AMAG Pharmaceuticals Announces FDA Approval of Vyleesi (bremelanotide injection) for Hypoactive Sexual Desire Disorder (HSDD) in Premenopausal Women

In continuation of my update on  bremelanotide

MAG Pharmaceuticals, Inc.    announced  that the U.S. Food and Drug Administration (FDA) has approved Vyleesi (bremelanotide injection), a melanocortin receptor agonist, to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. The Vyleesi autoinjector is the first treatment for this patient population that can be self-administered as needed in anticipation of sexual activity.

HSDD is characterized by low sexual desire that causes distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance.

“HSDD has been recognized as a medical condition since the 1970s, yet it has been widely underdiagnosed and undertreated,” said Anita H. Clayton, M.D., Chair, Department of Psychiatry & Neurobehavioral Sciences, University of Virginia School of Medicine, VA. “Women with HSDD often avoid situations that could lead to intimacy, the impact of which goes far beyond the bedroom and can often result in anxiety, loss of vitality, self-esteem issues and relationship stress. It is important that women suffering with this condition have a choice of treatment options available to them.”

HSDD is thought to have a neurobiologic basis which is supported by brain imaging studies. When study participants were shown visual sexual stimuli, there was a difference in the brain activation patterns between women with HSDD compared to those women without HSDD[i].

“Today’s approval underscores AMAG’s commitment to women’s health and dedication to raising awareness and improving education about HSDD,” said Julie Krop, M.D., chief medical officer at AMAG. “While HSDD is the most common female sexual dysfunction condition, it is largely under-recognized. I want to thank the thousands of women who participated in the clinical trials to support the approval of Vyleesi. Their participation in the trials helped to pave the way for a novel treatment option that offers hope to the nearly six million premenopausal women who have suffered in silence from HSDD—empowering them to reclaim their sexual desire.”

The FDA approval of Vyleesi is based upon data from approximately 1,200 women in two pivotal, double-blind placebo controlled Phase 3 trials (RECONNECT). In both clinical trials, Vyleesi met the pre-specified co-primary efficacy endpoints of improvement in desire and reductions in distress as measured by validated patient-reported outcome instruments. Upon completion of the trial, women had the option to continue in a voluntary open-label safety extension study for an additional 12 months. Nearly 80 percent of patients who completed the Phase 3 trials elected to remain in the open-label portion of the study, where all of these patients received Vyleesi.

In the pivotal trials, the most common adverse events were nausea, flushing, injection site reactions, and headache. The majority of events were reported to be transient and mild-to-moderate in intensity. In clinical trials, Vyleesi caused small, transient increases in blood pressure, and is contraindicated in women with uncontrolled high blood pressure or known cardiovascular risk.

AMAG is committed to working with payers and healthcare professionals to help ensure women with HSDD have access to Vyleesi. The product will be commercially available in September through select specialty pharmacies. To raise healthcare provider awareness of Vyleesi, AMAG will leverage its existing women’s and maternal health sales force of approximately 125 sales representatives calling on U.S. obstetrics, gynecologists and sexual medicine specialists, and will also offer patients the ability to connect with a physician through a telemedicine option. Patients and providers can learn more about HSDD and Vyleesi at www.vyleesi.com and sign up to receive information about how to obtain Vyleesi as soon as it is available.

AMAG in-licensed Vyleesi from Palatin Technologies, Inc. in February 2017. Under the terms of the agreement, the approval of Vyleesi by the FDA triggers a $60 million payment obligation to Palatin. In addition, AMAG will pay Palatin tiered royalties on annual net sales of Vyleesi ranging from the high-single digits to the low double-digits. AMAG will also pay Palatin sales milestones based on escalating annual net sales thresholds, the first of which is $25 million, triggered at annual net sales of $250 million.

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

FDA Approves Expanded Use of Vraylar (cariprazine) in the Treatment of Bipolar Depression

In continuation of my update on Cariprazine

Allergan plc (NYSE: AGN) and Gedeon Richter Plc.   announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Vraylar (cariprazine) for expanded use to treat depressive episodes associated with bipolar I disorder (bipolar depression) in adults. Vraylar is also approved in the U.S. to treat manic or mixed episodes associated with bipolar I disorder in adults. There are nearly 11 million adults in the U.S. living with bipolar disorder, a condition that causes extreme shifts in mood, energy, and activity levels.

