FDA grants approval for two drugs administered together to treat aggressive form of thyroid cancer

 In continuation of my update on dabrafenib & trametinib

     dabrafenib                 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).

"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.

New chemical trap catches trace glycoproteins, shows promise for targeted cancer treatments

Cancer drops sparse chemical hints of its presence early on, but unfortunately, many of them are in a class of biochemicals that could not be detected thoroughly, until now.

Researchers at the Georgia Institute of Technology have engineered a chemical trap that exhaustively catches what are called glycoproteins, including minuscule traces that have previously escaped detection.

Glycoproteins are protein molecules bonded with sugar molecules, and they're very common in all living things. Glycoproteins come in myriad varieties and sizes and make up important cell structures like cell receptors. They also wander around our bodies in secretions like mucus or hormones.

But some glycoproteins are very, very rare and can serve as an early signal, or biomarker, indicating there's something wrong in the body – like cancer. Existing methods to reel in glycoproteins for laboratory examination are relatively new and have had big holes in their nets, so many of these molecules, especially those very rare ones produced by cancer, have tended to slip by.

Cancerous traces

"These tiny traces are critically important for early disease detection," said principal investigator Ronghu Wu, a professor in Georgia Tech's School of Chemistry and Biochemistry. "When cancer is just getting started, aberrant glycoproteins are produced and secreted into body fluids such as blood and urine. Often their abundances are extremely low, but catching them is urgent."

This new chemical trap, which took Georgia Tech chemists several years to develop and is based on a boronic acid, has proven extremely effective in lab tests including on cultured human cells and mouse tissue samples.

"This method is very universal," said first author Haopeng Xiao, a graduate research assistant. "We get over 1,000 glycoproteins in a really small lab sample."

In comparison tests with existing methods, the chemical trap, a complex molecular construction reminiscent of an octopus, captured exponentially more glycoproteins, especially more of those trace glycoproteins.

Wu, Xiao and Weixuan Chen, a former Georgia Tech postdoctoral researcher, who was also first author of the study alongside Xiao, published their results in the journal Nature Communications. The research was funded by the National Science Foundation and the National Institutes of Health.

Boronic bungles

For chemistry whizzes, here's a short summary of how the researchers made the octopus. They took a good thing and doubled then tripled down on it.

Those who recall high school chemistry class may still know what boric acid is, as do people who use it to kill roaches. Its chemical structure is an atom of boron bonded with three hydroxyl groups (H3BO3).

Boronic acids are a family of organic compounds that build on boric acid. There are many members of the boronic acid family, and they tend to bond well with glycoproteins, but their bonds can be less reliable than needed.

"Most boronic acids let too many low-abundance glycoproteins get away," Wu said. "They can catch glycoproteins that are in high abundance but not those in low abundance, the ones that tell us more valuable things about cell development or about human disease."

Benzoboroxole octopus

But the Georgia Tech chemists were able to leverage the strengths of boronic acids to develop a glycoprotein capturing method that works exceptionally well.

First, they tested several boronic acid derivatives and found that one called benzoboroxole strongly bound with each sugar component on the glycopeptide. ("Peptide" refers to the basic chemical composition of a protein.)

Then they stitched many benzoboroxole molecules together with other components to form a "dendrimer," which refers to the resulting branch- or tentacle-like structure. The finished large molecule resembled an octopus ready to go after those sugar components.

In its middle, similarly positioned to an octopus's head, was a magnetic bead, which acted as a kind of handle. Once the dendrimer caught a glycoprotein, the researchers used a magnet to grab the bead and pull out their chemical octopus along with its ensnared glycopeptides (e.g. glycoproteins).

"Then we washed the dendrimer off with a low pH solution, and we had the glycoproteins analyzed with things like mass spectrometry," Wu said.

Cancer treatments?

The researchers have some ideas about how medical laboratory researchers could make practical use of the new Georgia Tech method to detect odd biomolecules emitted by cancer, such as antigens. For example, the chemical octopus could improve detection of prostate-specific antigens (PSA) in prostate cancer screenings.

