer-reviewed journal Nanomedicine: Nanotechnology, Biology and Medicine, was a collaboration between Dean Ho of the UCLA School of Dentistry and colleagues from the Lurie Children's Hospital of Chicago and Northwestern University's Feinberg School of Medicine. Ho co-directs UCLA Dentistry's Weintraub Center for Reconstructive Biotechnology and is a professor in the division of oral biology and medicine, the division of advanced prosthodontics, and the department of bioengineering.

Glioblastoma is the most common and lethal type of brain tumor. Despite treatment with surgery, radiation and chemotherapy, the median survival time for glioblastoma patients is less than one-and-a-half years. The tumors are notoriously difficult to treat, in part because chemotherapy drugs injected alone often are unable to penetrate the system of protective blood vessels that surround the brain, known as the blood–brain barrier. And those drugs that do cross the barrier do not stay concentrated in the tumor tissue long enough to be effective.

The drug doxorubicin, a common chemotherapy agent, has shown promise in a broad range of cancers, and it has served as model drug for the treatment brain tumors when injected directly into the tumor. Ho's team originally developed a strategy for strongly attaching doxorubicin molecules to nanodiamond surfaces, creating a combined substance called ND-DOX.

Nanodiamonds are carbon-based particles roughly 4 to 5 nanometers in diamter that can carry a broad range of drug compounds. And while tumor-cell proteins are able to eject most anticancer drugs that are injected into the cell before those drugs have time to work, they can't get rid of the nanodiamonds. Thus, drug–nanodiamond combinations remain in the cells much longer without affecting the tissue surrounding the tumor.

Ho and his colleagues hypothesized that glioblastoma might be efficiently treated with a nanodiamond-modified drug by using a direct-injection technique known as convection-enhanced delivery, or CED. They used this method to inject ND-DOX directly into brain tumors in rodent models.

The researchers found that ND-DOX levels in the tumors were retained for a duration far beyond that of doxorubicin alone, showing that doxorubicin was taken into the tumor and remained their longer when attached to nanodiamonds. In addition, ND-DOX was also found to increase apoptosis - programmed cancer-cell death - and to decrease cell viability in glioma (brain cancer) cell lines.

The results also demonstrated for the first time that the ND-DOX delivery limited the amount of doxorubicin that was distributed outside the tumor. This reduced toxic side effects and kept more of the drug in the tumor for longer, increasing the drug's tumor-killing efficiency without affecting the surrounding tissue. Survival time increased significantly in the rats treated with ND–DOX, compared with those given only unmodified doxorubicin.

Nanodiamonds have many facets, almost like the surface of a soccer ball, and can bind to doxorubicin very strongly and quickly, Ho noted. Further research will expand the list of brain-cancer chemotherapy drugs that can be attached to the nanodiamond surfaces to improve treatment and reduce side effects.

For a nanoparticle to have translational significance, it has to have as many benefits engineered into one system as simply as possible.

"Nanomaterials are promising vehicles for treating different types of cancer," Ho said. "We're looking for the drugs and situations where nanotechnology actually helps chemotherapy function better, making it easier on the patient and harder on the cancer."

This study showed that convection-enhanced delivery of ND-DOX offers a powerful treatment delivery system against these very difficult and deadly brain tumors, Ho said.

He noted that this large-scale project has been successful thanks to the multidisciplinary and proactive interactions between his team of bioengineers and their outstanding clinical collaborators from Northwestern University and Lurie Children's Hospital.

This research was supported by a National Science Foundation CAREER Award, the Center for Scalable and Integrated NanoManufacturing, a V Foundation for Cancer Research Scholars Award, a Wallace H. Coulter Foundation Translational Research Award, a Society for Laboratory Automation and Screening Endowed Fellowship, Beckman Coulter, the European Commission funding program, and the National Cancer Institute.

[GodFather]

Potential new drug target for cystic fibrosis


Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg and Regensburg University, both in Germany, and the University of Lisboa, in Portugal, have discovered a promising potential drug target for cystic fibrosis. Their work, published online in Cell, also uncovers a large set of genes not previously linked to the disease, demonstrating how a new screening technique can help identify new drug targets.

