Expand prescribing of buprenorphine for opioid abuse? Experts weigh pros and cons....

In continuation of my update on Buprenorphine

Buprenorphine is a critical part of treatment for the growing epidemic of opioid abuse--but also carries the potential for misuse and diversion. The debate over whether 'to expand or not to expand' prescribing of buprenorphine for opioid abuse is discussed in an expert review in the Journal of Psychiatric Practice, published by Wolters Kluwer.

Based on the strong evidence of effectiveness, "We should not limit or impede the use and expansion of buprenorphine therapy," write Drs. Xiaofan Li, Daryl Shorter, and Thomas Kosten, of the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. They propose specific strategies to promote buprenorphine use while ensuring quality of care and reducing the risk of diversion and abuse.

Focus on Expanding Buprenorphine Use 'Safely and Effectively'

A "partial agonist" of the μ-opioid receptor in the brain, buprenorphine has similar actions to other opioids, but with less potential for abuse and a more favorable safety profile. Because it reduces demand for opioids, buprenorphine therapy is an effective deterrence strategy to combat opioid abuse. The authors cite studies suggesting that access to buprenorphine therapy can sharply reduce heroin mortality--including reductions of more than 50 percent in France and 37 percent in Baltimore.

Compared to methadone--long the standard for treating opioid and heroin addiction--buprenorphine poses lower risks related to diversion and non-medical use. The most commonly prescribed form of buprenorphine includes the opioid antagonist (blocker) naloxone, decreasing the potential for intravenous abuse.

But there are strict controls on prescribing of buprenorphine, which is classified as a Schedule III controlled substance in the United States. To prescribe buprenorphine in office-based settings, physicians must receive a Drug Enforcement Agency (DEA) waiver, complete special training, and comply with limits on the number of treated patients.

While medical use of buprenorphine has skyrocketed over the past decade, most prescribers are located in urban areas. It is estimated that 53 percent of US counties do not have any physician with a DEA waiver to prescribe buprenorphine.

Measures to make buprenorphine treatment more accessible have been proposed, such as allowing prescribing by qualified advanced nurse practitioners and physician assistants and loosening limits on number of patients treated. But these measures have been controversial, reflecting legitimate concerns about increased potential for diversion and abuse. Data show that, as use of buprenorphine to treat opioid use disorder has increased, so have the rates of misuse and diversion.

Drs. Li, Shorter, and Kosten raise special concern about the recent emergence of intravenous buprenorphine abuse. They write, "This real-world, almost paradoxical, phenomenon demonstrates the complexity inherent in the treatment of addictive disorders--a medication intended to treat substance use disorder that has its own abuse potential, upon gaining popularity and increased availability, will inevitably be explored by drug abusers for reward and reinforcement purposes."

Earlier this year, President Obama announced an initiative to increase access to effective medications for treating opioid addiction--specifically, buprenorphine and naloxone. Drs. Li, Shorter, and Kosten outline strategies to expand effective treatment with buprenorphine while reducing the risks of diversion and abuse, including:

• Additional support for physicians with high caseloads and other measures to help prescribers comply with guidelines.
• Continuing medical education targeting improvements in office-based therapy for opioid abuse.
• Policies and regulations promoting safe practice.
• Financial incentives coupled with mandatory enforcement of essential components of safe practice.
• More active pharmacy involvement, including supervised dispensing.
• Identification of groups at high risk of intravenous buprenorphine abuse.

"The question is not whether or not to expand buprenorphine prescribing," the authors add. "It is how to expand buprenorphine prescribing safely and effectively."

Ref :1. http://journals.lww.com/practicalpsychiatry/pages/articleviewer.aspx?year=2016&issue=05000&article=00004&type=abstract

 http://dx.doi.org/10.1097/PRA.0000000000000154

Expand prescribing of buprenorphine for opioid abuse? Experts weigh pros and cons 

Ibrutinib: Indication of added benefit in one of three therapeutic indications...

In continuation of my update on Ibrutinib

Ibrutinib is a drug for the treatment of rare diseases. It has been approved for the treatment of adults with chronic lymphocytic leukemia (CLL) or with relapsed or refractory mantle cell lymphoma (MCL) since 2014, and since 2015 also for the treatment of adults with Waldenström macroglobulinaemia. Regarding the treatment of patients with CLL or MCL, the Federal Joint Committee (G-BA) already conducted a benefit assessment and made a decision in 2015.

