Kisqali (ribociclib) Approved for Additional Indications in HR+/HER2- Advanced Breast Cancer

In continuation of my update on ribociclib

Novartis  announced a new approval for Kisqali (ribociclib) from the US Food and Drug Administration (FDA) for women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer. Kisqali is now the only CDK4/6 inhibitor indicated for use with an aromatase inhibitor for the treatment of pre-, peri- or postmenopausal women in the US, and also is indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women[1]. FDA reviewed this supplemental New Drug Application (sNDA) under its Real-Time Oncology Review and Assessment Aid pilot programs and approved the application in less than one month after submission.

"Compelling data for Kisqali have led to the broadest first-line indications of any CDK4/6 inhibitor," said Liz Barrett, CEO, Novartis Oncology. "With this new approval Kisqali has the potential to help even more people in the US live a longer life without progression of disease from this incurable form of breast cancer."

This approval is based on the pivotal MONALEESA-7 and MONALEESA-3 Phase III clinical trials that demonstrated prolonged progression-free survival (PFS) and improvements as early as eight weeks for Kisqali-based regimens compared to endocrine therapy alone[1]. In MONALEESA-7, Kisqali plus an aromatase inhibitor and goserelin nearly doubled the median PFS compared to an aromatase inhibitor and goserelin alone (27.5 months compared to 13.8 months; HR=0.569; 95% CI: 0.436-0.743) in pre- or perimenopausal women[1]. In MONALEESA-3, Kisqali plus fulvestrant demonstrated a median PFS of 20.5 months compared to 12.8 months for fulvestrant alone (HR=0.593; 95% CI: 0.480-0.732) across the overall population of first-line and second-line postmenopausal women[1].

"These MONALEESA clinical trial program data add to the body of evidence that CDK 4/6 inhibition, in the case of these studies with ribociclib, gives women diagnosed with HR+/HER2- advanced breast cancer an important first-line treatment option," said Dennis J. Slamon, MD, Director of Clinical/Translational Research, University of California, Los Angeles Jonsson Comprehensive Cancer Center. "Based on Phase III trial results that consistently showed clinical benefit, physicians should be encouraged to re-evaluate treatment for advanced breast cancer in the first-line setting."

Approximately 155,000 people in the US are living with metastatic breast cancer[2]. Up to one-third of patients with early-stage breast cancer will subsequently develop advanced disease, for which there is currently no cure[3]. Advanced breast cancer in premenopausal women is a biologically distinct and more aggressive disease, and it is the leading cause of cancer death in women 20-59 years old[4],[5].

"Premenopausal women diagnosed with advanced breast cancer often face unique social challenges and a poorer prognosis. For the first time in nearly 20 years, we have results from a dedicated clinical trial among these women," said Jennifer Merschdorf, CEO, Young Survival Coalition. "With this approval, some younger women now have a new therapy indicated specifically for them that may help extend their lives without progression of disease."

FDA Approves Perseris (risperidone) for Extended-Release Injectable Suspension for the Treatment of Schizophrenia in Adults

In continuation of my update on risperidone

Indivior PLC,   announced that the U.S. Food and Drug Administration (FDA) has approved Perseris, the first once-monthly subcutaneous risperidone-containing, long-acting injectable (LAI) for the treatment of schizophrenia in adults. Clinically relevant levels were reached after the first injection of Perseris without use of a loading dose or any supplemental oral risperidone.

"Treatment adherence is a major challenge in schizophrenia due to the complexity of the disease. It is important to have additional treatment options available to physicians to help them improve their patients' symptom severity," said Maurizio Fava, Executive Vice Chair of the Massachusetts General Hospital (MGH) Department of Psychiatry and Indivior clinical research consultant. "The studies carried out by Indivior suggest that Perseris may offer patients, caregivers and physicians a new once-monthly subcutaneous medication option to treat adults with schizophrenia."

Perseris contains risperidone, a well-established treatment for schizophrenia, and uses the extended-release delivery system to form a subcutaneous (under the skin) depot that provides sustained levels of risperidone over one month. Initial peak risperidone plasma levels occur within 4 to 6 hours of dosing and are due to an initial release of the drug during the depot formation process.

"Schizophrenia is a devastating, chronic and often disabling mental health condition that impacts the lives of people suffering from this illness, their families and caregivers. The approval of Perseris brings us the opportunity to provide adult patients and their healthcare providers with an innovative treatment option that we believe will make a meaningful difference," said Shaun Thaxter, Chief Executive Officer of Indivior. "People with schizophrenia face a complex patient journey that can be hindered by ignorance, apathy and stigma. Indivior is committed to working with stakeholders to reduce the stigma of schizophrenia and expand access to evidence-based treatment."

