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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves new treatment Victoza (liraglutide) for pediatric patients with type 2 diabetes


The U.S. Food and Drug Administration today approved Victoza (liraglutide) injection for treatment of pediatric patients 10 years or older with type 2 diabetes. Victoza is the first non-insulin drug approved to treat type 2 diabetes in pediatric patients since metformin was approved for pediatric use in 2000. Victoza has been approved to treat adult patients with type 2 diabetes since 2010.

“The FDA encourages drugs to be made available to the widest number of patients possible when there is evidence of safety and efficacy,” said Lisa Yanoff, M.D, acting director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “Victoza has now been shown to improve blood sugar control in pediatric patients with type 2 diabetes. The expanded indication provides an additional treatment option at a time when

June 17, 2019

The U.S. Food and Drug Administration today approved Victoza (liraglutide) injection for treatment of pediatric patients 10 years or older with type 2 diabetes. Victoza is the first non-insulin drug approved to treat type 2 diabetes in pediatric patients since metformin was approved for pediatric use in 2000. Victoza has been approved to treat adult patients with type 2 diabetes since 2010.

“The FDA encourages drugs to be made available to the widest number of patients possible when there is evidence of safety and efficacy,” said Lisa Yanoff, M.D, acting director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “Victoza has now been shown to improve blood sugar control in pediatric patients with type 2 diabetes. The expanded indication provides an additional treatment option at a time when an increasing number of children are being diagnosed with this disease.”

Type 2 diabetes is the most common form of diabetes, occurring when the pancreas cannot make enough insulin to keep blood sugar at normal levels. Although type 2 diabetes primarily occurs in patients over the age of 45, the prevalence rate among younger patients has been rising dramatically over the past couple of decades. The Diabetes Report Card published by the U.S. Centers for Disease Control and Prevention estimates that more than 5,000 new cases of type 2 diabetes are diagnosed each year among U.S. youth younger than age 20.

Victoza improves blood sugar levels by creating the same effects in the body as the glucagon-like peptide (GLP-1) receptor protein in the pancreas. GLP-1 is often found in insufficient levels in type 2 diabetes patients. Like GLP-1, Victoza slows digestion, prevents the liver from making too much glucose (a simple sugar), and helps the pancreas produce more insulin when needed. As noted on the label, Victoza is not a substitute for insulin and is not indicated for patients with type 1 diabetes or those with diabetic ketoacidosis, a condition associated with diabetes where the body breaks down fat too quickly because there is inadequate insulin or none at all. Victoza is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease; however, its effect on major adverse cardiovascular events in pediatrics was not studied and it is not indicated for this use in children.

The efficacy and safety of Victoza for reducing blood sugar in patients with type 2 diabetes was studied in several placebo-controlled trials in adults and one placebo-controlled trial with 134 pediatric patients 10 years and older for more than 26 weeks. Approximately 64% of patients in the pediatric study had a reduction in their hemoglobin A1c (HbA1c) below 7% while on Victoza, compared to only 37% who achieved these results with the placebo. HbA1c is a blood test that is routinely performed to evaluate how well a patient’s diabetes is controlled, and a lower number indicates better control of the disease. These results occurred regardless of whether the patient also took insulin at the same time. Adult patients who took Victoza with insulin or other drugs that increase the amount of insulin the body makes (e.g., sulfonylurea) may have an increased risk of hypoglycemia (low blood sugar). Meanwhile, pediatric patients 10 years and older taking Victoza had a higher risk of hypoglycemia regardless of whether they took other therapies for diabetes.

The prescribing information for Victoza includes a Boxed Warning to advise health care professionals and patients about the increased risk of thyroid C-cell tumors. For this reason, patients who have had, or have family members who have ever had medullary thyroid carcinoma (MTC) should not use Victoza, nor should patients who have an endocrine system condition called multiple endocrine neoplasia syndrome type 2 (MEN 2). In addition, people who have a prior serious hypersensitivity reaction to Victoza or any of the product components should not use Victoza. Victoza also carries warnings about pancreatitis, Victoza pen sharing, hypoglycemia when used in conjunction with certain other drugs known to cause hypoglycemia including insulin and sulfonylurea, renal impairment or kidney failure, hypersensitivity and acute gallbladder disease. The most common side effects are nausea, diarrhea, vomiting, decreased appetite, indigestion and constipation.