On request of the G-BA, the drug manufacturer now submitted a new dossier because the turnover of the drug in the statutory health insurance exceeded 50 million euros in the preceding 12 months. The German Institute for Quality and Efficiency in Health Care (IQWiG) therefore examined in an early benefit assessment whether the drug offers an added benefit for patients with these diseases in comparison with the respective appropriate comparator therapies.

According to the findings, there is no hint of an added benefit in CLL and Waldenström macroglobulinaemia. In relapsed or refractory mantle cell lymphoma, there is an indication of major added benefit of ibrutinib for patients for whom temsirolimus is the individually optimized treatment option. An added benefit is not proven for patients for whom temsirolimus is no or only a secondary option.

Chronic lymphocytic leukemia

The G-BA differentiated between pretreated and treatment-naive patients within the therapeutic indication of CLL. Pretreated patients were separated into two subpopulations, resulting in three research questions.

Pretreated patients for whom chemotherapy is indicated were to be treated with individually optimized chemotherapy in the comparator arm. The manufacturer presented no relevant data for these patients in its dossier: The direct comparison and the indirect comparisons conducted by the manufacturer were unsuitable for the derivation of an added benefit of ibrutinib.

Pretreated patients for whom such chemotherapy is not an option were to be treated with idelalisib or best supportive care in the comparator arm. A non-quantifiable advantage in the outcome "mortality," but also potentially lesser benefit of ibrutinib in morbidity and health-related quality of life as well as potentially greater harm in severe and serious side effects resulted from the study data presented. In the consideration of the beneficial and harmful effects, an added benefit is therefore not proven for these patients either.

Idelalisib or best supportive care constituted the appropriate comparator therapy also for treatment-naive patients for whom chemo-immunotherapy is unsuitable due to mutations. The manufacturer presented only one study irrelevant for the research question so that an added benefit is not proven for this patient group either.

Waldenström macroglobulinaemia

Pretreated and treatment-naive patients were to be considered separately also in the therapeutic indication Waldenström macroglobulinaemia. In both cases, the appropriate comparator therapy was individually optimized treatment specified by the physician.

The manufacturer presented no data on first-line treatment so that an added benefit of ibrutinib for treatment-naive patients is not proven.

Regarding patients who have received at least one treatment, the manufacturer submitted a historical comparison based on uncontrolled studies because there were no randomized controlled trials. Due to the selective choice of data, among other reasons, this comparison was unsuitable for drawing conclusions on the added benefit. Hence there was no hint of an added benefit in this case either.

Relapsed or refractory mantle cell lymphoma

Two subpopulations have to be differentiated also in relapsed or refractory MCL: patients for whom temsirolimus is the individually optimized treatment, and patients for whom this is not the case.

Due to a lack of data, an added benefit of ibrutinib is not proven for patients for whom temsirolimus is no or only a secondary treatment Option.

For the other patient group, in contrast, the manufacturer presented data from the study MCL3001, in which ibrutinib was compared with temsirolimus. There was no statistically significant difference between the study arms regarding overall survival. Ibrutinib had positive effects in the outcomes "health status" and "side effects," which were not offset by negative effects in other outcomes. Overall, there is therefore an indication of major added benefit for patients for whom temsirolimus constitutes the individually optimized treatment.

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

Ibrutinib: Indication of added benefit in one of three therapeutic indications

Current cancer drug discovery method flawed, study suggests: Researchers develop new approach to assess drug sensitivity in cells ..

The primary method used to test compounds for anti-cancer activity in cells is flawed, Vanderbilt University researchers report May 2 in Nature Methods. The findings cast doubt on methods used by the entire scientific enterprise and pharmaceutical industry to discover new cancer drugs.

"More than 90 percent of candidate cancer drugs fail in late stage clinical trials, costing hundreds of millions of dollars," said Vito Quaranta, M.D., director of the Quantitative Systems Biology Center at Vanderbilt. "The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact."

Quaranta and his colleagues have developed a new metric to evaluate a compound's effect on cell proliferation -- called the DIP (drug-induced proliferation) rate -- that overcomes the flawed bias in the traditional method.

For more than 30 years, scientists have evaluated the ability of a compound to kill cells by adding the compound to cells and counting how many cells are alive after 72 hours. But these "proliferation assays" that measure cell number at a single time point don't take into account the bias introduced by exponential cell proliferation, even in the presence of the drug, said Darren Tyson, Ph.D., co-author and research assistant professor of Cancer Biology.

"Cells are not uniform; they all proliferate exponentially, but at different rates," said Quaranta, professor of Cancer Biology. "At 72 hours, some cells will have doubled three times and others will not have doubled at all."

