Cancer drug can neutralize toxic RNA that causes myotonic dystrophy

A group of researchers has shown for the first time in cells and in a mouse model that a drug used to treat cancer can neutralize the toxic RNA that causes the prolonged muscle contractions and other symptoms of myotonic dystrophy type 1, the most common form of adult-onset muscular dystrophy. The researchers report their findings today Dec. 10, 2015 in the journal Cell Reports. (actinomycin-D)

"This finding opens a new avenue for a therapeutic strategy for this disease," said Andrew Berglund, Ph.D., a professor of biochemistry and molecular biology in the University of Florida College of Medicine. "This is the first evidence that specifically inhibiting transcription can be effective in knocking down the toxic material that causes the disease."

In myotonic dystrophy and other related neurological disorders, the symptoms stem from repeated individual nucleotides, or "building blocks," in the RNA in muscle tissue cells that can build up over time. These repeats, called CTG expansions in myotonic dystrophy type 1, become 'toxic' when transcribed from DNA. The expansions disrupt the RNA binding proteins responsible for splicing, the 'editing' needed so that the RNA can create appropriate proteins that allow muscles to function properly.

Cancer drug can neutralize toxic RNA that causes myotonic dystrophy

Tetra begins human Phase 1 safety trials of BPN14770

Tetra Discovery Partners ("Tetra") today announced that the company has initiated human Phase 1 safety trials of its lead compound BPN14770, which Tetra is developing as a potential treatment to both improve memory and slow the progression of Alzheimer's disease.

"There is a rapidly rising need for improved therapies for Alzheimer's disease. BPN14770 offers a novel approach that intervenes in important neural pathways related to learning and memory storage that underlie daily cognitive function in patients with Alzheimer's disease," said Mark Gurney, Ph.D., chairman and chief executive officer of Tetra. "Tetra Discovery has begun an initial human safety study with the compound in healthy volunteers, and expects to expand this to initial explorations of the compound benefit for cognition during 2016."

Tetra's Phase I clinical trials are designed to first evaluate BPN14770 in a single ascending dose study (SAD) to assess the safety, tolerability and pharmacokinetics in 48 healthy human volunteers. Endpoints for the study are safety, tolerability, and pharmacokinetics. Afterward, a multiple ascending dose (MAD) study will take place, enrolling young and elderly subjects to provide preliminary efficacy assessment of BPN14770 on long-term memory and other cognitive processes.

BPN14770 was developed through a cooperative research agreement with the National Institutes of Health (NIH) Blueprint Neurotherapeutics Network. "Tetra benefited greatly from the deep industry experience and commitment of NIH Blueprint consultants, CROs, and staff, the National Institute of Neurological Disorders & Stroke (NINDS) and the National Institute of Aging (NIA). The cooperative research program was milestone driven with a rigorous focus on meeting pharmaceutical industry metrics for CNS drug quality and safety. BPN14770 has shown efficacy in multiple animal models of learning and memory with an excellent safety margin for human clinical trials," commented Dr. Gurney.

Tetra begins human Phase 1 safety trials of BPN14770

New class of diabetes drugs differs in efficacy and safety profiles, shows new research

Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) differ in their efficacy and safety profiles, according to new research by the University of Leicester.

Compared to other once-weekly GLP-1RAs which are licensed and available, dulaglutide 1.5mg and once weekly exenatide showed the greatest reduction of HbA1c and fasting plasma glucose.

GLP-1RAs are a relatively new class of drugs that stimulate insulin and inhibit glucagon secretion, slow gastric emptying, and reduce food intake. While the first approved GLP-1RAs are administered as subcutaneous daily injections, more recently GLP-1RAs available via once-weekly administration have emerged, reducing the number of injections and side effects and potentially improving patient compliance.

In clinical studies, these drugs improve glucose control and reduce body weight, without an increased risk for hypoglycaemia. To date, however, no direct comparisons between once-weekly GLP-1RAs are available.

