Pfizer Announces FDA Approval of Xeljanz (tofacitinib) and Xeljanz XR for the Treatment of Active Psoriatic Arthritis

In continuation of my update on tofacitinib 

Pfizer Inc.  announced that the United States Food and Drug Administration (FDA) has approved Xeljanz 5 mg twice daily (BID) and Xeljanz XR (tofacitinib) extended release 11 mg once daily (QD) for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). Xeljanz/Xeljanz XR is the first and only Janus kinase (JAK) inhibitor approved by the FDA for both moderate to severe rheumatoid arthritis (RA) and active PsA.

“Psoriatic arthritis is a complex and progressive disease with an unpredictable course,” said Angela Hwang, Global President, Inflammation and Immunology, Pfizer. “The approval of Xeljanz is an important step forward for patients seeking new treatments and is a testament to Pfizer’s unwavering commitment to advancing patient care.”

The recommended dose of Xeljanz/Xeljanz XR is in combination with nonbiologic DMARDs, and use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

The FDA approval of Xeljanz for the treatment of adult patients with active PsA was based on data from the Phase 3 Oral Psoriatic Arthritis Trial (OPAL) clinical development program, which consisted of two pivotal studies, OPAL Broaden and OPAL Beyond, as well as available data from an ongoing long-term extension trial, OPAL Balance. The findings from OPAL Broaden and OPAL Beyond were published in October 2017 in the New England Journal of Medicine.

Both pivotal studies met their two primary efficacy endpoints, demonstrating statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI) score at three months in patients receiving Xeljanz 5 mg BID treatment in combination with a nonbiologic DMARD, compared to those treated with placebo. In OPAL Broaden, 50% of patients taking Xeljanz 5 mg BID achieved an ACR20 response, compared to 33% of patients taking placebo (p≤0.05), at three months. In OPAL Beyond, 50% of patients achieved an ACR20 response with Xeljanz 5 mg BID, compared to 24% of patients taking placebo (p≤0.05), at three months. In both studies, statistically significant improvements in ACR20 response was also seen with Xeljanz 5 mg BID compared to placebo at week 2, a secondary endpoint and the first post-baseline assessment (OPAL Broaden: 22% and 6% [p=0.0003], respectively; OPAL Beyond: 27% and 13% [p=0.0046], respectively).

“As a practicing rheumatologist, I’ve seen the significant physical impact psoriatic arthritis has on people living with the disease, and many patients are looking for additional therapeutic options,” said Philip Mease, M.D., Swedish Medical Center, University of Washington and study investigator. “I’m pleased that Xeljanz is now available for use in the treatment of this chronic condition.”

The safety profile observed in patients with active psoriatic arthritis treated with Xeljanz was consistent with the safety profile observed in rheumatoid arthritis patients. The most common adverse events observed occurring in greater than 3% of patients on Xeljanz 5 mg BID were nasopharyngitis, upper respiratory tract infection, headache and diarrhea.

“Psoriatic arthritis is a serious and debilitating chronic illness that should be diagnosed and treated early,” said Randy Beranek, president and CEO, National Psoriasis Foundation. “As an organization that advocates for people living with psoriatic arthritis, we welcome the availability of new therapies for treating this disease.”

Pfizer Announces FDA Approval of Xeljanz (tofacitinib) and Xeljanz XR for the Treatment of Active Psoriatic Arthritis

Diabetes drug holds promise of being developed into new treatment for Alzheimer's

A drug developed for diabetes could be used to treat Alzheimer's after scientists found it "significantly reversed memory loss" in mice through a triple method of action.

The research, published in Brain Research, could bring substantial improvements in the treatment of Alzheimer's disease through the use of a drug originally created to treat type 2 diabetes.

Lead researcher Professor Christian Holscher of Lancaster University in the UK said the novel treatment "holds clear promise of being developed into a new treatment for chronic neurodegenerative disorders such as Alzheimer's disease."

Alzheimer's disease is the most common cause of dementia and the numbers are expected to rise to two million people in the UK by 2051 according to Alzheimer's Society, who part- funded the research.

Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: ""With no new treatments in nearly 15 years, we need to find new ways of tackling Alzheimer's. It's imperative that we explore whether drugs developed to treat other conditions can benefit people with Alzheimer's and other forms of dementia. This approach to research could make it much quicker to get promising new drugs to the people who need them."

Although the benefits of these 'triple agonist' drugs have so far only been found in mice, other studies with existing diabetes drugs such as liraglutide have shown real promise for people with Alzheimer's, so further development of this work is crucial."

This is the first time that a triple receptor drug has been used which acts in multiple ways to protect the brain from degeneration. It combines GLP-1, GIP and Glucagon which are all growth factors. Problems with growth factor signaling have been shown to be impaired in the brains of Alzheimer's patients.