"Treating bipolar disorder can be very difficult because people living with the illness experience a range of depressive and manic symptoms, sometimes both at the same time, and this FDA approval gives healthcare providers a new option to treat the full spectrum of bipolar I disorder symptoms, specifically manic, mixed, and depressive episodes, with just one medication," said Dr. Stephen Stahl, Professor of Psychiatry at the University of California San Diego and lead author of the post hoc analysis, Cariprazine Efficacy in Patients with Bipolar Depression and Concurrent Manic Symptoms. "Treating depression, mania and mixed episodes with a single medication is important for people living with, and healthcare providers treating, this complex illness. This approval can streamline a treatment decision while helping to stabilize the disorder."

Seventy percent of people living with bipolar disorder receive at least one misdiagnosis and consult an average of four doctors over approximately 10 years before being accurately diagnosed.3 Many patients take multiple medications to treat the symptoms of this condition.

The FDA approval for the expanded indication of Vraylar is based on three pivotal trials, including RGH-MD-53, RGH-MD-54 and RGH-MD-56, in which cariprazine demonstrated greater improvement than placebo for the change from baseline to week six on the Montgomery Asberg Depression Rating scale (MADRS) total score. In all three studies, the Vraylar 1.5 mg dose demonstrated statistical significance over placebo; additionally, in RGH-MD-54, the Vraylar 3 mg dose demonstrated statistical significance over placebo. Common adverse events reported in the pivotal trials were nausea, akathisia, restlessness, and extrapyramidal symptoms.

"This approval represents an important milestone in our efforts to help patients and prescribing healthcare providers effectively manage bipolar I disorder and demonstrates our ongoing focus on mental health," said David Nicholson, Chief Research & Development Officer at Allergan.  "We are committed to developing therapies for complex mental health disorders, including Vraylar, which is currently in Phase 3 clinical trials for the treatment of major depressive disorder."

"This approval is considered a notable achievement in the development process of cariprazine, our flagship product," said Dr. István Greiner, Research Director of Gedeon Richter Plc. "We are pleased that more and more patient groups suffering from psychiatric disorders will get access to cariprazine as a treatment option."

About Vraylar (cariprazine)

Vraylar is an oral, once daily atypical antipsychotic approved for the acute treatment of adults with manic or mixed episodes associated with bipolar I disorder (3 to 6 mg/day) and for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults (1.5 or 3 mg/day). Vraylar is also approved for the treatment of schizophrenia in adults (1.5 to 6 mg/day).

While the mechanism of action of Vraylar is unknown, the efficacy of Vraylar could be mediated through a combination of partial agonist activity at central dopamine D₂ and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Pharmacodynamic studies with cariprazine have shown that it acts as a partial agonist with high binding affinity at dopamine D3, dopamine D2, and serotonin 5-HT1A receptors. Cariprazine demonstrated up to ~8-fold greater in vitro affinity for dopamine D3 vs D2 receptors. Cariprazine also acts as an antagonist at serotonin 5-HT2B and 5-HT2A receptors with high and moderate binding affinity, respectively as well as it binds to the histamine H1 receptors.

Vraylar shows lower binding affinity to the serotonin 5-HT2C and α1A- adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors. The clinical significance of these in vitro data is unknown.

Vraylar was discovered and co-developed by Gedeon Richter Plc and is licensed by Allergan, in the U.S. and Canada. For more than a decade both companies have conducted over 20 clinical trials enrolling thousands of patients worldwide to evaluate the efficacy and safety of cariprazine for people living with a broad range of mental health illnesses.

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

FDA Approves Zerbaxa (ceftolozane and tazobactam) 3g Dose for the Treatment of Adults with Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP)

      

         Ceftolozane/tazobactam                                                           Tazobactam                                                

Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced that the U.S. Food and Drug Administration (FDA) has approved Merck’s supplemental New Drug Application (sNDA) for the use of Zerbaxa (ceftolozane and tazobactam) for the treatment of patients 18 years and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens. The sNDA for Zerbaxa had previously been designated Priority Review status by the FDA. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zerbaxa and other antibacterial drugs, Zerbaxa should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

This expanded use is based on results of the pivotal Phase 3 ASPECT-NP trial that compared Zerbaxa 3g (ceftolozane 2g and tazobactam 1g) intravenously every 8 hours to meropenem (1g intravenously every 8 hours) for 8 to 14 days for the treatment of adult patients with HABP/VABP.

Zerbaxa is contraindicated in patients with known serious hypersensitivity to the components of Zerbaxa (ceftolozane/tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Additionally, Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including Zerbaxa. See Important Safety Information below.

“Pneumonia in ventilated patients remains a significant clinical challenge and is associated with substantial morbidity and mortality,” said Dr. Andrew Shorr, head of pulmonary, critical care and respiratory services, Medstar Washington Hospital Center, Washington, D.C. “The need to cover diverse pathogens including Pseudomonas aeruginosa and certain Enterobacteriaceae adds to the challenge.”