Cystic fibrosis is a hereditary disease caused by mutations in a single gene called CFTR. These mutations cause problems in various organs, most notably making the lining of the lungs secrete unusually thick mucus. This leads to recurrent life-threatening lung infections, which make it increasingly hard for patients to breathe. The disease is estimated to affect 1 in every 2500-6000 newborns in Europe.

In patients with cystic fibrosis, the mutations to CFTR render it unable to carry out its normal tasks. Among other things, this means CFTR loses the ability to control a protein called the epithelial sodium channel (ENaC). Released from CFTR's control, ENaC becomes hyperactive, cells in the lungs absorb too much sodium and - as water follows the sodium - the mucus in patients' airways becomes thicker and the lining of the lungs becomes dehydrated. The only drug currently available that directly counteracts a cystic fibrosis-related mutation only works on the three percent of patients that carry one specific mutation out of the almost 2000 CFTR mutations scientists have found so far.

Thus, if you were looking for a more efficient way to fight cystic fibrosis, finding a therapy that would act upon ENaC instead of trying to correct that multitude of CFTR mutations would seem like a good option. But unfortunately, the drugs that inhibit ENaC, mostly developed to treat hypertension, don't transfer well to cystic fibrosis, where their effects don't last very long. So scientists at EMBL, Regensburg University and University of Lisboa set out to find alternatives.

"In our screen, we attempted to mimic a drug treatment," says Rainer Pepperkok, whose team at EMBL developed the technique, "we'd knock down a gene and see if ENaC became inhibited."

Starting with a list of around 7000 genes, the scientists systematically silenced each one, using a combination of genetics and automated microscopy, and analysed how this affected ENaC. They found over 700 genes which, when inhibited, brought down ENaC activity, including a number of genes no-one knew were involved in the process. Among their findings was a gene called DGKi. When they tested chemicals that inhibit DGKi in lung cells from cystic fibrosis patients, the scientists discovered that it appears to be a very promising drug target.

"Inhibiting DGKi seems to reverse the effects of cystic fibrosis, but not block ENaC completely," says Margarida Amaral from the University of Lisboa, "indeed, inhibiting DGKi reduces ENaC activity enough for cells to go back to normal, but not so much that they cause other problems, like pulmonary oedema."

These promising results have already raised the interest of the pharmaceutical industry and led the researchers to patent DGKi as a drug target, as they are keen to explore the issue further, searching for molecules that strongly inhibit DGKi without causing side-effects.

"Our results are encouraging, but these are still early days," says Karl Kunzelmann from Regensburg University. "We have DGKi in our cells because it is needed, so we need to be sure that these drugs are not going to cause problems in the rest of the body."

The search for genes that regulate ENaC was undertaken as part of the EU-funded TargetScreen2 project.

Joana Almaça et al. High-Content siRNA Screen Reveals Global ENaC Regulators and Potential Cystic Fibrosis Therapy Targets. Published online in Cell on 12 September 2013. DOI: 10.1016/j.cell.2013.08.045.

[GodFather]

Christoph Franz nominated to become new Roche Chairman

At the forthcoming Annual Shareholders Meeting on 4 March 2014, the Roche Board of Directors will propose Christoph Franz to be elected as Chairman of the Board. Christoph Franz is thus nominated to succeed Franz B. Humer, who announced at the last shareholder meeting that he would not be standing for re-election. Christoph Franz will not renew his contract as CEO of the Lufthansa Group, which expires on 31 May 2014.

Commenting on the nomination of Christoph Franz, Roche Chairman Franz B. Humer said: "With Christoph Franz, Roche is getting a chairman with outstanding personal qualities and an impressive record as head of a major global company. I am sure that his extensive experience, exceptional global network and strong links to Switzerland will be great assets."

Christoph Franz said: "I am delighted that the Board of Directors has nominated me to become the next chairman of the Roche Group. Roche is an outstanding company. As a board member I have had ample opportunity to get to know and admire its strong business performance and corporate culture. Strategically, Roche is in very good shape, and I am looking forward to taking on this opportunity."

About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company, with truly differentiated medicines in oncology, infectious diseases, inflammation, metabolism and neuroscience. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. Roche's personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2012 Roche had over 82,000 employees worldwide and invested over 8 billion Swiss francs in R&D. The Group posted sales of 45.5 billion Swiss francs. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan.

