Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

  

Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a clinical-stage pharmaceutical company,  announced that the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) action date for the New Drug Application (NDA) for selinexor. The NDA, which is currently under Priority Review by the FDA, is seeking accelerated approval for selinexor in combination with dexamethasone for the treatment of patients with relapsed refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody. The previously disclosed April 6, 2019 PDUFA date has been extended by three months to July 6, 2019.

On February 26, 2019, the FDA'sOncologic Drugs Advisory Committee (ODAC) met to discuss the selinexor NDA and voted 8 to 5 recommending that the FDA wait for the results from Karyopharm's randomized, open-label, Phase 3 BOSTON study evaluating selinexor in patients with relapsed or refractory multiple myeloma, before making a final decision regarding approval.  Although the FDA considers the recommendation of this panel, the final decision regarding the approval of the product is made by the FDA solely, and the recommendations by the panel are non-binding.

Following the ODAC meeting, at the FDA's request,  Karyopharm submitted additional, existing clinical information as an amendment to the NDA, which allowed the FDA to extend the PDUFA action date by three months. "We look forward to the continued collaboration with FDA in trying to meet the needs of patients with relapsed refractory multiple myeloma," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. In 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with triple class refractory multiple myeloma who have been previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm's New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with triple class refractory multiple myeloma. The Company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval and was granted accelerated assessment. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study.  Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm's clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

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

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

FDA Issues Complete Response Letter for Zynquista (sotagliflozin)

In continuation of my update on Zynquista (sotagliflozin)

 The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding the New Drug Application for investigational Zynquista (sotagliflozin)*, a dual SGLT1 and SGLT2 inhibitor for the treatment of adults with type 1 diabetes in combination with insulin.

A CRL is a communication from the FDA that informs companies that an application cannot be approved in its present form.

Sanofi and Lexicon will work closely with the FDA to determine the appropriate next steps.

About Lexicon Pharmaceuticals

Lexicon (NASDAQ: LXRX) is a fully integrated biopharmaceutical company that is applying a unique approach to gene science based on Nobel Prize-winning technology to discover and develop precise medicines for patients with serious, chronic conditions. Through its Genome5000™ program, Lexicon scientists have studied the role and function of nearly 5,000 genes over the last 20 years and have identified more than 100 protein targets with significant therapeutic potential in a range of diseases. Through the precise targeting of these proteins, Lexicon is pioneering the discovery and development of innovative medicines to safely and effectively treat disease. In addition to its first commercial product, XERMELO® (telotristat ethyl), Lexicon has a pipeline of promising drug candidates in clinical and pre-clinical development in diabetes and metabolism and neuropathic pain. For additional information please visit www.lexpharma.com.

*Sotagliflozin is an investigational drug and is under regulatory review by the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA). The EMA and FDA have conditionally accepted Zynquista™ as the trade name for sotagliflozin.

https://pubchem.ncbi.nlm.nih.gov/compound/lx-4211#section=Structures

FDA Approves Adhansia XR (methylphenidate hydrochloride) Extended-Release Capsules for the Treatment of ADHD

In continuation of my update on methylphenidate

Adlon Therapeutics L.P., a subsidiary of Purdue Pharma L.P., announced that the U.S. Food and Drug Administration (FDA) approved Adhansia XR (methylphenidate hydrochloride) extended-release capsules CII, a central nervous system (CNS) stimulant, for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in patients six years and older. In a simulated Adult Workplace Environment (AWE) study, Adhansia XR demonstrated statistically significant improvement over placebo at 1, 2, 5, 8, 11, and 16 hours post-dose, but not at hour 14 post-dose.1

“Methylphenidate medications, when used as prescribed and in conjunction with behavioral therapy and lifestyle interventions, are one of the preferred first-line treatments for certain patients diagnosed with ADHD,” said Marcelo Bigal, MD, PhD, chief medical officer, Purdue Pharma, and general manager, Adlon Therapeutics. “We are pleased to receive FDA approval for Adhansia XR, a new option for appropriate patients with ADHD who may benefit from a treatment with efficacy demonstrated at one hour and 16 hours post-dose in adults, and we look forward to making it available later this year.”

