FDA Approves Piqray (alpelisib) as First PI3K Inhibitor for Breast Cancer

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. 

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

https://pubchem.ncbi.nlm.nih.gov/compound/Alpelisib

FDA Approves Jakafi (ruxolitinib) for the Treatment of Patients with Acute Graft-Versus-Host Disease

In continuation of my update  on ruxolitinib

Incyte Corporation   announced that the U.S. Food and Drug Administration (FDA) has approved Jakafi (ruxolitinib) for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older. Jakafi is the first and only FDA-approved treatment for this indication.

“For the first time, patients with steroid-refractory acute GVHD, and the physicians that treat them, have an FDA-approved treatment for this serious disease,” stated Hervé Hoppenot, Chief Executive Officer, Incyte. “This approval is also an important milestone for Incyte, as it marks the third indication for Jakafi in the United States, further underscoring Incyte’s commitment to delivering innovative medicines for patients in need. We are proud of the impact Jakafi has had on patients’ lives to-date and are dedicated to advancing our ongoing research in JAK inhibition to serve more GVHD patients in the future.”

The approval was based on data from REACH1, an open-label, single-arm, multicenter study of Jakafi in combination with corticosteroids in patients with steroid-refractory grade II-IV acute GVHD. Of the 71 patients recruited into REACH1, 49 patients were refractory to steroids alone, 12 patients had received two or more prior anti-GVHD therapies and 10 patients did not otherwise meet the FDA definition of steroid-refractory. Jakafi was administered at 5 mg twice daily, and the dose could be increased to 10 mg twice daily after three days in the absence of toxicity.

The efficacy of Jakafi was evaluated based upon Day 28 overall response rate (ORR), defined as a complete response (CR), very good partial response or partial response based on the Center for International Blood and Marrow Transplant Research (CIBMTR) criteria. The Day 28 ORR in the 49 patients refractory to steroids alone was 57 percent with a CR rate of 31 percent. The most frequently reported adverse reactions among all 71 study participants were infections (55 percent) and edema (51 percent), and the most common laboratory abnormalities were anemia (75 percent), thrombocytopenia (75 percent) and neutropenia (58 percent).

GVHD is a condition that can occur after an allogeneic stem cell transplant (the transfer of stem cells from a donor) where the donated cells initiate an immune response and attack the transplant recipient’s organs, leading to significant morbidity and mortality. There are two major forms of GVHD, acute and chronic, that can affect multiple organ systems including the skin, gastrointestinal (digestive) tract and liver. Patients who develop steroid-refractory acute GVHD can progress to severe disease, with one-year mortality rates of approximately 70 percent.1

“Every year in the United States, about half of the people who develop acute GVHD do not respond adequately to steroids, making it an extremely challenging disease to treat,” said Madan Jagasia, M.B.B.S., M.S., M.M.H.C., a lead investigator on the REACH1 trial and Professor of Medicine, Vanderbilt University Medical Center, Department of Medicine, Division of Hematology-Oncology and Chief Medical Officer, Vanderbilt-Ingram Cancer Center. “While allogeneic stem cell transplants have the potential to transform people’s lives, the onset of acute GVHD can significantly impact their prognosis. I am excited that we now have Jakafi as a new treatment option for acute GVHD patients that do not respond to corticosteroids who, until now, have had limited choices.”

Previously, the FDA granted Jakafi Breakthrough Therapy Designation and Orphan Drug Designation for the treatment of patients with steroid-refractory acute GVHD, and the supplemental New Drug Application (sNDA) was reviewed under the FDA’s Priority Review program.

Jakafi will be made available to appropriate patients with steroid-refractory acute GVHD immediately. Incyte is committed to supporting patients and removing barriers to access medicines. Eligible patients in the U.S. who are prescribed Jakafi have access to IncyteCARES (Connecting to Access, Reimbursement, Education and Support), a comprehensive program offering patient support, including financial assistance and ongoing education and resources to eligible patients.

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

Ocular Therapeutix Announces FDA Approval of Dextenza (dexamethasone intracanalicular insert) for the Treatment of Ocular Inflammation Following Ophthalmic Surgery

In continuation of my update on Dextenza 

Ocular Therapeutix™, Inc. ), a biopharmaceutical company focused on the formulation, development, and commercialization of innovative therapies for diseases and conditions of the eye,   announced the U.S. Food and Drug Administration (FDA) approved a Supplemental New Drug Application (sNDA) for Dextenza to include the treatment of ocular inflammation following ophthalmic surgery as an additional indication. With the approval of the sNDA, Dextenza is now approved for the treatment of both ocular inflammation and pain following ophthalmic surgery.