The research – carried out by the university’s Diabetes Research Centre, which is based at the Leicester Diabetes Centre – used an innovative method to evaluate the efficacy and adverse effects of once-weekly GLP-1RAs in adults with Type 2 diabetes.

Researcher Dr Francesco Zaccardi and colleagues conducted a network meta-analysis of randomised trials. In the absence of direct evidence, network meta-analysis is an increasingly used statistical methodology that allows the estimation of the comparative effectiveness of multiple treatments.

Dr Zaccardi concluded:

Compared to other available once-weekly GLP-1RAs, dulaglutide 1.5mg and once weekly exenatide showed a greater reduction of HbA1c and fasting plasma glucose. The risk of hypoglycaemia among once-weekly GLP-1RAs was comparable. Taspoglutide, one of the agents evaluated, has already been withdrawn from the market for high rates of nausea, and this has been confirmed in the meta-analysis.

New class of diabetes drugs differs in efficacy and safety profiles, shows new research

Palbociclib and paclitaxel combination shrinks tumors in patient with ER positive breast cancer

Combining the new breast cancer drug palbociclib with paclitaxel (Taxol) shrank tumors in nearly half of patient with estrogen-receptor (ER) positive breast cancer, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The results will be presented Saturday at the 2015 San Antonio Breast Cancer Symposium (Abstract P6-13-08). A second study (Abstract P4-13-04), to be presented Friday provides new clues to how breast cancer develops resistance to the palbociclib, a common occurrence among many patients who take the drug.

"Results of the first study found that palbociclib and paclitaxel can be safely combined on an alternating dosing schedule," said Angela DeMichele, MD, MSCE, the Alan and Jill Miller Associate Professor in Breast Cancer Excellence in Penn's Abramson Cancer Center, and senior author on the study. "The high response rate we saw suggests this combination may hold benefits for patients over paclitaxel alone. Based on these results, a larger clinical trial to determine the benefits is warranted."

A Complementary Therapy

Palbociclib targets the rapid division of tumor cells by inhibiting the activity of the enzymes CDK4 and CDK6, which help drive cell division and are upregulated in most cancers. The researchers suspected that palbociclib's unique mechanism of action may make it a good partner for other breast cancer drugs such as paclitaxel, which kills dividing cells at a certain point in the cell division process (also known as the "cell cycle"). Palbociclib effectively halts the cell cycle before that point, and thus in principle can synchronize cancer cells in a way that makes them more vulnerable to a closely following dose of paclitaxel.

Palbociclib and paclitaxel combination shrinks tumors in patient with ER positive breast cancer

New three-drug delivery system shows promise for treatment of metastatic melanoma

Researchers have developed a new three-drug delivery system for cancer treatment, especially metastatic melanoma, the deadliest form of skin cancer - and shown that the system may have particular value with cancers like this that often spread through the lymphatic system.

The new technology takes advantage of nanoparticles that can migrate to, and increase the effectiveness of an attack on cancer cells in the body's lymph nodes. This can also reduce the development of drug resistance and the broader toxicity often associated with this type of chemotherapy.

The findings were made with laboratory animals, and just published in the Journal of Controlled Release by researchers from the College of Pharmacy at Oregon State University. The work was supported by an OSU startup fund, and a provisional patent has been granted for this technology.

"Melanoma can be a very difficult cancer to treat because it often metastasizes and travels through the lymphatic system," said Adam Alani, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author on this research.

"Melanoma has a high mortality rate because the lymph nodes tend to act as a haven for cancer cells, and allow them to resist treatment through chemotherapy," he said.

New three-drug delivery system shows promise for treatment of metastatic melanoma

Ibrutinib more effective than traditional chemotherapy in older untreated patients with CLL

In continuation of my update on ibrutinib

A multi-center, international, randomized, Phase III study of older untreated patients with chronic lymphocytic leukemia (CLL) demonstrated that ibrutinib, a kinase inhibitor, is significantly more effective than traditional chemotherapy with chlorambucil.

