Mylan Introduces Symfi (efavirenz, lamivudine and tenofovir disoproxil fumarate) Triple Combo Once-Daily HIV Treatment in the U.S.

             

Tenofovir disoproxil fumarate                              Lamivudine                   Efavirenz           

In continuation of my update, on Tenofovir, Lamivudine and Efavirenz

Global pharmaceutical company Mylan N.V.  announced that it will introduce in the U.S. a third cost-saving HIV combination. The U.S. Food and Drug Administration (FDA) approved Symfi (efavirenz, lamivudine and tenofovir disoproxil fumarate) 600 mg/300 mg/300 mg tablets, a once-daily, single-tablet regimen (STR), indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 40 kg.

"As the largest supplier of antiretrovirals by volume in the world, Mylan has a longstanding commitment to expanding affordable access to treatments for people living with HIV," said Mylan CEO Heather Bresch. "As we continue to grow our U.S. portfolio of ARV products, now including Symfi Lo™, Symfi™, and Cimduo™, we are providing access to patients and empowering them to choose the lower-cost ARV treatment option that is right for them."

The introduction of Symfi™ comes after the FDA's recent approval of two Mylan ARVs: Cimduo™ (lamivudine and tenofovir disoproxil fumarate) 300 mg/300 mg tablets, a once-daily combination of two nucleo(t)side reverse transcriptase inhibitors, which is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 35 kg.; and Symfi Lo™ (efavirenz, lamivudine and tenofovir disoproxil fumarate) 400 mg/300 mg/300 mg tablets, also approved for patients with HIV-1 in adults and pediatric patients weighing at least 35 kg.

Following FDA approval, Mylan launched Symfi Lo™ earlier in March. It expects Cimduo™ and Symfi™ to launch in the second quarter of 2018.

Symfi™ and Symfi Lo™ feature the same triple combination of molecules; however, Symfi Lo™ features a reduced dose of efavirenz while Symfi™ uses a dosing similar to other efavirenz products already on the market. The combination represented by Symfi™ (efavirenz, lamivudine and tenofovir disoproxil fumarate) 600 mg/300 mg/300 mg tablets is the most widely-taken ARV regimen outside of the U.S., with more than 7 million users worldwide in 2016¹.

In 2017, HIV was the category with highest pharmacy spend for Medicaid, the third highest for health exchange plans and the fifth highest for commercial plans.² According to IQVIA, total spending on HIV drugs has more than tripled since 2007, outpacing the approximate 60% growth in overall drug spending.

To help reduce the high cost of HIV treatment in the U.S, the list price of these Mylan ARVs will be discounted significantly from the wholesale acquisition cost of similar medicines on the market.

"Mylan has been on the forefront of bringing innovative delivery and dosage forms of ARVs to millions of patients in the developing world," said Mylan President Rajiv Malik. "We've already extended our reach to people in the U.S. living with HIV with the introduction of Symfi Lo™ and Cimduo™. Adding Symfi™ to our portfolio further strengthens our commitment to investing in developing and manufacturing these important products."

Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including lamivudine and tenofovir disoproxil fumarate. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus and HIV who have discontinued lamivudine and tenofovir disoproxil fumarate.

Mylan Introduces Symfi (efavirenz, lamivudine and tenofovir disoproxil fumarate) Triple Combo Once-Daily HIV Treatment in the U.S.

Pacira Announces FDA Approval of Exparel as a Nerve Block to Produce Regional Analgesia

Pacira Pharmaceuticals, Inc., announced that the U.S. Food and Drug Administration (FDA) has approved its supplemental new drug application (sNDA) to broaden the use of Exparel (bupivacaine liposome injectable suspension) to include administration via interscalene brachial plexus block to produce postsurgical regional analgesia. With this approval, Exparel is the first long-acting, single-dose nerve block available for patients undergoing upper extremity surgeries, such as total shoulder arthroplasty or rotator cuff repair.

“Brachial plexus blocks are emerging as a mainstay of postsurgical pain control for upper extremity procedures, and are well positioned to comprise more than 60 percent of all regional nerve block procedures within the next two years, ” said Dave Stack, chairman and chief executive officer at Pacira Pharmaceuticals. “In line with our corporate mission, we are very gratified to offer clinicians and patients another option for achieving long-lasting non-opioid pain control with Exparel, and to provide an increased ability to transition procedures commonly thought of as inpatient to the ambulatory setting.”

Since its initial approval in 2011 for single-dose infiltration into the surgical site, more than 3.75 million patients have been treated with Exparel in the post-marketing setting. The expansion of the Exparel label to now also include interscalene brachial plexus nerve block allows clinicians to potentially eliminate the need for cumbersome catheters and pumps traditionally used to extend the duration of regional analgesia.