The efficacy of Perseris was evaluated in a pivotal Phase 3 randomized, double-blind, placebo-controlled, 8-week study of 354 patients (NCT 02109562). Perseris efficacy was demonstrated by an improvement in the primary clinical endpoint, Positive and Negative Syndrome Scale (PANSS) total score at day 57. The improvement in Clinical Global Impression Severity of Illness (CGI-S) was also statistically significant at day 57. Clinical trials of Perseris were designed for the product to be initiated with neither a loading dose nor any supplemental risperidone.

The safety of Perseris was evaluated in 814 adults with schizophrenia who received at least one dose of Perseris during clinical trials. A total of 322 patients were treated with Perseris for at least six months, with 234 of those treated with Perseris for at least 12 months. The systemic safety profile of Perseris was consistent with the known safety profile of oral risperidone. The most common systemic adverse reactions in the pivotal Phase 3 trial (in ≥5% of Perseris patients and greater than twice placebo) were increased weight, sedation/somnolence and musculoskeletal pain. The most common injection site reactions (≥5% of all patients across Perseris and placebo groups) were injection site pain and reddening of the skin.

https://www.drugs.com/history/perseris.html

United Therapeutics Announces FDA Approval of the Implantable System for Remodulin

In continuation of my update on treprostinil

United Therapeutics Corporation,  announced approval by the U.S. Food and Drug Administration (FDA) of a New Drug Application (NDA) for the use of Remodulin (treprostinil) Injection in the Implantable System for Remodulin® (ISR).

The ISR has been developed under a collaboration with Medtronic (NYSE: MDT). In December 2017, Medtronic received FDA approval of a premarket application (PMA) for a proprietary intravascular infusion catheter to be used with its SynchroMed™ II implantable infusion pump and related infusion system components (together referred to as the Implantable System for Remodulin) in order to deliver Remodulin for the treatment of pulmonary arterial hypertension (PAH).

"We are extremely excited to offer this new option to patients suffering from PAH," said Martine Rothblatt, Ph.D., Chairman and Chief Executive Officer of United Therapeutics. "During the course of the DelIVery study, we received considerable physician and patient interest in the ISR. We are grateful to our collaborators at Medtronic for reaching this milestone and look forward to continuing our collaboration."

Remodulin was originally approved by the FDA to treat PAH by continuous subcutaneous and intravenous routes of administration in 2002 and 2004, respectively, using external pumps. In the case of intravenous users, the therapy can be very burdensome and brings a risk of sepsis due to the use of a central indwelling catheter.

The ISR provides patients a new option for delivery of intravenous Remodulin, where the entire delivery system is implanted into the body and will be refilled by healthcare professionals at intervals of up to 16 weeks depending on the patient's dose, using a syringe needle through the patient's skin.

"External infusion pumps have been used to deliver prostacyclins for PAH, but managing the therapy places a significant burden on patients, interferes with their daily activities, and runs a high risk of infections," said David Steinhaus, M.D., general manager of the Heart Failure business, part of the Cardiac and Vascular Group at Medtronic. "This fully implantable drug delivery system was designed to address these serious patient care concerns."

United Therapeutics funded and Medtronic conducted the DelIVery for PAH clinical trial, which was a safety study of a new implantable catheter designed for intravascular drug (Remodulin) delivery with the SynchroMed™ II implantable infusion pump. In 2013, the study met its primary objective of demonstrating a rate of catheter-related complications below 2.5 per 1,000 patient-days while using the fully implantable system (p < 0.0001).

https://www.drugs.com/newdrugs/united-therapeutics-announces-fda-approval-implantable-remodulin-4790.html

FDA Approves Mulpleta (lusutrombopag) for Thrombocytopenia in Adults with Chronic Liver Disease

FDA, approved lusutrombopag (Mulpleta, Shionogi Inc.) for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.

Approval was based on two randomized, double-blind, placebo-controlled trials (L-PLUS 1 and L-PLUS 2, NCT02389621) involving 312 patients with chronic liver disease and severe thrombocytopenia who were undergoing an invasive procedure and had a platelet count less than 50 x 109/L. Patients were randomized 1:1 to receive 3 mg of lusutrombopag or placebo once daily for up to 7 days.

In L-PLUS 1, 78% of patients (38/49) receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure, compared with 13% (6/48) who received placebo (95% CI for treatment difference: 49%, 79%; p<0.0001). In L-PLUS 2, 65% (70/108) of patients who received lusutrombopag required no platelet transfusion prior to the primary invasive procedure or rescue therapy for bleeding from randomization through 7 days after the procedure, compared with 29% (31/107) receiving placebo (95% CI for treatment difference: 25%, 49%; p<0.0001).

The most common adverse reaction in ≥ 3% of patients was headache.

The recommended lusutrombopag dosage is 3 mg orally once daily with or without food for 7 days.