The study, which followed 269 patients, revealed a 24-month overall survival rate of 97.8 percent for patients taking ibrutinib versus 85.3 percent for those on chlorambucil. Minor adverse effects were reported.

Results from the study, led by Jan Burger, M.D., Ph.D. from The University of Texas MD Anderson Cancer Center, were published in today's online issue of the New England Journal of Medicine.

"Ibrutinib was superior to chlorambucil in CLL patients with no prior treatment, as measured by progression-free survival, overall survival, and response" said Burger, an associate professor in Leukemia. "The study also revealed significant improvements in hemoglobin and platelet levels."

Ibrutinib more effective than traditional chemotherapy in older untreated patients with CLL

XARELTO reduces rates of major bleeding, recurrent blood clots in people with deep vein thrombosis

In continuation of my update on rivaroxaban

Janssen Pharmaceuticals, Inc. (Janssen) and its development partner, Bayer HealthCare, today announced the results from their real-world study XALIA showing that, in people with deep vein thrombosis (DVT), the rates of major bleeding and recurrent blood clots for XARELTO® (rivaroxaban) in routine clinical practice were generally consistent with those observed in Phase 3 research. Patients taking XARELTO® also had shorter length of hospital stays than those given standard anticoagulation. The prospective study was presented at the 2015 American Society of Hematology (ASH) Annual Meeting and simultaneously published in Lancet Hematology.

"On average, every 37 seconds someone in the Western world dies from a venous blood clot, so it is important we understand the effectiveness and safety of available treatment options for these potentially life-threatening blood clots," said XALIA principal investigator Professor Alexander G. G. Turpie, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. "The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the Phase 3 EINSTEIN-DVT study, signalling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice."

XALIA – which included approximately 5,000 patients from 21 countries – evaluated the safety and effectiveness of XARELTO®, taken once daily, for the treatment of DVT in routine clinical practice as compared to standard anticoagulation. The primary outcome was the incidence of adverse events (major bleeding, recurrent blood clots and all-cause mortality). Healthcare resource utilization, including length of stay, also was evaluated. A propensity score analysis was completed to address differences in baseline characteristics and help correct any selection bias. Methodological and other differences between the studies limit the ability to directly compare results of XALIA to the pivotal Phase 3 EINSTEIN-DVT study, which was used by regulatory authorities worldwide to approve XARELTO®.

XARELTO reduces rates of major bleeding, recurrent blood clots in people with deep vein thrombosis

American scientists synthesize glycopolymers that prolong lifetime of healthy cells

Glycoproteins such as the mucins are assumed to be heavily involved in oncogenesis and metastasic spread. They are part of a strategy developed by malignant cells to resist or dodge the cell death machinery specialized for cells that show insufficient signaling through adhesions. Developing models for the mucins is very challenging, but American scientists have now synthesized glycopolymers that are not only recycled in the membrane, but also prolong the lifetime of healthy cells, as described in the journal Angewandte Chemie.

Glycosylated proteins like the mucins are regarded as responsible for promoting the survival mechanisms of malignant cells by segregating certain signaling proteins in the membrane. A major obstacle to studying this mechanism in detail has long been the lack of suitable model compounds that mimic the mucin functions. The group of Carolyn R. Bertozzi at Stanford University, CA, has now found a way to prepare such model compounds: They synthesize glycosylated polymers with lipid anchors that are readily inserted in the plasma membrane, but, thanks to further attachment of the polymer to a sterol compound, they are not degraded after ingestion in the cell, as the authors explain: "Cholesterylamine, a lipid known to recycle back to the cell surface after internalization, is capable of shuttling glycopolymers through this pathway continuously for up to ten days, resulting in the persistent display of glycopolymers on the plasma membrane." And, interestingly, the glycopolymers are not only persistent on the plasma membrane, they are also inherited in the dividing cells, as the authors say:

American scientists synthesize glycopolymers that prolong lifetime of healthy cells

Helsinn one step closer to bringing anamorelin HCI to market for treatment of anorexia, cachexia in NSCLC patients

Helsinn, the Swiss pharmaceutical Group focused on building quality cancer care, today announced that the European Medicines Agency (EMA) accepted for review, the marketing authorization application (MAA) for anamorelin HCI, a novel, orally active selective ghrelin receptor agonist under development for the treatment of anorexia, cachexia, or unintended weight loss in non-small cell lung cancer (NSCLC) patients.

