FDA Corner. Molecular and Cellular Pharmacology

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1 FDA Corner FDA Approves Drug to Treat Duchenne Muscular Dystrophy approved Emflaza (deflazacort) tablets and oral suspension to treat patients age 5 years and older with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness. Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system. Corticosteroids are commonly used to treat DMD across the world. This is the first FDA approval of any corticosteroid to treat DMD and the first approval of deflazacort for any use in the United States. This is the first treatment approved for a wide range of patients with Duchenne muscular dystrophy, said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA s Center for Drug Evaluation and Research. We hope that this treatment option will benefit many patients with DMD. DMD is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between 3 and 5 years of age and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one of every 3,600 male infants worldwide. People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary. The effectiveness of deflazacort was shown in a clinical study of 196 male patients who were 5 to 15 years old at the beginning of the trial with documented mutation of the dystrophin gene and onset of weakness before age 5. At week 12, patients taking deflazacort had improvements in a clinical assessment of muscle strength across a number of muscles compared to those taking a placebo. An overall stability in average muscle strength was maintained through the end of study at week 52 in Molecular and Cellular Pharmacology the deflazacort-treated patients. In another trial with 29 male patients that lasted 104 weeks, deflazacort demonstrated a numerical advantage over placebo on an assessment of average muscle strength. In addition, although not statistically controlled for multiple comparisons, patients on deflazacort appeared to lose the ability to walk later than those treated with placebo. The side effects caused by Emflaza are similar to those experienced with other corticosteroids. The most common side effects include facial puffiness (Cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism) and excessive fat around the stomach (central obesity). Other side effects that are less common include problems with endocrine function, increased susceptibility to infection, elevation in blood pressure, risk of gastrointestinal perforation, serious skin rashes, behavioral and mood changes, decrease in the density of the bones and vision problems such as cataracts. Patients receiving immunosuppressive doses of corticosteroids should not be given live or live attenuated vaccines. The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the ninth rare pediatric disease priority review voucher issued by the FDA since the program began. Emflaza is marketed by Marathon Pharmaceuticals of Northbrook, Illinois. FDA News released Feb 9, FDA Approves Drug to Treat Parkinson s Disease approved Xadago (safinamide) tablets as an add-on treatment for patients with Parkinson s disease who are currently taking levodopa/carbidopa and experiencing off episodes. An off episode is a time when a patient s medications are not working well, 5

2 6 FDA Corner causing an increase in Parkinson s symptoms, such as tremor and difficulty walking. Parkinson s is a relentless disease without a cure, said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA s Center for Drug Evaluation and Research. We are committed to helping make additional treatments for Parkinson s disease available to patients. An estimated 50,000 Americans are diagnosed with Parkinson s disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, though it can occur earlier, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement such as eating, writing, and shaving. Early symptoms of the disease are subtle and occur gradually. In some people, Parkinson s disease progresses more quickly than in others. The efficacy of Xadago in treating Parkinson s disease was shown in a clinical trial of 645 participants who were also taking levodopa and were experiencing off time. Those receiving Xadago experienced more beneficial on time, a time when Parkinson s symptoms are reduced, without troublesome uncontrolled involuntary movement (dyskinesia), compared to those receiving a placebo. The increase in on time was accompanied by a reduction in off time and better scores on a measure of motor function assessed during on time than before treatment. In another clinical trial of 549 participants, the participants adding Xadago to their levodopa treatment had more on time without troublesome uncontrolled involuntary movement compared to those taking a placebo, and also had better scores on a measure of motor function assessed during on time than before treatment. Certain patients should not take Xadago. These include patients who have severe liver problems, or who take a medicine used to treat a cough or cold called dextromethorphan. It also should not be taken by patients who take another medicine called a monoamine oxidase inhibitor (MAOI) because it may cause a sudden severe increase in blood pressure, or by those who take an opioid drug, St. John s wort, certain antidepressants (such as serotoninnorepinephrine reuptake inhibitors, tricyclics, tetracyclics, and triazolopyridines), or cyclobenzaprine, because it may cause a lifethreatening reaction called serotonin syndrome. The most common adverse reactions observed in patients taking Xadago were uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia). Serious, but less common, risks include the following: exacerbated high blood pressure (hypertension); serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs; falling asleep during activities of daily living; hallucinations and psychotic behavior; problems with impulse control/compulsive behaviors; withdrawal-emergent hyperpyrexia (fever) and confusion; and retinal pathology. The FDA granted approval of Xadago to Newron Pharmaceuticals. FDA News released March 21, FDA Approves Two Hepatitis C Drugs For Pediatric Patients approved supplemental applications for Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir) to treat hepatitis C virus (HCV) in children ages 12 to 17. Harvoni and Sovaldi were previously approved to treat HCV in adults. These are the first direct-acting antiviral treatments approved for children and adolescents with HCV. Direct-acting antiviral drugs reduce the amount of HCV in the body by preventing the virus from multiplying, and in most cases, they cure HCV. These approvals will help change the landscape for HCV treatment by addressing an unmet need in children and adolescents, said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA s Center for Drug Evaluation and Research. Today s approvals provide pediatric treatment options for six major genotypes, or strains, of HCV. Harvoni is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 77 pounds (35 kilograms) with HCV genotype 1, 4, 5 or 6 infection without cirrhosis (liver disease) or with mild cirrhosis. Sovaldi in combination with ribavirin is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 77 pounds (35 kilograms) with genotype 2 or 3 HCV infection without cirrhosis or with mild cirrhosis.