[GodFather]

Mental fog with tamoxifen is real; URMC finds possible antidote

A team from the University of Rochester Medical Center has shown scientifically what many women report anecdotally: that the breast cancer drug tamoxifen is toxic to cells of the brain and central nervous system, producing mental fogginess similar to "chemo brain." However, in the Journal of Neuroscience, researchers also report they've discovered an existing drug compound that appears to counteract or rescue brain cells from the adverse effects of the breast cancer drug.

Corresponding author Mark Noble, Ph.D., professor of Biomedical Genetics and director of the UR Stem Cell and Regenerative Medicine Institute, said it's exciting to potentially be able to prevent a toxic reaction to one of the oldest and most widely used breast cancer medications on the market. Although tamoxifen is relatively benign compared to most cancer treatments, it nonetheless produces troubling side effects in a subset of the large number of people who take it.

By studying tamoxifen's impact on central nervous system cell populations and then screening a library of 1,040 compounds already in clinical use or clinical trials, his team identified a substance known as AZD6244, and showed that it essentially eliminated tamoxifen-induced killing of brain cells in mice.

"As far as I know, no one else has discovered an agent that singles out and protects brain and central nervous system cells while also not protecting cancer cells," Noble said. "This creates a whole new paradigm; it's where we need to go."

The research is the result of two separate but related projects from Noble's lab. One investigates the science underlying a condition known as "chemo brain," and another is looking at how to exploit tamoxifen's attributes for use in other types of cancer besides early-stage, less-aggressive breast cancer. (The drug is a type of hormonal therapy, which works by stopping the growth of estrogen-sensitive tumors.)

In the Journal of Neuroscience paper, Noble's team first identified central nervous system (CNS) cells that are most vulnerable to tamoxifen toxicity. Chief among these were oligodendrocyte-type 2 astrocyte progenitor cells (O-2A/OPCs), cells that are essential for making the insulating sheaths (called myelin) required for nerve cells to work properly. Exposure to clinically relevant levels of tamoxifen for 48 hours killed more than 75 percent of these cells.

In earlier work, while studying the biology of the cognitive difficulties that linger in some people being treated for cancer, Noble and colleagues discovered that 5-fluorouracil, (cisplatin, cytarabine, carmustine), and multiple other types of chemotherapy, damages populations of stem cells in the CNS. Published in the Journal of Biology in 2006 and 2008, these studies pioneered analysis of the biological foundations of chemo brain.

"It's critical to find safe treatments that can rescue the brain from impairment," Noble said, "because despite increasing awareness and research in this area, some people continue to endure short-term memory loss, mental cloudiness, and trouble concentrating. For some patients the effects wear off over time, but others experience symptoms that can lead to job loss, depression, and other debilitating events."

Noble's lab, led by post-doctoral fellow Hsing-Yu Chen, Ph.D., identified 27 drugs that protected O-2A/OPCs from the effects of tamoxifen. Further testing resulted in singling out AZD6244, by other laboratories as a potential cancer therapy.

In mice co-treated with tamoxifen plus AZD6244, cell death in the corpus callosum, the largest white matter (myelinated) structure in the brain, was prevented, the paper reported. Meanwhile, several national clinical trials are testing the safety and effectiveness of AZD6244 in treating multiple cancers, from breast and colon to melanoma and lung.

Researchers were also optimistic about finding that while AZD6244 protected brain cells, it did not also protect cancer cells. New drug compounds have greater value if they do not compromise the effects of existing treatments, and in this case, Noble said, the experiments in his laboratory agreed with studies by other research groups, who found that the combined use of AZD6244 and chemotherapy enhances targeting of cancer cells.

In future work, Noble's group plans to identify the dosage of AZD6244 that provides maximum protection and minimum disruption to differentiating brain cells. Their research was supported by the U.S. Department of Defense, National Institutes of Health, Susan Komen Race for the Cure, and the Carlson Stem Cell Fund.

This is the second tamoxifen-related study to come from Noble's lab in 2013. In April they showed in pre-clinical research they could leverage the drug's various cellular activities so that it might work on more aggressive triple-negative breast cancer. In the journal EMBO Molecular Medicine, Noble and Chen also reported finding an experimental compound that enhances tamoxifen's ability to work in this new way.