The Full Prescribing Information for Adhansia XR contains a boxed warning for abuse and dependence. CNS stimulants, including Adhansia XR, other methylphenidate-containing products, and amphetamines have a high potential for abuse and dependence. Healthcare professionals should assess the risk of abuse prior to prescribing Adhansia XR and monitor for signs of abuse and dependence while patients are on therapy.

“Some of my patients with ADHD, especially those who are balancing school or work and participating in social or civic activities, require the ability to sustain attention throughout the day,” said Andrew J. Cutler, MD, chief medical officer, Meridien Research, and an investigator on Adhansia XR clinical studies. “The approval of Adhansia XR offers a methylphenidate treatment option with a longer duration of efficacy, which may be appropriate for these patients.”

Adhansia XR is not appropriate for all patients, and healthcare professionals should work with their patients to determine the most appropriate treatment option. Additionally, Adhansia XR is contraindicated in patients with a known hypersensitivity to methylphenidate or product components, as well as patients receiving concurrent treatment with a monoamine oxidase inhibitor (MAOI) or who have used an MAOI within the preceding 14 days.

The Full Prescribing Information for Adhansia XR, including Boxed Warning, is available at this link. Additionally, please see Important Safety Information for Adhansia XR below, including the Boxed Warning, Contraindications, Warnings and Precautions including the potential for abuse and dependence, serious cardiovascular events, blood pressure and heart rate increases, psychiatric adverse reactions, priapism, peripheral vasculopathy, long-term suppression of growth, allergic-type reactions, and Adverse Reactions.

“ADHD affects a significant number of adolescents and adults and, when not optimally treated, can negatively impact various aspects of their lives. A subset of these patients experience impairment throughout the day. While Adhansia XR is not appropriate for all patients, a methylphenidate medication available in a single daily dose that, in adults, demonstrated efficacy at one hour and at 16 hours post-dose, has the potential to address the needs of certain individuals with ADHD,” said Craig Landau, MD, president and CEO, Purdue Pharma. “We are committed to providing information on safe prescribing practices for this medication and initiatives to support the responsible use, storage, and disposal of all medications in this class."

The FDA approval of Adhansia XR was based on four clinical studies evaluating the efficacy and safety of Adhansia XR in patients who met DSM-5 criteria for ADHD. Eight hundred and eighty-three (883) patients were exposed to Adhansia XR during 1- to 4-week long, controlled treatment periods (434 adult patients and 449 pediatric patients [156 (6 to 12 years); 293 (12 to 17 years)] from two clinical studies in adults, one analog classroom trial over a 13-hour study day in pediatric patients ages 6 to 12 years, and one safety and efficacy study in pediatric patients ages 12 to 17 years). The safety data for adult patients are based on two randomized, double-blind, placebo-controlled studies in doses of 25 mg to 100 mg per day. The safety data for pediatric patients (6 to 17 years) are based on randomized, double-blind, placebo-controlled studies in doses of 25 mg to 85 mg per day.

A double-blind, randomized, placebo-controlled crossover AWE study evaluated Adhansia XR in adult patients with ADHD. Efficacy assessments were conducted at pre-dose and 1, 2, 5, 8, 11, 14, and 16 hours post-dose. The primary endpoint was the mean Permanent Measure of Performance Total scores (PERMP-T), averaged across all time points compared to placebo. PERMP-T, an objective, validated skill-adjusted math test, is the combined score obtained by adding PERMP-A (number of math problems attempted) and PERMP-C (number of math problems answered correctly).