The study used APP/PS1 mice, which are transgenic mice that express human mutated genes that cause Alzheimer's. Those genes have been found in people who have a form of Alzheimer's that can be inherited. Aged transgenic mice in the advanced stages of neurodegeneration were treated.

In a maze test, learning and memory formation were much improved by the drug which also:-

• enhanced levels of a brain growth factor which protects nerve cell functioning
• reduced the amount of amyloid plaques in the brain linked with Alzheimer's
• reduced both chronic inflammation and oxidative stress
• slowed down the rate of nerve cell loss

Professor Holscher said: "These very promising outcomes demonstrate the efficacy of these novel multiple receptor drugs that originally were developed to treat type 2 diabetes but have shown consistent neuro- protective effects in several studies."

"Clinical studies with an older version of this drug type already showed very promising results in people with Alzheimer's disease or with mood disorders"

"Here we show that a novel triple receptor drug shows promise as a potential treatment for Alzheimer's but further dose-response tests and direct comparisons with other drugs have to be conducted in order to evaluate if this new drugs is superior to previous ones."

Type 2 diabetes is a risk factor for Alzheimer's and has been implicated in the progression of the disease. Impaired insulin has been linked to cerebral degenerative processes in type 2 diabetes and Alzheimer's disease. Insulin desensitisation has also been observed in the Alzheimer's disease brain. The desensitisation could play a role in the development of neurodegenerative disorders as insulin is a growth factor with neuroprotective properties.

Ref : http://www.research.lancs.ac.uk/portal/en/publications/-(ccd64550-72ab-4d4b-9e42-986da99f7b36).html

Diabetes drug holds promise of being developed into new treatment for Alzheimer's

CutisPharma Announces FDA Approval of Firvanq (vancomycin) for Treatment of Clostridium Difficile Associated Diarrhea and Staphylococcus Aureus Colitis

In continuation of my update on Firvanq

CutisPharma announced that the US Food and Drug Administration (FDA) has approved Firvanq (vancomycin hydrochloride) for oral solution, for the treatment of Clostridium difficile associated diarrhea and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains.

“We are pleased to announce the FDA approval of Firvanq,” said Neal I. Muni, MD, MSPH, Chief Executive Officer of CutisPharma. “Firvanq's approval is an important step forward to providing patients the only FDA-approved vancomycin oral liquid treatment option for Clostridium difficile associated diarrhea, a life-threatening condition that affects over a half-million patients in the United States annually.”

Upon its launch, which is targeted to be April 2, 2018, Firvanq will replace CutisPharma’s FIRST®-Vancomycin Unit-of-Use Compounding Kit, which has been available to pharmacists that need a convenient, accurate, and compliant way to compound vancomycin oral liquid therapy. Firvanq will be commercially available in 25 mg/mL and 50 mg/mL strengths in convenient 150 mL and 300 mL sizes. Firvanq is designed to be easy to use and has the potential to be a cost-effective alternative to existing vancomycin therapies.

“As a practicing infectious disease physician treating many patients with CDAD, having an FDA-approved vancomycin oral liquid formulation that is affordable and accessible to my patients is very beneficial,” said Stuart Johnson, MD, Loyola University Medical Center. “Patient access is currently limited by the fact that only a select few pharmacies perform compounding in the outpatient setting these days, given the many new regulations in place. Availability of an FDA-approved vancomycin oral liquid treatment will effectively allow any pharmacy to stock this therapy, and hopefully encourage third-party payer reimbursement, significantly improving accessibility and convenience for patients.”

Ref : https://www.drugs.com/history/firvanq.html

CutisPharma Announces FDA Approval of Firvanq (vancomycin) for Treatment of Clostridium Difficile Associated Diarrhea and Staphylococcus Aureus Colitis

FDA Approves Lynparza (olaparib tablets) for Germline BRCA-Mutated Metastatic Breast Cancer

In continuation of my update on  Lynparza (olaparib tablets)

The U.S. Food and Drug Administration today expanded the approved use of Lynparza (olaparib tablets) to include the treatment of patients with certain types of breast cancer that have spread (metastasized) and whose tumors have a specific inherited (germline) genetic mutation, making it the first drug in its class (PARP inhibitor) approved to treat breast cancer, and it is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a “BRCA” gene mutation. Patients are selected for treatment with Lynparza based on an FDA-approved genetic test, called the BRACAnalysis CDx.

“This class of drugs has been used to treat advanced, BRCA-mutated ovarian cancer and has now shown efficacy in treating certain types of BRCA-mutated breast cancer,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval demonstrates the current paradigm of developing drugs that target the underlying genetic causes of a cancer, often across cancer types.”

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 252,710 women will be diagnosed with breast cancer this year, and 40,610 will die of the disease. Approximately 20-25 percent of patients with hereditary breast cancers and 5-10 percent of patients with any type of breast cancer have a BRCA mutation. BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including breast cancers.