In addition, he noted, drugs don't all behave the same way on every cell line -- for example, a drug might have an immediate effect on one cell line and a delayed effect on another.

In a close collaboration with computational biologist Carlos Lopez, assistant professor of Cancer Biology, Quaranta's team used a systems biology approach -- a mixture of experimentation and mathematical modeling -- to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

"Systems biology is what really makes the difference here," Quaranta said. "It's about understanding cells -- and life -- as dynamic systems."

Tyson, an experimentalist, conceived the method with Leonard Harris, Ph.D., a systems biology postdoctoral fellow and co-first author Peter Frick, Ph.D., a recent Vanderbilt graduate.

The findings have particular importance in light of recent international efforts to generate data sets that include the responses of "thousands of cell lines to hundreds of compounds," Quaranta said. The Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases include drug response data along with genomic and proteomic data that detail each cell line's molecular makeup.

"The idea is to look for statistical correlations -- these particular cell lines with this particular makeup are sensitive to these types of compounds -- to use these large databases as discovery tools for new therapeutic targets in cancer," Quaranta said. "If the metric by which you've evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good." The researchers evaluated the responses of four different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric -- used for the CCLE and GDSC databases -- and with the DIP rate. In one cell line, they found a stark disagreement between the two metrics.

"The static metric says that the cell line is very sensitive to vemurafenib. However, our analysis shows this is not the case," Harris said. "A brief period of drug sensitivity, quickly followed by rebound, fools the static metric, but not the DIP rate."

The findings "suggest we should expect melanoma tumors treated with this drug to come back, and that's what has happened, puzzling investigators," Quaranta said. "DIP rate analyses may help solve this conundrum, leading to better treatment strategies."

The DIP rate metric offers another advantage -- it can reveal which drugs are truly cytotoxic (cell-killing), rather than merely cytostatic (cell growth-inhibiting). Although cytostatic drugs may initially have promising therapeutic effects, they may leave tumor cells alive that then have the potential to cause the cancer to recur.

Quaranta noted that using the DIP rate is possible because of advances in automation, robotics, microscopy and image processing.

His team has developed a software package that will be available to other researchers through a hyperlink in the Nature Methods paper. Quaranta is working with the Vanderbilt Center for Technology Transfer and 

Current cancer drug discovery method flawed, study suggests: Researchers develop new approach to assess drug sensitivity in cells  

FDA Approves Bayer's Gadavist (gadobutrol) Injection for use with Magnetic Resonance Angiography of Supra-Aortic Arteries

Bayer announced  that the U.S. Food and Drug Administration (FDA) has approved Gadavist (gadobutrol) injection for use with magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates).1 The FDA approval is based on the results of two, multi-center, Phase 3, open-label clinical studies – the GEMSAV study of patients with known, or suspected vascular disease, of the supra-aortic arteries and the GRAMS study of patients with known or suspected renal artery disease. 

"Until now, no contrast agents were FDA approved for use with MRA of the supra-aortic arteries," said Dr. Elias Melhem, M.D., Chair, Department of Diagnostic Radiology & Nuclear Medicine, University of Maryland, and principal investigator for the GEMSAV study. "With FDA's action, radiologists now have an approved MRA contrast agent to help visualize supra-aortic arteries in patients with known or suspected supra-aortic arterial disease, including conditions such as prior stroke or transient ischemic attack (TIA)."

In the GEMSAV and GRAMS studies, gadobutrol met the primary objective of superior assessability (ability to see more vessel segments) and non-inferior sensitivity and specificity as compared to non-contrast MRA. Gadobutrol-enhanced MRA demonstrated statistically significant higher assessability (visualization) versus non-contrast MRA images.

"Bayer is delighted to obtain FDA approval for the use of Gadavist for MRA to evaluate known or suspected supra-aortic or renal artery disease," said Dennis Durmis, Vice President of Radiology Commercial Operations – Region Americas. "As an industry leader in contrast media, this is the third expansion of the Gadavist label in the past 24 months based on a robust clinical development program."

Collegium Receives FDA Approval for Xtampza ER, an Analgesic with Abuse-Deterrent Properties

In continuation of my update on oxycodone

Collegium Pharmaceutical, Inc.   announced that the U.S. Food and Drug Administration (FDA) approved Xtampza ER (oxycodone) extended-release (ER) capsules CII, a twice-daily, oxycodone medication for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Xtampza ER is Collegium’s first product utilizing its proprietary DETERx® technology platform, and is designed to provide adequate pain control while maintaining its drug release profile after being subjected to common methods of manipulation including chewing and crushing the product prior to administration. The Xtampza ER label contains information supporting the administration of the product by sprinkling the capsule contents on soft foods or into a cup, and then directly into the mouth, or through a gastrostomy or nasogastric feeding tube.