Dextenza is the first FDA-approved intracanalicular insert, a novel route of administration that delivers drug to the surface of the eye without the need for eye drops. Dextenza is a preservative-free, resorbable hydrogel insert that delivers 0.4mg of dexamethasone to treat post-surgical ocular inflammation and pain for up to 30 days with a single administration. Dextenza originally received FDA approval in November 2018 for the treatment of ocular pain following ophthalmic surgery.

“We could not be more excited about both the approval and its earlier-than-expected timing,” said Antony Mattessich, the Company’s President and Chief Executive Officer. “With our C-Code and pass-through payment status effective on July 1, the expanded indication gives us tremendous momentum as we approach our commercial launch.”

The approval of the sNDA is supported by three Phase 3 randomized, vehicle-controlled trials; patients received Dextenza or a vehicle immediately upon completion of cataract surgery. In all three trials, Dextenza had, at a statistically significant level, a higher proportion of patients than the vehicle group who were pain free on post-operative Day 8. On post-operative Day 14, in two of the three studies, Dextenza had a higher proportion of patients than the vehicle group, at a statistically significant level, who had an absence of anterior chamber cells.

http://www.chemdiv.com/dextenza-dexamethasone-ophthalmic-insert-first-intracanalicular-insert-drug-delivery/

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

FDA Approves Wakix (pitolisant), a First-in-Class Medication for the Treatment of Excessive Daytime Sleepiness in Adult Patients with Narcolepsy

Harmony Biosciences, LLC (Harmony) announced the U.S. Food and Drug Administration (FDA) approval of Wakix (pitolisant) for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. Wakix is the first and only treatment approved for patients with narcolepsy that is not scheduled as a controlled substance by the U.S. Drug Enforcement Administration (DEA).

“We are extremely proud to bring Wakix to market for those living with narcolepsy, a chronic, debilitating, rare neurologic disorder,” said Harmony’s Chairman and Chief Executive Officer, John C. Jacobs. “At Harmony we share a vision to develop novel treatment options for people living with rare diseases, with a focus on those that affect the central nervous system. The approval of Wakix strengthens our commitment to making that vision a reality.”

Wakix, a first-in-class medication, is a selective histamine 3 (H₃) receptor antagonist/inverse agonist that works through a novel mechanism of action to increase the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain. Wakix is administered orally once daily in the morning upon wakening.

“The approval of Wakix provides healthcare professionals managing people living with narcolepsy a new and important treatment option for their patients,” said Harmony’s Chief Medical Officer, Jeffrey Dayno, M.D. “Additionally, Wakix is the only non-scheduled treatment option approved for adult patients with narcolepsy, and it offers an important benefit/risk profile to address the unmet medical need that exists in people living with narcolepsy.”

The efficacy of Wakix for the treatment of EDS in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (HARMONY 1 and HARMONY 1bis). These studies included a total of 261 patients who were randomized to receive Wakix, placebo, or active control; these patients had a median age of 37 (HARMONY 1) and 40 (HARMONY 1bis). Treatment duration was eight weeks, with a three-week dose titration phase followed by a 5-week stable dose phase; 75% to 80% of the patients in these studies had a history of cataplexy. In both of these studies, WAKIX demonstrated a statistically significant improvement in EDS as measured by the Epworth Sleepiness Scale (ESS) score. In the placebo-controlled trials conducted in patients with narcolepsy with or without cataplexy, the most common adverse reactions (occurring in ≥5% of patients and at twice the rate of placebo) with the use of WAKIX were insomnia (6%), nausea (6%), and anxiety (5%).

Wakix will be commercially available to healthcare professionals and appropriate patients in the U.S. in the fourth quarter of 2019.

About Wakix (pitolisant)

Wakix is a first-in-class medication approved for use in the U.S. for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. It was granted orphan drug designation for the treatment of narcolepsy in 2010. WAKIX is a selective histamine 3 (H₃) receptor antagonist/inverse agonist. The mechanism of action of Wakix is unclear; however, its efficacy could be mediated through its activity at H₃ receptors, thereby increasing the synthesis and release of histamine, a wake promoting neurotransmitter. WAKIX was designed and developed by Bioprojet Societe Civile de Recherche (Bioprojet), who has marketed the product in Europe since its approval by the European Medicines Agency in 2016. Harmony has an exclusive license from Bioprojet to develop, manufacture and commercialize pitolisant in the United States.