Lynparza is a PARP (poly ADP-ribose polymerase) inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth. Lynparza was first approved by the FDA in 2014 to treat certain patients with ovarian cancer and is now indicated for the treatment of patients with germline breast cancer susceptibility gene (BRCA) mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, who have been previously treated with chemotherapy. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior hormonal (endocrine) therapy or be considered inappropriate for endocrine treatment.

Today, the FDA also expanded the approval of the BRACAnalysis CDx, an approved companion diagnostic to Lynparza, to include the detection of BRCA mutations in blood samples from patients with breast cancer.

The safety and efficacy of Lynparza for the treatment of breast cancer was based on a randomized clinical trial of 302 patients with HER2-negative metastatic breast cancer with a germline BRCA mutation. The trial measured the length of time the tumors did not have significant growth after treatment (progression-free survival). The median progression-free survival for patients taking Lynparza was 7 months compared to 4.2 months for patients taking chemotherapy only.

Common side effects of Lynparza include low levels of red blood cells (anemia), low levels of certain white blood cells (neutropenia, leukopenia), nausea, fatigue, vomiting, common cold (nasopharyngitis), respiratory tract infection, influenza, diarrhea, joint pain (arthralgia/myalgia), unusual taste sensation (dysgeusia), headache, indigestion (dyspepsia), decreased appetite, constipation and inflammation and sores in the mouth (stomatitis).

Severe side effects of Lynparza include development of certain blood or bone marrow cancers (myelodysplastic syndrome/acute myeloid leukemia) and inflammation in the lungs (pneumonitis). Lynparza can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Women taking Lynparza should not breastfeed as it could cause harm to a newborn baby.

This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

Lynparza is also approved for the treatment of patients with BRCA-mutated, advanced ovarian cancer who have received three or more treatments of chemotherapy, and for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer whose tumors have completely or partially responded to chemotherapy.

FDA Approves Lynparza (olaparib tablets) for Germline BRCA-Mutated Metastatic Breast Cancer

Synergy Pharmaceuticals Announces FDA Approval of Trulance (plecanatide) for the Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Adults

Synergy Pharmaceuticals Inc. announced  that the U.S. Food and Drug Administration (FDA) has approved Trulance (plecanatide) 3 mg tablet for the once-daily treatment of irritable bowel syndrome with constipation (IBS-C) in adults. This is the second indication for Trulance, which is already approved for the treatment of adults with chronic idiopathic constipation (CIC).

“The IBS-C approval is a pivotal milestone for Synergy, representing the second approved indication for Trulance in the past 12 months,” said Troy Hamilton, Pharm.D., CEO of Synergy Pharmaceuticals Inc. “This approval demonstrates our unwavering commitment to provide a safe and effective treatment option for those patients living with these chronic GI disorders.”

Trulance is the only prescription medication for adults with CIC and now IBS-C that can be taken once-daily, with or without food, at any time of the day. Trulance is packaged in a unique, 30-day calendar blister pack.

“Approximately 1 in 20 Americans are living with IBS-C, many of whom are not satisfied with currently available treatment options,” said William D. Chey, M.D., Professor of Medicine, Director of the GI Physiology Laboratory, and Co-Director of the Michigan Bowel Control Program at the University of Michigan. “With this second indication for Trulance, patients and physicians will have a much-needed, new treatment option with an established safety profile that can effectively address abdominal pain and constipation experienced by patients with IBS-C.”

“The Trulance label reflects the strong and remarkably consistent efficacy and safety profile Trulance has demonstrated in treating over 4,700 patients across both CIC and IBS-C clinical trials,” said Patrick H. Griffin, MD, Chief Medical Officer of Synergy. “To-date, real world patient experience has supported the clinical trial data, highlighted by a post-marketing diarrhea rate of less than 0.5% and no reports of severe diarrhea requiring hospitalization since the launch of the Trulance CIC indication. The IBS-C approval today builds on the already strong CIC label and further establishes Trulance as the first and only uroguanylin analog.”

With the exception of a single amino acid substitution for greater binding affinity, Trulance is structurally identical to human uroguanylin and is the only treatment thought to replicate the pH-sensitive activity of uroguanylin.

Ref : https://ir.synergypharma.com/press-releases/detail/1861/synergy-pharmaceuticals-announces-fda-approval-of

Synergy Pharmaceuticals Announces FDA Approval of Trulance (plecanatide) for the Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Adults

Blueberry extract can enhance effectiveness of cervical cancer treatment

In continuation of my update on blueberries 

According to the Centers for Disease Control and Prevention, approximately 12,000 women in the United States are diagnosed with cervical cancer each year. One of the most common treatments for cervical cancer is radiation. While radiation therapy destroys cancer cells, it also destroys nearby healthy cells. University of Missouri School of Medicine researchers studied in vitro human cancer cells to show that combining blueberry extract with radiation can increase the treatment's effectiveness.