“The FDA approval of Xtampza ER is a major milestone for Collegium. Our DETERx technology platform was developed internally and our lead product completed an extensive battery of abuse-deterrent testing consistent with the FDA Guidance on Abuse-Deterrent Opioids. Collegium is committed to supporting responsible, appropriate prescribing for only those patients suffering from chronic pain who don’t have alternative non-opioid treatment options. Xtampza ER will provide clinicians with another treatment option for these patients,” said Michael Heffernan, CEO of Collegium.

Exelixis Announces FDA Approval of Cabometyx (cabozantinib) for Patients with Advanced Renal Cell Carcinoma

In continuation of my update on  cabozantinib

Exelixis, Inc.   announced that the U.S. Food and Drug Administration (FDA) has approved Cabometyx (cabozantinib) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. RCC is the most common form of kidney cancer in adults. Cabometyx, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first therapy to demonstrate in a phase 3 trial for patients with advanced RCC, robust and clinically meaningful improvements in all three key efficacy parameters — overall survival, progression-free survival and objective response rate.

“With  this announcement, patients with previously treated advanced kidney cancer now have a new option, the first and only approved product demonstrated to help patients live longer while also delaying the progression of their cancer,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “We are proud to bring new hope to this community, who are looking for more therapies that can help extend lives. Exelixis is committed to making Cabometyx available to patients in need within the next couple weeks.”

“The efficacy profile demonstrated by Cabometyx in the METEOR trial, now complemented by the overall survival benefit, is highly compelling,” said Toni Choueiri, MD, Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “Cabometyx is distinct from other approved treatment options, as it targets multiple tyrosine kinases involved in the development of RCC, including MET, AXL and three VEGF receptors. At the same time, physicians are very familiar with this class of drug and how to use dose adjustments to balance safety and efficacy. The approval of Cabometyx is wonderful news for physicians who are looking for a new option for their previously treated patients with advanced kidney cancer.”

The approval of Cabometyx is based on results of the phase 3 METEOR trial, which met its primary endpoint of improving progression-free survival. Compared with everolimus, a standard of care therapy for second-line RCC, Cabometyx was associated with a 42 percent reduction in the rate of disease progression or death. Median progression-free survival for cabozantinib was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). Cabometyx also significantly improved the objective response rate compared with everolimus. These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.

As announced in February 2016, Cabometyx also demonstrated a statistically significant and clinically meaningful increase in overall survival in the METEOR trial. Compared with everolimus, Cabometyx was associated with a 34 percent reduction in the rate of death. Median overall survival was 21.4 months for patients receiving Cabometyx versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).

Bevespi Aerosphere Approved by the FDA for Patients with COPD

In continuation of my update on Formoterol

 Formoterol     glycopyrrolate

AstraZeneca announced that the US Food and Drug Administration has approved Bevespi Aerosphere (glycopyrrolate and formoterol fumarate) inhalation aerosol indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Sean Bohen, Executive Vice-President, Global Medicines Development and Chief Medical Officer, said: “With the approval of Bevespi Aerosphere we are pleased to provide patients with the first LAMA/LABA in a pressurised metered-dose inhaler, delivered using our unique formulation technology. LAMA/LABAs are emerging as a preferred treatment option for many COPD patients. This class aims to provide maximum bronchodilation, which enables patients to breathe better and may help them be more active.”

Bevespi Aerosphere is a twice-daily, fixed-dose dual bronchodilator combining glycopyrrolate, a long-acting muscarinic antagonist (LAMA), and formoterol fumarate, a long-acting beta-2 agonist (LABA). The FDA approval is based on the PINNACLE trial programme, which demonstrated that Bevespi Aerosphere achieved statistically significant improvement in morning pre-dose forced expiratory volume in 1 second (FEV1) at 24 weeks (p<0.001) versus its mono-components and placebo.

Bevespi Aerosphere is the first product approved using AstraZeneca’s Co-Suspension Technology. This technology enables consistent delivery of one or more different medicines from a single pMDI. The technology is being applied to a range of AstraZeneca respiratory inhaled combination therapies currently in clinical development, such as the fixed-dose triple combination of LAMA/LABA/Inhaled corticosteroid (PT010).

Bevespi Aerosphere Approved by the FDA for Patients with COPD

FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion

In continuation of my update on Venclexta

Food and Drug Administration today approved Venclexta (venetoclax) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. Venclexta is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with CLL.