Riccardo Braglia, Chief Executive Officer of Helsinn Group commented, "With this EMA submission, we are one step closer to bringing this new and potentially effective treatment to market, meaning that the quality of life for patients with non-small cell lung cancer who suffer from anorexia, cachexia, could soon improve. Anamorelin is part of our pipeline of products dedicated to cancer supportive care, all of which address areas of significant unmet medical need."

Helsinn one step closer to bringing anamorelin HCI to market for treatment of anorexia, cachexia in NSCLC patients

Innovative compound with anti-MRSA qualities may help develop new class of antibiotics

With global health services increasingly worried about the rise of antibiotic resistant diseases, researchers at Maynooth University have discovered a compound whose anti-MRSA qualities pave the way for the development of a new class of antibiotics. The new research is published today in the internationally renowned journalBioorganic and Medicinal Chemistry Letters. The findings mark the culmination of three years of work on the part of the team led by Dr John Stephens, Maynooth University Department of Chemistry, in collaboration with Dr Kevin Kavanagh, Maynooth University Department of Biology.

According to recent studies, on any given day one in 18 hospitalised patients are suffering from healthcare associated infections, with MRSA and E. coli responsible for 64% of cases. Doctors struggling with these infections are confronted with the increased prevalence of antibiotic resistant strains, but this represents only part of the problem. Of the antibiotics used today, almost all of them belong to classes discovered before the 1980s and this research was motivated by the urgent need to identify and synthesise new antibiotic classes.

Commenting on this discovery, Dr John Stephens observes:

As today’s infections develop increasing resistance to the antibiotics of the past, there is an urgent need for researchers to develop new therapeutics. Without this action, we are seriously at risk of entering a post-antibiotic world where common and traditionally minor infections could once again prove fatal. Discovering the antibacterial properties of our lead compound, the highly active quinoline thiourea, at Maynooth University is a significant first step. With further research and development, it has the potential to pave the way for a new class of antibiotic.

Ref : http://www.sciencedirect.com/science/article/pii/S0960894X15302663

Innovative compound with anti-MRSA qualities may help develop new class of antibiotics

Novel class of antimicrobials could be effective in fighting drug-resistant MRSA infection

A novel class of antimicrobials that inhibits the function of a key disease-causing component of bacteria could be effective in fighting methicillin-resistant Staphylococcus aureus (MRSA), one of the major drug-resistant bacterial pathogens, according to researchers at Georgia State University.

Their study showed that small molecule analogs that target the functions of SecA, a central part of the general bacterial secretion system required for viability and virulence, have potent antimicrobial activities, reduce the secretion of toxins and can overcome the effect of efflux pumps, which are responsible for multi-drug resistance.

Their findings indicate that targeting SecA is an attractive antimicrobial strategy against MRSA and may be several times more effective than the antibiotics now available for treating the infection.

MRSA causes serious hospital and community-acquired infections. Healthcare-associated MRSA infections are typically linked to invasive procedures or devices, such as surgeries, intravenous tubing or artificial joints. Community-acquired MRSA often begins as a skin boil and is spread by skin-to-skin contact. Individuals at risk include competitive wrestlers, child care workers and those living in crowded conditions.

"We've found that SecA inhibitors are broad-spectrum antimicrobials and are very effective against strains of bacteria that are resistant to existing antibiotics," said Binghe Wang, Regents' Professor of Chemistry at Georgia State, Georgia Research Alliance Eminent Scholar in Drug Discovery and Georgia Cancer Coalition Distinguished Cancer Scholar. He co-led the study with Phang C. Tai, Regents' Professor of Biology at Georgia State, who is an expert on the functions of SecA in bacteria. Their findings were published in the journal Bioorganic & Medicinal Chemistry in November.