"Radiation therapy uses high-energy X-rays and other particles such as gamma rays to destroy cancer cells," said Yujiang Fang, M.D., Ph.D., a visiting professor at the MU School of Medicine and lead author of the study. "For some cancers, such as late-stage cervical cancer, radiation is a good treatment option. However, collateral damage to healthy cells always occurs. Based on previous research, we studied blueberry extract to verify it could be used as a radiosensitizer."

Radiosensitizers are non-toxic chemicals that make cancer cells more responsive to radiation therapy. In a previous study, Fang and his research team showed that resveratrol, a compound in red grapes, could be used as a radiosensitizer for treating prostate cancer. Blueberries also contain resveratrol.

"In addition to resveratrol, blueberries also contain flavonoids," said Fang, who also has appointments as an academic pathologist and assistant professor of microbiology and immunology at Des Moines University in Iowa. "Flavonoids are chemicals that may have antioxidant, anti-inflammatory and antibacterial properties."

The researchers used human cervical cancer cell lines to mimic clinical treatment. The cell lines were divided into four groups that included a control group, a group that received only radiation, a group that received only blueberry extract, and a group that received both radiation and the extract.

"Our team used three different measures to confirm results of the study," Fang said. "Radiation decreased cancer cells by approximately 20 percent. Interestingly, the cell group that received only blueberry extract had a 25 percent decrease in cancer. However, the biggest decline in cancer cells occurred in the radiation and extract group, with a decrease of about 70 percent."

Fang explained that the mechanism that makes blueberry extract a radiosensitizer also reduces the abnormal explosion of cell growth? which is what cancer is.

"Cancer cells avoid death by remodeling themselves," Fang said. "Along with reducing cell proliferation, the extract also 'tricks' cancer cells into dying. So it inhibits the birth and promotes the death of cancer cells."

Fang said an animal study is the next step to confirm that his team can achieve the same results.

"Blueberries are very common and found all over the world," Fang said. "They are readily accessible and inexpensive. As a natural treatment option for boosting the effectiveness of existing therapies, I feel they would be enthusiastically accepted."

Blueberry extract can enhance effectiveness of cervical cancer treatment

A salad a day may keep memory problems away, study says

A new study published yesterday in Neurology, the online medical journal of the American Academy of Neurology, Neurology, suggested that consuming about one serving of leafy vegetables per day may be associated with a slower rate of brain aging.

According to the study, people who consumed at least one serving of green, leafy vegetables daily had a decreased rate of decline on tests of memory and thinking skills, when compared with people who rarely or never eat such vegetables.

The study author Martha Clare Morris, ScD, from Rush University Medical Center, Chicago, said that the difference between the two groups was the same as being 11 years younger in age.

"Adding a daily serving of green, leafy vegetables to your diet may be a simple way to foster your brain health. Projections show sharp increases in the percentage of people with dementia as the oldest age groups continue to grow in number, so effective strategies to prevent dementia are critical."

Martha Clare Morris, Rush University Medical Center

The study enrolled 960 participants with a median age of 81 who had no dementia, and were followed for an average of 4.7 years. During the study period, they were asked to complete a questionnaire on how often and how many servings they ate of three green leafy vegetables---kale/collards/greens, half cup cooked; spinach, half cup cooked; and lettuce salad, one cup raw.

Based on how often they ate green leafy vegetables, the participants were divided into five equal groups. Those in the top serving group consumed an average of nearly 1.3 servings a day while those in the lowest serving group consumed an average of 0.1 servings a day.

The participants attended tests on thinking and memory skills. As a whole, the scores on the thinking and memory tests for the participants reduced over time at a rate of 0.08 standardized units per year.

After more than 10 years of follow-up it was found that, for participants who consumed the leafiest vegetables, the rate of decline was slower by 0.05 standardized units per year than those who consumed the least leafy greens.

According to the study, the above stated difference was the same as being 11 years younger in age, as aforementioned. Even after considering other factors that may affect brain health like high blood pressure, smoking, obesity, amount of physical and cognitive activities, as well as education level, the findings remained valid.

Morris also explained that the study does not provide evidence for consuming green, leafy vegetables to decelerate brain aging, but only shows a link. In her opinion, ruling out other possible reasons for the association cannot be done. Also, as the study focuses on older adults and the majority of participants were white, the results may not be applicable to younger adults and people of color.

Ref : https://www.eurekalert.org/pub_releases/2017-12/aaon-was121517.php

A salad a day may keep memory problems away, study says

Diet rich in tomatoes and apples may help restore lung damage caused by smoking

A study from the Johns Hopkins Bloomberg School of Public Health found the natural decline in lung function over a 10-year period was slower among former smokers with a diet high in tomatoes and fruits, especially apples, suggesting certain components in these foods might help restore lung damage caused by smoking.

