Old drug provides promising new avenue for treatment of MND

In continuation of my update on ebselen

An international study led by biochemists at the University of Liverpool has shown that the drug-molecule ebselen can correct many of the toxic characteristics of a protein that causes some cases of hereditary motor neurone disease (MND).

MND is an incurable, progressive disease that attacks the nerves controlling movement so muscles no longer work. MND affects about 5000 people in the UK at any one time and present treatment options have only a modest effect in improving the patient's quality of life.

Inherited MND is a rare form of the disease (5-10% of total cases) that runs in families. Around 20% of hereditary MND cases are caused by mutations in a gene which codes for a protein called SOD1. When the SOD1 gene is mutated, the protein assembly process malfunctions and steps are missed out. This makes the SOD1 protein structurally unstable leading to formation of protein 'clumps' in the motor neurones, causing them to die.

In a paper published in Nature Communications, scientists from the Universities of Liverpool (UK), Florence (Italy) and Wollongong (Australia) used state-of-the-art crystallography, mass-spectrometry and in-cell NMR technologies to search for a drug molecule which could 'correct' the SOD1 assembly line.

They found that ebselen, a drug which was discovered in the 1980s and has been investigated as a potential treatment for a variety of nervous system disorders, can effectively restore several important steps in the SOD1 assembly process including folding, dimerization and zinc binding.

Dr. Gareth Wright, an MND researcher at the University of Liverpool, said: "This discovery has the potential to prevent the accumulation of SOD1 into the large aggregates we see within the motor neurons of effected individuals. If we can stop that, we might be able to stop the neurons dying."

Professor Samar Hasnain, a structural biologist at the University of Liverpool, added: "The next step is to test ebselen in settings more accurately resembling human neuronal cells and optimising it so that it can become useful as a drug for motor neuron disease."

Commenting on the study, Dr Brian Dickie, Director of Research Development at the Motor Neurone Disease Association, said: "A causal link between the SOD1 gene and certain forms of hereditary motor neuron disease was established a quarter of a century ago. It is very encouraging to see new therapeutic strategies starting to emerge from the considerable advances in scientific understanding that have occurred in recent years."

FDA approves non-opioid treatment for opioid withdrawal

Lucemyra, an oral selective alpha 2-adrenergic receptor agonist, limits the body's output of norepinephrine, the hormone believed to play a role in symptoms of opioid withdrawal, the FDA said.

The safety and efficacy of Lucemyra was validated in two randomized, double-blind, placebo-controlled clinical trials of 866 adults who were physically dependent on opioids and undergoing abrupt opioid discontinuation. Compared to placebo, Short Opiate Withdrawal Scale of Gossop scores were found to be lower for patients treated with Lucemyra, and more patients finished the treatment in the Lucemyra group versus the placebo group.

The agency stressed that Lucemyra is not specifically approved for Opioid Use Disorder, and the drug's use shouldn't extend beyond 14 days. Lucemyra's side effects could include hypotension, bradycardia, sleepiness, and dizziness. Less common reactions could include fainting and abnormal heart rhythms. The drug has not been evaluated in people under age 17, the FDA said. The agency added that it's requiring 15 additional studies in both people and animals to evaluate factors such as longer-term use and the drug's effects on the liver.

Sustained use of oxymetazoline cream efficacious for rosacea

In continuation of my update on oxymetazoline

Zoe Diana Draelos, M.D., from Dermatology Consulting Services in High Point, Tenn., and colleagues examined the long-term safety (one year) and efficacy of oxymetazoline cream 1.0 percent in 440 patients with rosacea with moderate-to-severe persistent facial erythema. Assessments were conducted at three and six hours after the dose on day one, and at weeks four, 26, and 52.

The researchers found that 8.2 percent of patients reported treatment-emergent adverse events (TEAEs), the most common were application site dermatitis, paresthesia, pain, and pruritus. The rate of discontinuation mostly due to application-site TEAEs was 3.2 percent. There was no clinically meaningful skin blanching, inflammatory lesions, or telangiectasia. At week 52, a 2-grade or greater composite improvement from baseline in both Clinician Erythema Assessment and Subject Self-Assessment three and six hours after a dose was seen in 36.7 and 43.4 percent of patients, respectively. Following treatment cessation, less than 1 percent of patients experienced a rebound effect.