According to a recent publication by the Foundation for the National Institutes of Health Biomarkers Consortium, ventilated patients with HABP have a higher rate of mortality (39%) than those with VABP (27%). In addition, Pseudomonas aeruginosa is the most common Gram-negative pathogen in HABP/VABP and is becoming increasingly difficult to treat.

“We are grateful to all of the patients who participated in the studies which led to the approval of Zerbaxa for the treatment of HABP/VABP,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “This approval reflects Merck’s longstanding commitment to helping alleviate the burden of infectious diseases, including serious infections caused by Gram-negative pathogens.”

Clinical Data Supporting Use of Zerbaxa (Ceftolozane and Tazobactam) in HABP/VABP

A total of 726 adult patients hospitalized with HABP/VABP were enrolled in a multinational, double-blind study (NCT 02070757) comparing Zerbaxa 3g (ceftolozane 2g and tazobactam 1g) intravenously every 8 hours to meropenem (1g intravenously every 8 hours) for 8 to 14 days of therapy. All patients had to be intubated and on mechanical ventilation at randomization.

Efficacy was assessed based on all-cause mortality at Day 28 and clinical cure, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 7 to 14 days after the end of treatment. The analysis population was the intent-to-treat (ITT) population, which included all randomized patients.

Of the 726 patients in the ITT population, the median age was 62 years and 44% of the population was greater than or equal to 65 years of age, with 22% of the population greater than or equal to 75 years of age. The majority of patients were white (83%), male (71%) and were from Eastern Europe (64%). The median APACHE II score was 17 and 33% of patients had a baseline APACHE II score of greater than or equal to 20. All patients were on mechanical ventilation and 519 (71%) had VABP. At randomization, the majority of patients had been hospitalized for greater than or equal to 5 days (77%) and were in an ICU (92%), with 49% of patients ventilated for greater than or equal to 5 days. At baseline, 36% of patients had creatinine clearance (CrCl) less than 80 mL/min. Of these, 14% had CrCl less than 50 mL/min.

Approximately 13% of patients were failing their current antibacterial drug therapy for HABP/VABP, and bacteremia was present at baseline in 15% of patients. Key comorbidities included diabetes mellitus, congestive heart failure, and chronic obstructive pulmonary disease at rates of 22%, 16% and 12%, respectively.

Zerbaxa (ceftolozane and tazobactam) was non-inferior to meropenem for 28-day all-cause mortality in the ITT population (all randomized patients), 24.0% (87/362) and 25.3% (92/364) respectively, for a weighted proportion difference of 1.1 (stratified 95% CI: -5.13, 7.39; non-inferiority margin of 10%). In addition, Zerbaxa was non-inferior to meropenem for clinical response at Test-of-Cure (7-14 days after the end of therapy) in the ITT population, 54.4% (197/362) and 53.3% (194/364) respectively, for a weighted proportion difference of 1.1 (stratified 95% CI: -6.17, 8.29; non-inferiority margin of 12.5%).

In the ventilated HABP sub-group, a favorable response for Zerbaxa in 28-day all-cause mortality was observed, 24.2% (24/99) for Zerbaxa and 37.0% (40/108) for meropenem, respectively, for a weighted proportion difference of 12.8 (stratified 95% CI: 0.18, 24.75). In the VABP subgroup, 28-day all-cause mortality was 24.0% (63/263) for Zerbaxa and 20.3% (52/256) for meropenem, for a weighted proportion difference of -3.6 (stratified 95% CI: -10.74, 3.52).

Adverse reactions occurring in 2% or greater of patients receiving Zerbaxa in this study include hepatic transaminase increased 11.9% (43/361), renal impairment/renal failure 8.9% (32/361), diarrhea 6.4% (23/361), intracranial hemorrhage 4.4% (16/361), vomiting 3.3% (12/361), and Clostridium difficile colitis 2.8% (10/361). Treatment discontinuation due to adverse reactions occurred in 1.1% (4/361) of patients receiving Zerbaxa and 1.4% (5/359) of patients receiving meropenem.

FDA Approves Zerbaxa (ceftolozane and tazobactam) 3g Dose for the Treatment of Adults with 

Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP)

FDA Approves Expanded Use of Vraylar (cariprazine) in the Treatment of Bipolar Depression

In continuation of my update on VRAYLAR (cariprazine)

Allergan plc (NYSE: AGN) and Gedeon Richter Plc.   announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Vraylar (cariprazine) for expanded use to treat depressive episodes associated with bipolar I disorder (bipolar depression) in adults. Vraylar is also approved in the U.S. to treat manic or mixed episodes associated with bipolar I disorder in adults. There are nearly 11 million adults in the U.S. living with bipolar disorder, a condition that causes extreme shifts in mood, energy, and activity levels.