While receiving Adhansia XR, adults achieved statistically significant improvement over placebo, achieving greater mean PERMP-T scores averaged across all time points on the AWE days (post-dose score of 281.3 vs. 254.5; difference of 26.80, 95% CI [15.19, 38.41]). The secondary efficacy endpoints were onset and duration of clinical effect, as assessed by the treatment difference in PERMP-T scores at post-dose time points. Adhansia XR demonstrated statistically significant improvement over placebo at 1, 2, 5, 8, 11, and 16 hours post-dose, but not at hour 14 post-dose.

In this study, 10% of Adhansia XR-treated patients discontinued due to adverse reactions compared to 0% of placebo-treated patients. The following adverse reactions led to discontinuation at a frequency of 2% of Adhansia XR-treated patients: nausea, bronchitis, viral gastroenteritis, viral infection, increased blood pressure, and hypomania.

Sudden death, stroke and myocardial infarction have occurred in patients treated with CNS stimulants at recommended doses. Additional information about serious cardiovascular risks can be found in the Important Safety Information section below.

Adhansia XR will be available in six capsule strengths (25, 35, 45, 55, 70, and 85 mg), allowing for flexible dosing. The recommended starting dose of Adhansia XR for patients six years or older is 25 mg once daily. Healthcare professionals should titrate the dose in increments of 10 mg to 15 mg at intervals of no less than five days. Adhansia XR should be taken orally once daily in the morning, with or without food. Capsules may be taken whole or, for patients who have difficulty swallowing, capsules may be opened and the entire contents sprinkled onto a tablespoon of applesauce or yogurt. The entire mixture should be consumed without crushing or chewing, immediately or within 10 minutes. If the mixture is not consumed within 10 minutes after mixing, it should be discarded and not stored. The dose of a single capsule should not be divided and patients should not take anything less than one capsule per day. In the event of a missed dose, patients should not take their medication later in the day.

Prior to initiating treatment with Adhansia XR, healthcare professionals should also assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam). Healthcare professionals should assess the risk of abuse prior to prescribing Adhansia XR and monitor for signs of abuse and dependence while patients are on therapy. After prescribing and while patients are on therapy, healthcare professionals should maintain careful prescription records, educate patients and their families about abuse and proper storage and disposal of CNS stimulants, and periodically re-evaluate the need for Adhansia XR use.

Dosages above 85 mg daily in adults and 70 mg and above daily in pediatric patients are associated with disproportionate increases in the incidence of certain adverse reactions. If paradoxical aggravation of symptoms or other adverse reactions occur, healthcare professionals should reduce the dosage, or, if necessary, discontinue treatment with Adhansia XR. Treatment with Adhansia XR should also be periodically discontinued to assess the patient's condition. If improvement is not observed in a patient after appropriate dosage adjustment over a one-month period, healthcare providers should discontinue treatment with Adhansia XR.1 Healthcare professionals should refer to the Full Prescribing Information for additional Dosage and Administration information.

Prescription stimulants, which include methylphenidate, the active ingredient in Adhansia XR, are federally controlled substances (CII) and have a high potential for abuse and dependence.1,2 The selling or giving away of methylphenidate medications may harm others or lead to death, and is against the law. It is important for healthcare professionals to ask patients if they or a family member have ever misused prescription medicines or abused alcohol or street drugs. Patients should be counseled that they should not give Adhansia XR to anyone else, and to keep methylphenidate medications in a safe place, such as a locked cabinet, to help prevent accidental exposure, diversion, and abuse.  They should also be advised to dispose of remaining, unused, or expired Adhansia XR by a medicine take-back program at authorized collection sites such as pharmacies or law enforcement locations, if available. If no take-back program or authorized collector is available, patients should mix Adhansia XR with an undesirable, nontoxic substance to make it less appealing to children and pets, place the mixture in a container such as a sealed plastic bag, and discard of it in the household trash.1 Patients should be encouraged to read the Medication Guide that accompanies their stimulant prescription, which contains the most important FDA-approved information that a patient should know about the medication

REf: https://en.wikipedia.org/wiki/Methylphenidate

FDA Approves Jatenzo (testosterone undecanoate) for Certain Forms of Hypogonadism

 The U.S. Food and Drug Administration  approved Jatenzo (testosterone undecanoate), an oral testosterone capsule to treat men with certain forms of hypogonadism. These men have low testosterone levels due to specific medical conditions, such as genetic disorders like Klinefelter syndrome or tumors that have damaged the pituitary gland. Jatenzo should not be used to treat men with “age-related hypogonadism,” in which testosterone levels decline due to aging, even if these men have symptoms that appear to be related to low testosterone. Jatenzo’s benefits do not outweigh its risks for that use.