The FDA granted this application Priority Review. The approval of Victoza was granted to Novo Nordisk.

https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pediatric-patients-type-2-diabetes?utm_campaign=061719_PR_FDA%20approves%20new%20treatment%20for%20pediatric%20patients%20with%20type%202%20diabetes&utm_medium=email&utm_source=Eloqua

//////Victoza, liraglutide, FDA 2019, Priority Review, Novo Nordisk, DIABETES

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FDA approves new treatment for hospital-acquired and ventilator-associated bacterial pneumonia


The U.S. Food and Drug Administration today approved a new indication for the previously FDA-approved drug, Zerbaxa (ceftolozane and tazobactam) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years and older. The FDA initially approved Zerbaxa in 2014 to treat complicated intra-abdominal infections and for complicated urinary tract infections.

“A key global challenge we face as a public health agency is addressing the threat of antimicrobial-resistant infections,” said FDA Principal Deputy Commissioner Amy Abernethy, M.D., Ph.D. “Hospital-acquired and ventilator-associated bacterial pneumonia are serious infections that can result in death in some patients. New therapies to treat these infections are important to …

https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hospital-acquired-and-ventilator-associated-bacterial-pneumonia?utm_campaign=060319_PR_FDA%20approves%20treatment%20for%20hospital-acquired%20and%20ventilator-associated%20bacterial%20pneumonia&utm_medium=email&utm_source=Eloqua

June 03, 2019

The U.S. Food and Drug Administration today approved a new indication for the previously FDA-approved drug, Zerbaxa (ceftolozane and tazobactam) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years and older. The FDA initially approved Zerbaxa in 2014to treat complicated intra-abdominal infections and for complicated urinary tract infections.

“A key global challenge we face as a public health agency is addressing the threat of antimicrobial-resistant infections,” said FDA Principal Deputy Commissioner Amy Abernethy, M.D., Ph.D. “Hospital-acquired and ventilator-associated bacterial pneumonia are serious infections that can result in death in some patients. New therapies to treat these infections are important to meet patient needs because of increasing antimicrobial resistance. That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections.”

HABP/VABP occur in patients in hospitals or other health care facilities and can be caused by a variety of bacteria. According to data from the U.S. Centers for Disease Control and Prevention, HABP and VABP are currently the second most common type of hospital-acquired infection in the United States, and are a significant issue in patients in the intensive care unit (ICU).

The safety and efficacy of Zerbaxa for the treatment of HABP/VABP, administered via injection, was demonstrated in a multinational, double-blind study that compared Zerbaxa to another antibacterial drug in 726 adult patients hospitalized with HABP/VABP. The study showed that mortality and cure rates were similar between Zerbaxa and the comparator treatment.

The most common adverse reactions observed in the HABP/VABP trial among patients treated with Zerbaxa were elevated liver enzyme levels, renal impairment or failure, and diarrhea.
Zerbaxa should not be used in patients with known serious hypersensitivity to components of Zerbaxa, as well as hypersensitivity to piperacillin/tazobactam or other members of the beta lactam class of antibacterial drugs.

Zerbaxa received FDA’s Qualified Infectious Disease Product (QIDP) designation for the treatment of HABP/VABP. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Zerbaxa marketing application for the HABP/VABP indication was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted the approval of Zerbaxa for the treatment of HABP/VABP to Merck & Co., Inc.

//////////////ceftolozane,  tazobactam, FDA 2019,  Zerbaxa,  HABP/VABP, Merck , Qualified Infectious Disease Product,  (QIDP),  Priority Review

FDA approves first PI3K inhibitor Piqray (alpelisib) for breast cancer


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FDA approves first PI3K inhibitor for breast cancer

syn https://newdrugapprovals.org/2018/06/25/alpelisib-byl-719/

Today, the U.S. Food and Drug Administration approved Piqray (alpelisib) tablets, to be used in combination with the FDA-approved endocrine therapy fulvestrant, to treat postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test) following progression on or after an endocrine-based regimen.

The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by

May 24, 2019

Today, the U.S. Food and Drug Administration approved Piqray (alpelisib) tablets, to be used in combination with the FDA-approved endocrine therapy fulvestrant, to treat postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test) following progression on or after an endocrine-based regimen.

The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by the therascreen test using the liquid biopsy should undergo tumor biopsy for PIK3CA mutation testing.