INDICATION AND USAGE

Wakix (pitolisant) is approved for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.

IMPORTANT SAFETY INFORMATION

Do not use Wakix if you have severe liver disease.

Tell your healthcare provider about all your medical conditions, including if you have heart rhythm irregularities, were born with a heart condition, or the levels of electrolytes in your blood are too high or too low. Wakix has an effect on the electrical activity of the heart known as QT/QTc prolongation. Medicines with this effect can lead to disturbances in heart rhythm, which are more likely in patients with risk factors such as certain heart conditions, or when taken in combination with other interacting medicines. Tell your healthcare provider about all the other medicines you take.

The risk of QT prolongation may be greater in patients with liver or kidney disease. Wakix is not recommended in patients with end stage kidney disease.

The most common side effects seen with Wakix were insomnia, nausea and anxiety. Other side effects included headache, upper respiratory infection, musculoskeletal pain, heart rate increased, and decreased appetite. These are not all the possible side effects of Wakix. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Tell your healthcare provider about all the medicines you take or plan to take, including prescription and over-the-counter medicines. Some medicines can increase the amount of Wakix that gets into your blood and some medicines can decrease the amount of Wakix that gets into your blood. The dosage of Wakix may need to be adjusted if you are taking these medicines.

Wakix can also decrease the effectiveness of some medicines, including hormonal birth control methods. You should use an alternative non-hormonal birth control method during treatment with Wakix and for at least 21 days after discontinuation of treatment.

Tell your healthcare provider if you are pregnant or planning to become pregnant. There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to Wakix during pregnancy. You are encouraged to enroll in the Wakix pregnancy registry if you become pregnant while taking WAKIX. To enroll or obtain information from the registry, call 1-800-833-7460.

The safety and effectiveness of Wakix have not been established in patients less than 18 years of age.

https://pubchem.ncbi.nlm.nih.gov/compound/Pitolisant#section=2D-Structure

FDA Approves Boxed Warning About Increased Risk of Blood Clots and Death with Higher Dose of Tofacitinib (Xeljanz, Xeljanz XR)

In continuation of my update on tofacitinib 

The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. We approved these changes, including adding our most prominent Boxed Warning, after reviewing interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower and this higher dose of the medicine.

The 10 mg twice daily dose of tofacitinib is not approved for RA or psoriatic arthritis (PsA). This dose is only approved for ulcerative colitis for initial treatment and for long-term use in limited situations. While the increased risks of blood clots and of death were seen in patients taking this dose for RA, these risks may also apply to those taking tofacitinib for ulcerative colitis.

Tofacitinib works by decreasing the activity of the immune system; an overactive immune system contributes to RA, PsA, and ulcerative colitis. Tofacitinib was first approved in 2012 to treat adult patients with RA who did not respond well to the medicine methotrexate. In RA, the body attacks its own joints, causing pain, swelling, and loss of function. In 2017, we approved the medicine to treat patients with a second condition that causes joint pain and swelling, PsA, who did not respond well to methotrexate or other similar medicines. In 2018, we approved tofacitinib to treat ulcerative colitis, which is a chronic, inflammatory disease affecting the colon.

Patients should tell your health care professionals if you have a history of blood clots or heart problems, and talk to them about any questions or concerns. Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:

• Sudden shortness of breath
• Chest pain that worsens with breathing
• Swelling of a leg or arm
• Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm

Do not stop taking tofacitinib without first talking to your health care professional, as doing so can worsen your condition.

Health care professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed (See Additional Information for Health Care Professionals for more recommendations).

When FDA first approved tofacitinib in 2012, we required a postmarketing clinical trial in patients with RA on background methotrexate, to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10 mg twice daily dosage) in comparison to a TNF blocker. An interim analysis of the trial’s results found an increased occurrence of blood clots and of death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF blocker. Based on these results, the 10 mg twice daily treatment was stopped and patients were allowed to continue treatment on 5 mg twice daily.

This safety trial is ongoing. Patients in the 5 mg twice daily group and the TNF blocker group continue to be followed. FDA will reassess these safety issues when the trial has completed and final, verified data are available. We will update the public when additional information is available.

The interim results of the trial, as of January 2019, have identified the following:

• 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF blockers
• 45 cases of death from all causes out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 25 cases out of 3,982 patient-years in patients who received TNF blockers

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