“Jatenzo’s oral route of administration provides an important addition to current treatment options available for men with certain hypogonadal conditions who up until now have most commonly been treated with testosterone products that are applied to the skin or injected,” said Hylton V. Joffe, M.D, M.M.Sc., director of the Division of Bone, Reproductive and Urologic Products in the FDA’s Center for Drug Evaluation and Research. “But it’s important to emphasize that this drug should not, like other testosterone treatments, be used to treat older men with ‘age-related hypogonadism.’ The benefits of testosterone therapy, including Jatenzo, have not been established for this use, and Jatenzo’s effects on raising blood pressure can increase the risks of heart attack, stroke and cardiovascular death in this population.”

The efficacy of Jatenzo was demonstrated in a four-month clinical trial involving 166 men with hypogonadism. Study participants initially were given Jatenzo at a dose of 237 mg twice per day, and the dose was adjusted downward or upward to a maximum of 396 mg twice per day on the basis of testosterone levels. Eighty-seven percent of Jatenzo-treated men achieved an average testosterone level within the normal range, which was the primary study endpoint.

Jatenzo contains a boxed warning on its labeling stating that the drug can cause blood pressure to rise, increasing the risk of heart attack, stroke and cardiovascular death. Health care providers should consider a patient’s individual heart disease risks and ensure that blood pressure is adequately controlled before prescribing Jatenzo; they should also periodically monitor patient blood pressure during treatment. Jatenzo is currently one of two testosterone products that have this boxed warning. The FDA is requiring all testosterone product manufacturers to conduct blood pressure postmarketing trials to more clearly address whether these products increase blood pressure.

Common side effects, occurring in more than 2 percent of patients in the Jatenzo clinical trial, included headache, an increase in hematocrit (red blood cell count), a decrease in high-density lipoprotein cholesterol (“good” cholesterol), high blood pressure and nausea. An increase in prostate specific antigen (PSA) was also observed. Patients should have their hematocrit, cholesterol and PSA monitored regularly to check for changes. Those with benign prostate hyperplasia should be monitored for worsening of symptoms.

Ref: https://en.wikipedia.org/wiki/Testosterone_undecanoate

FDA Approves Jatenzo (testosterone undecanoate) for Certain Forms of Hypogonadism

FDA Approves Mavenclad (cladribine) Tablets for Multiple Sclerosis

In continuation of my update on Cladribine

The U.S. Food and Drug Administration,  approved Mavenclad (cladribine) tablets to treat relapsing forms of multiple sclerosis (MS) in adults, to include relapsing-remitting disease and active secondary progressive disease. Mavenclad is not recommended for MS patients with clinically isolated syndrome. Because of its safety profile, the use of Mavenclad is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS.

“We are committed to supporting the development of safe and effective treatments for patients with multiple sclerosis,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “The approval of Mavenclad represents an additional option for patients who have tried another treatment without success.”

MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communications between the brain and other parts of the body. Most people experience their first symptoms of MS between the ages of 20 and 40. MS is among the most common causes of neurological disability in young adults and occurs more frequently in women than in men.

For most people, MS starts with a relapsing-remitting course, in which episodes of worsening function (relapses) are followed by recovery periods (remissions). These remissions may not be complete and may leave patients with some degree of residual disability. Many, but not all, patients with MS experience some degree of persistent disability that gradually worsens over time. In some patients, disability may progress independent of relapses, a process termed secondary progressive multiple sclerosis (SPMS). In the first few years of this process, many patients continue to experience relapses, a phase of the disease described as active SPMS. Active SPMS is one of the relapsing forms of MS, and drugs approved for the treatment of relapsing forms of MS can be used to treat active SPMS.