“There is a critical need in the postsurgical setting for non-opioid options that turn off pain at the surgical site and reduce the need for opioids,” said Jeffrey Gadsden, MD, Chief of Orthopaedics, Plastics, and Regional Anesthesiology and Associate Professor of Anesthesiology at Duke University School of Medicine. “The ability to provide effective regional analgesia with a single dose of Exparel is a tremendous victory for patients and advances the imperative need for low- or no-opioid pain management strategies.”

The sNDA approval was based on positive data from a Phase 3 study of Exparel in brachial plexus block for shoulder surgeries, in which Exparel demonstrated statistical significance for the primary endpoint of cumulative pain scores over 48 hours as measured by the area under the curve (P<0.0001). Exparel also achieved statistical significance versus placebo for the study’s key secondary endpoints as follows: total postsurgical opioid consumption through 48 hours (P<0.0001); opioid-free subjects through 48 hours (P<0.01); and time to first opioid rescue through 48 hours (P<0.0001).

The safety profile for Exparel in the interscalene brachial plexus nerve block study was consistent with the previously reported safety profile of Exparel in wound infiltration, and also with the profile of bupivacaine when used as a brachial plexus nerve block.

The study randomized 156 patients across 17 sites in a 1:1 ratio to receive a single dose of either Exparel 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total volume of 20 mL or placebo 20 mL. Exparel was administered as a single-dose brachial plexus block under ultrasound guidance at least one hour prior to surgery. All patients were eligible to receive postsurgical rescue opioids upon request for pain control.

UCB Announces Briviact (brivaracetam) Now Approved by FDA to Treat Partial-Onset (Focal) Seizures in Pediatric Epilepsy Patients

 In continuation of my update on brivaracetam

UCB announced today that the U.S. Food and Drug Administration (FDA) has approved a supplemental new drug application (sNDA) for the company’s newest anti-epileptic drug (AED) Briviact (brivaracetam) oral formulations indicated as monotherapy and adjunctive therapy in the treatment of partial onset (focal) seizures in patients age four years and older.

This approval provides clinicians with the convenient option to prescribe Briviact to their pediatric patients as a tablet or oral solution, providing flexible administration options which are important considerations when treating children.

As the safety of Briviact injection has not been established in pediatric patients, Briviact injection is indicated for the treatment of partial-onset seizures only in patients 16 years of age and older.

As a result of the FDA’s decision, children age four years and older with partial-onset seizures in the U.S. can now be treated with Briviact. This extends the clinical application for Briviact which already has a similar indication for adults.

Briviact is the newest anti-epileptic drug (AED) in the synaptic vesicle protein 2A (SV2A) family of medicines – a class of medicines discovered and developed by UCB. Briviact demonstrates a high and selective affinity for SV2A in the brain. It is highly permeable and is rapidly and almost completely absorbed which may contribute to its anticonvulsant effects. Gradual dose escalation is not required when initiating treatment with Briviact for monotherapy or adjunctive therapy, allowing clinicians to initiate treatment at a therapeutic dose from day one.

“As a pediatric neurologist, one of the most challenging aspects in treating epilepsy in children is establishing, quickly, which anti-epilepsy drug will support them best in managing their seizures. The impact of poor seizure control can be extremely detrimental – both to overall quality of life for patients and caregivers and for a child’s development. There is a real sense of urgency for parents and healthcare providers to know whether a particular therapeutic approach is likely to be successful, minimizing some of the challenges associated with epilepsy and potentially allowing them to live a normal and active life,” explained Dr. James Wheless, Director, Neuroscience Institute & Le Bonheur Comprehensive Epilepsy Program - Le Bonheur Children’s Hospital. “The availability of an approved treatment option, such as Briviact, has potential to help improve the lives of children and their families by providing an additional choice to support them in their epilepsy journey.”

 Epilepsy in childhood is a complex disorder that can have a significant impact on many aspects of a child's development and function. Pediatric epilepsy is the most common, serious neurological disorder among children and young adults, thought to affect nearly 470,000 children in the U.S.1,2 Social and societal stigma still associated with epilepsy can be especially cruel for children. The prevalence of pediatric epilepsy has been steadily increasing in the U.S.3 Today, it is estimated that nearly 470,000 children in the U.S. under the age of 18 have epilepsy, representing around a quarter of the total worldwide population who develop the condition each year.4 The U.S. Centers for Disease Control and Prevention (CDC) estimate that 0.6 percent of children in the U.S. ages 0 to 17 have active epilepsy – equivalent to six students in a school of 1000.5 Despite its growing prevalence, approximately 10 to 20 percent of pediatric epilepsy patients experience inadequate seizure control with available anti-epileptic drugs.6,7,8 Alongside close partnerships with educators, family members, and healthcare providers, there is a need for newer AEDs with better seizure control which can support and maximize a child’s potential for academic success.

“We believe there is a real need for newer AEDs to support and maximize the potential for success for children with epilepsy,” explained Jeff Wren, Executive Vice-President, Head of UCB’s Neurology Patient Value Unit. “The approval of Briviact in the U.S for pediatric patients represents an important milestone for patients, families, doctors, UCB, and the wider epilepsy community, and has the potential to provide additional value for patients - both today and for their future. We are very excited to be able to provide a new pediatric treatment choice, and we are proud to support patients as they progress on their epilepsy journey.”