“Piqray is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating patients with this type of breast cancer. The ability to target treatment to a patient’s specific genetic mutation or biomarker is becoming increasingly common in cancer treatment, and companion diagnostic tests assist oncologists in selecting patients who may benefit from these targeted treatments,” 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. “For this approval, we employed some of our newer regulatory tools to streamline reviews without compromising the quality of our assessment. This drug is the first novel drug approved under the Real-Time Oncology Review pilot program. We also used the updated Assessment Aid, a multidisciplinary review template that helps focus our written review on critical thinking and consistency and reduces time spent on administrative tasks.”

Metastatic breast cancer is breast cancer that has spread beyond the breast to other organs in the body (most often the bones, lungs, liver or brain). When breast cancer is hormone-receptor positive, patients may be treated with anti-hormonal treatment (also called endocrine therapy), alone or in combination with other medicines, or chemotherapy.

The efficacy of Piqray was studied in the SOLAR-1 trial, a randomized trial of 572 postmenopausal women and men with HR-positive, HER2-negative, advanced or metastatic breast cancer whose cancer had progressed while on or after receiving an aromatase inhibitor. Results from the trial showed the addition of Piqray to fulvestrant significantly prolonged progression- free survival (median of 11 months vs. 5.7 months) in patients whose tumors had a PIK3CA mutation.

Common side effects of Piqray are high blood sugar levels, increase in creatinine, diarrhea, rash, decrease in lymphocyte count in the blood, elevated liver enzymes, nausea, fatigue, low red blood cell count, increase in lipase (enzymes released by the pancreas), decreased appetite, stomatitis, vomiting, weight loss, low calcium levels, aPTT prolonged (blood clotting taking longer to occur than it should), and hair loss.

Health care professionals are advised to monitor patients taking Piqray for severe hypersensitivity reactions (intolerance). Patients are warned of potentially severe skin reactions (rashes that may result in peeling and blistering of skin or mucous membranes like the lips and gums). Health care professionals are advised not to initiate treatment in patients with a history of severe skin reactions such as Stevens-Johnson Syndrome, erythema multiforme, or toxic epidermal necrolysis. Patients on Piqray have reported severe hyperglycemia (high blood sugar), and the safety of Piqray in patients with Type 1 or uncontrolled Type 2 diabetes has not been established. Before initiating treatment with Piqray, health care professionals are advised to check fasting glucose and HbA1c, and to optimize glycemic control. Patients should be monitored for pneumonitis/interstitial lung disease (inflammation of lung tissue) and diarrhea during treatment. Piqray must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Piqray is the first new drug application (NDA) for a new molecular entity approved under the Real-Time Oncology Review (RTOR) pilot program, which permits the FDA to begin analyzing key efficacy and safety datasets prior to the official submission of an application, allowing the review team to begin their review and communicate with the applicant earlier. Piqray also used the updated Assessment Aid (AAid), a multidisciplinary review template intended to focus the FDA’s written review on critical thinking and consistency and reduce time spent on administrative tasks. With these two pilot programs, today’s approval of Piqray comes approximately three months ahead of the Prescription Drug User Fee Act (PDUFA) VI deadline of August 18, 2019.

The FDA granted this application Priority Review designation. The FDA granted approval of Piqray to Novartis. The FDA granted approval of the therascreen PIK3CA RGQ PCR Kit to QIAGEN Manchester, Ltd.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-pi3k-inhibitor-breast-cancer?utm_campaign=052419_PR_FDA%20approves%20first%20PI3K%20inhibitor%20for%20breast%20cancer&utm_medium=email&utm_source=Eloqua

//////////////FDA,  PI3K inhibitor,  breast cancer, fda 2019, Piqray, alpelisib, therascreen PIK3CA RGQ PCR Kit,  QIAGEN Manchester, Priority Review, BYL719, BYL 719

FDA approves first treatment Ruzurgi (amifampridine) for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder


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FDA approves first treatment Ruzurgi (amifampridine)  for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with …

May 06, 2019

The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. LEMS can occur at any age. The prevalence of LEMS specifically in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide.

Use of Ruzurgi in patients 6 to less than 17 years of age is supported by evidence from adequate and well-controlled studies of the drug in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients and safety data from pediatric patients 6 to less than 17 years of age.