The researchers found that adults who on average ate more than two tomatoes or more than three portions of fresh fruit a day had a slower decline in lung function compared to those who ate less than one tomato or less than one portion of fruit a day, respectively. The researchers inquired about other dietary sources such as dishes and processed foods containing fruits and vegetables (e.g. tomato sauce) but the protective effect was only observed in fresh fruit and vegetables.

The paper, which is part of the Ageing Lungs in European Cohorts (ALEC) Study, funded by the European Commission and led by Imperial College London, also found a slower decline in lung function among all adults, including those who had never or had stopped smoking, with the highest tomato consumption. Poor lung function has been linked with mortality risks from all diseases, including chronic obstructive pulmonary disease (COPD), heart disease, and lung cancer.

The findings appear in the December issue of the European Respiratory Journal.

"This study shows that diet might help repair lung damage in people who have stopped smoking. It also suggests that a diet rich in fruits can slow down the lung's natural aging process even if you have never smoked," says Vanessa Garcia-Larsen, assistant professor in the Bloomberg School's Department of International Health and the study's lead author. "The findings support the need for dietary recommendations, especially for people at risk of developing respiratory diseases such as COPD."

For the study, the research team assessed diet and lung function of more than 650 adults in 2002, and then repeated lung function tests on the same group of participants 10 years later. Participants from three European countries -- Germany, Norway and the United Kingdom - completed questionnaires assessing their diets and overall nutritional intake. They also underwent spirometry, a procedure that measures the capacity of lungs to take in oxygen.

The test collects two standard measurements of lung function: Forced Exhaled Volume in 1 second (FEV1), which measures how much air a person can expel from their lungs in one second; and Forced Vital Capacity (FVC), the total amount of air a person can inhale in 6 seconds. The study controlled for factors such as age, height, sex, body mass index (an indicator of obesity), socio-economic status, physical activity and total energy intake.

Among former smokers, the diet-lung-function connection was even more striking. Ex-smokers who ate a diet high in tomatoes and fruits had around 80 ml slower decline over the ten-year period. This suggests that nutrients in their diets are helping to repair damage done by smoking.

"Lung function starts to decline at around age 30 at variable speed depending on the general and specific health of individuals," explains Garcia-Larsen "Our study suggests that eating more fruits on a regular basis can help attenuate the decline as people age, and might even help repair damage caused by smoking. Diet could become one way of combating rising diagnosis of COPD around the world."

http://erj.ersjournals.com/content/50/6/1602286

Diet rich in tomatoes and apples may help restore lung damage caused by smoking

Novartis announces FDA approval of its first and only CML therapy with TFR data in product label

In continuation of my update on nilotinib

Novartis announced today that the US Food and Drug Administration (FDA) approved the inclusion of Treatment-free Remission (TFR) data in the Tasigna® (nilotinib) US product label. Tasigna is now the first and only BCR-ABL tyrosine kinase inhibitor (TKI) to include data about attempting treatment discontinuation in eligible adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP) after achieving sustained deep molecular response of MR4.5 (BCR-ABL1 International Scale [IS] <= 0.0032%) in its FDA-approved prescribing information. TFR is the ability to maintain a sustained molecular response* after stopping TKI therapy in patients with Ph+ CML-CP. TFR requires scheduled monitoring of BCR-ABL1 levels to identify possible loss of molecular response.

"It has long been our ambition at Novartis to make it possible for some people with CML to discontinue therapy," said Bruno Strigini, CEO, Novartis Oncology. "We are proud that Tasigna is now the first and only TKI with TFR data in its labeling in the US and several countries around the globe. This achievement would not have been possible without the partnership of patients around the world who participated in our groundbreaking TFR trials, helping Novartis to once again reimagine what is possible for people living with CML."

With this label update, Tasigna is the only TKI that provides defined, approved criteria to attempt and monitor TFR. This approval follows a priority review for a supplemental New Drug Application (sNDA) for Tasigna seeking the addition of TFR information and is based on safety and efficacy results from the 96-week analyses of two open label trials, ENESTfreedom and ENESTop. These trials evaluated the potential to maintain MMR (BCR-ABL1 <= 0.1%) after stopping Tasigna therapy among eligible adult patients with Ph+ CML-CP. Patients in the trials had achieved a sustained MR4.5 with Tasigna in both the first-line setting or after switching from Glivec® (imatinib). The trials demonstrated that almost half of the Ph+ CML-CP patients who discontinued Tasigna remained in TFR approximately two years after stopping treatment[1]. Among patients who did lose molecular response during the TFR phase of the trials, nearly all regained MMR when Tasigna therapy was promptly reinitiated[1]. The safety data are consistent with previously published studies and the known safety profile of Tasigna.