The expanded FDA indication for Briviact is based on the principle of extrapolation of its efficacy data from adults to children, and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are generally similar to those seen in adult patients9. This principle of extrapolating clinical data from well controlled studies in adults has been recognized by the FDA as potentially addressing the challenge of limited pediatric data availability.

The safety and effectiveness of Briviact in the treatment of partial-onset seizures have been established in patients four years of age and older. Use of Briviact in these age groups is supported by evidence from placebo-controlled partial-onset seizure studies of Briviact in adults with additional pharmacokinetic and open-label safety studies in pediatric patients age 4 to younger than 16 years of age. Partial-onset seizures in pediatric patients aged 4 to 16 years of age are similar to those in adults and a similar AED exposure-response relationship has been demonstrated. Weight-based dose adaptations have been established in the pediatric population to achieve similar plasma concentrations as observed in adults. The safety and tolerability profile for Briviact in pediatric patients 4 to 16 years of age is generally similar to that seen with adult patients. 

The most common adverse reactions recorded for adults (at least 5 percent for Briviact and at least 2 percent more frequently than placebo) are somnolence and sedation, dizziness, fatigue, and nausea and vomiting symptoms

Novartis Receives FDA Approval of Tafinlar + Mekinist for Adjuvant Treatment of BRAF V600-Mutant Melanoma

Novartis announced that the US Food and Drug Administration (FDA) has approved Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. The FDA granted the combination Breakthrough Therapy Designation for this indication in October 2017 and Priority Review in December 2017.

"Since the initial approval of Tafinlar and Mekinist in metastatic melanoma in 2013, the combination has become an important therapy for many patients carrying a BRAF mutation in both melanoma and lung cancers," said Liz Barrett, CEO, Novartis Oncology. "Today's FDA approval is an important milestone for patients who previously had limited treatment options in the adjuvant setting, and reflects our commitment to the ongoing development of this breakthrough treatment."

The melanoma approval is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with Tafinlar + Mekinist after complete surgical resection[1]. Patients received the Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432)[1]. After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53% as compared to placebo (HR: 0.47 [95% CI: 0.39-0.58]; p<0.0001; median not reached with combination therapy vs. 16.6 months with placebo)[1]. The RFS benefit among the combination arm was observed across all patient subgroups, including disease sub-stage[1]. Improvements were also observed in key secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS) and freedom from relapse (FFR)[1]. These results were published in the New England Journal of Medicine, October 2017[1].

"The purpose of adjuvant therapy is to improve recurrence-free and overall survival in our patients with melanoma. Adjuvant therapy options are crucial today because more than half of patients have a recurrence after surgery," said John M. Kirkwood, M.D., Usher Professor of Medicine, Director of Melanoma and Skin Cancer, University of Pittsburgh. "We developed the first adjuvant therapy approved by the FDA 22 years ago, and now we have the first effective oral targeted therapy combination that prevents relapse among patients with BRAF-mutated melanoma that has spread to lymph nodes."

"Prevention and early detection are important safeguards from melanoma, but that's only half the picture. Melanoma is an aggressive cancer that can recur, particularly when it shows certain warning signs like increased depth, ulceration, or spread to the lymph nodes," said Sancy Leachman, M.D., Ph.D., Chair of the Department of Dermatology at OHSU School of Medicine. "With proven treatment options for these patients, it is important for dermatologists to assure that appropriate patients are offered adjuvant treatment options - a 'watch and wait' approach is no longer the standard of care. Collaborating with a multidisciplinary care team of surgeons, pathologists and oncologists, and determining the right treatment based on the patient's individual circumstances and mutational status is crucial to our patients' care plans."

Novartis Receives FDA Approval of Tafinlar + Mekinist for Adjuvant Treatment of BRAF V600-Mutant Melanoma

FDA Expands Approval of Gilenya (fingolimod) to Treat Multiple Sclerosis in Pediatric Patients

In continuation of my update on fingolimod

The U.S. Food and Drug Administration today approved Gilenya (fingolimod) to treat relapsing multiple sclerosis (MS) in children and adolescents age 10 years and older. This is the first FDA approval of a drug to treat MS in pediatric patients.

“For the first time, we have an FDA-approved treatment specifically for children and adolescents with multiple sclerosis,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Multiple sclerosis can have a profound impact on a child’s life. This approval represents an important and needed advance in the care of pediatric patients with multiple sclerosis.”

Gilenya was first approved by the FDA in 2010 to treat adults with relapsing MS.

MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. It is among the most common causes of neurological disability in young adults and occurs more frequently in women than men. For most people with MS, episodes of worsening function and appearance of new symptoms, called relapses or flare-ups, are initially followed by recovery periods (remissions). Over time, recovery may be incomplete, leading to progressive decline in function and increased disability. Most people with MS experience their first symptoms, like vision problems or muscle weakness, between the ages of 20 to 40. Two to five percent of people with MS have symptom onset before age 18 and estimates suggest that 8,000 to 10,000 children and adolescents in the U.S. have MS.

The clinical trial evaluating the effectiveness of Gilenya in treating pediatric patients with MS included 214 evaluated patients aged 10 to 17 and compared Gilenya to another MS drug, interferon beta-1a. In the study, 86 percent of patients receiving Gilenya remained relapse-free after 24 months of treatment, compared to 46 percent of those receiving interferon beta-1a.

The side effects of Gilenya in pediatric trial participants were similar to those seen in adults. The most common side effects were headache, liver enzyme elevation, diarrhea, cough, flu, sinusitis, back pain, abdominal pain and pain in extremities.

Gilenya must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Serious risks include slowing of the heart rate, especially after the first dose. Gilenya may increase the risk of serious infections. Patients should be monitored for infection during treatment and for two months after discontinuation of treatment. A rare brain infection that usually leads to death or severe disability, called progressive multifocal leukoencephalopathy (PML) has been reported in patients being treated with Gilenya. PML cases usually occur in patients with weakened immune systems. Gilenya can cause vision problems. Gilenya may increase the risk for swelling and narrowing of the blood vessels in the brain (posterior reversible encephalopathy syndrome). Other serious risks include respiratory problems, liver injury, increased blood pressure and skin cancer. Gilenya can cause harm to a developing fetus; women of child-bearing age should be advised of the potential risk to the fetus and to use effective contraception.

Neonicotinoids may alter estrogen production in humans | INRS

Neonicotinoids-a class of neuro-active insecticides chemically similar to nicotine (family includes acetamiprid, clothianidin, imidacloprid, nitenpyram, nithiazine, thiacloprid and thiamethoxam) are currently the most widely used pesticides in the world and frequently make headlines because of their harmful effects on honeybees and other insect pollinators. Now, a study published in the prestigious journal Environmental Health Perspectives, indicates they may also have an impact on human health by disrupting our hormonal systems. This study by INRS professor Thomas Sanderson indicates that more work must be done on the potential endocrine-disrupting effects of neonicotinoids. 

The Quebec government has recently decided to more strictly regulate the use of certain pesticides, including neonicotinoids, which are widely used by Quebec farmers to control crop pests. Neonicotinoids act on insects’ nervous systems, killing them by paralysis. Very little research has been done on their effects on human health, but INRS Professor Sanderson and Ph.D. student Élyse Caron-Beaudoin have taken on the challenge. 

Both researchers have long been interested in the mechanisms of endocrine disrupting chemicals and they wanted to determine whether neonicotinoids belong to this class of compounds. “Endocrine disrupters are natural or synthetic molecules that can alter hormone function,” says Caron-Beaudoin, the study’s main author. ”They affect the synthesis, action, or elimination of natural hormones, which can lead to a wide variety of health effects.”  

The research duo has developed methods to test the effect of neonicotinoids on the production of estrogens, essential hormones with several biological functions. By targeting aromatase, a key enzyme in the synthesis of estrogens, they were able to test the impact of three neonicotinoids on breast cancer cells in culture after exposure to concentrations similar to those found in the environment in agricultural areas. 

The results of the study show an increase in aromatase expression and a unique change in the pattern in which aromatase was expressed, which is similar to that observed in the development of certain breast cancers. “However, as these results were obtained in a cellular model of breast cancer, we cannot necessarily conclude that exposure to pesticides at concentrations similar to those in the human environment would cause or promote cancer,” cautions Professor Sanderson. This study is the first evidence that neonicotinoids have an effect on aromatase gene expression and may potentially alter estrogen production. Hormonal disturbance by these pesticides will need to be confirmed in future studies, but the results obtained by the INRS team indicate that it caution should be exercised in the management and use of neonicotinoid insecticides.

Ref : https://ehp.niehs.nih.gov/EHP2698/

Neonicotinoids may alter estrogen production in humans | INRS

FDA Approves Jynarque (tolvaptan) to Slow Kidney Function Decline in Rapidly Progressing Autosomal Dominant Polycystic Kidney Disease

Otsuka Pharmaceutical Co., Ltd. (Otsuka) announces that the U.S. Food and Drug Administration (FDA) has approved Jynarque (tolvaptan) as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).

ADPKD is a genetic disease with consequences that can lead to dialysis or kidney transplantation. It is a progressively debilitating and often painful disorder in which fluid-filled cysts develop in the kidneys over time. These cysts enlarge the kidneys and impair their ability to function normally, leading to kidney failure in most patients.3 ADPKD is diagnosed in approximately 140,000 people in the U.S.,4,5 and impacts families across multiple generations, since a parent with ADPKD has a 50 percent chance of passing the disease on to each of their children. 