"PSA is a glycoprotein. Right now, if the level is very high, we know that the patient may have cancer, and if it's very low, we know cancer is not likely," Wu said. "But there is a gray area in between, and this method could lead to much more detailed information in that gray area."

The researchers also believe that developers could leverage the chemical invention to produce targeted cancer treatments. Immune cells could be trained to recognize the aberrant glycoproteins, track down their source cancer cells in the body and kill them.

The research's potential for science goes far beyond its possible future medical applications.

The fields of genomics and proteomics have made great strides. Following in their footsteps, this new molecular trap could advance the study of the rising field of glycoscience.

Source:http://www.rh.gatech.edu/news/605861/chemical-octopus-catches-sneaky-cancer-clues-trace-glycoproteins

New chemical trap catches trace glycoproteins, shows promise for targeted cancer treatments

Once-Daily Trelegy Ellipta Gains Expanded Indication in the US for the Treatment of Patients with COPD

In continuation of my update on fluticasone furoate, umeclidinium and vilanterol

GlaxoSmithKline plc   and Innoviva, Inc.    announced that the US Food and Drug Administration,  has approved an expanded indication for Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol ‘FF/UMEC/VI’), which means this medicine can now be used by US physicians to treat a broader population of chronic obstructive pulmonary disease (COPD) patients with airflow limitation or who have experienced an acute worsening of respiratory symptoms.

fluticasonefuroate

  umeclidinium

 vilanterol

The new indication is for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. It is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. It is not indicated for relief of acute bronchospasm or for the treatment of asthma.

Dr. Hal Barron, Chief Scientific Officer and President of Research and Development, GSK, said, “Following the initial approval of Trelegy Ellipta in September, we have analysed the data from the IMPACT study and identified additional benefits that this important medicine offers patients with chronic obstructive pulmonary disease. We are pleased that the robust data from the IMPACT study has enabled the expanded indication announced today and the FDA action has been taken so swiftly. We will continue to analyse the data from the IMPACT trial and our ongoing Trelegy Ellipta studies to demonstrate further the value of this important medicine to patients.”

The approval is based on a supplemental New Drug Application (sNDA) supported by data from the landmark InforMing the PAthway of COPD Treatment (IMPACT) study which showed Trelegy Ellipta was superior to the inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA), Relvar/Breo Ellipta (FF/VI), and long-acting muscarinic antagonist/long-acting beta2-adrenergic agonist (LAMA/LABA), Anoro Ellipta (UMEC/VI), on multiple clinically important endpoints, including reducing exacerbations and improving lung function and health related quality of life.

Dr Ted Witek, Senior Vice President and Chief Scientific Officer at Innoviva added: “Up to half of patients with COPD on maintenance therapy will have experienced at least one exacerbation in the past 12 months, so gaining an indication that reflects the role Trelegy Ellipta can play in reducing this risk is important.We welcome this regulatory update which will allow physicians to offer the benefits of once-daily single inhaler triple therapy to appropriate patients with COPD.”1

Trelegy Ellipta was originally approved for use in the US in September 2017 for the long-term, once-daily, maintenance treatment of COPD patients who are receiving Breo and require additional bronchodilation or who are receiving Breo and Incruse (UMEC). A type II variation to support an expanded label in Europe was submitted to the European Medicines Agency (EMA) in February 2018 and is currently under review.

The boxed warning has also been removed from the Trelegy Ellipta prescribing information, in line with the recent updates to the ICS/LABA class. Labelling changes to ICS/LABA combination medicines were implemented following a review of safety data submitted to the FDA by three companies including GSK and approved on December 20, 2017.

FDA Advisory Committee Votes in Favor of Lucemyra (lofexidine) for the Mitigation of Opioid Withdrawal Symptoms

US WorldMeds,  announced that the US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee voted 11 to 1 to recommend approval of lofexidine for mitigating opioid withdrawal symptoms. If approved, lofexidine will be marketed under the brand name Lucemyra.

The Advisory Committee's discussions were based on US WorldMeds' New Drug Application (NDA) for Lucemyra, which is currently under priority review by the FDA. The NDA includes data from two randomized, double-blind, placebo-controlled clinical trials and several supporting studies that examined the safety and efficacy of Lucemyra.