The TFR data in the Tasigna label approved by the FDA included the use of the MolecularMD MRDxTM BCR-ABL test, a FDA-authorized companion diagnostic validated to measure BCR-ABL transcript levels down to MR4.5. Discontinuation of Tasigna should only be attempted under the close supervision of a physician. Frequently scheduled patient monitoring after Tasigna discontinuation is required so that possible loss of MMR and MR4.0 (BCR-ABL1 IS <= 0.01%) is quickly identified and treatment re-initiation is started promptly.

Ref : https://www.novartis.com/news/media-releases/novartis-drug-tasignar-approved-fda-first-and-only-cml-therapy-treatment-free-remission-data-its-label

Novartis announces FDA approval of its first and only CML therapy with TFR data in product label

Antidepressant may also alleviate multiple sclerosis symptoms

The antidepressant clomipramine may also alleviate symptoms of multiple sclerosis (MS), specifically in its progressive form, i.e. when it occurs without relapses or remissions. As yet, drugs for this type of MS have been virtually non-existent. Researchers collaborating with Prof V. Wee Yong, PhD, from the University of Calgary and Dr Simon Faissner from Ruhr-Universität Bochum screened 1,040 generic therapeutics and, based on preclinical studies, identified one that is suitable for the treatment of multiple sclerosis. They published their results in the journal "Nature Communications" from December 19, 2017.

Today, twelve drugs have been approved for the treatment of relapsing-remitting multiple sclerosis; for the progressive types, on the other hand, only a few therapy approaches exist. "The mechanisms causing damage in progressive MS are not always the same as in relapsing-remitting MS. This is why the latter requires different therapeutic approaches," says Simon Faissner. As postdoctoral researcher of the Department of Neurology at St Josef-Hospital in Bochum, he contributed to a study carried out at the Cumming School of Medicine, University of Calgary as a visiting scholar, funded by the grant for medical research awarded by the Ruhr-Universität's Faculty of Medicine.

Potential side effects already well-documented

The team worked with approved drugs, the side effects of which have already been amply documented. From among those drugs, the researchers selected 249 well-tolerated therapeutics that enter the nervous system safely; this is where chronic inflammation occurs in progressive MS. Using cell cultures, they tested which of the 249 substances are capable of protecting nerve cells from the damaging influence of iron. In MS patients, iron is released due to cell damage, damaging nerve cells in turn.

Following those tests, 35 potential candidates were identified; the researchers subsequently analyzed them with regard to additional properties: investigating, for example, if they can reduce damage to mitochondria - the powerhouses of the cells - or if they minimise the activity of leucocytes that attack the insulation of nerve cells in MS patients. In the process, the drug clomipramine proved promising.

Positive results in preclinical studies

In the next step, the researchers analyzed the substance in mice suffering from a disease comparable with relapsing-remitting multiple sclerosis in humans. The therapy suppressed the neurological disturbances completely; as a result, damages to the nerve cells and inflammation were minimised.

In a subsequent test, they treated mice with a disease that resembles progressive MS in humans. Here, too, the therapy proved effective, provided the researchers applied it immediately after the first clinical symptoms became apparent. Symptoms such as paralysis were thus reduced - unlike in control animals that were treated with placebo drugs.

Clinical studies planned

Simon Faissner returned from Canada to Bochum in January 2017. As a member of Prof Dr Ralf Gold's research group, he is continuously striving to identify new drugs with the potential of protecting from MS and to gain a better understanding of the mechanisms underlying the progressive type of the disease.

"Based on promising preclinical data, our long-term objective is to study clomipramine as well as other therapeutics selected in the screening process on patients in clinical studies," explains Faissner. "An advantage of generic drugs is the fact that there is ample clinical experience regarding their potential side effects." Accordingly, there is no need to perform phase-1 trials to study the tolerance of the drug in healthy volunteers. "The funding of such studies always poses a considerable challenge," concludes Faissner.

Progressive multiple sclerosis

In the Western world, multiple sclerosis is the most common cause of neurological disabilities in young people. In MS patients, leukocytes damage the layer surrounding nerve cells, the so-called myelin sheath. This results in neurological disturbances; in 85 percent of patients, the disease is characterized by clearly defined relapses and may cause e.g. visual impairment, paralysis or numbness. The majority of patients experience gradual deterioration after 15 to 20 years, which is referred to as progression. In ten percent of the patients, the disease is progressive from the outset, without any relapses along the way.

Ref : http://news.rub.de/english/press-releases/2017-12-20-medicine-antidepressant-may-help-combat-course-multiple-sclerosis

Antidepressant may also alleviate multiple sclerosis symptoms

FDA-approved drug to treat high blood pressure increases life span in worms

UT Southwestern Medical Center researchers find that an FDA-approved drug to treat high blood pressure seems to extend life span in worms via a cell signaling pathway that may mimic caloric restriction.