The efficacy of Mavenclad was shown in a clinical trial in 1,326 patients with relapsing forms of MS who had least one relapse in the previous 12 months. Mavenclad significantly decreased the number of relapses experienced by these patients compared to placebo. Mavenclad also reduced the progression of disability compared to placebo.

Mavenclad must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Mavenclad has a Boxed Warning for an increased risk of malignancy and fetal harm. Mavenclad is not to be used in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, health care professionals should evaluate the benefits and risks of the use of Mavenclad on an individual patient basis. Health care professionals should follow standard cancer screening guidelines in patients treated with Mavenclad. The drug should not be used in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception during treatment and for six months after the course of therapy because of the potential for fetal harm. Mavenclad should be stopped if the patient becomes pregnant.

Other warnings include the risk of decreased lymphocyte (white blood cell) counts; lymphocyte counts should be monitored before, during and after treatment. Mavenclad may increase the risk of infections; health care professionals should screen patients for infections and treatment with Mavenclad should be delayed if necessary. Mavenclad may cause hematologic toxicity and bone marrow suppression so health care professionals should measure a patient’s complete blood counts before, during and after therapy. The drug has been associated with graft-versus-host-disease following blood transfusions with non-irradiated blood. Mavenclad may cause liver injury and treatment should be interrupted or discontinued, as appropriate, if clinically significant liver injury is suspected.

The most common adverse reactions reported by patients receiving Mavenclad in the clinical trials include upper respiratory tract infections, headache and decreased lymphocyte counts. 

Ref : https://en.wikipedia.org/wiki/Cladribine

FDA Approves Mavenclad (cladribine) Tablets for Multiple Sclerosis

FDA Approves Spravato (esketamine) Nasal Spray for Treatment-Resistant Depression

  In continuation of my update on esketamine

The U.S. Food and Drug Administration   approved Spravato (esketamine) nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them (treatment-resistant depression). Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by Spravato administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).

"There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition," said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research. "Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment. Because of safey concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient."

Patients with major depressive disorder who, despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment are considered to have treatment-resistant depression.

The Spravato labeling contains a Boxed Warning that cautions that patients are at risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. Because of the risk of sedation and dissociation, patients must be monitored by a health care provider for at least two hours after receiving their Spravato dose. The REMS requires the prescriber and the patient to both sign a Patient Enrollment Form that clearly states that the patient understands they should make arrangements to safely leave the health care setting to get home and that the patient should not drive or use heavy machinery for the rest of the day on which they receved the drug. Additionally, Spravato must be dispensed with a patient Medication Guide that outlines the drug’s uses and risks.

The patient self-administers Spravato nasal spray under the supervision of a health care provider in a certified doctor’s office or clinic, and the spray cannot be taken home. The health care provider will instruct the patient on how to operate the nasal spray device. During and after each use of the nasal spray device, the health care provider will check the patient and determine when the patient is ready to leave.

The efficacy of Spravato was evaluated in three short-term (four-week) clinical trials and one longer-term maintenance-of-effect trial. In the three short-term studies, patients were randomized to receive Spravato or a placebo nasal spray. In light of the serious nature of treatment-resistant depresison and the need for patients to receive some form of treatment, all patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.

The most common side effects experienced by patients treated with Spravato in the clinical trials were disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting and feeling drunk.

Patients with unstable or poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Spravato may impair attention, judgment, thinking, reaction speed and motor skills. Patients should not drive or operate machinery until the next day after a restful sleep. Spravato may cause fetal harm and women of reproductive potential should consider pregnancy planning and prevention; women should not breastfeed while being treated.

