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Top 20 World Pharma News of 2016 ! - ...
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Top 20 World Pharma News of 2016 ! – PART 4
Pharma News

Bristol-Myers Squibb and Pfizer announce global real-world data program and present new analyses of Eliquis (apixaban)



Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer Inc. (NYSE: PFE) announced today that 17 abstracts will be presented at the American College of Cardiology’s 65th Annual Scientific Session (ACC.16), to be held April 2-4 in Chicago, IL. The new analyses contribute to the Bristol-Myers Squibb and Pfizer Alliance’s body of evidence on the use of Eliquis to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) and for the treatment of patients with venous thromboembolism (VTE). Abstracts include new analyses from Phase 3 ARISTOTLE and AMPLIFY clinical studies, as well as a number of retrospective analyses of real-world data. “The Alliance is pleased to present new analyses from both Phase 3 clinical trials and real-world databases at this important cardiology conference,” said Douglas Manion, M.D., head of specialty development, Bristol-Myers Squibb. “Clinical trial data help to evaluate the safety and efficacy of Eliquis under well-controlled circumstances, while real-world data can offer additional insight into the use of Eliquis for its approved indications in routine clinical practice.”The real-world data to be presented at ACC.16 are part of ACROPOLIS™ (Apixaban ExperienCe Through Real-WOrldPOpuLatIon Studies), a global real-world data research program designed to further evaluate the effectiveness and safety of Eliquisin routine clinical practice. “Retrospective analyses of real-world data add an important component to our knowledge of Eliquis and may help to inform healthcare practitioners in their treatment decisions,” said Rory O’Connor, M.D., senior vice president and head of Global Medical Affairs, Global Innovative Pharmaceuticals Business, Pfizer Inc.

About Eliquis
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquisdecreases thrombin generation and blood clot formation. Eliquis is approved for multiple indications in the U.S. based on efficacy and safety data from seven Phase 3 clinical trials. Eliquis is a prescription medicine indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF); for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE, following initial therapy.

ACROPOLIS™ (Apixaban ExperienCe Through Real-WOrld POpuLatIon Studies) is the Eliquis (apixaban) global real-world data program designed to generate additional evidence from routine clinical practice settings to further inform healthcare decision makers, including healthcare providers and payers. The ACROPOLIS program will include retrospective, outcomes-based analyses from over 10 databases around the world, including medical records, medical and pharmacy health insurance claims data, and national health data systems.

Analyses of real-world data allow for a broader understanding of patient outcomes associated with Eliquis outside of the clinical trial setting, as well as insight into other measures of healthcare delivery, such as hospitalization and costs.

The AMPLIFY (Apixaban for the initial Management of PuLmonary embolIsm and deep vein thrombosis as First-line therapY) trial was a double-blind, randomized, multicenter study that compared the efficacy and safety of Eliquis (at a dose of 10 mg orally twice daily for seven days, followed by 5 mg orally twice daily for six months) with those of conventional therapy in 5,395 patients with symptomatic proximal DVT or symptomatic PE with or without DVT. The primary efficacy outcome was the incidence of the adjudicated composite of recurrent symptomatic VTE or death related to VTE that occurred by the end of the treatment period. The primary safety outcome was adjudicated major bleeding that occurred by the end of the treatment period.

ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation) was designed to evaluate the efficacy and safety of Eliquis versus warfarin for the prevention of stroke or systemic embolism. In ARISTOTLE, 18,201 patients were randomized (9,120 patients to Eliquis and 9,081 to warfarin). ARISTOTLE was an active-controlled, randomized, double-blind, multi-national trial in patients with nonvalvular atrial fibrillation or atrial flutter, and at least one additional risk factor for stroke. Patients were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients, representing 4.7 percent of all patients) or warfarin (target INR range 2.0-3.0), and followed for a median of 1.8 years.

About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize apixaban, an oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb’s long-standing strengths in cardiovascular drug development and commercialization with Pfizer’s global scale and expertise in this field.

About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases.

About Pfizer Inc.: Working together for a healthier world®
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us.

Human medicines: highlights of 2015



The European Medicines Agency (EMA) has released an overview of its 2015 key recommendations in relation to the marketing authorisations of new medicines and the safety monitoring of authorised medicines.2015 was an important year for public health in the European Union (EU). Therapeutic innovations that have the potential to make a difference to people’s lives were seen in particular for the treatment of certain cancers, cardiovascular diseases, and in the areas of haematology (diseases of the blood) and neurology (disorders of the nervous system).