"This long-term study demonstrated sustained safety, tolerability, and efficacy of oxymetazoline for moderate-to-severe persistent erythema of rosacea," the authors write.Zoe Diana Draelos, M.D., from Dermatology Consulting Services in High Point, Tenn., and colleagues examined the long-term safety (one year) and efficacy of oxymetazoline cream 1.0 percent in 440 patients with rosacea with moderate-to-severe persistent facial erythema. Assessments were conducted at three and six hours after the dose on day one, and at weeks four, 26, and 52.

The researchers found that 8.2 percent of patients reported treatment-emergent adverse events (TEAEs), the most common were application site dermatitis, paresthesia, pain, and pruritus. The rate of discontinuation mostly due to application-site TEAEs was 3.2 percent. There was no clinically meaningful skin blanching, inflammatory lesions, or telangiectasia. At week 52, a 2-grade or greater composite improvement from baseline in both Clinician Erythema Assessment and Subject Self-Assessment three and six hours after a dose was seen in 36.7 and 43.4 percent of patients, respectively. Following treatment cessation, less than 1 percent of patients experienced a rebound effect.

"This long-term study demonstrated sustained safety, tolerability, and efficacy of oxymetazoline for moderate-to-severe persistent erythema of rosacea," the authors write.

New diabetes drug may help people with obesity lose weight

In continuation of my update on semaglutide

A compound that mimics a naturally occurring hormone that regulates appetite may help people who have obesity but not diabetes to lose weight, a new study suggests. The research will be presented Sunday, March 18, at ENDO 2018, the Endocrine Society's 100th annual meeting in Chicago, Ill

The compound, semaglutide, has a chemical structure that is very similar to the hormone glucagon-like peptide 1 (GLP-1), which regulates both insulin secretion and appetite. In December, the U.S. Food and Drug Administration approved the semaglutide injection Ozempic as a once-weekly adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

"This randomized study of weight loss induced with semaglutide in people with obesity but without diabetes has shown the highest weight reductions yet seen for any pharmaceutical intervention," said lead author Patrick M. O'Neil, Ph.D., Director of the Weight Management Center and Professor of Psychiatry and Behavioral Sciences at the Medical University of South Carolina in Charleston, S.C.

The new study included 957 participants, 35 percent of whom were male. All participants had a body mass index (BMI) of at least 30, but did not have diabetes. They were randomly assigned to seven different groups. Five groups received different doses of semaglutide (between 0.05 mg and 0.4 mg) via injection once daily; a sixth group received a placebo, and a seventh group received 3 mg of the diabetes drug liraglutide. All participants received monthly diet and exercise counseling.

After one year, all participants receiving semaglutide had lost significantly more weight than those receiving placebo. The higher the dose participants received, the greater their average weight loss. Participants who received 0.05 mg of semaglutide daily lost an average of 6.0 percent of their body weight; the 0.1 mg group lost an average of 8.6 percent; the 0.3 mg group lost an average of 11.2 percent; and those receiving a daily dose of 0.4 mg lost an average of 13.8 percent. Those receiving liraglutide lost an average of 7.8 percent of their body weight, while those in the placebo group lost only 2.3 percent on average.

Sixty five percent of participants who received 0.4 mg of semaglutide per day lost at least 10 percent of their body weight, compared with 10 percent of those in the placebo group and 34 percent of the liraglutide group.

The most common adverse events in those taking semaglutide were mild/moderate nausea, as seen previously with GLP-1 receptor agonists.

https://www.endocrine.org/news-room/2018/new-diabetes-drug-may-help-people-with-obesity-lose-weight

Drug used to treat daytime sleepiness does not appear to improve driving in those with sleep apnea

 Armodafinil

 In "Does Armodafinil Improve Driving Task Performance and Weight Loss in Sleep Apnea? A Randomized Trial," Nathaniel Marshall, Ph.D., and his colleagues at the Woolcock Institute for Medical Research, University of Sydney, report on their study of armodafinil, which has been approved by the U.S. Food and Drug Administration to treat excessive daytime sleepiness due to OSA, narcolepsy and other conditions.