Esketamine is the s-enantiomer of ketamine. Ketamine is a mixture of two enantiomers (mirror image molecules). This is the first FDA approval of esketamine for any use. The FDA approved ketamine (Ketalar) in 1970.

Ref  https://en.wikipedia.org/wiki/Esketamine

FDA Approves Spravato (esketamine) Nasal Spray for Treatment-Resistant Depression

FDA Approves Rocklatan (netarsudil and latanoprost ophthalmic solution) for the Reduction of Intraocular Pressure in Open-Angle Glaucoma or Ocular Hypertension

In continuation of my update on latanoprost 

Aerie Pharmaceuticals, Inc. (NASDAQ:AERI) (Aerie or the Company), an ophthalmic pharmaceutical company focused on the discovery, development and commercialization of first-in-class therapies for the treatment of patients with open-angle glaucoma, retinal diseases and other diseases of the eye,   announced that the U.S. Food and Drug Administration (FDA) has approved Rocklatan (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. 

Rocklatan is a once-daily eye drop that is a fixed-dose combination of latanoprost, the most widely-prescribed prostaglandin analog (PGA), and netarsudil, the active ingredient in Rhopressa (netarsudil ophthalmic solution) 0.02%, a first-in-class Rho kinase (ROCK) inhibitor specifically designed to target the trabecular meshwork (the eye’s principal drainage pathway). The diseased trabecular meshwork is considered to be the main cause of elevated IOP in open-angle glaucoma and ocular hypertension. Rhopressa® works by restoring outflow through the trabecular meshwork, while latanoprost increases fluid outflow through a secondary mechanism known as the uveoscleral pathway.

Aerie launched Rhopressa® in the United States in April 2018. The Company plans to launch Rocklatan™ in the United States in the second quarter of 2019.

“We are in the unique position of receiving FDA approval on a second glaucoma treatment less than a year from the U.S. launch of Rhopressa®,” said Vicente Anido, Jr., Ph.D., chairman and chief executive officer at Aerie. “Together, Rocklatan™ and Rhopressa® give us a broad therapeutic franchise, based on our ROCK inhibitor netarsudil, that addresses many of the needs of clinicians and patients in a wide variety of treatment settings. Our existing salesforce, which has been calling on U.S. eye-care professionals since last May, is very well positioned to introduce Rocklatan™ to these doctors and help them understand the clinical utility of both products in the care of their patients with glaucoma. We have also been working diligently on securing favorable reimbursement for our products, with Rhopressa® now enjoying broad commercial and Medicare Part D coverage, and Rocklatan™ already under review by major payers.”

The FDA approval of Rocklatan is based on data from two Phase 3 registration trials, MERCURY 1 and MERCURY 2. In these studies, Rocklatan™ achieved its primary 90-day efficacy endpoint as well as positive 12-month safety and efficacy results, demonstrating statistically superior IOP reduction over latanoprost and netarsudil at every measured time point. More than 60% of patients taking Rocklatan™ in the two MERCURY studies achieved an IOP reduction of 30% or more, a frequency that was nearly twice that achieved by participants taking latanoprost alone. Rocklatan™ also helped more patients get to low target pressures. Nearly twice as many patients taking Rocklatan™ reached 16 mmHg or lower and nearly three times as many reached 14 mmHg or lower compared to latanoprost.

In the two MERCURY studies, Rocklatan treatment was associated with generally mild and tolerable ocular adverse events, with minimal systemic side effects. The most common ocular adverse event in controlled clinical studies with Rocklatan™ was conjunctival hyperemia. Ninety percent of patients who experienced hyperemia reported it as mild and 5% discontinued because of it. Other common ocular adverse effects reported in the studies include instillation site pain, corneal verticillata and conjunctival hemorrhage.

About Rocklatan

Indications and Usage

Rocklatan (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Select Important Safety Information

Although not observed in the two MERCURY studies, latanoprost has been reported to cause changes to pigmented tissues, including pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Iris pigmentation is likely to be permanent. Latanoprost has also been associated with gradual changes to eyelashes including increased length, thickness and number of lashes. These changes are usually reversible.