In 2015, EMA recommended 93 medicines for marketing authorisation. This includes recommendations for 39 new active substances.

Monitoring in real life – optimising safe and effective use
Once a medicine is available to patients, EMA and the national competent authorities of the EU continuously monitor the benefits and risks that patients experience with the medicine in real life.

In 2015, EMA gave new safety advice to manage risks observed with a number of medicines on the market in the EU. The product information of these medicines was updated to provide the best information possible to patients and healthcare professionals to enable informed decisions when using or prescribing a medicine

18. Beiging’ white fat cells to fight diabetes

Researchers are getting closer to learning how to turn white fat cells into brown fat cells, in a process called “beiging,” to bring down blood sugar levels and fight diabetes. The team, led by Joseph Baur, PhD, an assistant professor of Physiology in the Perelman School of Medicine at the University of Pennsylvania published their findings this month in the journal Diabetes.”Beiging of white fat could be harnessed to fight diabetes by burning excess calories to cause a decrease in blood sugar,” Baur said. “Our work suggests that activation of the mTOR pathway plays a critical role in this process.” Induction of beige fat cells is considered a promising strategy to combat obesity because of this cell type’s ability to metabolize glucose and lipids, dissipating the resulting energy as heat.

Brown and white fat cells, or adipocytes, play different roles in the body. While white adipocytes store energy as large fat droplets, brown adipocytes contain smaller fat droplets and are specialized to burn fat to produce heat. To do this brown adipocytes are packed with the powerhouses called mitochondria that contain iron, which gives them their brown color. In fact, babies are born with brown fat along the upper back and shoulders to keep warm.

In adult humans, the recent discovery of brown fat “depots” is also associated with lower body weight. Brown-like fat cells, called beige adipocytes, also appear within white fat deposits in response to cold and other signals. The energy balance within the body is influenced by brown and beige adipocytes, which are stimulated into action by cold temperatures and other signals to burn fat and carbohydrates.

The primary tool used in these studies was rapamycin, a drug that inhibits the protein mTOR (mechanistic target of rapamycin), which can be found in two distinct protein complexes. It was first discovered as a byproduct of Streptomycin hygroscopicus, a bacterium found in a soil sample from Easter Island, an island also known as Rapa Nui, hence the name. Rapamycin is currently used as an immunosuppressant in organ transplant, but has recently attracted attention when it was discovered to extend lifespan in mice.

Interestingly, in 2012, Baur’s lab discovered that rapamycin also causes insulin resistance due to its ability to inhibit both arms of the mTOR signaling pathway controlled by the protein complexes mTORC1 and mTORC2. They showed in an animal model that these two arms could, in principle, be separated to dissect which pathway controls longevity versus endocrine effects.

In terms of physiology, mTOR signaling is involved in the control of blood sugar and cholesterol levels, and its inhibition increases the risk of diabetes. While previous studies suggested that mTORC1 inhibition would promote beiging of white fat cells, Baur’s present work supports the notion that mTORC1 activity is actually required for cold-induced beiging of white fat cells. If activating mTORC1 directly can bring about the same result, then this approach could potentially be applied to combat diabetes.

In the Diabetes study, the team shows that rapamycin blocks the ability of cold or drugs that activate a specific neurotransmitter pathway to induce the appearance of beige fat cells. Accordingly, rapamycin-treated mice are cold-intolerant and fail to maintain body temperature and weight when moved to a colder environment.

The findings demonstrate a positive role for mTORC1 in the recruitment of beige fat cells to white fat depots, which could explain some of the negative metabolic effects of mTOR inhibition.

“Our study highlights the complex interconnection between mTOR signaling and metabolism,” said first author Cassie Tran, PhD, a postdoctoral fellow in the Baur lab. “It will be critical in moving forward to determine the specific targets downstream of mTOR that are causing the negative metabolic effects in order to create better drugs and one day drugs that might also extend heathspan. The discovery of a critical signaling pathway for beige-fat formation also suggests the opportunity to target this pathway to therapeutically increase the number of heat-producing cells in obese or diabetic patients.”

Other co-authors include Sarmistha Mukherjee, David W. Frederick, Megan Kissig, James G. Davis, and Patrick Seale, all from Penn.

This work was supported by grants from the National Institutes of Health (R01 AG043483, R01 DK098656, T32 DK07314, K99/R00, AG041765).