According to the National Cancer Institute, CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed each year. CLL is characterized by the progressive accumulation of abnormal lymphocytes, a type of white blood cell. Patients with CLL who have a 17p deletion lack a portion of the chromosome that acts to suppress cancer growth. This chromosomal abnormality occurs in approximately 10 percent of patients with untreated CLL and in approximately 20 percent of patients with relapsed CLL.

“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumor cells alive,” said Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For certain patients with CLL who have not had favorable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

The efficacy of Venclexta was tested in a single-arm clinical trial of 106 patients with CLL who have a 17p deletion and who had received at least one prior therapy. Trial participants took Venclexta orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg. Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer.

Venclexta is indicated for daily use after detection of 17p deletion is confirmed through the use of the FDA-approved companion diagnostic Vysis CLL FISH probe kit.

The most common side effects of Venclexta include low white blood cell count (neutropenia), diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count (thrombocytopenia) and fatigue. Serious complications can include pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia and metabolic abnormalities known as tumor lysis syndrome. Live attenuated vaccines should not be given to patients taking Venclexta.

The FDA granted the Venclexta application breakthrough therapy designation, priority review status, and accelerated approval for this indication. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions. Venclexta also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Venclexta is manufactured by AbbVie Inc. of North Chicago, Illinois, and marketed by AbbVie and Genentech USA Inc. of South San Francisco, California. The Vysis CLL FISH probe kit is manufactured by Abbott Molecular of Des Plaines, Illinois.

FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion

Sun Pharma Receives FDA Approval For BromSite (bromfenac ophthalmic solution)

Sun Pharmaceutical Industries Ltd and includes its subsidiaries or associate companies) recently announced that one of its wholly owned subsidiaries has received approval from USFDA for its New Drug Application (NDA) related to BromSite™ (bromfenac ophthalmic solution) 0.075% for the treatment of postoperative inflammation and prevention of ocular pain in patients undergoing cataract surgery. BromSite™ is the first non-steroidal antiinflammatory drug (NSAID) approved by the USFDA to prevent pain and treat inflammation in the eye for patients undergoing cataract surgery; other NSAIDs in this class are currently indicated for the treatment of inflammation and reduction of pain.

BromSite™ developed by InSite Vision, is the first bromfenac ophthalmic solution formulated in DuraSite™, a polymer-based formulation that can be used to improve solubility, absorption, bioavailability, and residence time as compared to conventional topical therapies. Sun Pharma acquired InSite Vision in November 2015 and is likely to commercialize BromSite™ through its newly formed, US-based division, Sun Ophthalmics, in the second half of 2016. As per IMS MAT January 2016, the U.S. NSAID Ophthalmic market grew by 8%, generating approximately US$400mn in sales and about 4 million prescriptions, providing an attractive market for Sun Pharma to participate.

Sun Ophthalmics has crossed a key business milestone through BromSite’s approval. Sun Ophthalmics targets to provide eye care practitioners products that enhance their practice patterns and treatment options and to deliver those products through its unique, concierge level approach to customer care. With BromSite’s approval and additional late-stage candidates in its pipeline, Sun Ophthalmics is strongly positioned to offer a range of beneficial products and establish itself as a respected and trusted partner.

In two multi-center, randomized, placebo-controlled Phase-3 studies, a significantly higher proportion of BromSite treated patients were pain-free at Day 1 post-surgery (77% and 82%) compared to patients treated with vehicle control (48% and 62%) (p<0.001). Additionally, a significantly higher proportion of subjects administered BromSite™ were inflammation-free at day 15 post-cataract surgery (57% and 38%), compared to a vehicle control group (19% and 22%) (p<0.001 and p=0.035).

“Over the years, I’ve worked closely with the InSite team and watched them develop multiple high quality products using the DuraSite platform,” commented Dr. Richard L. Lindstrom, MD, founder and attending surgeon of Minnesota Eye Consultants and Adjunct Professor Emeritus at the University of Minnesota Department of Ophthalmology. “Today, I am pleased to see BromSite™ advance from development to market. I am confident there will be significant clinician interest in this new product. As the first NSAID labeled to prevent pain and reduce inflammation post-cataract surgery, BromSite’s approval is timely and will be welcomed by patients and clinicians alike.”

Sun Pharma Receives FDA Approval For BromSite (bromfenac ophthalmic solution)

Rapamycin drug could target neural damage linked to Leigh syndrome

In continuation of my update on rapamycin

Salk Institute scientists showed how an FDA-approved drug boosts the health of brain cells by limiting their energy use. Like removing unnecessary lighting from a financially strapped household to save on electricity bills, the drug--called rapamycin--prolongs the survival of diseased neurons by forcing them to reduce protein production to conserve cellular energy.