The drug, hydralazine, extended life span about 25 percent in two strains of C. elegans(roundworms), one a wild type and the other bred to generate high levels of a neurotoxic protein called tau that in humans is associated with Alzheimer's disease.

"This is the first report of hydralazine treatment activating the NRF2/SKN-1 signaling pathway. We found the drug extends the life span of worms as well as or better than other potential anti-aging compounds such as curcumin and metformin. The treatment also appeared to maintain their health as measured by tests of flexibility and wiggling speed," said Dr. Hamid Mirzaei, Assistant Professor of Biochemistry at UT Southwestern and senior author of the study, published today in Nature Communications.

The NRF2 pathway protects human cells from oxidative stress. The body's ability to protect itself against damaging oxygen free radicals diminishes with age, he said.

One of the hallmarks of aging and neurodegenerative diseases such as Alzheimer's and Parkinson's is oxidative stress, which is believed to result cumulatively from inflammatory and infectious illnesses throughout life, Dr. Mirzaei explained. SKN-1, a C. eleganstranscription factor, corresponds to NRF2 in humans. Both play a pivotal role in their respective species' responses to oxidative stress and life span, he said.

The UT Southwestern researchers were searching for a chemical probe they could use in experiments to identify proteins that get oxidized and become toxic during aging. Their screen for a substance that would cross the blood-brain barrier and be nontoxic led them to hydralazine.

"Age-related neurodegenerative diseases are devastating, and those conditions are on the rise due to the increase in the life span of humans. For that reason, it is important to develop treatments to maintain human health as long as possible," said Dr. Mirzaei, who is also an investigator in the Center for Alzheimer's and Neurodegenerative Diseases, part of the Peter O'Donnell Jr. Brain Institute at UT Southwestern.

http://www.utsouthwestern.edu/newsroom/articles/year-2017/hbp-drug.html

FDA-approved drug to treat high blood pressure increases life span in worms

Novel drug shows promise in treating metastatic kidney cancer

                    

Metastatic kidney cancer remains largely incurable. Despite a dozen treatments and several immunotherapies, survival rates beyond 5 years remain around 10 percent. A study published in the Journal of Clinical Oncology reports initial findings with a novel drug belonging to a new class of medicines called HIF-2a inhibitors that show promise in treating metastatic kidney cancer.

Among 51 patients with aggressive kidney cancer that had progressed through four prior treatments on average, PT2385, the first HIF-2a inhibitor to be evaluated in clinical trials, blocked tumor growth for at least 4 months in 40 percent of the patients. Furthermore, cancer growth was stopped for more than a year in 25 percent of the patients. In addition, side effects were minimal.

"The combination of activity and tolerability is very encouraging," said corresponding author Dr. Kevin Courtney, Assistant Professor of Internal Medicine at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center. "We treated multiple patients on this trial in the Kidney Cancer Program at UT Southwestern, more than at any other institution. In our experience, this HIF-2a inhibitor offers a combination of safety and potential activity that is unique compared to current treatments for advanced kidney cancer."

PT2385, developed by Peloton Therapeutics Inc., represents the culmination of two decades of research at UT Southwestern beginning with the discovery of HIF-2a by Dr. Steven McKnight, Professor of Biochemistry who holds the Distinguished Chair in Basic Biomedical Research, and Dr. David Russell, Vice Provost, Dean of Research, and holder of the Eugene McDermott Distinguished Chair in Molecular Genetics. Next was the finding of a vulnerability in HIF-2a by Dr. Richard Bruick, Professor of Biochemistry and the Michael L. Rosenberg Scholar in Biomedical Research, and Dr. Kevin Gardner, Professor of Biophysics. This research was followed by the identification of chemicals that exploit a crevice in HIF-2a to destroy its activity. These chemicals were then licensed to Peloton Therapeutics, in the UT Southwestern BioCenter at Southwestern Medical District, which developed the HIF-2a blocking drug.

In a manuscript published in Nature last year, Dr. James Brugarolas, Professor of Internal Medicine, showed that blocking HIF-2a successfully reduced the growth of 50 percent of kidney cancers that were transplanted from patients into mice. In fact, the HIF-2a drug had greater activity in this study and was better tolerated than sunitinib, the most commonly prescribed drug for kidney cancer.

Dr. Brugarolas, who directs the Kidney Cancer Program and is the Principal Investigator of one of only two Specialized Programs of Research Excellence (SPORE) in kidney cancer designated by the National Cancer Institute, is now working to identify patients who are most likely to benefit from treatment with PT2385. "One of the biggest challenges we face across all treatments for kidney cancer is pairing the right drug with the right patient," said Dr. Brugarolas, who also holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D.