The researchers found that armodafinil did not improve the driving performance of those with OSA after six months of use, the study's primary outcome. Nor did those taking the drug report less daytime sleepiness than those receiving a placebo, as measured by the Epworth Sleepiness Scale and the Functional Outcomes of Sleep Questionnaire.

In the study, 113 participants (ages 18 to 70) were randomly assigned to either receive 150 mg of armodafinil daily or a placebo. Participants had moderate to severe OSA, were moderately obese and did not use continuous positive airway pressure (CPAP) or an oral appliance that advances their lower jaw. Both therapies treat OSA by preventing the pauses in breathing that occur in OSA when the back of the throat collapses.

All participants were also randomly assigned to one of two popular diets in Australia: the Australian Guide to Healthy Eating diet, which is similar to the American Dietary Guidelines "Choose My Plate," or a low-glycemic index, high-protein diet. Driving ability was assessed during a simulated 90-minute drive.

According to Dr. Marshall, a clinical trials epidemiologist, about half of patients seen in sleep clinics fall into the category of having sleep apnea and abdominal obesity but being unable to tolerate CPAP or an oral appliance. "My clinical colleagues and I call these patients the 'forgotten patients,'" he said. "We felt we needed to help our patients lose weight to address their metabolic risks over the longer term whilst addressing their sleepiness and neurocognitive dysfunction immediately with armodafinil."

He added that sporadic reports indicate that patients using armodafinil and its cousin modafinil to improve wakefulness experienced weight loss, so he and his coauthors wanted to test whether the drugs might increase the success of a deliberate weight loss program.

 modafinil

In the current study, armodafinil did, in fact, have a positive effect on body mass. Participants on the drug lost more body fat on either of the diets, which appeared to reduce weight equally well, than those who received the placebo. At six months, those in the armodafinil arm of the study lost an average of 6.4 pounds more body fat than those receiving the placebo. The researchers said that some of this additional weight loss may be due to the increased activity levels of those receiving the drug, as measured by an activity tracker. Importantly, the authors noted that armodafinil did not appear to increase blood pressure.

Armodafinil also appeared to improve driving ability after three months. The researchers speculate that those taking armodafinil learned their simulated driving tasks faster than those receiving the placebo because by six months there was no difference between the two groups. Even with the improvements that came with practice, the authors noted that, on average, driving ability among these participants with untreated OSA was two standard deviations worse than healthy people without OSA.

Novartis Drug Tasigna Approved by FDA to Treat Children with Rare Form of Leukemia

In continuation of my update on Nilotinib

Novartis announced today that the US Food and Drug Administration (FDA) expanded the indication for Tasigna (nilotinib) to include treatment of first- and second-line pediatric patients one year of age or older with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP)

In the United States, Tasigna is now indicated for the treatment of adult and pediatric patients one year of age or older with newly diagnosed Ph+ CML-CP. Tasigna is also indicated for the treatment of pediatric patients one year of age or older with Ph+ CML-CP resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy, as well as adult patients with Ph+ CML in chronic phase and accelerated phase, resistant or intolerant to prior therapy that included imatinib.

This approval is the latest in a series of regulatory milestones that broadens the understanding and clinical use of Tasigna.

CML is a type of blood cancer where the body produces malignant white blood cells. Almost all patients with CML have an abnormality known as the "Philadelphia chromosome," which produces a protein called BCR-ABL. This protein aids the proliferation of malignant white blood cells in affected patients. Worldwide, CML accounts for approximately 3% of newly diagnosed childhood leukemia[1].

"Novartis' commitment to people living with CML is reinforced by today's FDA approval of Tasigna in children," said Liz Barrett, CEO, Novartis Oncology. "This expanded use, along with the other recent global regulatory Tasigna milestones, underscores our dedication to reimagining medicine and addressing the needs for people with CML, including children with this cancer."

The new indications, granted under the FDA's Priority Review designation, are based on two studies evaluating the efficacy and safety of nilotinib in pediatric patients (two years to less than 18 years of age) with Ph+ CML-CP. A total of 69 Ph+ CML-CP pediatric patients, either newly diagnosed (first-line) or who were resistant or intolerant to prior TKI therapy (second-line), received nilotinib[2]. In newly diagnosed pediatric patients, the major molecular response (MMR; BCR ABL/ABL <=0.1% International Scale [IS]) rate was 60.0% (95% confidence interval [CI]: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR[2]. The cumulative MMR rate among newly diagnosed pediatric patients was 64.0% by cycle 12, and the median time to first MMR was 5.6 months (range: 2.7 to 16.6). In pediatric patients with resistance or intolerance to prior TKI therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR[2]. The cumulative MMR rate among pediatric patients with resistance or intolerance was 47.7% by cycle 12, and the median time to first MMR was 2.8 months (range: 0.0 to 11.3)[2].