The efficacy of tolvaptan was demonstrated in two pivotal trials, lasting one year and three years, respectively. In the one-year REPRISE study, the primary endpoint was the treatment difference in the change of eGFR from pretreatment baseline to post-treatment follow-up, annualized by dividing by each subject’s treatment duration. In the randomized period, the change of eGFR from pretreatment baseline to post-treatment follow-up was −2.3 mL/min/1.73 m2/year with tolvaptan as compared with −3.6 mL/min/1.73 m2/year with placebo, corresponding to a treatment effect of 1.3 mL/min/1.73 m2/year (p <0.0001). In the three-year TEMPO 3:4 study, tolvaptan reduced the rate of decline in eGFR by 1.0 mL /min /1.73m2 /year (95 % confidence interval of 0.6 to 1.4) as compared to placebo in patients with earlier stages of ADPKD. In the extension trial, eGFR differences produced by the third year of the TEMPO 3:4 trial were maintained over the next 2 years of Jynarque treatment.

The primary endpoint in TEMPO 3:4 study was the intergroup difference for rate of change of total kidney volume (TKV) normalized as a percentage. The trial met its pre-specified primary endpoint of 3-year change in TKV (p<0.0001). The difference in TKV between treatment groups mostly developed within the first year, the earliest assessment, with little further difference in years two and three. In years 4 and 5 during the TEMPO 3:4 extension trial, both groups received Jynarque and the difference between the groups in TKV was not maintained. Tolvaptan has little effect on kidney size beyond what accrues during the first year of treatment. The key secondary composite endpoint (ADPKD progression) was time to multiple clinical progression events of: 1) worsening kidney function (defined as a persistent 25% reduction in reciprocal serum creatinine during treatment (from end of titration to last on-drug visit); 2) medically significant kidney pain (defined as requiring prescribed leave, last-resort analgesics, narcotic and anti-nociceptive, radiologic or surgical interventions); 3) worsening hypertension (defined as a persistent increase in blood pressure category or an increased anti-hypertensive prescription); 4) worsening albuminuria (defined as a persistent increase in albumin/creatinine ratio category). The relative rate of ADPKD-related events was decreased by 13.5% in tolvaptan-treated patients, (44 vs. 50 events per 100 person-years; hazard ratio, 0.87; 95% CI, 0.78 to 0.97; p=0.0095). As shown in the table below, the result of the key secondary composite endpoint was driven by effects on worsening kidney function and kidney pain events. In contrast, there was no effect of tolvaptan on either progression of hypertension or albuminuria. Few subjects in either arm required a radiologic or surgical intervention for kidney pain. Most kidney pain events reflected use of a medication to treat pain such as use of paracetamol, tricyclic antidepressants, narcotics and other non-narcotic agents.

Jynarque can cause serious and potentially fatal liver injury, and acute liver failure requiring liver transplantation has been reported. Jynarque has been associated with elevations of blood alanine and aspartate aminotransferases (ALT and AST), with infrequent cases of concomitant elevations in bilirubin-total (BT). To ensure the safety of patients taking Jynarque, it is necessary to measure ALT, AST and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter, for as long as the patient is on Jynarque (tolvaptan) treatment. Because of the risks of serious liver injury, Jynarque is available only through a restricted distribution program supported by a Risk Evaluation and Mitigation Strategy (REMS) Program approved by the FDA. For more information about Jynarque, please visit www.JYNARQUE.com.

"The progressive nature of ADPKD means that kidney function gets worse over time, eventually leading to end-stage renal disease. This progression happens more rapidly for some patients than others.” said Michal Mrug, M.D., Associate Professor at the University of Alabama at Birmingham and investigator on the REPRISE trial. “Today’s approval is great news for adults at risk of rapidly progressing ADPKD because by slowing the decline in kidney function, this therapy may give them more time before kidney transplant or dialysis.”

Andy Betts, CEO of the PKD Foundation, observed, “Today is an historic day in providing hope to patients with autosomal dominant polycystic kidney disease, and we are thrilled to be a part of this first milestone in treatment. For the past 35 years, our goal has been to walk with PKD patients every step of the way. It is gratifying to play a part in the inception of the discovery of this treatment, and to see it come to fruition. We hope that this is just the beginning of a new chapter for adults at risk of rapidly progressing ADPKD who suffer from the disease.”

Also, Tatsuo Higuchi, president and representative director of Otsuka Pharmaceutical Co., Ltd., commented, “This approval is important news for many adults at risk of rapidly progressing ADPKD in the U.S., who have had no therapeutic alternatives to delay the eventual end-stage interventions of dialysis or kidney transplantation. We are humbled to be able to offer an earlier, proactive course of action to slow the progression of this disease, which we know means so much to patients, their families and healthcare providers. Simultaneously, we are grateful to the patients and researchers who through their continued commitment made this milestone possible.”

FDA Approves Jynarque (tolvaptan) to Slow Kidney Function Decline in Rapidly Progressing Autosomal Dominant Polycystic Kidney Disease

What Does the Research Say About Coffee and Your Health?