Rapamycin has been shown to extend lifespan and reduce symptoms in a broad range of diseases and, at the cellular level, is known to slow down the rate at which proteins are made. But the new Salk research, published in the journal eLife, suggests that rapamycin could also target the neural damage associated with Leigh syndrome, a rare genetic disease, and potentially other forms of neurodegeneration as well.

"Our study shows that protein production in neurons is one of the major utilizers of energy and that neurons of Leigh syndrome degenerate because they can't sustain a high enough level of energy," says Tony Hunter, the Renato Dulbecco Chair and American Cancer Society Professor in Salk's Molecular and Cell Biology Laboratory, who led the research.

Previous studies on rapamycin, which blocks a key energy sensor in cells, found that it can alter the immune system, extend lifespan and treat disorders, including lupus and Alzheimer's disease. Researchers assumed that the drug prevented the neurodegeneration seen in Alzheimer's by encouraging cells to degrade damaged components and aggregated proteins. But recent data hinted that the drug might also have an effect on the mitochondria, organelles that act as cells' powerhouses, producing energy in the form of adenosine triphosphate (ATP).

Xinde Zheng, a research associate in the Hunter lab, was already studying the properties of cells affected by Leigh syndrome, whose inherited neurodegeneration is caused by a mutation in mitochondrial DNA that reduces ATP production. Zheng wondered how rapamycin would affect the neurons plagued by the diseased mitochondria. He and Hunter teamed up with the lab of Rusty Gage, a professor in Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. Zheng, together with Leah Boyer, then a researcher in Gage's lab and now director of Salk's Stem Cell Core, generated diseased neurons by taking skin cells from patients with Leigh syndrome, reprogramming them into stem cells in culture and then coaxing them to develop into brain cells in a dish.

Though cells must make proteins to survive, protein production is a highly energy-consuming process and, for diseased cells, the process leaves too few energy reserves to deal with cellular stress or other demands.

"Reducing protein production in aging neurons allows more energy for the cell to put toward folding proteins correctly and handling stress," says Zheng, the first author of the new paper. "The impact of our finding is that modulation of protein synthesis could be a general approach to treating neurodegeneration."

In their study, the team found that Leigh Syndrome neurons decayed in the dish and showed clear signs of energy depletion. Meanwhile, Leigh syndrome neurons exposed to rapamycin had more ATP and showed less degeneration. By turning down the dial on protein production, the diseased and damaged neurons were able to survive longer.

"We are surprised and delighted that rapamycin's effect to reduce protein synthesis as an energy-austerity approach may lead to a potential treatment for mitochondria-related neurodegenerative diseases," says Gage.

This is a good example of the value of studying a disease in a dish, according to Hunter. "It's led to a lot of new insights into the underlying biology of this rare and understudied condition," he adds.

More work is needed to determine whether the findings on rapamycin hold true in animal models of Leigh syndrome and other neurodegenerative diseases, and to ascertain how exactly rapamycin is altering the metabolism of the cells.

Rapamycin drug could target neural damage linked to Leigh syndrome

Small doses of cancer drug may be potential treatment for sepsis and other pandemics

Results from laboratory experiments and mouse studies suggest that small doses of drugs from a specific class of approved cancer medications called topoisomerase 1 (top1) inhibitors may protect against the overwhelming immune response to infection that sometimes leads to sepsis, a bacterial condition that kills as many as 500,000 people in the United States each year. The research, supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), appears in the April 28, 2016 issue of Science.

Viral and bacterial infections can cause the human body to produce a massive inflammatory response leading to sepsis, which often results in tissue damage, organ failure and in some cases, death. Anyone with an infection can develop sepsis; however, people with weakened immune systems; babies and young children; the elderly; individuals with chronic illnesses, such as diabetes; and people with severe burns and wounds are at greatest risk. Viruses such as Ebola and novel influenza strains also can trigger similar and sometimes deadly immune responses. Treatments to dampen this over-exuberant inflammatory response without weakening the body's ability to fight infection are urgently needed, according to the authors.

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

In continuation of my update on Rimonabant

A new version of an obesity drug that caused serious psychiatric side effects could help people lose pounds without experiencing the anxiety, depression and suicidal thoughts previously associated with it. The research, published in Bioorganic and Medicinal Chemistry, shows that the new version of the drug can still work without reaching the brain in rats, avoiding the side effects.