[GodFather]

Bayer fights Chagas disease in Argentina together with Caritas

The Bayer Cares Foundation and Caritas Argentina have laid the foundation for a new project to combat the Chagas disease in Argentina. Chagas disease is still an indication with a high unmet medical need because the minor, flu-like symptoms are rather non-specific and therefore often misinterpreted. The collaboration's aims over the next four years are to educate people about Chagas disease, improve early diagnosis in rural areas of Argentina, and make the population more aware of ways in which they can protect themselves. The Bayer Foundation will fund the implementation of the project with donations of EUR 665,000 spread over four years.

Chagas is an infectious disease that affects approximately 10 million people, mainly in the rural areas of South America. The pathogen is a single-celled parasite called Trypanosoma cruzi, which is transmitted by assassin bugs. The disease is often fatal if left untreated, but it can be cured by timely treatment during the acute stage.

Under the project, Caritas and Bayer staff will visit schools in rural areas, which are often cut off from healthcare services, to provide comprehensive and age-appropriate, on-the-spot education about Chagas disease. They will focus on using playful methods to teach the school children. They represent a particularly vulnerable risk group who can also pass on what they learn to their families. To increase the people's knowledge about how the disease spreads, blood tests for diagnosing people infected with the disease will also be conducted, especially in remote areas. A project office in Buenos Aires will pool the findings and, in close collaboration with the public health authorities, subject the data to further analysis and use it to develop preventive measures.

"Screening could prevent many cases of Chagas disease. Much more effort must therefore be invested in education and enlightenment," said Horacio Cristiani, Head of Caritas Argentina. "In Bayer we have found a strong partner who can help us not only to improve the data situation - enabling us to take more targeted measures against the disease - but also to reduce the number of new infections by means of active health education."

"We want to sustainably improve people's health and quality of life," says Professor Dr. Wolfgang Plischke, CEO of Bayer HealthCare AG. "This is a task that no aid organization, government, company or research institute can manage alone. Together with Caritas Argentina we want to raise the population's awareness of the threat posed by Chagas disease."

The concept was developed by a multidisciplinary team made up of international, up-and-coming Bayer managers and Bayer staff members from Argentina within the framework of a Group-wide program, uniting global talent management with the promotion of volunteering by Bayer HealthCare staff in the respective project country. The task is to jointly work out a sustainable plan of action against Chagas disease - one that can also be adopted as a model by other countries and projects.

"This program has shown us the kind of social contribution a team of highly motivated and creative members of staff can make," says Bayer Foundation Board member Thimo V. Schmitt-Lord. "By pooling all the skills that Bayer has in the health field, we have succeeded in getting an innovative project off the ground that can help fill a healthcare gap."

Bayer HealthCare has also been supporting the fight against Chagas disease in another way since 2004. The company supplies the WHO with nifurtimox tablets, and provides financial support for logistics and distributing the drug. In addition, Bayer HealthCare and twelve other pharmaceutical companies have jointly signed the London Declaration on Neglected Tropical Diseases, which has set itself the goal of controlling or eliminating ten neglected tropical diseases.

About the Bayer Cares Foundation
As the social welfare foundation of the innovation company Bayer, the Bayer Cares Foundation sees itself especially as an initiator, promoter and partner for innovation at the interface between industry and the social sector. The sponsorship programs are focused on people - their commitment to public welfare, their wealth of ideas in resolving social tasks, as well as their need in times of emergency. The foundation's funding activities are a central element of Bayer's global social commitment amounting to approximately EUR 50 million annually - with the focus on promoting scientific education and leading-edge research, and on providing health care and meeting the basic social needs of people who live near the company's sites.

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]

New class of drug targets heart disease


Researchers at the University of Alberta have developed a synthetic peptide that could be the first in a new class of drugs to treat heart disease, high blood pressure and diabetes. Researchers found that a deficiency in the peptide apelin is associated with heart failure, pulmonary hypertension and diabetes. They also developed a synthetic version that targets pathways in the heart and promotes blood vessel growth.

Lead author Gavin Oudit, an associate professor in the Faculty of Medicine & Dentistry, said the synthetic form of apelin is far more stable and potent than the naturally occurring peptide, making drug therapies possible.

"It's a new group of drugs that we hope can be used for a wide variety of disorders, all of which have a huge economic burden on the health-care system," said Oudit, a cardiologist and clinician-scientist at the Mazankowski Alberta Heart Institute.

Oudit's research group studied apelin deficiency in the hearts of mice and humans through the Human Explanted Heart Program, or HELP. The HELP program allows for the study of specimens obtained from patients undergoing a heart transplant.