Ewf https://www.drugbank.ca/drugs/DB00654

https://www.biospace.com/article/fda-approves-aerie-pharma-s-glaucoma-combo-eye-drops/

FDA Approves Sunosi

 Jazz Pharmaceuticals plc   announced that the U.S. Food and Drug Administration (FDA) approved Sunosi (solriamfetol) to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA). Once-daily Sunosi is approved with doses of 75 mg and 150 mg for patients with narcolepsy and doses of 37.5 mg, 75 mg, and 150 mg for patients with OSA. Sunosi is the first dual-acting dopamine and norepinephrine reuptake inhibitor (DNRI) approved to treat excessive daytime sleepiness in adults living with narcolepsy or OSA.

Sunosi is expected to be commercially available in the U.S. following the final scheduling decision by the U.S. Drug Enforcement Administration (DEA), which is typically within 90 days of FDA approval.

"Excessive daytime sleepiness can negatively impact the daily lives of people living with narcolepsy or obstructive sleep apnea at work, at home or in daily activities. With this approval, a new, daytime medicine that can provide sustained wakefulness throughout the day will be available for patients," said Bruce Cozadd, chairman and chief executive officer of Jazz Pharmaceuticals. "The FDA approval of Sunosi also represents an important milestone for Jazz as we continue to offer new treatment options that address unmet needs for people living with chronic, and often debilitating, sleep disorders."

At Week 12, 150 mg of Sunosi for narcolepsy patients and all doses for OSA patients demonstrated improvements in wakefulness compared to placebo as assessed in test sessions 1 (approximately one hour post-dose) through 5 (approximately nine hours post-dose) of the maintenance of wakefulness test (MWT).

The FDA's approval of Sunosi is based on data from the Treatment of Obstructive sleep apnea and Narcolepsy Excessive Sleepiness (TONES) Phase 3 clinical program, which included four randomized placebo-controlled studies that demonstrated the superiority of Sunosi relative to placebo. The most common adverse reactions (incidence ≥5% and higher than placebo) reported in both the narcolepsy and OSA study populations were headache, nausea, decreased appetite, and anxiety. Sunosi was evaluated in more than 900 adults with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea and was shown to maintain its effect relative to placebo after six months of use.

"We're excited about this new therapeutic option for patients, and we are pleased with the information included in the Sunosi label as we believe it will give physicians the information needed to appropriately manage the vast majority of obstructive sleep apnea and narcolepsy patients with excessive daytime sleepiness," said Daniel Swisher, president and chief operating officer of Jazz Pharmaceuticals.

In 12 week clinical studies, approximately 68-74% of people taking Sunosi at the 75 mg dose and 78-90% of people taking Sunosi at the 150 mg dose reported improvement in their overall clinical condition, as assessed by the Patient Global Impression of Change (PGIc) scale.

Although the exact mechanism of action is unknown, the effects of Sunosi are thought to be mediated through its activity as a DNRI.

"Sunosi is an effective treatment option with a novel mechanism of action as a dual-acting dopamine and norepinephrine reuptake inhibitor," said Richard K. Bogan, MD, FCCP, FAASM, Associate Clinical Professor at the University of South Carolina School of Medicine and Chief Medical Officer at SleepMed in Columbia, SC. "Excessive daytime sleepiness is the most common symptom for people with narcolepsy and a major complaint of people with obstructive sleep apnea. In some people with obstructive sleep apnea, excessive daytime sleepiness may persist despite using CPAP."

Sunosi is not indicated to treat the underlying airway obstruction in OSA. Ensure that the underlying airway obstruction is treated (e.g., with continuous positive airway pressure (CPAP)) for at least one month prior to initiating Sunosi for excessive daytime sleepiness in OSA. Modalities to treat the underlying airway obstruction should be continued during treatment with Sunosi. Sunosi is not a substitute for these modalities.