3 FDA Corner 7 HVC is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV, and children born to HCV-positive mothers are at risk for HCV infection. It is estimated that there are 23,000 to 46,000 children in the United States with HCV infection. The safety, pharmacokinetics (how the body absorbs, distributes and rids itself of a drug) and efficacy of Harvoni for the treatment of HCV genotype 1 infection were established in an openlabel, multicenter clinical trial that included 100 pediatric patients 12 years of age and older. The results were comparable to those observed in adults and demonstrated that 98 percent of patients had no virus detected in the blood 12 weeks after finishing treatment, suggesting the patients infections were cured. The safety and efficacy of Harvoni for treatment of HCV genotypes 4, 5 or 6 infection in pediatric patients 12 years of age and older is based on data showing similar exposures (amount of drug in the body) to Harvoni in adults and adolescents with HCV genotype 1 infection, as well as similar efficacy and exposures to Harvoni across HCV genotypes 1, 4, 5 and 6 in adults. The most common adverse reactions observed with treatment with Harvoni were fatigue and headache. Sovaldi in combination with ribavirin was evaluated in an open-label clinical trial that included 50 pediatric patients 12 years of age and older. The results were comparable to those observed in adults and 100 percent of patients with HCV genotype 2, and 97 percent of patients with HCV genotype 3 had no virus detected in the blood 12 weeks after finishing treatment. The most common adverse events observed with Sovaldi in combination with ribavirin were fatigue and headache. All contraindications to ribavirin also apply to Sovaldi combination therapy. Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines resulted in serious liver problems or death. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Harvoni or Sovaldi. Harvoni and Sovaldi are marketed by Gilead Sciences, Inc. FDA News released April 7, FDA Approves New Combination Treatment for Acute Myeloid Leukemia approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML. AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. The National Cancer Institute estimated that approximately 19,930 people would be diagnosed with AML in 2016 and 10,430 were projected to die of the disease. Rydapt is the first targeted therapy to treat patients with AML, in combination with chemotherapy, said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA s Center for Drug Evaluation and Research and director of the FDA s Oncology Center of Excellence. The ability to detect the gene mutation with a diagnostic test means doctors can identify specific patients who may benefit from this treatment. Rydapt is a kinase inhibitor that works by blocking several enzymes that promote cell growth. If the FLT3 mutation is detected in blood or bone marrow samples using the LeukoStrat CDx FLT3 Mutation Assay, the patient may be eligible for treatment with Rydapt in combination with chemotherapy. The safety and efficacy of Rydapt for patients with AML were studied in a randomized trial of 717 patients who had not been treated previously for AML. In the trial, patients who received Rydapt in combination with chemotherapy lived longer than patients who received chemotherapy alone, although a specific median survival rate could not be reliably estimated. In addition, patients who received Rydapt in combination with chemotherapy in the

4 8 FDA Corner trial went longer (median 8.2 months) without certain complications (failure to achieve complete remission within 60 days of starting treatment, progression of leukemia or death) than patients who received chemotherapy alone (median three months). Common side effects of Rydapt in patients with AML include low levels of white blood cells with fever (febrile neutropenia), nausea, inflammation of the mucous membranes (mucositis), vomiting, headache, spots on the skin due to bleeding (petechiae), musculoskeletal pain, nosebleeds (epistaxis), device-related infection, high blood sugar (hyperglycemia) and upper respiratory tract infection. Rydapt should not be used in patients with hypersensitivity to midostaurin or other ingredients in Rydapt. Women who are pregnant or breastfeeding should not take Rydapt because it may cause harm to a developing fetus or a newborn baby. Patients who experience signs or symptoms of lung damage (pulmonary toxicity) should stop using Rydapt. Rydapt was also approved today for adults with certain types of rare blood disorders (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm or mast cell leukemia). Common side effects of Rydapt in these patients include nausea, vomiting, diarrhea, swelling (edema), musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, fever, headache and shortness of breath. The FDA granted this application Priority Review, Fast Track (for the mastocytosis indication) and Breakthrough Therapy (for the AML indication) designations. The FDA granted the approval of Rydapt to Novartis Pharmaceuticals Corporation. The FDA granted the approval of the LeukoStrat CDx FLT3 Mutation Assay to Invivoscribe Technologies Inc. FDA News released April 28, advised to consult their healthcare providers regarding potential use of products mentioned herein. The journal including its staff, editors, publishing service and publishers do not take legal responsibility for any harm caused by use of any of the mentioned products.. Source: FDA The above information is exactly as released by the FDA. Readers are advised to contact the FDA ( for latest updates as information contained herein may have changed since the release date. The FDA News Releases are in public domain and, to preserve the integrity of contents contained therein, have not been altered in any way by this journal. Furthermore, the information provided herein is solely for informational/educational use and is not intended to replace advice of healthcare providers. Any reference to any company is not an endorsement expressed or implied of its products, readers are

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