The effectiveness of Ruzurgi for the treatment of LEMS was established by a randomized, double-blind, placebo-controlled withdrawal study of 32 adult patients in which patients were taking Ruzurgi for at least three months prior to entering the study. The study compared patients continuing on Ruzurgi to patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients that continued on Ruzurgi experienced less impairment than those on placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness that evaluated the feeling of weakening or strengthening. The scores indicated greater perceived weakening in the patients switched to placebo.

The most common side effects experienced by pediatric and adult patients taking Ruzurgi were burning or prickling sensation (paresthesia), abdominal pain, indigestion, dizziness and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Patients should inform their health care professional immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Fast Track designations. Ruzurgi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Ruzurgi to Jacobus Pharmaceutical Company, Inc.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-children-lambert-eaton-myasthenic-syndrome-rare-autoimmune-disorder?utm_campaign=050619_PR_FDA%20approves%20first%20treatment%20for%20children%20with%20LEMS&utm_medium=email&utm_source=Eloqua

/////////////////FDA 2019, Ruzurgi, amifampridine,  Lambert-Eaton myasthenic syndrome, LEMS,  RARE DISEASES, CHILDREN, Jacobus Pharmaceutical Company, Priority Review,  Fast Track designations, Orphan Drug designation

First FDA-approved vaccine Dengvaxia for the prevention of dengue disease in endemic regions


Image result for dengue

First FDA-approved vaccine for the prevention of dengue disease in endemic regions

May 01, 2019

The U.S. Food and Drug Administration announced today the approval of Dengvaxia, the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico and the U.S. Virgin Islands.

“Dengue disease is the most common mosquito-borne viral disease in the world and global incidence has increased in recent decades,” said Anna Abram, FDA deputy commissioner for policy, legislation, and international affairs. “The FDA is committed to working proactively with our partners at the U.S. Centers for Disease Control and Prevention, as well as international partners, including the World Health Organization, to combat public health threats, including through facilitating the development and availability of medical products to address emerging infectious diseases. While there is no cure for dengue disease, today’s approval is an important step toward helping to reduce the impact of this virus in endemic regions of the United States.”

The CDC estimates more than one-third of the world’s population is living in areas at risk for infection by dengue virus which causes dengue fever, a leading cause of illness among people living in the tropics and subtropics. The first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu or another viral infection. A subsequent infection can lead to severe dengue, including dengue hemorrhagic fever (DHF), a more severe form of the disease that can be fatal. Symptoms may include stomach pain, persistent vomiting, bleeding, confusion and difficulty breathing. Approximately 95 percent of all severe/hospitalized cases of dengue are associated with second dengue virus infection. Because there are no specific drugs approved for the treatment of dengue disease, care is limited to the management of symptoms.

Each year, an estimated 400 million dengue virus infections occur globally according to the CDC. Of these, approximately 500,000 cases develop into DHF, which contributes to about 20,000 deaths, primarily among children. Although dengue cases are rare in the continental U.S., the disease is regularly found in American Samoa, Puerto Rico, Guam, the U.S. Virgin Islands, as well as Latin America, Southeast Asia and the Pacific islands.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease, which may lead to hospitalization or even death,” said Peter Marks, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “As the second infection with dengue is often much more severe than the first, the FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease.”

The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region. The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease. Dengvaxia has already been approved in 19 countries and the European Union.

The most commonly reported side effects by those who received Dengvaxia were headache, muscle pain, joint pain, fatigue, injection site pain and low-grade fever. The frequency of side effects was similar across Dengvaxia and placebo recipients and tended to decrease after each subsequent dose of the vaccine.

Dengvaxia is not approved for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown. This is because in people who have not been infected with dengue virus, Dengvaxia appears to act like a first dengue infection – without actually infecting the person with wild-type dengue virus – such that a subsequent infection can result in severe dengue disease.Therefore, health care professionals should evaluate individuals for prior dengue infection to avoid vaccinating individuals who have not been previously infected by dengue virus. This can be assessed through a medical record of a previous laboratory-confirmed dengue infection or through serological testing (tests using blood samples from the patient) prior to vaccination.

Dengvaxia is a live, attenuated vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.

The FDA granted this application Priority Review and a Tropical Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of certain tropical diseases. The approval was granted to Sanofi Pasteur.

https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-dengue-disease-endemic-regions?utm_campaign=050119_PR_First%20FDA-approved%20vaccine%20for%20prevention%20of%20dengue%20in%20endemic%20areas&utm_medium=email&utm_source=Eloqua

//////////fda 2019, Priority Review, Tropical Disease Priority Review Voucher , Sanofi Pasteur,  Dengvaxia, vaccine, dengue

FDA approves first treatment for pediatric patients with lupus


The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.
“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of …

April 26, 2019

Release

The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.