Novel class of antimicrobials could be effective in fighting drug-resistant MRSA infection

Lexicon announces top-line results from TELECAST Phase 3 study of telotristat etiprate

Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX) announced today that top-line data from its TELECAST Phase 3 study showed results of telotristat etiprate in treating carcinoid syndrome in cancer patients with metastatic neuroendocrine tumors consistent with the clinical benefit observed in its pivotal TELESTAR study. The TELECAST study was designed as a companion to TELESTAR primarily to provide additional safety exposure while further evaluating telotristat etiprate's activity in carcinoid syndrome. TELECAST mostly enrolled patients treated with somatostatin analog (SSA) therapy, the current standard of care, with carcinoid syndrome characterized by less severe bowel movement frequency than those patients in the TELESTAR study, together with a smaller number of carcinoid syndrome patients not treated with SSA therapy.

Telotristat etiprate met the study's primary efficacy endpoint, the percent change from baseline in urinary 5-hydroxyindoleacetic acid (5-HIAA, the main metabolite of serotonin) at week 12, the final week of the double-blind treatment portion of the study (p<0.001 for both dose arms compared to placebo). In addition, despite the lower baseline bowel movement frequency than in TELESTAR, telotristat etiprate achieved statistically significant reductions in daily bowel movement frequency over the 12 weeks of the study (p=0.004 for the 250 mg dose arm and p<0.001 for the 500 mg dose arm compared to placebo). Safety and tolerability was one of the primary objectives of the TELECAST study, and telotristat etiprate was well tolerated during the double-blind treatment period, with profiles similar to placebo for both the 250 mg and 500 mg dose arms and no overall differences observed in gastrointestinal disorders or psychiatric disorders, including changes in mood.

"We are very pleased with the efficacy and safety results of telotristat etiprate in this study, notably including evidence of benefit in a patient population whose bowel movement frequency was lower at baseline than was the case in TELESTAR," said Lexicon Executive Vice President and Chief Medical Officer Pablo Lapuerta, M.D. "TELECAST was intended to complement our pivotal Phase 3 trial, TELESTAR. We now have experience in more than 200 patients with carcinoid syndrome, with TELECAST contributing consistent efficacy data and favorable safety results. The data further support that the compound is acting directly on the cause of carcinoid syndrome, by reducing serotonin production within tumor cells."

Lexicon announces top-line results from TELECAST Phase 3 study of telotristat etiprate

Seaweed extract shows promise in treating H. pylori-related diseases, gastric cancer

Effective treatments for H. pylori are limited with a rising percentage of treatment failures, primarily due to antibiotic resistance. Alternative and additional treatment options are widely recognised as a significant global healthcare issue. Results from this latest study show that fucoidan, a sulphated polysaccharide found in brown seaweed, may offer a solution.

The study took place at the University of Western Australia in the laboratories of Nobel Prize Laureate Professor Barry Marshall, who is recognised for his discovery of H. pylori and its role in gastritis and peptic ulcer disease. The research involved testing fucoidan extracts derived from the Fucus vesiculosus and Undaria pinnatifida species of brown seaweed. These certified organic, high-purity extracts were developed and produced by Australian biotechnology company, Marinova Pty Ltd.

The in vitro studies showed fucoidan extracts are extremely effective at dislodging H. pylori from infected human stomach cancer cells. This significant result positions fucoidan as a potential alternative to the increasingly inadequate antibiotic treatments.

Dr Alfred Chin-Yen Tay, Research Associate at The Marshall Centre for Infectious Diseases who supervised the study, said:

These research findings are an encouraging step forward in the control of H. pylori-related diseases. Fucoidan is a natural extract and oral delivery to the stomach is simple. It would be a welcome option for suffering patients, especially before having to undergo invasive diagnosis and treatment options.