Adverse reactions observed in these pediatric studies were generally consistent with those observed in adults, except for laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%)-a condition where there is too much bilirubin in the blood-and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), which were reported at a higher frequency than in adult patients. One resistant or intolerant pediatric CML patient progressed to advance phase/blast crisis (AP/BC) after about 10 months on treatment.

Oral drug reduces venous thromboembolism recurrence among cancer patients

In continuation of my update on  rivaroxaban

Research from the University of Warwick indicates that taking a tablet a day can help treat cancer patients of a potentially deadly condition.

People with cancer have an increased risk of developing blood clots, with roughly one in five experiencing venous thromboembolism (VTE) - either deep vein thrombosis (DVT) or pulmonary embolism (PE). Blood clots in the deep veins of the leg may travel to the lungs causing a pulmonary embolism. These two conditions are referred to as VTE - a dangerous and potentially deadly medical condition of which there are 10 million cases worldwide.

Current international guidelines recommend cancer patients are injected with an anticoagulant (a low molecular weight heparin) to treat and prevent recurrence of VTE. However, new results from a large pilot trial run at the University's Warwick Medical School called 'select-d' suggest that a daily tablet could be a beneficial alternative for treating VTE in selected patients.

Research led by Professor Annie Young of Warwick Medical School found that prescribing the oral drug rivaroxaban (Xarelto) significantly reduced venous thromboembolism recurrence among patients with cancer and VTE. She said: "Clinicians were already adopting the oral drug into practice for non-cancer patients and now they have data from this study to indicate that this form of treatment is an alternative option for many cancer patients who have a clot."

 

Although there are many causes and risk factors for VTE, cancer patients are particularly at risk due to a combination of factors such as immobility (if in bed poorly), pancreatic and gastric tumours, and chemotherapy. Because VTE can be life-threatening, blood thinners are used to shrink existing clots and prevent others from forming.

The 'select-d' trial enrolled 406 patients who had cancer and VTE; most (69 percent) were receiving cancer treatment (typically chemotherapy) at the time of their VTE. Half were randomly assigned to receive low-molecular-weight heparin (dalteparin) and half were given the oral drug rivaroxaban. After six months of treatment, the VTE recurrence rate was four percent among those taking the tablet and 11 percent in those receiving dalteparin.

The results for secondary outcomes were mixed. In patients receiving rivaroxaban, there were around the same percentage of major bleeding events (6%) as those receiving dalteparin (4%) but a marked and significant increase in clinically relevant non-major bleeds (13%) with rivaroxaban compared to those having low molecular weight heparin (4%). The reason for increased bleeding is not known, it may be because rivaroxaban is more 'potent'.

Professor Young added: "We now need to be sitting down with each one of our cancer patients with VTE, discussing their preference alongside looking at all their clinical details including whether the cancer lesion is still there, what other medications are being taken and what other conditions the patient has so that we can choose the optimal VTE treatment for each patient."

Osteoporosis drug may be cardioprotective in hip fracture patients

In continuation of my update on alendronate

The osteoporosis drug alendronate was linked with a reduced risk of cardiovascular death, heart attack, and stroke in a Journal of Bone and Mineral Research study of patients with hip fractures. The association was seen for up to 10 years after fracture.

In the study, patients newly diagnosed with hip fracture from 2005 through 2013 were followed until late 2016. Among 34,991 patients, 4602 (13%) received osteoporosis treatment during follow-up.

Alendronate was associated with 67% and 45% lower risks of one-year cardiovascular death and heart attack, respectively. It was associated with an 18% reduced risk of stroke within five years and a 17% reduced risk of stroke within 10 years. Protective effects were not evident for other classes of osteoporosis treatments.

"It is well established that there is a world-wide crisis in the treatment of osteoporosis, due to patients' awareness of the extremely rare side effects," said senior author Dr. Ching-Lung Cheung, of the University of Hong Kong. "Our findings show that alendronate is potentially cardioprotective in hip fracture patients.