“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of improving their quality of life and lowering their risk of long-term organ damage and disability,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

While childhood-onset SLE is rare, when diagnosed, it is generally more active in children and adolescents than adult patients, particularly in how it impacts organs such as the kidneys and central nervous system. As a result of the disease starting early in life, pediatric patients with SLE are at a higher risk for developing increased organ damage and complications from the disease as well as adverse events from the life-long treatments usually required.

The efficacy of Benlysta IV for the treatment of SLE in pediatric patients was studied over 52 weeks in 93 pediatric patients with SLE. The proportion of pediatric patients achieving the composite primary endpoint, the SLE response index (SRI-4), was higher in pediatric patients receiving Benlysta IV plus standard therapy compared to placebo plus standard therapy. Pediatric patients who received Benlysta IV plus standard therapy also had a lower risk of experiencing a severe flare, as well as longer duration of time until a severe flare (160 days versus 82 days). The drug’s safety and pharmacokinetic profiles in pediatric patients were consistent with those in adults with SLE.

Benlysta’s doctor and patient information includes a warning for mortality, serious infections, hypersensitivity and depression, based on data from the clinical studies in adults with SLE. The drug should not be administered with live vaccines. The manufacturer is required to provide a Medication Guide to inform patients of the risks associated with Benlysta.

The most common side effects in patients included nausea, diarrhea and fever. Patients also commonly experienced infusion reactions, so healthcare professionals are advised to pre-treat patients with an antihistamine.

The FDA granted this application a Priority Review designation. The FDA granted the approval of Benlysta to GlaxoSmithKline.

////////////Benlysta, belimumab, fda 2019, Priority Review, GlaxoSmithKline

ブレキサノロン , Brexanolone, Allopregnanolone


Allopregnanolone.png

ChemSpider 2D Image | Allopregnanolone | C21H34O2

Image result for Brexanolone

Brexanolone

318.501 g/mol, C21H34O2

CAS: 516-54-1

ブレキサノロン

MFCD00003677
Pregnan-20-one, 3-hydroxy-, (3α,5α)-
Pregnan-20-one, 3-hydroxy-, (3α,5α)- [ACD/Index Name]
S39XZ5QV8Y
TU4383000
UNII:S39XZ5QV8Y
(1S,2S,7S,11S,14S,15S,5R,10R)-14-acetyl-5-hydroxy-2,15-dimethyltetracyclo[8.7.0.0<2,7>.0<11,15>]heptadecane
(+)-3a-Hydroxy-5a-pregnan-20-one
(+)-3α-Hydroxy-5α-pregnan-20-one
(3α,5α)-3-Hydroxypregnan-20-one [ACD/IUPAC Name]
10446
3211363 [Beilstein]
3a-Hydroxy-5a-pregnan-20-one

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD. 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633919.htm?utm_campaign=031919_PR_FDA%20approves%20new%20drug%20for%20post-partum%20depression&utm_medium=email&utm_source=Eloqua

March 19, 2019

Release

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD.

“Postpartum depression is a serious condition that, when severe, can be life-threatening. Women may experience thoughts about harming themselves or harming their child. Postpartum depression can also interfere with the maternal-infant bond. This approval marks the first time a drug has been specifically approved to treat postpartum depression, providing an important new treatment option,” said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Because of concerns about serious risks, including excessive sedation or sudden loss of consciousness during administration, Zulresso has been approved with a Risk Evaluation and Mitigation Strategy (REMS) and is only available to patients through a restricted distribution program at certified health care facilities where the health care provider can carefully monitor the patient.”

PPD is a major depressive episode that occurs following childbirth, although symptoms can start during pregnancy. As with other forms of depression, it is characterized by sadness and/or loss of interest in activities that one used to enjoy and a decreased ability to feel pleasure (anhedonia) and may present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, or suicidal ideation.

Zulresso will be available only through a restricted program called the Zulresso REMS Program that requires the drug be administered by a health care provider in a certified health care facility. The REMS requires that patients be enrolled in the program prior to administration of the drug. Zulresso is administered as a continuous IV infusion over a total of 60 hours (2.5 days). Because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring (monitors oxygen levels in the blood). While receiving the infusion, patients must be accompanied during interactions with their child(ren). The need for these steps is addressed in a Boxed Warning in the drug’s prescribing information. Patients will be counseled on the risks of Zulresso treatment and instructed that they must be monitored for these effects at a health care facility for the entire 60 hours of infusion. Patients should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away.