"Treating bipolar disorder can be very difficult because people living with the illness experience a range of depressive and manic symptoms, sometimes both at the same time, and this FDA approval gives healthcare providers a new option to treat the full spectrum of bipolar I disorder symptoms, specifically manic, mixed, and depressive episodes, with just one medication," said Dr. Stephen Stahl, Professor of Psychiatry at the University of California San Diego and lead author of the post hoc analysis, Cariprazine Efficacy in Patients with Bipolar Depression and Concurrent Manic Symptoms. "Treating depression, mania and mixed episodes with a single medication is important for people living with, and healthcare providers treating, this complex illness. This approval can streamline a treatment decision while helping to stabilize the disorder."

Seventy percent of people living with bipolar disorder receive at least one misdiagnosis and consult an average of four doctors over approximately 10 years before being accurately diagnosed.3 Many patients take multiple medications to treat the symptoms of this condition.

The FDA approval for the expanded indication of Vraylar is based on three pivotal trials, including RGH-MD-53, RGH-MD-54 and RGH-MD-56, in which cariprazine demonstrated greater improvement than placebo for the change from baseline to week six on the Montgomery Asberg Depression Rating scale (MADRS) total score. In all three studies, the Vraylar 1.5 mg dose demonstrated statistical significance over placebo; additionally, in RGH-MD-54, the Vraylar 3 mg dose demonstrated statistical significance over placebo. Common adverse events reported in the pivotal trials were nausea, akathisia, restlessness, and extrapyramidal symptoms.

"This approval represents an important milestone in our efforts to help patients and prescribing healthcare providers effectively manage bipolar I disorder and demonstrates our ongoing focus on mental health," said David Nicholson, Chief Research & Development Officer at Allergan.  "We are committed to developing therapies for complex mental health disorders, including Vraylar, which is currently in Phase 3 clinical trials for the treatment of major depressive disorder."

"This approval is considered a notable achievement in the development process of cariprazine, our flagship product," said Dr. István Greiner, Research Director of Gedeon Richter Plc. "We are pleased that more and more patient groups suffering from psychiatric disorders will get access to cariprazine as a treatment option."

About Vraylar (cariprazine)

Vraylar is an oral, once daily atypical antipsychotic approved for the acute treatment of adults with manic or mixed episodes associated with bipolar I disorder (3 to 6 mg/day) and for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults (1.5 or 3 mg/day). Vraylar is also approved for the treatment of schizophrenia in adults (1.5 to 6 mg/day).

While the mechanism of action of Vraylar is unknown, the efficacy of Vraylar could be mediated through a combination of partial agonist activity at central dopamine D₂ and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Pharmacodynamic studies with cariprazine have shown that it acts as a partial agonist with high binding affinity at dopamine D3, dopamine D2, and serotonin 5-HT1A receptors. Cariprazine demonstrated up to ~8-fold greater in vitro affinity for dopamine D3 vs D2 receptors. Cariprazine also acts as an antagonist at serotonin 5-HT2B and 5-HT2A receptors with high and moderate binding affinity, respectively as well as it binds to the histamine H1 receptors.

Vraylar shows lower binding affinity to the serotonin 5-HT2C and α1A- adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors. The clinical significance of these in vitro data is unknown.

Vraylar was discovered and co-developed by Gedeon Richter Plc and is licensed by Allergan, in the U.S. and Canada. For more than a decade both companies have conducted over 20 clinical trials enrolling thousands of patients worldwide to evaluate the efficacy and safety of cariprazine for people living with a broad range of mental health illnesses.

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

PTC Therapeutics Receives FDA Approval for the Expansion of the Emflaza (deflazacort) Labeling to Include Patients 2-5 Years of Age

    

PTC Therapeutics, Inc. (NASDAQ: PTCT)   announced that the U.S. Food and Drug Administration (FDA) approved the company's supplemental New Drug Application (sNDA) for Emflaza (deflazacort) to expand its labeling to include patients with Duchenne muscular dystrophy who are between 2- and 5-years-old. Duchenne is a rare childhood genetic disorder that causes progressive irreversible muscle deterioration and weakness. Emflaza was first approved by the FDA in February 2017 for the treatment of Duchenne in patients 5-years and older.

"We are excited to be able to bring Emflaza to younger boys living with Duchenne muscular dystrophy," said Stuart Peltz, Ph.D., Chief Executive Officer of PTC Therapeutics. "The standard of care is to start Emflaza at the time of diagnosis. We believe that treating patients as young as possible, when they still have a substantial amount of muscle, will have the greatest benefit for patients that are two years and older."

https://musculardystrophynews.com/emflaza-deflazacort-duchenne-muscular-dystrophy/

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