Seaweed extract shows promise in treating H. pylori-related diseases, gastric cancer

Second-line bosutinib offers ‘durable’ response for chronic phase CML patients

In continuation of my update on bosutinib

Four-year results for an ongoing study of second-line bosutinib indicate that the tyrosine kinase inhibitor (TKI) offers long-term efficacy with manageable side effects for patients with chronic phase chronic myeloid leukaemia (CP CML).

“Overall, these findings highlight the therapeutic potential of bosutinib as second-line therapy in IM-R [imatinib resistant] or IM-I [imatinib intolerant] CP CML patients”, say Tim Brümmendorf (Universitätsklinikum der RWTH Aachen, Germany) and co-investigators.

In the phase I/II trial, bosutinib 500 mg/day was given for a median of 24.8 months to 196 IM-R and 90 IM-I patients; 59% of 264 evaluable patients achieved or maintained a major cytogenetic response (MCyR) for at least 4 weeks, including 59% of the IM-R and 61% of the IM-I groups.

Of the 248 patients without a complete cytogenetic response (CCyR) at baseline, 57% achieved a MCyR and 47% a CCyR during bosutinib therapy. And 14 of the 16 patients with a baseline CCyR maintained this response for between 12 and 288 weeks; two discontinued bosutinib because of adverse events (AEs) and were not reassessed.

The median times to MCyR and CCyR were 12.3 and 24.0 weeks, respectively.

The 4-year cumulative incidences of MCyR and CCyR, at 59% and 49%, respectively, were similar to the previously reported 2-year figures of 59% and 48%, prompting the authors to suggest that “most initial responses occur within 2 years from bosutinib treatment initiation.”

The rate of cumulative progression or death during treatment was an estimated 19% at 4 years.

The Kaplan–Meier-estimated probability of maintaining MCyR at 4 years was found to be high for the whole population and the IM-R and IM-I groups, at 74.5%, 69.3% and 86.3%, respectively, and the median duration of this response had not yet been reached.

Second-line bosutinib offers ‘durable’ response for chronic phase CML patients

New data shows ALS-008176 drug safe and effective against RSV infection

Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies announced that the New England Journal of Medicine (NEJM) will publish findings from a respiratory syncytial virus (RSV) challenge study for ALS-008176, a cytidine nucleoside analog with activity against RSV. Among infants and young children, RSV is the leading cause of severe respiratory illness and remains the most frequent cause of hospitalization in industrialized countries. This Phase 2a study has now established human proof-of-concept for the antiviral activity of ALS-008176 in healthy adults and highlights its potential as a therapy for managing clinical disease in naturally infected patients.

“The data suggest that ALS-008176 has the potential to be a safe and effective treatment for RSV infection. The primary endpoint of the study was met and ALS-008176 significantly reduced viral load and symptoms of disease severity compared to placebo,” said John DeVincenzo, M.D., the lead study author and Professor of Pediatrics, and Professor of Microbiology, Immunology and Biochemistry at the University of Tennessee Health Science Center, and Medical Director of Molecular and Viral Diagnostics at Le Bonheur Children's Hospital. “ALS-008176 can inhibit the replication of RSV even if the cells of the respiratory tract have already been infected with the virus. As a result, this treatment has an antiviral effect and is likely to be effective even if started at a later stage of RSV infection.”

In this randomized, double-blind study, 62 healthy volunteers were inoculated with RSV and subsequently randomized to receive ALS-008176 or placebo. Compared to placebo, treatment with ALS-00876 resulted in a significant reduction of viral load (73-88% reduction in viral load area under the curve) and faster viral clearance (1.3–2.3 days vs 7.2 days) versus placebo. At the time that the peak viral load occurred in the placebo group, the mean viral load in each of the three ALS-007186 treatment groups was more than one thousand times lower. In addition, statistically significant reductions in symptom scores and a reduction of the amount of congesting respiratory secretions were also observed.

New data shows ALS-008176 drug safe and effective against RSV infection