The efficacy of Zulresso was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of Zulresso or placebo and were then followed for four weeks. One study included patients with severe PPD and the other included patients with moderate PPD. The primary measure in the study was the mean change from baseline in depressive symptoms as measured by a depression rating scale. In both placebo controlled studies, Zulresso demonstrated superiority to placebo in improvement of depressive symptoms at the end of the first infusion. The improvement in depression was also observed at the end of the 30-day follow-up period.

The most common adverse reactions reported by patients treated with Zulresso in clinical trials include sleepiness, dry mouth, loss of consciousness and flushing. Health care providers should consider changing the therapeutic regimen, including discontinuing Zulresso in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors.

The FDA granted this application Priority Review and Breakthrough Therapydesignation.

Approval of Zulresso was granted to Sage Therapeutics, Inc.

Allopregnanolone, also known as 5α-pregnan-3α-ol-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP), as well as brexanolone (USAN),[1] is an endogenous inhibitory pregnane neurosteroid[2] which has been approved by the FDA as a treatment for post-partum depression. It is synthesized from progesterone, and is a potent positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.[2] Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolyticsedative, and anticonvulsant activity.[2][3][4] Endogenously produced allopregnanolone exerts a pivotal neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.[5] The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD).[2]

Biochemistry

Biosynthesis

The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.[2] Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[6]

Biological activity

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[2] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunitsexhibit the greatest potentiation.[7] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear.[8][9] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[10] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[11] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDAAMPAkainate, and glycine receptors.[12]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).[12] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.[13] In addition, allopregnanolone has recently been found to be an agonist of the newly discovered membrane progesterone receptors (mPR), including mPRδmPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[14][15] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[14][16] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[12][17]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[18] including α1 subtypes Cav1.2 and Cav1.3.[19] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.[19] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[19] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[20] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.[20]

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressantanxiolyticstress-reducingrewarding,[21] prosocial,[22] antiaggressive,[23]prosexual,[22] sedativepro-sleep,[24] cognitivememory-impairmentanalgesic,[25] anestheticanticonvulsantneuroprotective, and neurogenic effects.[2] Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of moodanxietypremenstrual syndromecatamenial epilepsy, and various other neuropsychiatric conditions.[26][27][28]

Increased levels of allopregnanolone can produce paradoxical effects, including negative moodanxietyirritability, and aggression.[29][30][31] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.[29][30] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[26][31] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[32]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[33][34]

Chemistry

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is very closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone(5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one).

Derivatives

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione).

Research

Allopregnanolone and the other endogenous inhibitory neurosteroids have short terminal half-lives and poor oral bioavailability, and for these reason, have not been pursued for clinical use as oral therapies, although development as a parenteral therapy for multiple indications has been carried out. However, synthetic analogs with improved pharmacokineticprofiles have been synthesized and are being investigated as potential oral therapeutic agents.

In other studies of compounds related to allopregnanolone, exogenous progesterone, such as oral micronized progesterone (OMP), elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[35] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.[35] As a result, there has been some interest in using OMP to treat catamenial epilepsy,[36] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to OMP, oral pregnenolonehas also been found to act as a prodrug of allopregnanolone,[37][38][39] though also of pregnenolone sulfate.[40]

Allopregnanolone has been under development by Sage Therapeutics as an intravenously administered drug for the treatment of super-refractory status epilepticuspostpartum depression, and essential tremor.[41] As of 19 March 2019 the FDA has approved allopregnanolone for postpartum depression.

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Further reading

Allopregnanolone
Skeletal formula of allopregnanolone
Ball-and-stick model of the allopregnanolone molecule
Names
IUPAC name

1-(3-Hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone
Other names

ALLO; Allo; ALLOP; AlloP; Brexanolone; 5α-Pregnan-3α-ol-20-one; 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP; Zulresso
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
Properties
C21H34O2
Molar mass 318.501 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////Brexanolone, Priority Review, Breakthrough Therapy designation, Zulresso, Sage Therapeutics Inc, FDA 2019, ブレキサノロン , Brexanolone, Allopregnanolone

CC(=O)C1CCC2C1(CCC3C2CCC4C3(CCC(C4)O)C)C

Caplacizumab-yhdp, カプラシズマブ


FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ  , for the treatment of adult patients with a rare blood clotting disorder

FDA

February 6, 2019

The U.S. Food and Drug Administration today approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” 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. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus or infections, or after having surgery, bone marrow transplantation or chemotherapy.