The researchers behind the study, from RTI International in the US, say this means the new version of the drug could be used in the future for treating obesity. And their approach could also support the development of drugs to tackle liver disease, metabolic conditions and high blood cholesterol.

In our bodies we have cannabinoid receptors that control appetite, mood, memory and pain. The obesity drug Rimonabant stops these receptors from working. But the drug was found to have serious psychiatric side effects in a small number of the people who took it. Because of this, the drug was never approved in the US and manufacturer Sanofi-Aventis pulled from the European market voluntarily.

In the new study, the researchers altered the drug so it no longer gets into the brain, which stops it from having psychiatric side effects.

Study author Dr. Rangan Maitra, from RTI International in the US, explained: "There is a real need for new medicines to treat metabolic conditions like obesity. We are working with chemists to alter the drug Rimonabant and create compounds that cannot get into the brain. We hope this will help create drugs that can treat people with these conditions, without them having to suffer the side effects."

Dr. Maitra and colleagues modified the original Rimonabant compound by changing its weight, polarity and other properties to try to stop it from getting into the brain.

Tests in rats found that one of the versions, called 8c, blocks the target receptor and is much less likely than the original drug to get into the brain and affect the central nervous system.

The researchers found that 8c mostly stays in the blood and works on cannabinoid receptors found in parts of the body other than the brain. In comparison, more than half of the original drug Rimonabant entered the brain.

It's early days for the research, and the new version of the drug will need to go through testing before it can be used to treat people, but the researchers say it's a step in the right direction. Their study also outlines how scientists can test drugs designed to target cannabinoid receptors to make sure they are working outside the brain.

"Drug development is a long and arduous process," said Dr. George Amato, co-author of the study. "You have to develop hundreds, if not thousands, of compounds before you get the right one. The challenge is that some medicines that are absorbed in the gut also get into the brain. We set out to find compounds that absorb across the gut barrier but not the brain barrier. We've identified some, and they'll now serve as lead structures for further refinement."

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

Nuplazid (pimavanserin) tablets approved to treat hallucinations and delusions

In continuation of my update on Nuplazid (pimavanserin)

The U.S. Food and Drug Administration today approved Nuplazid (pimavanserin) tablets, the first drug approved to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson's disease.

Hallucinations or delusions can occur in as many as 50 percent of patients with Parkinson's disease at some time during the course of their illness. People who experience them see or hear things that are not there (hallucinations) and/or have false beliefs (delusions). The hallucinations and delusions experienced with Parkinson's disease are serious symptoms, and can lead to thinking and emotions that are so impaired that the people experiencing them may not relate to loved ones well or take appropriate care of themselves.

"Hallucinations and delusions can be profoundly disturbing and disabling," said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research. "Nuplazid represents an important treatment for people with Parkinson's disease who experience these symptoms."

An estimated 50,000 Americans are diagnosed with Parkinson's disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement -- like eating, writing and shaving. Early symptoms of the disease are subtle and occur gradually. In some people Parkinson's disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of people with Parkinson's disease, may begin to interfere with daily activities. Other symptoms may include depression and other emotional changes; hallucinations and delusions; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions.

The effectiveness of Nuplazid was shown in a six-week clinical trial of 199 participants. Nuplazid was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms of Parkinson's disease.

As with other atypical antipsychotic drugs, Nuplazid has a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs to treat older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.

In clinical trials, the most common side effects reported by participants taking Nuplazid were: swelling, usually of the ankles, legs, and feet due to the accumulation of excessive fluid in the tissue (peripheral edema); nausea; and abnormal state of mind (confused state).

Nuplazid was granted breakthrough therapy designation for the treatment of hallucinations and delusions associated with Parkinson's disease. Breakthrough therapy designation is a program designed to expedite the development and review of drugs that are intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. The drug was also granted a priority review. The FDA's priority review program provides for an expedited review of drugs that offer a significant improvement in the safety or effectiveness for the treatment, prevention, or diagnosis of a serious condition.

Nuplazid (pimavanserin) tablets approved to treat hallucinations and delusions

Drinking tea flavored with herbs may improve mood and memory

  Chamomile      Rosemary 

 Peppermint

The herbs peppermint, chamomile, rosemary and lavender have been proven to have an impact on mood and memory, with significant benefits displayed for older people, according to new research from Northumbria University.

Researchers from the University's Department of Psychology have found that drinking peppermint tea improves alertness, while chamomile tea has a calming effect. They also found that smelling the aromas of rosemary and lavender impacted on memory in people over 65, with the scent of rosemary enhancing their memory, while lavender impaired it.