The research team found that hearts from patients who suffered heart attacks were deficient in apelin, which is needed for angiogenesis—the formation of new blood vessels that helps the body adapt after tissue damage from heart attacks.

Oudit's team has filed a provisional patent on the synthetic apelin and will continue work developing the drug to be more potent and clinically applicable. Once the drug is perfected, they'll move into the first phase of clinical trials in two to three years.

Oudit said the breakthrough could not have happened without the contributions of U of A colleagues, including John Vederas, a medicinal chemist and professor in the Department of Chemistry, and Allan Murray, a clinician-scientist and nephrologist in the Department of Medicine. Wang Wang and Shaun McKinnie, both PhD students in Oudit's and Vederas's laboratories, also played a key role in this discovery.

"Having this kind of environment that's multidisciplinary and collaborative is absolutely critical to take a discovery to the next level," Oudit said. "We showed this kind of translational work can be done here, in Edmonton, at the University of Alberta."

The study was published in the August issue of the Journal of the American Heart Association. Oudit's research was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada and Alberta Innovates - Health Solutions.

[GodFather]

Novartis marks World CML Day with update on global research program to evaluate whether Ph+ CML patients can live treatment-free

Novartis commemorates World CML Day by announcing the latest milestone in its unique clinical trial program evaluating the potential for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) to maintain undetectable levels of disease after stopping drug therapy - a concept called treatment-free remission. More than 100 study sites are now enrolling patients to the trial program.

Since 2008, organizations around the world have recognized World CML Day[1]. The date, September 22 or 9/22, was symbolically chosen to represent the genetic material that is associated with CML - the missing section from chromosome 22 shifts to chromosome 9 and vice versa, in a phenomenon called "translocation[2]." Known as the Philadelphia chromosome, this genetic mutation is present in about 95% of CML patients[3].

"As a leader in CML, Novartis is proud to support World CML Day through our continued dedication to ongoing research in this disease," said Hervé Hoppenot, President, Novartis Oncology. "Given that nilotinib has been shown in large clinical trials to drive deeper levels of responses in more than twice as many patients as imatinib, we are now looking to the next phase and exploring if nilotinib can treat the disease to a point where drug therapy is no longer needed, representing the next step in what may be possible for patients living with Ph+ CML."

Over the past decades, Novartis research in Ph+ CML has helped transform the disease from a fatal diagnosis to a chronic condition for many patients. Today, the company continues its long-standing commitment to the global CML community. The Novartis treatment-free remission clinical trial program* includes eight studies that are now underway and actively enrolling Ph+ CML patients in more than 100 global sites across 40 countries[4]. In total, it is planned that more than 2,500 patients will be enrolled in these studies and an estimated nearly 1,000 patients will aim to stop treatment as part of these studies[4].

Globally, Novartis is sponsoring four treatment-free remission studies, including:

ENESTfreedom[5] - a Phase II study in Ph+ CML patients in chronic phase who achieved and maintained MR4.5 on nilotinib as first-line treatment. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01784068.
ENESTop[6] - a Phase II study in Ph+ CML patients in chronic phase who have achieved and maintained MR4.5 on nilotinib after switching from imatinib. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01698905.
ENESTpath[7] - a Phase III study in Ph+ CML patients in chronic phase who have switched to nilotinib from imatinib and have achieved and maintained MR4.0. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01743989.
ENESTgoal[8] - a Phase II study in Ph+ CML patients in chronic phase who have achieved and maintained MR4.5 on nilotinib after switching from imatinib. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01744665.

Novartis is also providing support for four investigator-initiated studies (STAT-2, NILst, CML V, NILO POST-STIM)[4]. These studies are led by independent investigators in sites in Japan, Germany and France.

Stopping treatment is not a clinical recommendation and should only be attempted in the context of a well conducted clinical study. A very important part of these treatment-free remission studies is the inclusion of regular molecular monitoring with International Scale Real-Time Quantitative Polymerase Chain Reaction (IS RT-Q-PCR) testing. Once treatment is stopped molecular monitoring is used to identify if a patient's level of disease remains in deep molecular response or if the reintroduction of treatment is needed[5]-[8].