The efficacy of Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.

Common side effects of Cablivi reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Cablivi includes a warning to advise health care providers and patients about the risk of severe bleeding.

Health care providers are advised to monitor patients closely for bleeding when administering Cablivi to patients who currently take anticoagulants.

The FDA granted this application Priority Review designation. Cablivi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Cablivi to Ablynx.

 EU

Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP   1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP   2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

http://hugin.info/152918/R/2213684/863478.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

Image result for Caplacizumab

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA
51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG
101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR
151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT
201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG
251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

  • 1: PN: WO2011067160 SEQID: 1 claimed protein
  • 98: PN: WO2006122825 SEQID: 98 claimed protein
  • ALX 0081
  • ALX 0681
  • Caplacizumab
FORMULA
C1213H1891N357O380S10
CAS
915810-67-2
MOL WEIGHT
27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.[1][2]

This drug was developed by Ablynx NV.[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.[4]

It is an anti-von Willebrand factor humanized immunoglobulin.[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.[5] Results of the phase II TITAN trial have been reported.[5]

In February 2019, caplacizumab-yhdp (CABLIVI, Ablynx NV) has been approved by the Food and Drug Administration for treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. [6]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

Caplacizumab
Monoclonal antibody
Type Single domain antibody
Source Humanized
Target VWF
Clinical data
Synonyms ALX-0081
ATC code
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C1213H1891N357O380S10
Molar mass 27.88 kg/mol

CLIP

https://www.tandfonline.com/doi/full/10.1080/19420862.2016.1269580

Caplacizumab (ALX-0081) is a humanized single-variable-domain immunoglobulin (Nanobody) that targets von Willebrand factor, and thereby inhibits the interaction between von Willebrand factor multimers and platelets. In a Phase 2 study (NCT01151423) of 75 patients with acquired thrombotic thrombocytopenic purpura who received SC caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 d afterward, the time to a response was significantly reduced with caplacizumab compared with placebo (39% reduction in median time, P = 0.005).39Peyvandi FScully MKremer Hovinga JACataland SKnöbl PWu HArtoni AWestwood JPMansouri Taleghani MJilma B, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374(6):51122; PMID:26863353; http://dx.doi.org/10.1056/NEJMoa1505533[Crossref][PubMed][Web of Science ®][Google Scholar] The double-blind, placebo-controlled, randomized Phase 3 HERCULES study (NCT02553317) study will evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Patients will receive an initial IV dose of either caplacizumab or placebo followed by daily SC injections for a maximum period of 6 months. The primary outcome measure is the time to platelet count response. The estimated enrollment is 92 patients, and the estimated primary completion date of the study is October 2017. A Phase 3 follow-up study (NCT02878603) for patients who completed the HERCULES study is planned.

References

///////////////caplacizumab, Cablivi,  Ablynx, Priority Review, Orphan Drug designation,  fda 2019, eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ  , PEPTIDE, ALX 0081

Tagraxofusp タグラクソフスプ


MGADDVVDSS KSFVMENFSS YHGTKPGYVD SIQKGIQKPK SGTQGNYDDD WKGFYSTDNK
YDAAGYSVDN ENPLSGKAGG VVKVTYPGLT KVLALKVDNA ETIKKELGLS LTEPLMEQVG
TEEFIKRFGD GASRVVLSLP FAEGSSSVEY INNWEQAKAL SVELEINFET RGKRGQDAMY
EYMAQACAGN RVRRSVGSSL SCINLDWDVI RDKTKTKIES LKEHGPIKNK MSESPNKTVS
EEKAKQYLEE FHQTALEHPE LSELKTVTGT NPVFAGANYA AWAVNVAQVI DSETADNLEK
TTAALSILPG IGSVMGIADG AVHHNTEEIV AQSIALSSLM VAQAIPLVGE LVDIGFAAYN
FVESIINLFQ VVHNSYNRPA YSPGHKTRPH MAPMTQTTSL KTSWVNCSNM IDEIITHLKQ
PPLPLLDFNN LNGEDQDILM ENNLRRPNLE AFNRAVKSLQ NASAIESILK NLLPCLPLAT
AAPTRHPIHI KDGDWNEFRR KLTFYLKTLE NAQAQQTTLS LAIF
(disulfide bridge: 187-202, 407-475)