19. Use of and barriers to access to opioid analgesics worldwide

Use of common opioid painkillers such as codeine, morphine and oxycodone has more than quadrupled in Australia over the past decade and doubled worldwide over the same period a report published today in The Lancet by the International Narcotics Control Board (INCB) reveals. Yet at the same time the authors warn that the majority of countries, particularly those in developing and poorer regions have little or no access to basic pain medication and there has been little change over the decade.A research team from the INCB including Professor Richard Mattick of the National Drug and Alcohol Research Centre at UNSW Australia calculated the daily use of opioid analgesics for countries and regions globally over the period 2001 to 2013, compared the data against the prevalence of health conditions requiring pain relief and surveyed 214 countries about any impediments to availability of the medications.

The authors found that the bulk of the increase occurred in high income western countries and regions including North America, Western and Central Europe and Australia and New Zealand, which together accounted for more than 95 per cent of global opioid use. In Australia use of the medications increased more than four-fold from 3,287 doses per day per million (22 million doses annually) to 13,440 doses per day per million (106 million doses). The needs of the ageing population for cancer pain and increased pain management for chronic non-cancer pain in Western countries are thought to be the main drivers of the increase. As there is no recognised level of appropriate prescribing, it is not known if this use is excessive or appropriate.

By contrast, the majority of poorer and less developed nations including Central America and the Caribbean, Africa, South Asia, East Asia, South East Asia and Eastern Europe had little or no access to opioid pain relief and there had been no significant increase in use in these regions over the period. Over five and a half billion people are estimated to have little or no access to essential pain relief.

“Much of the increased usage that has occurred in high income countries is probably partly due to long term prescribing for non-cancer pain but the absence of real growth in most of the world indicates an ongoing lack of provision of these essential medications,” write the authors.

They also caution that increased access will not necessarily lead to misuse but that a balance must be maintained.

“Ensuring access does not necessarily mean increased abuse and diversion, but it is necessary to maintain a balance between control on the one hand, and overly liberal availability on the other,” the authors write. “Countries can review legislation and regulatory systems to remove unduly restrictive provisions, while still preventing diversion.”

The authors warn that the lack of access in developing nations is highly inequitable and is in contravention of international agreements such as the Universal Declaration of Human Rights which includes the right to medical care including palliative care and the United Nations Convention.

The paper found that the low levels of prescribing in poorer developing countries did not reflect the need for the medications. For example data from the International Agency for Research on Cancer shows that more than half of all cancer cases and cancer deaths occurred in less developed regions. “In these regions the disease is mostly discovered when it is at an advanced stage… By then palliation is often required and access to opioid analgesics is essential,” the authors write. Levels of prescribing of opioid painkillers are also well below what is needed to manage AIDS related pain in developing regions, in particular Sub-Saharan Africa and Asia, the report finds.

The authors found that barriers to use in poorer and developing countries included affordability, lack of awareness and training among medical professionals, fear of dependence, limited financial resources, problems in sourcing, fear of misuse and onerous regulations.

Professor Mattick, senior author on the paper said that the correct level of opioid use was unclear. “The ageing populations and greater care for chronic non-cancer pain are likely drivers of increased use in high-income countries,” he said. However in lower income developing countries it was clear the low levels of prescribing did not reflect the need for the medications. “The lack of availability of these medications in low-income countries for the management of cancer pain is a terrible situation causing massive suffering,” said Professor Mattick.

The report will be available for the Commission on Narcotic Drugs of all countries in March in Vienna and the UNGASS (UN General Assembly Special Session on the World Drug Problem) in New York in April.

20. Dangerous drug interactions uncovered with data science

Dangerous drug interactions

Dangerous drug interactions

Researchers at Columbia University Medical Center and the Data Science Institute at Columbia University have uncovered a potentially dangerous drug interaction using data science. Their findings were published in the latest issue of the Journal of the American College of Cardiology. Safe when taken on their own, some prescription drugs become deadly when combined. Many of these interactions are well known, but others remain hidden to doctors, drug companies, and patients. Identifying these risky combinations has become a priority as the number of Americans on multiple medications rises.Leveraging the power of big data, the researchers found a way to expand and improve the search for drug interactions. Mining a government database of reported drug side effects and a university hospital archive of patient records, they discovered eight pairs of drugs that are associated with a higher risk of a potentially deadly heart condition. Testing one of the pairs on individual heart cells in the lab, they discovered why the drug combination may disrupt the heart’s normal electrical activity in some patients.