About Sunosi (solriamfetol)

Sunosi is a dual-acting dopamine and norepinephrine reuptake inhibitor (DNRI) indicated to improve wakefulness in adults living with excessive daytime sleepiness due to narcolepsy or obstructive sleep apnea (OSA). In 2014, Jazz Pharmaceuticals acquired a license to develop and commercialize Sunosi from Aerial Biopharma. Jazz Pharmaceuticals has worldwide development, manufacturing, and commercialization rights to Sunosi, excluding certain jurisdictions in Asia. SK Biopharmaceuticals, the discoverer of the compound, maintains rights in 12 Asian markets, including Korea, China and Japan. Sunosi has orphan drug designation for narcolepsy in the United States. 

Important Safety Information

Sunosi can be a target for people who abuse prescription medicines or street drugs. Keep Sunosi in a safe place to protect it from theft. Never give your Sunosi to anyone else, because it may cause death or harm them. Selling or giving away Sunosi may harm others and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.

Do not take Sunosi if you are taking or have stopped taking within the past 14 days a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI).

Before taking Sunosi, tell your doctor about all of your medical conditions, including if you:

• have heart problems, high blood pressure, kidney problems, diabetes, or high cholesterol
• have had a heart attack or a stroke
• have kidney problems or diabetes
• have a history of mental health problems, (including psychosis and bipolar disorders), or of drug or alcohol abuse or addiction
• are pregnant or planning to become pregnant. It is not known if Sunosi will harm your unborn baby.
• Pregnancy Registry: There is a pregnancy registry for women who take Sunosi during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. It is not known if Sunosi passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take Sunosi.

Especially tell your healthcare provider if you take a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI).

Ref : https://en.wikipedia.org/wiki/Solriamfetol

FDA Approves Sunosi (solriamfetol) for Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea..

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Eating blueberries every day could help decrease blood pressure

In continuation of my update on blueberries

A new study published in the Journal of Gerontology Series A has found that eating 200g of blueberries every day for a month can lead to an improvement in blood vessel function and a decrease in systolic blood pressure in healthy people.

Researchers from King's College London studied 40 healthy volunteers for one month. They were randomly given either a drink containing 200g of blueberries, or a matched control drink daily.

The team monitored chemicals in volunteers' blood and urine as well as their blood pressure and flow-mediated dilation (FMD) of the brachial artery: a measure of how the artery widens when blood flow increases, which is considered a sensitive biomarker of cardiovascular disease risk.

In a further study, researchers compared the effects of a blueberry drink with those of purified anthocyanins, a type of phytochemical responsible for the blue, red, pink and purple colour of some fruits and vegetables such as berries and red grapes. They also compared this with control drinks containing either similar levels of fiber, mineral or vitamins found in blueberries.

They found that:

• Effects on blood vessel function were seen two hours after consumption of the blueberry drinks and were sustained for one month even after an overnight fast.
• Over the course of the month, blood pressure was reduced by 5mmHg. This is similar to what is commonly seen in studies using blood pressure lowering medication.
• The drinks containing purified anthocyanins led to improvements in endothelial function. Endothelial cells act as a barrier between the blood or lymph and the surrounding body tissue, as well as playing key roles in blood clotting and regulating blood pressure.
• Neither the control drink, the control with fiber or the control with minerals and vitamins had a significant effect on FMD at two and six hours after consumption.

Lead researcher Dr Ana Rodriguez-Mateos from the Department of Nutritional Sciences at King's College London said: "Although it is best to eat the whole blueberry to get the full benefit, our study finds that the majority of the effects can be explained by anthocyanins.

"If the changes we saw in blood vessel function after eating blueberries every day could be sustained for a person's whole life, it could reduce their risk of developing cardiovascular disease by up to 20%."

https://www.kcl.ac.uk/news/news-article?id=af4e7b3e-2c7d-4d8f-ae9e-fe6d1014d0eb

Eating blueberries every day could help decrease blood pressure