ENESTfreedom study details[5]
ENESTfreedom is a Phase II, single-arm, open-label study to determine if adults with Ph+ CML can live without drug therapy after stopping treatment with nilotinib. Eligible patients must have maintained MR4.5 with nilotinib treatment in the first-line setting for at least two years before entering the study. Following a one-year consolidation phase, patients who continue to sustain MR4.5 will enter the treatment-free phase. Patients will be monitored closely with regular IS RT-Q-PCR testing.

The primary endpoint is the percentage of patients who are in major molecular response (MMR) at 48 weeks after starting the treatment-free phase and no restarting of nilotinib treatment.

ENESTop study details[6]
ENESTop is a Phase II, single-arm, open-label study designed to determine if adults with Ph+ CML can live without drug therapy after stopping treatment with nilotinib. Eligible patients have been on treatment with nilotinib for at least two years (with the combined time on imatinib and nilotinib for at least three years) and have maintained MR4.5 for at least one year before entering the treatment-free phase. Patients will be monitored closely with regular IS RT-Q-PCR testing.

The primary endpoint is the proportion of patients in treatment-free remission and no loss of MMR or MR4 within the first 12 months of nilotinib cessation.

ENESTpath study details[7]
ENESTpath is a prospective, randomized, open-label, two arm Phase III study designed to evaluate the rate of treatment-free remission in Ph+ CML patients at 12 months after two different durations of consolidation treatment with nilotinib. Eligible patients must have been treated with imatinib for a minimum of two years, being at least in complete cytogenetic response, but have not achieved MR4.0 at study start. Patients entering the study will have two years of nilotinib treatment. If sustained MR4.0 is achieved during the second year of nilotinib treatment, patients will be eligible to be randomized to either enter the treatment-free remission phase immediately, or continue for another year of consolidation with nilotinib treatment and, if still in sustained MR4.0, enter the treatment-free remission phase. Patients will be monitored closely with regular IS RT-Q-PCR testing.

The primary endpoint is the proportion of patients who remain in treatment-free remission (>= MR4.0) without molecular relapse at the end of 12 months in the treatment-free remission phase of the study. This study compares the nilotinib 12-month consolidation treatment arm (arm 1) with the nilotinib 24-month consolidation treatment arm (arm 2) to determine the optimal duration of the consolidation phase.

ENESTgoal study details[8]
ENESTgoal is a US-only Phase II randomized, open-label, two arm, multicenter study designed to determine if adults with Ph+ CML can live without drug therapy after stopping treatment with nilotinib. Eligible patients must have been on treatment with imatinib for at least one year and have achieved a BCR-ABL level of less than or equal to MMR and greater than MR4.5 as measured by IS RT-Q-PCR testing. Patients will switch to nilotinib once entering the study and will have three years of treatment. If MR4.5 is achieved during the third year of treatment, patients will be eligible to be randomized to either enter the treatment-free remission phase immediately, or continue receiving nilotinib for another year before being eligible to enter the treatment-free phase. Patients will be monitored closely with regu

lar IS RT-Q-PCR testing.

The primary endpoint is the percentage of patients remaining in the remission phase (no confirmed loss of MR4.0 and no restarting of treatment with nilotinib) at six months from the start of treatment-free phase, with no confirmed loss of MR4.0 and no restarting of treatment with nilotinib.

About Tasigna (nilotinib)
Tasigna® (nilotinib) is approved in more than 90 countries for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec+, and for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. Take twice daily 12 hours apart. Do not take with food. No food to be consumed for 2 hours before or one hour after dosing. Avoid grapefruit juice and CYP3A4 inhibitors.

About Glivec (imatinib)
Glivec® (imatinib) is approved in more than 110 countries for the treatment of all phases of Ph+ CML, for the treatment of adult patients with KIT (CD117)-positive gastrointestinal stromal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST. Take with food and a large glass of water.

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2012, the Group achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 131,000 full-time-equivalent associates and operate in more than 140 countries around the world.

* In the Novartis treatment-free remission clinical trial program, molecular response (reduction of BCR-ABL transcripts in the blood of patients) is measured at four levels, based on an international standard:

MMR (<= 0.1% BCR-ABL)
MR4 (<= 0.01% BCR-ABL)
MR4.5 (<= 0.0032% BCR-ABL)
Undetectable BCR-ABL (no detectable BCR-ABL transcript level with sample sensitivity of at least 4.5 log)

+ Known as Gleevec® (imatinib mesylate) tablets in the US, Canada and Israel.