Therefore, physicians should consider prescribing alendronate or other nitrogen-containing bisphosphonates to hip fracture patients soon after their fracture, and patients should also have good compliance with alendronate treatment, as this is not only good for your bones, but also your heart."

In addition to clinical management, the study also has important implications in clinical trial design of anti-osteoporosis medications. The US Food and Drug Administration recently requested more data before reaching a decision on whether to approve the osteoporosis drug romosozumab, due to excess cardiovascular adverse events in the romosozumab arm compared with the alendronate arm. "In light of these important deliberations, our results suggest that such differences in cardiovascular adverse events could be potentially related to a protective association of alendronate, rather than an increase in cardiovascular adverse events related to romosozumab use, said Dr. Cheung."

 Ref : http://newsroom.wiley.com/press-release/osteoporosis-drug-may-benefit-heart-health

Osteoporosis drug may be cardioprotective in hip fracture patients

New drug reduces symptoms of Rett syndrome in preclinical models

A new article published in the Cell Reports describes how a new drug is able to reduce the symptoms and activate the dormant neurons characteristic of Rett Syndrome in preclinical models. The study, led by Dr. Manel Esteller, Director of the Epigenetics and Cancer Biology Program (PEBC) of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA Researcher and Professor of Genetics of the University of Barcelona, and Dr. Sonia Guil, researcher at the same IDIBELL group, has been possible thanks to the support from the Catalan and Spanish associations of the Rett Syndrome, the Carla Regatta, a Verkami crowfunding campaign, the Jérôme Leujene Foundation and the Dischrom project funded by EU.

Rett Syndrome is the second most frequent cause of intellectual disability in women, only after Down Syndrome. The main genetic cause of Rett Syndrome is the appearance of mutations in the embryo affecting the MECP2 gene, a regulator of the expression of other genes in the genome. There is no specific pharmacological treatment for the disease, so current efforts are focused on trying to control its most serious manifestations, such as epileptic and respiratory crises.

"We knew for some years that the brains of Rett syndrome girls were inflamed, so we decided to test whether a drug that inhibits a central neuroinflammatory protein called glycogen synthase kinase-3B (GSK3B) could reverse part of the symptoms. As with any experimental treatment, we started with a preclinical model of the disease, studying it in mice that have the same MECP2 deficiency as in human Rett syndrome" says Dr. Manel Esteller.

"The results have been very promising; agent SB216763 has been able to lengthen the life of the animals, significantly reducing tremors, breathing difficulties and mobility limitations. But what is really remarkable is that the inhibition of GSK3B also causes an "awakening" of the sleeping neurons of the syndrome: these brain cells are now beginning to regain contact between them and communication between neuronal synapses increases", explains the IDIBELL researcher, and he concludes: "Our findings provide a new way of improving the quality of life of these patients and now it is the neurologists' job to demonstrate their applicability in patients with Rett Syndrome. In any case, we have to be aware that the mutation in the MECP2 gene is still there, and only by correcting it would we arrive at a definitive treatment of the disease."

Ref : http://www.idibell.cat/modul/news/en/1076/a-new-drug-shows-preclinical-efficacy-in-rett-syndrome

FDA Approves Supplemental New Drug Application for Myrbetriq (mirabegron) for Use in Combination with Solifenacin Succinate for the Treatment of Overactive Bladder Symptoms

In continuation of my update on mirabegron

Astellas Pharma Inc. announced  that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for the use of mirabegron in combination with the muscarinic antagonist solifenacin succinate for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and urinary frequency.

In the United States, mirabegron and solifenacin succinate are marketed as Myrbetriq® and VESIcare®, respectively. Each is approved by the FDA as a monotherapy for OAB. 

"OAB patients may have symptoms that are not fully managed with their current treatment," said Carol Schermer, M.D., M.P.H., senior medical director, urology, Astellas. "With the FDA approval of Myrbetriq in combination with solifenacin succinate, Astellas is able to offer an additional treatment option to individuals living with symptoms of OAB."

The sNDA submission was based on data from the global Phase 3 SYNERGY I, SYNERGY II and BESIDE studies. These studies evaluated combination therapy with mirabegron and solifenacin succinate compared with each drug as monotherapy or placebo.