The pair they studied – ceftriaxone, an antibiotic sold under the brand name Rocephin, and lansoprazole, a heartburn medication sold as Prevacid – are widely prescribed, and alone carry no known heart-related risks. But together, they may increase the chance that patients develop a heart condition known as long QT syndrome, which can cause abnormal heart rhythms and, in rare cases, sudden death. The study finds that patients taking ceftriaxone and lansoprazole together were 1.4 times more likely to have a prolonged QT interval than people who were taking either of these drugs alone.

“What’s most surprising is that you can go from a database of billions of data points to making a prediction that two molecules together can change the functions of a protein in a single heart cell,” said the study’s senior author, Nicholas Tatonetti, PhD, assistant professor of biomedical informatics at Columbia University Medical Center and a member of Columbia’s Data Science Institute. “It means these algorithms are really useful in medical research.”

An unusual collaboration sparked the investigation. A journalist with The Chicago Tribune contacted Tatonetti about his previous work in developing algorithms to uncover dangerous drug interactions. At the time, Tatonetti was focused on diabetes and finding drug combinations that raised blood sugar but was frustrated by a lack of interest in his work. The journalist, Sam Roe, had an idea. What if Tatonetti shifted his search to identifying potentially fatal heart drug interactions? That might make more people pay attention.

Roe introduced Tatonetti to Raymond Woosley, MD, PhD, a national expert on drug-induced long QT syndrome whose earlier work led to the removal of a dangerous allergy medication from the market. Woosley gave Tatonetti a list of drugs known to cause QT prolongation and a constellation of side effects, which Tatonetti used to write an algorithm to search the U.S. Food and Drug Administration’s drug-side effect database for drug pairs matching a constellation of side effects associated with QT prolongation.

Looking at side effects alone, the algorithm turned up hundreds of suspect drug pairs. To narrow the search, the researchers turned to a Columbia database of patient records to see if the drug pairs produced measurable effects on the heart. Consulting the electrocardiograms of those in the database, they found the QT prolongation signal with several dozen drug pairs.

For further validation, Woosley introduced Tatonetti to a former colleague, Robert Kass, PhD, the chair of Columbia’s Department of Pharmacology who also has a research interest in cardiac drug interactions. Of the four pairs with the largest effect, the researchers tested the most widely used combination first: ceftriaxone and lansoprazole.

As anticipated, neither drug on its own had an effect on an electrical pathway called the hERG channel, which helps the heart maintain a normal rhythm. When combined, however, they found that the drugs blocked the channel’s electrical signal responsible for maintaining a normal QT interval.

The researchers have informed the FDA and the companies that discovered the drugs, Roche for ceftriaxone, and Takeda for lansoprazole, of their findings and are moving ahead to test the other three pairs of drugs.

Drug safety advocates are also excited. The study may provide the most convincing evidence yet that data science tools can ferret out meaningful signals in oceans of data. “Drug interactions occur often, but they often go unrecognized, and we have needed better methods of detection,” said study coauthor Woosley, founding president of ACZERT, an Arizona nonprofit organization focused on drug safety. “Nick’s techniques open up new avenues of data exploration for medical researchers.”

In an editorial published in the same issue of the journal, Dan Roden, MD, of Vanderbilt University Medical Center cautioned that the findings were not yet conclusive enough for doctors to advise all patients, or even patients at risk for QT prolongation, to avoid the drug pair. But he expressed support for the approach, and recommended the authors consider conducting a small clinical trial to confirm the interaction.

“Three independent lines of evidence show us that this is a signal worth paying attention to,” said the study’s lead author Tal Lorberbaum, a graduate student at Columbia. “We hope that a clinical trial will confirm that this is an actionable discovery.”

The study was supported by grants from the National Institute 0f General Medical Sciences (T32GM082797 and R01GM107145) and the National Institutes of Health (5R01GM109762-02 and K08HL116790).

The authors report no conflicts of interest. NPT is a paid advisor to Advera Health. RLW is an unpaid officer of AZERT.org, which is supported by a contract from the FDA’s Safe Use Initiative.

Lorberbaum T, Sampson KJ, Chang JB, et al.
Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.
J Am Coll Cardiol. 2016;68(16):1756-1764. doi: 10.1016/j.jacc.2016.07.761.


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