In continuation of my update on coffee...

Coffee-Cup of joe. Java. No matter what you call it, millions of people worldwide wake up and fuel their day with it. And though consumers might be jittery about the recent court battle in California over cancer warnings, experts say most of the science actually indicates coffee could have health benefits.

"The overall picture is quite clear," said Dr. Frank Hu, chair of nutrition at Harvard University's T.H. Chan School of Public Health. "There is no long-term increased risk of major chronic disease, including diabetes, cardiovascular disease or even cancer."

The java confusion stems over an eight-year court case. A Los Angeles-based judge's preliminary decision last month requires cancer warning labels because of concerns about acrylamide, a chemical produced during the roasting process. Acrylamide also is present in some fried or roasted starchy foods, including french fries, potato chips, breakfast cereals and toast. It's also found in cigarette smoke. The judge gave the coffee industry a few weeks to file appeals and could issue a final ruling late this month.

But there's little evidence acrylamide levels in food cause cancer in humans. Studies have found no consistent evidence acrylamide exposure in food is associated with cancer risk, according to the U.S. National Cancer Institute. The World Health Organization's International Agency for Research on Cancer reviewed more than 1,000 human and animal studies and issued a statement in 2016 that "found no conclusive evidence for a carcinogenic effect of drinking coffee."

"The California judge's decision to label coffee as a cancer risk is really inconsistent with the scientific literature," Hu said. "It's very misleading and has already caused a huge amount of confusion in the general public. The health outcomes have been remarkably consistent."

Hu was senior author of a 2015 study in the journal Circulation that concluded people who regularly drink moderate amounts of coffee daily -- fewer than five cups -- experienced a lower risk of death from heart and neurological diseases.

About four years ago, the U.S. government gave coffee its OK, too. The Department of Agriculture's dietary guidelines for all Americans, published every five years as a go-to source for nutrition advice, said three to five cups a day, which can be up to 400 milligrams a day of caffeine, can be part of a healthy diet. The American Heart Association suggests that people who have an arrhythmia, an abnormal heart rhythm, talk to their health care provider about caffeine intake.

"This guidance on coffee is informed by strong and consistent evidence showing that, in healthy adults, moderate coffee consumption is not associated with an increased risk of major chronic diseases (e.g., cancer) or premature death, especially from cardiovascular disease," the federal guidelines say. "However, individuals who do not consume caffeinated coffee or other caffeinated beverages are not encouraged to incorporate them into their eating pattern."

More recently, a review of more than 200 studies published last fall in the BMJ concluded three to four cups a day may be "more likely to benefit health than harm." It found a lower risk of liver disease and some cancers in coffee drinkers, and a lower risk of dying from stroke.

All of that should be good news to the people around the world who drink more than 1.1 billion cups of coffee each day.

But it's still easy to be confused. A quick search for coffee and health online yields hundreds, even thousands, of results.

Studies abound -- some funded by the coffee industry. For example, a European Journal of Nutritionstudy investigated the effects of coffee and its antioxidant properties and found no effect. Researchers took blood samples of 160 volunteers who drank up to three to five cups of coffee or water each day for eight weeks.

"Up to five cups of coffee per day had no detectable effect, either beneficial or harmful, on human health," that study concluded. It was funded by Kraft Foods, which makes Maxwell House coffees.

Of course, "no one is talking about coffee as a magic bullet," Hu said. He and other experts say it's important to keep track of the bigger picture, with the focus on moderation and dietary patterns.

"You can't pin anything on any one specific lifestyle behavior, particularly with diet," said Alice Lichtenstein, a senior scientist and director of the Cardiovascular Nutrition Laboratory at Tufts University in Boston.

"When we talk about diet, it should really be about the whole package, not single items. Right now, the majority of the evidence suggests there may be a health benefit from drinking coffee and there doesn't seem to be any disadvantage. Of course, with a caveat that you don't want to add a lot of cream and sugar, or to use it as an excuse to have a few cookies or a pastry. Then, there is a downside," said Lichtenstein, a professor of nutrition science and policy who also was an advisor on the federal dietary guidelines.

"We have a tendency to focus on one or two specific foods or beverages, and that's when the whole floor falls out from under us."

FDA Approves Tavalisse (fostamatinib disodium hexahydrate) for Chronic Immune Thrombocytopenia

Rigel Pharmaceuticals, Inc.   announced that the U.S. Food and Drug Administration (FDA) approved Tavalisse (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Tavalisse is an oral spleen tyrosine kinase (SYK) inhibitor that targets the underlying autoimmune cause of the disease by impeding platelet destruction, providing an important new treatment option for adult patients with chronic ITP. Rigel plans to launch Tavalisse in the United States in late May 2018.