Mepivacaine is found to be an effective spinal anesthetic for knee replacement surgery

A numbing medicine largely abandoned decades ago for pain control during surgery could be making a comeback as an effective spinal anesthetic for today's modern-day knee replacement.

In two companion studies by Henry Ford Health System, mepivacaine was found to be as effective for controlling pain with less side effects as bupivacaine, which for years has been the standard spinal anesthetic favored by anesthesiologists and orthopedic surgeons. Patients who received mepivacaine recovered normal function faster, which allowed for a quicker recovery and shorter hospital stay.

While the results proved promising, researchers say more research is needed to evaluate mepivacaine's effectiveness on a larger scale for medium length surgery. The findings – one study was published recently in The Journal of Arthroplasty – add to a growing body of research involving similar shorter acting medications with improved results.

"Our studies suggests that mepivacaine has multiple advantages and few drawbacks compared to bupivacaine as a spinal anesthetic in knee replacement surgery," says Jason Davis, M.D., a Henry Ford joint replacement surgeon and the study's senior author. "It shows promise as an ideal anesthetic by working long enough for most knee replacements without the excessive duration that can delay patients' recovery."

As the popularity of bupivacaine was established in the 1990s, mepivacaine use became limited after research showed it had a higher incidence of post-surgery complications like nerve irritation. More recent studies have refuted those previous concerns and shown improved side effects, while allowing for a faster return of nerve function.

Total knee replacement is one of the most commonly performed orthopedic procedures. It's estimated that the number of knee replacements is expected to increase by nearly 700 percent by 2030 as the population ages. Recent studies show up to 25 percent or more of these patients may benefit from a partial knee replacement, an alternative to total knee replacement, making the potential for outpatient surgery even more feasible.

During a knee replacement procedure, the surgeon replaces the damaged joint surface with a knee implant to restore the alignment and function of the knee. More than 90 percent of knee replacements are functioning 15 years and more after surgery, according to the American Academy of Orthopaedic Surgeons.

In the Henry Ford studies, researchers sought to evaluate the safety and effectiveness of mepivacaine compared to bupivacaine as a spinal anesthetic for pain control during surgery. One involved a retrospective review of the clinical results of 156 knee replacement patients. The second involved a smaller randomized study of 32 patients that looked specifically at the timing of nerve recovery in the legs and for urinary control.

In both, Dr. Davis noted patients who received mepivacaine had better urinary control, faster recovery of nerve function and accelerated recovery compared to those who received bupivacaine. Patients fared no worse with other side effects like nerve complications, pain control or nausea.

"Advances in surgical technique and pain control have made for improved early outcomes in recent years," Dr. Davis says. "Choosing the right anesthetic may now be the key to attain a faster recovery with a lower risk of complications after surgery. Such shorter acting medications have the potential to become the new standard for regional anesthesia during the migration to outpatient joint replacement."

Ref: https://www.henryford.com/news/2018/05/knee-replacement-study

FDA Approves Tafinlar + Mekinist for the Treatment of BRAF-Positive Anaplastic Thyroid Cancer

In continuation of my update on Tafinlar (dabrafenib) and Mekinist (trametinib)

The U.S. Food and Drug Administration approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive).

  dabrafenib      trametinib

“This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat,” 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 that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.”

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1 to 2 percent of all thyroid cancers.

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.

The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea).

Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.

Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.

Both Tafinlar and Mekinist can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

Methylene blue could hold the key to future anti-aging treatment

In continuation of my update on Methylene Blue

In a  keynote address to the 19th World Dermatology Congress, renowned dermatologist Dr. Saad Sami AlSogair noted that the past could hold the key to the future of anti-aging.

Dr. AlSogair's presentation to a packed house, titled "Anti-Aging Potentials of Methylene Blue for Human Skin Longevity," provided compelling evidence of methylene blue's ability to delay aging-related mitochondrial dysfunction and stimulate collagen and elastin. Together, these factors point to an anti-aging breakthrough nearly 150 years in the making.