Image result for Tagraxofusp US FDA APPROVAL

methionyl (1)-Corynebacterium diphtheriae toxin fragment (catalytic and transmembrane domains) (2-389, Q388R variant)-His390-Met391-human interleukin 3 (392-524, natural P399S variant) fusion protein, produced in Escherichia coli antineoplastic,https://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf

Tagraxofusp

タグラクソフスプ

CAS: 2055491-00-2
C2553H4026N692O798S16, 57694.4811

FDA 2018/12/21, Elzonris APPROVED

Antineoplastic, Immunotoxin, Peptide

DT-3881L3 / DT388IL3 / Molecule 129 / Molecule-129 / SL-401

UNII8ZHS5657EH

Diphteria toxin fusion protein with peptide and interleukin 3 Treatment of blastic plasmacytoid dendritic cell neoplasm (CD123-directed)

FDA approves first treatment for rare blood disease

>>tagraxofusp<<< MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF

December 21, 2018

Release

The U.S. Food and Drug Administration today approved Elzonris (tagraxofusp-erzs) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, two years of age and older.

“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” 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.

BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia. The disease is more common in men than women and in patients 60 years and older.

The efficacy of Elzonris was studied in two cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and seven patients (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and one patient achieved CRc.

Common side effects reported by patients in clinical trials were capillary leak syndrome (fluid and proteins leaking out of tiny blood vessels into surrounding tissues), nausea, fatigue, swelling of legs and hands (peripheral edema), fever (pyrexia), chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (ALT and AST). Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby.

The labeling for Elzonris contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignation. Elzonris also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Elzonris to Stemline Therapeutics.

Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.[4] It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.[67] Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.[3] This drug achieved approval after being designed with the title of breakthrough therapy, priority review, and orphan drug status.[2] Tagraxofusp has been designed as an orphan drug in EU since November 2015.[7]

Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.[2]

BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens.[1] A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.[6]

Associated Conditions

PharmacodynamicsIn vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.[6] One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.[5]

In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.[2]

Mechanism of actionTagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC).[5] To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.[4,6]

As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.[6]

Absorption

The reported Cmax in clinical trials was of around 23 ng/ml.[6] After a 15 min infusion of a dose of 12 mcg/kg the registered AUC and Cmax was 231 mcg.h/L and 162 mcg/L respectively.[Label]

Volume of distributionIn BPDCN patients, the reported volume of distribution is of 5.1 L.[Label]

Protein bindingTagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.[6]

MetabolismFor the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.

Route of eliminationTagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.

Half lifeThe reported half-life of tagraxofusp is of around 51 minutes.[6]

ClearanceThe clearance of tagraxofusp was reported to fit a mono-exponential model.[6] The reported clearance rate is reported to be of 7.1 L/h.[Label]

ToxicityThere haven’t been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.[Label]

  1. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [PubMed:23396213]
  2. FDA news [Link]
  3. FDA approvals [Link]
  4. Oncology nursing news [Link]
  5. Stemline therapeutics news [Link]
  6. Blood journal [Link]
  7. NHS reports [Link]

FDA label, Download (455 KB)

/////////Antineoplastic, Immunotoxin, Peptide, Tagraxofusp, Elzonris, タグラクソフスプ  , Stemline Therapeutics, Breakthrough Therapy,  Priority Review designation,  Orphan Drug designation, fda 2018, DT-3881L3 , DT388IL3 ,  Molecule 129 ,  Molecule-129 ,  SL-401, 

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder


 

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM627093.htm?utm_campaign=11282018_PR_FDA%20approves%20treatment%20for%20LEMS&utm_medium=email&utm_source=Eloqua

 

November 28, 2018

Release

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

“There has been a long-standing need for a treatment for this rare disorder,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Patients with LEMS have significant weakness and fatigue that can often cause great difficulties with daily activities.”

In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. The prevalence of LEMS is estimated to be three per million individuals worldwide.

The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo.

The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Firdapse also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Firdapse to Catalyst Pharmaceuticals, Inc.

///////////Priority Review,  Breakthrough Therapy,  Firdapse,  Orphan Drug designation, fda 2018, amifampridine

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