"Chronic ITP is challenging to treat because the heterogeneity of the disease makes it difficult to predict how an individual patient will respond to available treatments and not all patients can find a treatment that works well for them," said James Bussel, M.D., professor emeritus of pediatrics at Weill Cornell Medicine and the principal study investigator on the FIT Phase 3 program. Dr. Bussel has served as a consultant and paid member of the advisory board for Rigel Pharmaceuticals, Inc. "The FDA approval of fostamatinib arms physicians with a new treatment option, which works via a novel mechanism."

The FDA approval of Tavalisse was supported by data from the FIT clinical program, which included two randomized placebo-controlled Phase 3 trials (Studies 047 and 048) and an open-label extension (Study 049), as well as an initial proof of concept study. The New Drug Application (NDA) included data from 163 ITP patients and was supported by a safety database of more than 4,600 subjects across other indications in which fostamatinib has been evaluated.

"People living with chronic ITP often feel they have an invisible disease -- one that can not only impact quality of life, but also be life threatening," said Caroline Kruse, executive director of the Platelet Disorder Support Association, a patient advocacy organization dedicated to ITP patients. "That's why we encourage members of our community to learn about their disease, understand treatment strategies, and seek support so that they can advocate for their best care. The availability of a new treatment option provides the ITP community with more choices."

FDA Approves Tavalisse (fostamatinib disodium hexahydrate) for Chronic Immune Thrombocytopenia

Scientists successfully test anti-alcoholism drug in animal models

Scientists at The University of Texas at Austin have successfully tested in animals a drug that, they say, may one day help block the withdrawal symptoms and cravings that incessantly coax people with alcoholism to drink. If eventually brought to market, it could help the more than 15 million Americans, and many more around the world who suffer from alcoholism stay sober.

If what has been shown to work in worms and rats addicted to alcohol can eventually be demonstrated to work in humans with minimal side effects, it would be a true breakthrough. Scientists point out, however, that the drug has more hoops to go through before that happens.

There are already drugs on the market prescribed to help people break their addiction to alcohol, but for many patients, they are not very effective and have negative side effects. The new drug, called JVW-1034, targets a different molecular pathway in the body and so far, in animal models, has no obvious side effects.

"There's clearly a huge need for something different and better," said James Sahn, research scientist in chemistry at UT Austin and co-first author of a new paper. "That's where our approach shines. It's modulating a pathway that doesn't seem to be associated with any of the other drugs that are available."

The researchers reported their findings in the journal Neuropsychopharmacology and have filed a patent on the drug.

The paper's other co-first authors are Luisa Scott, a research associate in neuroscience at UT Austin; and Antonio Ferragud, a postdoctoral associate at Boston University School of Medicine (BUSM). Senior authors are Stephen Martin, professor of chemistry, and Jonathan Pierce, associate professor of neuroscience, both at UT Austin; and Valentina Sabino, associate professor of pharmacology and psychiatry at BUSM.

While the drug is promising, the researchers plan to optimize its chemical properties to have a better chance of being effective in humans. They envision a pill that could one day be taken to block alcohol withdrawal symptoms and cravings, helping people avoid relapsing. But it isn't clear whether such a drug could actually cure alcoholism. That's because there are genetic and regulatory underpinnings to the disorder that researchers don't fully understand yet and that may not be permanently altered by this drug. But even a drug that could be taken chronically or in times of stress could have a huge benefit for people suffering from alcoholism.

"If we could achieve a medication that is effective for more people and doesn't have the negative side effects that some of these drugs have, that would be game-changing," said Martin.

It might also make a dent in the $250 billion annual cost of alcohol misuse in the U.S., as estimated by a 2015 study.

This work was supported by The Robert A. Welch Foundation, the Dell Medical School's Texas Health Catalyst program, donations from individuals including Tom Calhoon and June Waggoner through a crowdfunding program called Hornraiser, and the National Institute on Alcohol Abuse and Alcoholism.

Screening in Worm and Rat Models

The drug JVW-1034 was named in honor of James Virgil Waggoner, a UT Austin alumnus, businessman and philanthropist who donated funds to establish the university's Waggoner Center for Alcohol and Addiction Research.

It was one of many potential compounds developed in the lab by chemists Stephen Martin and James Sahn, which they suspected would interact with a cell receptor found throughout the central nervous systems of animals, called sigma 2. Other researchers had shown that that receptor was involved in cocaine addiction. So Martin and Sahn wondered whether it might also be involved in alcoholism.

To screen their compounds, their colleague Luisa Scott created hungover worms. She exposed C. elegans worms to alcohol for a day and then took it away. She could tell they were hungover because when she placed a tasty-smelling substance on the other side of their petri dish, they sluggishly meandered over.

"It smells like movie theater popcorn," Scott said. "Normal worms are quite speedy, but withdrawal worms go very slowly."

When she administered JVW-1034 to the hungover worms, they once again raced across the dish just like worms that had never been exposed to alcohol.