Lucemyra suppresses the neurochemical surge that produces the acute and painful symptoms of opioid withdrawal. In clinical trials compared to placebo, participants treated with Lucemyra experienced less severe withdrawal symptoms and were more likely to complete a seven-day opioid discontinuation treatment. If approved, Lucemyra will be the first and only non-opioid medication indicated for the mitigation of opioid withdrawal symptoms. Opioid withdrawal symptoms may include feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches/pains, yawning, runny eyes, insomnia/problems sleeping.

"Today's favorable recommendation brings us one step closer to providing evidence-based medication, and hope for recovery, to people who want to discontinue opioid use and are struggling with the agonizing symptoms of opioid withdrawal, one of the most powerful factors driving opioid dependence and addictive behaviors," said Mark Pirner, M.D., Ph.D., senior medical director. "We look forward to working closely with the FDA to bring this much-needed medication to people in the United States."

The FDA will consider the Advisory Committee's non-binding recommendation in its review of the NDA for Lucemyra. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date in the second quarter of 2018.

https://en.wikipedia.org/wiki/Lofexidine

FDA Advisory Committee Votes in Favor of Lucemyra (lofexidine) for the Mitigation of Opioid Withdrawal Symptoms

Paratek’s New Drug Applications for Oral and Intravenous Omadacycline Accepted for Priority Review by FDA

Paratek Pharmaceuticals, Inc.   announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Applications (NDAs) and granted a priority review for omadacycline, an investigational once-daily oral and intravenous (IV) broad spectrum antibiotic. Paratek is seeking approval of omadacycline, a modernized tetracycline, for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). The two NDAs were granted priority review based on the significant unmet medical need for new agents to treat ABSSSI and CABP. In addition to Priority review, omadacycline has previously been granted Qualified Infectious Disease Product (QIDP) and Fast Track designations for the treatment of CABP and ABSSSI.

“Antibiotic resistance is on the rise, and the need for new antibiotics is urgent. The FDA acceptance of these applications brings us one step closer to providing physicians an important new option in the fight against community-acquired infections,” said Evan Loh, MD, President, Chief Operating Officer and Chief Medical Officer of Paratek. “With both oral and IV formulations, omadacycline has the potential to be the first once-daily oral and IV tetracycline antibiotic approved in nearly 20 years. Based upon its demonstrated clinical profile, omadacycline enables physicians to transition their patients from hospital to home faster, thereby reducing overall health care costs.”

The NDAs are supported by the Company’s Phase 3 program for omadacycline, which included three pivotal registration studies: two studies in ABSSSI and one study in CABP. Omadacycline met all required FDA and European Medicines Agency (EMA) primary endpoints in each study and demonstrated a generally safe and well-tolerated profile.

In the NDA acceptance letter, the FDA stated that no filing or potential review issues were identified at this time. The FDA stated that it is currently planning to hold an advisory committee meeting to review these applications.

“The FDA’s acceptance of our NDA filings with Priority Review represents an important step forward for omadacycline and Paratek,” said Michael Bigham, Chairman and Chief Executive Officer. “We look forward to continue working with the FDA during the review process. We remain excited about the potential for omadacycline to serve as a much-needed new antibiotic for patients and physicians.”

Rubraca (rucaparib) Approved in the U.S. as Maintenance Treatment of Recurrent Ovarian Cancer

In continuation of my update on Rucaparib

Clovis Oncology, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved Rubraca (rucaparib) tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. FDA granted regular approval for Rubraca in this second, broader and earlier-line indication on a priority review timeline based on positive data from the phase 3 ARIEL3 clinical trial. Biomarker testing is not required for patients to be prescribed Rubraca in this maintenance treatment indication. Warnings and precautions include Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and embryo-fetal toxicity.

In addition to granting Rubraca approval in this second indication, the FDA converted the approval of the initial treatment indication from accelerated to regular approval.