The findings have been presented at the annual British Psychological Society Conference in Nottingham this week (26-28 April 2016).

In one study, the researchers asked 180 volunteers to consume either a chamomile or peppermint tea drink and tested their cognition and mood before and after drinking. A control group drank hot water for comparison.

They found that peppermint enhanced and aroused both mood and cognition, helping to improve long term memory, working memory and alertness, while chamomile had a calming and sedative effect which significantly slowed memory and attention speed.

In a separate study, 150 healthy people aged 65 and over were placed in rooms which had been scented with rosemary and lavender essential oils, or a control room which had no scent. They were asked to undertake tests that assessed their prospective memory - the ability to remember to do something at a given time, such as taking medication, or after receiving a prompt, such as posting a letter after seeing a post box. They also completed a mood assessment test.

Those who had been in the rosemary scented room displayed significantly enhanced prospective memory, with test scores 15% higher than those who had been in the room with no aroma. They were also more alert.

In contrast, those who had spent time in the lavender scented room displayed significantly increased calmness and contentedness, with a decrease in their ability to remember to do something at a given time.

Dr Mark Moss, Head of the Department of Psychology, said: "Peppermint has a reputation for being psychologically or mentally alerting. It picks you up and makes you feel a little bit brighter, so we endeavoured to test this out by giving people peppermint tea, or chamomile tea, which is a more calming drink and then put them through some computerised tests. We found that those people who had drunk the peppermint tea had better long-term memory. They were able to remember more words and pictures that they had seen. In contrast, the people who had the chamomile were slower in responding to tasks.

"Rosemary meanwhile has a reputation about being associated with memory - even Shakespeare said 'rosemary is for remembrance' - and it's also associated with being invigorating. We have found that people are more alert after being in a room that has rosemary aroma in it. We tested prospective memory - our ability to remember to remember to do something - on people over 65 years of age, to see if we could improve their ability and we found that rosemary could do that. This is potentially very important because prospective memory, for example, enables you to remember to take your medication at certain times of the day.

Drinking tea flavored with herbs may improve mood and memory

Janssen gets positive CHMP opinion for IMBRUVICA (ibrutinib) to treat patients with previously untreated CLL

Recommendation based on RESONATE™-2 trial which showed IMBRUVICA significantly improved progression-free survival and prolonged overall survival versus chlorambucil.

Janssen-Cilag International NV today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a Positive Opinion, recommending broadening the existing marketing authorisation for ibrutinib as a single agent for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Ibrutinib is approved for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), or adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation (genetic mutations typically associated with poor treatment outcomes) in patients unsuitable for chemo-immunotherapy and in adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.

 Ibrutinib

The Positive Opinion of the CHMP was based on data from the Phase 3, randomised, open-label RESONATE™-2 (PCYC-1115) clinical trial, as recently published in The New England Journal of Medicine (NEJM). Findings showed ibrutinib provided a significant improvement in all efficacy endpoints versus chlorambucil in patients aged 65 or older with newly diagnosed CLL. The progression-free survival (PFS) rate at 18 months was 90 percent for ibrutinib versus 52 percent for chlorambucil. Ibrutinib also significantly prolonged overall survival (OS) (HR=0.16 percent CI, 0.05, 0.56; P=0.001), with a 24-month survival rate of 98 percent, compared to 85 percent for patients in the chlorambucil arm. The safety of ibrutinib in the treatment-naïve CLL patient population was consistent with previously reported studies.2 The most common adverse reactions (ARs) (≥20 percent) of any Grade in the RESONATE-2 trial for ibrutinib were diarrhoea (42 percent), fatigue (30 percent), cough (22 percent) and nausea (22 percent).

CLL is a chronic disease, and the prevalence rate in Europe among men and women is approximately 5.87 and 4.01 cases per 100,000 persons per year, respectively. Median overall survival ranges between 18 months and more than 10 years according to the stage of disease. 

“Janssen is proud to be leading the charge with our ongoing efforts to transform the treatment experience for patients with difficult to treat blood cancers, such as CLL,” said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. “Ibrutinib continues to demonstrate impressive clinical results, and the data on which this recommendation is based once again highlight its potential to deliver improved patient outcomes for suitable patients.”

This regulatory milestone follows the decision by the U.S. Food and Drug Administration on 04 March 2016, to approve the expanded use of ibrutinib capsules for treatment-naïve patients with CLL.

Janssen gets positive CHMP opinion for IMBRUVICA (ibrutinib) to treat patients with previously untreated CLL