In follow-up experiments, Scott demonstrated that the receptor sigma 2 was in fact the target of JVW-1034. This also demonstrated for the first time that sigma 2 is involved in alcohol addiction. She noted that it can be difficult to identify which parts of an animal's cells a drug interacts with. In fact, scientists still don't know the targets of many drugs that have been in use for many years.

"So for me, being able to show that this really is the target it binds to, that's a big deal," she said.

Finally, a group of collaborators led by Valentina Sabino tested JVW-1034 in alcoholic rats. Alcoholic rats that could freely access alcohol and were then given JVW-1034 dramatically reduced their alcohol consumption.

The researchers are developing several other promising drugs that target the sigma 2 receptor to treat other neurological disorders, including traumatic brain injury, neuropathic pain and Alzheimer's disease.

FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer

In continuation of my update on Osimertinib, AstraZeneca,announced that the US Food and Drug Administration (FDA) has approved Tagrisso (osimertinib) for the 1st-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or exon 21 L858R mutations), as detected by an FDA-approved test. The approval is based on results from the Phase III FLAURA trial, which were presented at the European Society of Medical Oncology 2017 Congress and published in the New England Journal of Medicine.

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: “Today’s FDA approval of Tagrisso in the 1st-line setting is an exciting milestone for patients and our company. Tagrisso delivered unprecedented median progression-free survival data across all pre-specified patient subgroups, including patients with or without CNS metastases, and could prolong the lives of more patients without their tumors growing or spreading.”

Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial, from Winship Cancer Institute of Emory University, Atlanta, said: “The approval of osimertinib (Tagrisso) in the 1st-line setting represents a major advance in the treatment of patients with EGFR mutations and a significant change in the treatment paradigm. Osimertinib (Tagrisso) provides robust improvements in progression-free survival with no unexpected safety signals compared to the previous generation of EGFR inhibitors.”

The FLAURA trial compared Tagrisso to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib, in previously untreated patients with locally advanced or metastatic EGFR-mutated (EGFRm) NSCLC. Tagrisso met the primary endpoint of progression-free survival (PFS) (see table below). PFS results with Tagrisso were consistent across all pre-specified patient subgroups, including in patients with or without central nervous system (CNS) metastases. Overall survival data were not mature at the time of the final PFS analysis.

*Confirmed responses

Safety data for Tagrisso in the FLAURA trial were in line with those observed in prior clinical trials. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 34% of patients taking Tagrisso and 45% in the comparator arm. The most common adverse reactions (≥20%) in patients treated with Tagrisso were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), fatigue (21%) and decreased appetite (20%).

In the US, Tagrisso is already approved for the 2nd-line treatment of patients with metastatic EGFRm NSCLC, whose disease has progressed on or after a 1st-line EGFR-TKI therapy and who have developed the secondary T790M mutation, as detected by an FDA-approved test. In 2017, Tagrisso was granted Breakthrough Therapy and Priority Review designations by the US FDA in the 1st-line treatment setting. Tagrisso is under regulatory review in the European Union and Japan for use in the 1st-line treatment setting with regulatory decisions anticipated in the second half of 2018.

Tagrisso received its first approval for 1st-line use based on the FLAURA data in Brazil in patients with metastatic EGFRm NSCLC on April 16, 2018.

FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer

FDA Approves Intravenous Formulation of Akynzeo (fosnetupitant/palonosetron) for Chemotherapy-Induced Nausea and Vomiting

Helsinn, a Swiss pharmaceutical group focused on building quality cancer care products, today announces that the U.S. Food and Drug Administration (FDA) has approved the intravenous formulation of Akynzeo (NEPA, a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg) as an alternative treatment option for patients experiencing CINV.

     

The FDA has approved Akynzeo IV (formulation of fosnetupitant first structure  and palonosetron second structure) in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Akynzeo for injection has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy.

Oral Akynzeo was previously approved by the FDA as a fixed combination oral agent in 2014 for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Akynzeo is an oral fixed combination of palonosetron and netupitant: palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

The bioequivalence of the IV with the oral formulation of netupitant was demonstrated and the safety of IV NEPA was established through a repeated dose safety study in cancer patients to potentially uncover adverse drug reactions that may appear during subsequent clinical practice. No anaphylactic and injection site reactions related to IV NEPA were reported in this study.

Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting.

The prevention of CINV has been refined in treatment guidelines over the past several decades. Currently the combination treatment of antiemetic medicines with different mechanisms of actions are recommended for the prevention of CINV.

The approval of Akynzeo in IV formulation will offer to US patients and healthcare providers an alternative route of administration of the only fixed antiemetic combination targeting two distinct CINV pathways in a single dose.

Riccardo Braglia, Helsinn Group Vice Chairman and CEO, commented: “The approval of the intravenous formulation of Akynzeo paves the way to bring this important therapeutic option to more patients in a new formulation, and we are delighted that we are now able to push ahead with launching this product in the United States in May 2018”

FDA Approves Intravenous Formulation of Akynzeo (fosnetupitant/palonosetron) for Chemotherapy-Induced Nausea and Vomiting