1. What is World CML Day? CML Advocates Network. www.cmladvocates.net/worldcmlday/what-is-world-cml-day
2. National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, V.4.2013. Available at: www.nccn.org/professionals/physician_gls/pdf/cml.pdf.
3. Faderl, Stefan, et al. "The biology of chronic myeloid leukemia." New England Journal of Medicine.1999; 341.3: 164-172.
4. Novartis data on file.
5. Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients (ENESTFreedom). Trial identifier NCT01784068 . www.clinicaltrials.gov. Accessed August 2013.
6. A Phase II, Single Arm, Open Label Study of Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop). Trial identifier NCT01698905. www.clinicaltrials.gov. Accessed August 2013.
7. A Randomized Phase III Study to Assess the Effect of a Longer Duration of Consolidation Treatment With Nilotinib on TFR in CP CML (ENESTPath). Trial identifier NCT01743989. www.clinicaltrials.gov. Accessed August 2013.
8. Safety and Efficacy of CML Patients Who Switch to Nilotinib and Stop Treatment After Achieving Sustaining MR4.5. (ENESTgoal). Trial identifier NCT01744665. www.clinicaltrials.gov. Accessed August 2013.

[GodFather]

GSK signs a multi-year agreement with BARDA to supply the US government with anthrax treatment

GlaxoSmithKline (GSK) plc has announced a new four year contract with the Biomedical Advanced Research and Development Authority (BARDA), part of the US Department of Health and Human Services (HHS), for the provision of its inhalation anthrax treatment, raxibacumab. The US government is purchasing the medicine as a counter measure against a potential bioterrorist attack.

Under the terms of the new contract, GSK will provide 60,000 doses to the US government over four years, at a value of approximately $196m. This forms part of a broader five year base contract. Raxibacumab was approved by the FDA in December 2012 for the treatment of adult and pediatric patients with inhalation anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalation anthrax when alternative therapies are not available or are not appropriate. It has not been approved outside of the US.

Since 2001 the US Centers for Disease Control and Prevention (CDC) has classified anthrax as a Category A biothreat, as it poses a severe threat to public health and safety. Anthrax is one of the most likely agents to be used in a bioterrorist attack as its spores are easily found in nature and can be produced in a lab. It can be released into the environment quietly and remain there for a long time.

"We have been collaborating with BARDA for a number of years and raxibacumab is now an important part of the US Government's emergency counter measures against bioterrorism. Through this agreement, we are proud to be helping protect US citizens against such threats," said Sheri Mullen, Vice President of Immunology & Rare Diseases, US Pharmaceuticals, GSK.

Mary Kerr, global commercial lead for infectious diseases at GSK, said "As a pharmaceutical company we believe we have a responsibility to support governments in protecting their citizens against infectious diseases. This agreement highlights the ongoing successful collaboration between GSK and BARDA and is just one example of our commitment to working with governments globally to fight major public health threats."

Earlier this year, GSK and BARDA entered into a portfolio-based agreement for up to five years under which BARDA agreed to support the development of new antibiotics by GSK to fight antibiotic resistance and bioterrorism. This marks the first time that HHS has provided a private pharmaceutical partner the flexibility to move funding around their portfolio of drug candidates.

GSK is committed to working in partnership with governments worldwide to provide emergency preparedness measures and help protect citizens against a number of different health threats including bioterrorism, flu pandemics, malaria and other infectious diseases.

About raxibacumab
Raxibacumab is a monoclonal anti-toxin for the treatment of inhalation anthrax due to Bacillus anthracis and has orphan drug designation in the US. Anthrax is a rare and lethal disease, caused by a toxin-producing bacterium. While antibiotics target the anthrax bacteria, raxibacumab offers an additional mechanism of action by blocking the activity of the anthrax toxin, which plays a key role in the progression of the disease.

The efficacy of raxibacumab is based solely on five studies in animal models of inhalation anthrax where the medicine demonstrated an improved survival rate, when administered both in combination with antibiotics and as monotherapy. Its safety has been evaluated in 326 healthy adult volunteers treated with the recommended dose. The most frequently reported adverse reactions (greater than or equal to 1.5%) were rash, pain in an extremity (arms and legs), pruritis (itching) and somnolence.

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.