"Methylene blue was first synthesized in 1876 and has been in use in clinical medicine ever since," Dr. AlSogair explained. "It is a powerful antioxidant and has proven effective in treating a variety of conditions from malaria to Alzheimer's disease, with a very low risk of side effects. But, it is only recently that methylene blue has been shown to be a promising treatment for mitochondrial dysfunction, which causes a wide variety of diseases and problems, including visible aging of the skin."

Dr. AlSogair, a board-certified dermatologist from Saudi Arabia, was tapped to deliver the keynote due to his prominence in the medical community. In 2013, the World Organization of Aesthetic Medicine Doctors named Dr. AlSogair "Dermatologist of the Year" for outstanding contributions to his field. In 2015, the Swiss Academy of Cosmetic Dermatology and Aesthetic Medicine elected Dr. AlSogair as its Middle East Ambassador. And since 2016, Dr. AlSogair has served as vice president of the Middle East International Dermatology and Aesthetic Medicine Conference and Exhibition (MEIDAM).

Among Dr. AlSogair's findings: Methylene blue can delay the deterioration that was once thought to be an unavoidable sign of aging. Methylene blue has been shown to enhance cellular oxygen consumption--a key weapon in the fight against free radicals--by 37% to 70%. It is highly soluble in both water and organic solvents with a low redox potential.

In the most promising and buzz-worthy part of his keynote, Dr. AlSogair informed the crowd that methylene blue actually reverses aging, has a neuroprotective effect on Alzheimer's patients, extended the life of female mice by 6%, and showed promise in the treatment of progeria, a rare genetic disorder that causes rapid-aging in children.

What's more, when applied to a 3D skin model, methylene blue promoted wound healing, increased skin hydration, and thickened the skin to a more youthful depth. But one of the most exciting dermatological findings learned was centered on one of the most obvious--and reviled--signs of aging: Wrinkles.

"Wrinkling is a highly visible feature of aged skin, and in the dermatology field, it is one of the top reasons patients seek treatment," Dr. AlSogair explained. "Skin wrinkling in aging is due to a reduction in collagen. Upon treatment with methylene blue, however, we see an increase in collagen production and skin hydration, as well as the prevention of collagen degradation. Taken together, our findings indicate methylene blue has promise in anti-aging cosmetic formulations."

The 19th World Dermatology Congress was held in Tokyo on May 7th and 8th, 2018. Other prominent speakers were Mexico's Andrea Merino-Ruisanchez, Italy's Roberto Dell'Avanzato, and China's Yan Li.

Phase 2 study of dexpramipexole in hypereosinophilic syndromes meets its co-primary endpoints

Knopp Biosciences LLC today announced the publication of a report in the journal Bloodthat a Phase 2 study of dexpramipexole in hypereosinophilic syndromes (HES) met its co-primary endpoints.

A team of investigators led by Dr. Amy Klion at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), undertook the open-label study of dexpramipexole as a steroid-sparing agent in subjects with HES. Dexpramipexole had been observed to produce a significant, targeted reduction of peripheral blood eosinophils in earlier clinical trials in amyotrophic lateral sclerosis.

Subjects with HES on glucocorticoid therapy were eligible for the study if they required ≥10 mg prednisone or equivalent for control of symptoms and eosinophilia. Prior to study treatment, subjects underwent a standardized glucocorticoid taper to determine their minimally effective glucocorticoid dose (MED). Subjects for whom the MED had been determined within the past year or with an eosinophil count ≥1000/µL at the time of enrollment were eligible to proceed directly to dexpramipexole treatment at the discretion of the principal investigator. After 12 weeks of oral dexpramipexole treatment (150 mg twice daily) on a stable glucocorticoid dose, a glucocorticoid taper was attempted and the MED on dexpramipexole (MEDD) was determined.

The trial enrolled 10 subjects and met the co-primary endpoints of: 1) percentage of subjects experiencing a ≥50% reduction in MED and 2) reduction of glucocorticoid requirement among all subjects. Notably, three of the four responders meeting the primary endpoint exhibited complete hematological responses (eosinophil count of zero or near-zero) and were able to discontinue prednisone completely. These subjects have remained symptom-free, eosinophil-free, and steroid-free for 13-32 months while continuing dexpramipexole treatment, as reported in the article.

The investigators also reported that three of four responders who underwent biopsies had complete resolution of eosinophilia in affected skin or gastrointestinal tissue. Delayed and partial hematological responses were also noted in the trial.