“Rubraca provided statistically-significant improvement in PFS versus placebo to all patients, regardless of BRCA mutation status,” said Robert L. Coleman, MD, Professor & Executive Director, Cancer Network Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the Principal Investigators in the ARIEL3 clinical trial program. “Both the efficacy and safety results from the ARIEL3 study reinforce the important role of Rubraca in the treatment of recurrent ovarian cancer and expands the treatment options for patients and physicians battling this disease.”

“This FDA approval provides a meaningful advancement for the treatment of women with recurrent ovarian cancer, offering them the potential to reduce their risk of disease progression following platinum-based chemotherapy,” said Patrick J. Mahaffy, CEO and President of Clovis Oncology. “We are grateful that the FDA expedited review of this maintenance treatment indication, so that physicians can begin offering it to appropriate patients beginning today.”

On February 28, 2018, Rubraca was added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Ovarian Cancer, as maintenance therapy for patients with platinum-sensitive epithelial ovarian, fallopian tube and primary peritoneal cancer who are in partial or complete response after completion of two or more lines of platinum-based therapy. The NCCN designated Rubraca as a category 2A treatment.

NCCN is a not-for-profit alliance that includes 27 of the world’s leading cancer institutions. The NCCN Guidelines document evidence-based, consensus-driven management to ensure that all patients receive preventive, diagnostic, treatment, and supportive services that are most likely to lead to optimal outcomes.[1]

In December 2017, FDA accepted the Rubraca supplemental New Drug Application (sNDA) application and granted priority review status. Priority review designation is granted to proposed medicines that FDA has determined have the potential, if approved, to offer a significant improvement in the safety or effectiveness for the treatment, prevention or diagnosis of a serious condition when compared to standard applications. The Rubraca maintenance treatment approval is based on positive results from the ARIEL3 study, which evaluated Rubraca in the ovarian cancer maintenance-treatment setting among three populations: 1) BRCA mutant (BRCAmut+) 2) HRD positive inclusive of BRCAmut+ and, 3) all patients treated in ARIEL3. The study enrolled a total of 564 patients.

ARIEL3 successfully achieved both its primary and key secondary endpoints, extending investigator assessed progression-free survival (PFS) versus placebo in all patients treated, regardless of BRCA status.

Clovis announced topline results from the ARIEL3 clinical trial in June 2017. Additional data from the trial were presented at the 2017 European Society for Medical Oncology (ESMO) Annual Conference in Madrid, Spain, and subsequently published in The Lancet.

“The FDA approval of Rubraca in the maintenance treatment setting is an important milestone for physicians and their patients with recurrent ovarian cancer because it offers them greater flexibility to use this novel PARP inhibitor, which has demonstrated significant clinical efficacy and has been well received in practice,” said Professor Jonathan Ledermann, MD, Professor of Medical Oncology, Clinical Director, UCL Cancer Institute, and European and the rest of world Principal Investigator for the ARIEL3 study. “This will enable physicians to offer Rubraca to more women with platinum-sensitive, recurrent ovarian cancer.”

"Tens of thousands of women will battle ovarian cancer every year,” said David Barley, Chief Executive Officer, National Ovarian Cancer Coalition. “We need therapies that provide clinically meaningful improvements in reducing the risk of disease progression, among women with recurrent disease."

The safety evaluation of Rubraca 600 mg twice daily as monotherapy for maintenance treatment is based on data from 561 patients with recurrent ovarian cancer treated in the ARIEL3 trial. The safety and tolerability of Rubraca observed in this study was consistent with the previous Rubraca studies. The most common adverse reactions (greater than or equal to 20% of patients; CTCAE Grade 1-4) were nausea, fatigue/asthenia, abdominal pain/distention, rash, dysgeusia, anemia, AST/ALT elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/upper respiratory tract infection, stomatitis, decreased appetite and neutropenia. The most common laboratory abnormalities (greater than or equal to 25% of patients; CTCAE Grade 1-4) were increase in creatinine, decrease in hemoglobin, increase in cholesterol, increase in alanine aminotransferase (ALT), increase in increase in aspartate aminotransferase (AST), decrease in platelets, decrease in leukocytes, decrease in neutrophils, increase in alkaline phosphatase and decrease in lymphocytes. The majority of adverse reactions and laboratory abnormalities were Grade 1-2.

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