"HIF-2a, which fuels cell growth, is the most important driver of kidney cancer and the development of a drug that is helping patients is a remarkable outgrowth of our research," said Dr. Russell.

UT Southwestern Medical Center owns stock in Peloton Therapeutics and has a financial interest in the clinical trial described in the Journal of Clinical Oncology article. Drs. Bruick, Gardner, and McKnight have financial interests related to consulting; and Drs. McKnight, Bruick, and Gardner related to investment.

http://www.utsouthwestern.edu/newsroom/articles/year-2017/kidney-cancer-drug.html

Novel drug shows promise in treating metastatic kidney cancer

Tapeworm drug could provide new hope for patients with Parkinson's disease

In continuation of Niclosamide

Researchers at Cardiff University, in collaboration with the University of Dundee, have identified a drug molecule within a medicine used to treat tapeworm infections which could lead to new treatments for patients with Parkinson's disease.

Parkinson's disease is a long-term degenerative disorder of the central nervous system that, according to the charity, Parkinson's UK, affects one person in every 500. That means an estimated 127,000 people are currently living with Parkinson's disease in the UK alone.

Over the last decade or so, researchers striving to find a cure for this debilitating disease have focused their attention on a protein found in the human body known as PINK1. It's understood that the malfunction of this protein is one of the leading causes of Parkinson's disease.

Several studies have suggested that discovering a drug which is capable of enhancing the function of PINK1 could be a significant step in halting neurodegeneration and therefore slow down or even treat Parkinson's disease.

With this knowledge in mind, researchers at Cardiff and Dundee Universities have discovered that a drug traditionally used to treat tapeworm infections, named Niclosamide, is also an effective activator of the PINK1 protein.

Furthermore, the research, funded by The Welcome Trust, revealed that Niclosamide and some of its derivatives could enhance PINK1 performance within cells and neurons. This has given the researchers reason to believe that this drug could provide new hope for patients living with Parkinson's disease.

Dr Youcef Mehellou, from Cardiff University's School of Pharmacy and Pharmaceutical Sciences, who co-lead the study, said: 'This work represents the first report of a clinically used drug to activate PINK1 and may hold promise in treating Parkinson's disease. We will now take our findings to the next level by evaluating the ability of Niclosamide to treat Parkinson's disease in disease models. This is an exciting stage of our research and we are positive about the long term impact it could have on patients' lives."

Ref : http://www.cardiff.ac.uk/news/view/1027540-tapeworm-drug-could-lead-the-fight-against-parkinsons-disease

Tapeworm drug could provide new hope for patients with Parkinson's disease

Anti-stress compounds provide new treatment approach for diabetes and obesity

For the first time, scientists from the Max Planck Institute of Psychiatry in Munich could prove that a stress protein found in muscle has a diabetes promoting effect. This finding could pave the way to a completely new treatment approach.

For some time, researchers have known that the protein FKBP51 is associated with depression and anxiety disorders. It is involved in the regulation of the stress system - when the system does not function properly; mental disorders may develop. Now, researchers at the Max Planck Institute of Psychiatry have discovered a new, surprising role for this protein: It acts as a molecular link between the stress regulatory system and metabolic processes in the body.

"FKBP51 influences a signaling cascade in muscle tissue, which with excessive calorie intake leads to the development of glucose intolerance, i.e., the key indicator of diabetes type 2," project leader Mathias Schmidt summarizes. An unhealthy diet, rich in fat means stress for the body. If FKBP51 is increasingly produced in the muscle it leads to reduced absorption of glucose - as a result, diabetes and obesity may develop.

If FKBP51 is blocked, diabetes will not develop, even if too many calories are consumed or the body is still stressed. Less FKBP51 in the muscle tissue means reduced glucose intolerance and thus maintenance of normal metabolism.

Antagonist provides novel treatment approach

The protein FKBP51 can be pharmacologically blocked by antagonist compounds that were developed at the Max Planck Institute by Felix Hausch (presently at University of Darmstadt). In collaboration with the scientists at the Technical University Darmstadt and funded by the Bavarian State Ministry of Economic Affairs and Media, Energy and Technology, these compounds will be further developed for use in clinical trials. "These findings may provide a completely new treatment approach for diabetes and other metabolic diseases," states Alon Chen, Director at the Max Planck Institute of Psychiatry.​

Ref : https://www.mpg.de/11850791/diabetes-fkbp511

Anti-stress compounds provide new treatment approach for diabetes and obesity

Study: Ketamine more effective than common sedative in reducing suicidal thoughts

In continuation of my update on ketamine

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine's anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

"There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm," said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. "Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients."

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine's effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

"This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression," said Dr. Grunebaum. "Additional research to evaluate ketamine's antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments."

Study: Ketamine more effective than common sedative in reducing suicidal thoughts