Dexpramipexole was well tolerated, with no adverse events leading to drug interruption or discontinuation.

The article concluded, "Well-tolerated and with a dosing schedule convenient for routine outpatient treatment, dexpramipexole shows great promise as a novel oral therapy for HES."

Michael Bozik, M.D., President and CEO of Knopp Biosciences, said, "The Blood publication demonstrates that dexpramipexole merits Phase 3 development in HES, a rare hematological disease with significant morbidity and limited treatment options. We are grateful for our collaboration with Dr. Klion and her NIH colleagues, and we look forward to initiating the Phase 3 study later this year."

HES comprises a heterogeneous group of rare disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. The NIH trial enrolled subjects with the FIP1L1-PGDFRA-negative form of the disease, which accounts for 85-90% of all HES. Although glucocorticoid therapy is the first-line treatment for patients with FIP1L1-PGDFRA-negative HES, many patients develop serious side effects or resistance over time.

The Phase 2 study was conducted as part of an agreement between Knopp Biosciences and NIAID, demonstrating industry-government collaboration in the field of rare disease drug development.

Ref : http://knoppbio.com/news-events/show.php?40

Study identifies molecule that may be critical to repair of white matter

In continuation of my update on hyaluronic acid (HA)

A new study identifies a molecule that may be critical to the repair of white matter, the fatty tissue wrapped around parts of brain cells that helps speed up communication. Damage to white matter is associated with several conditions, including multiple sclerosis and cerebral palsy, and can occur in the brains of preterm babies. New findings suggest that the molecule triggers a pathway that is normally used by the immune system to prevent excessive damage but may contribute to chronic white matter injury by completely blocking repair operations. The study, published in the May issue of Journal of Clinical Investigation, was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"This study uncovers a new player in white matter disease and identifies a potential drug target," said Jim Koenig, Ph.D., program director at NINDS. "It also describes a unique situation in which the brain tries to take over immune system functions, with devastating results."

White matter, also known as myelin, is formed by oligodendrocytes, specialized cells that come from developing cells called oligodendrocyte progenitor cells (OPCs). Studies have shown that in cases of chronic white matter injury, OPCs accumulate in the lesions, ready to help, but for some reason are not able to produce myelin. A very large molecule called hyaluronic acid (HA) also accumulates in the lesions and is broken down into small fragments that are thought to prevent OPCs from producing myelin.

A team led by Stephen Back, M.D., Ph.D., professor of pediatrics and neurology at the Oregon Health & Science University in Portland, took a detailed look at the HA fragments to see how they block myelin repair. Using state-of-the-art techniques, Dr. Back and his colleagues were able to create HA fragments of different sizes.

Results showed that only one specific size of HA, the 210 kDa fragment, had an effect on OPC proliferation.

Dr. Back and his team treated rat cells that mimicked white matter disease with the 210 kDa HA fragment. They discovered that the HA initially turned on molecules associated with myelination but then shut them down completely, a strategy that is similar to immune tolerance, which is used by the immune system to prevent severe tissue injury from an ongoing, damaging response to bacteria and viruses.

"We showed that HA creates not just a roadblock to myelin repair after injury, it also shuts down all of the possible detours," said Dr. Back. "Tolerance can be helpful in preventing the brain from repairing itself too quickly, but in some disease conditions, it can turn into a detrimental response."

Dr. Back and his team also discovered that the 210 kDa fragment signals to TLR4, a protein that oversees immune tolerance, to activate FoxO3, which helps control the activity of genes involved in myelin repair. This activation of FoxO3 eventually leads to a decrease in the activity of myelin-related genes and a slowdown in white matter repair. However, this process only takes place if HA is present.

When Dr. Back and his group looked at human brain tissue affected by white matter injury and multiple sclerosis, they found activated FoxO3 in OPCs that were blocked from producing myelin.

In the brain, the large, intact HA makes up most of the extracellular matrix, the substance found between cells. Damage to the extracellular matrix leads to inflammation and this can occur in white matter injury.

"For decades HA was thought of as simply a glue holding everything together. In recent years, we have come to learn how critical this molecule is for various pathways and potentially, many neurological disorders," said Dr. Back.

More research is needed to learn about the molecules involved in white matter repair as well as the role of different HA fragments in these processes.