FDA granted this application priority review and fast track designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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

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FDA Approves Mulpleta (lusutrombopag) for Thrombocytopenia in Adults with Chronic Liver Disease

FDA Approves Orilissa (elagolix) for the Management of Moderate to Severe Pain Associated with Endometriosis

In continuation of my update on elagolix

AbbVie a research-based global biopharmaceutical company, in cooperation with Neurocrine Biosciences, Inc. , announced that the U.S. Food and Drug Administration (FDA) approved Orilissa (elagolix), the first and only oral gonadotropin-releasing hormone (GnRH) antagonist specifically developed for women with moderate to severe endometriosis pain. The FDA approved Orilissa under priority review. Orilissa represents the first FDA-approved oral treatment for the management of moderate to severe pain associated with endometriosis in over a decade and is expected to be available in U.S. retail pharmacies in early August 2018.

"Orilissa represents a significant advancement for women with endometriosis and physicians who need more options for the medical management of this disease," said Michael Severino, M.D., Executive Vice President, Research and Development and Chief Scientific Officer, AbbVie. "The approval of Orilissa demonstrates AbbVie's continued commitment to address serious diseases and unmet needs."

Endometriosis is one of the most common gynecologic disorders in the U.S.3 It affects an estimated one in 10 women of reproductive age and can be associated with pain symptoms that can be debilitating.3,4 Women can suffer for up to six to 10 years and visit multiple physicians before receiving a proper diagnosis.5,6

Endometriosis-associated pain is often managed with medicines such as oral contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids and hormonal therapies, which can work for some women but very few are specifically indicated for the treatment of endometriosis.3,7 In more extensive cases, surgical interventions (e.g., laparotomy, laparoscopy or hysterectomy) are often pursued, and may not be curative for all individuals.8

"Endometriosis is often characterized by chronic pelvic pain that can impact women's daily activities," said Hugh S. Taylor, M.D., study investigator and Chair of the Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine. "Women with endometriosis may undergo multiple medical treatments and surgical procedures seeking pain relief and this approval gives physicians another option for treatment based on a woman's specific type and severity of endometriosis pain."

The approval is supported by data from two replicate studies in the largest endometriosis Phase 3 study program conducted to date, which evaluated nearly 1,700 women with moderate to severe endometriosis pain. Clinical trial data demonstrated Orilissa significantly reduced the three most common types of endometriosis pain: daily menstrual pelvic pain, non-menstrual pelvic pain and pain with sex. A higher proportion of women treated with Orilissa 150 mg once daily and 200 mg twice daily were responders for daily menstrual pain and non-menstrual pelvic pain compared to placebo in a dose-dependent manner at month three. Women were defined as responders if they experienced a reduction in daily menstrual pain and non-menstrual pelvic pain with no increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid) for endometriosis-associated pain.

Both Orilissa treatment groups showed statistically significant greater mean decreases from baseline compared to placebo in daily menstrual pain and non-menstrual pelvic pain at month six. Women in the Phase 3 studies also provided a daily self-assessment of their endometriosis pain using a numeric rating scale (NRS) and women taking Orilissa 150 mg once daily and 200 mg twice daily reported a statistically (p <0.001) significant reduction from baseline in NRS scores compared to placebo at month three. Clinical trial data also demonstrated women taking Orilissa 200 mg twice daily showed statistically significant greater reduction in pain with sex from baseline to month three compared to placebo.

The recommended duration of use for Orilissa is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months. Orilissa is recommended to be taken orally at approximately the same time each day, with or without food.

"Together with AbbVie, we are proud to offer a treatment option for the many women suffering from pain associated with endometriosis," said Kevin Gorman, Ph.D., Chief Executive Officer of Neurocrine Biosciences. "Neurocrine discovered Orilissa nearly twenty years ago and through our partnership with AbbVie, the approval of Orilissa reflects our joint commitment to develop therapies for difficult to manage conditions in underserved patient populations."

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

FDA Approves Orilissa (elagolix) for the Management of Moderate to Severe Pain Associated with Endometriosis

FDA Approves Onpattro (patisiran) Targeted RNA-based Therapy for Polyneuropathy Caused by hATTR

The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.

“This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms. In this case, the effects of the disease cause a degeneration of the nerves, which can manifest in pain, weakness and loss of mobility,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses. We’re committed to advancing scientific principles that enable the efficient development and review of safe, effective and groundbreaking treatments that have the potential to change patients’ lives.”

RNA acts as a messenger within the body’s cells, carrying instructions from DNA for controlling the synthesis of proteins. RNA interference is a process that occurs naturally within our cells to block how certain genes are expressed. Since its discovery in 1998, scientists have used RNA interference as a tool to investigate gene function and its involvement in health and disease. Researchers at the National Institutes of Health, for example, have used robotic technologies to introduce siRNAs into human cells to individually turn off nearly 22,000 genes.

This new class of drugs, called siRNAs, work by silencing a portion of RNA involved in causing the disease. More specifically, Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.

Affecting about 50,000 people worldwide, hATTR is a rare condition. It is characterized by the buildup of abnormal deposits of protein fibers called amyloid in the body's organs and tissues, interfering with their normal functioning. These protein deposits most frequently occur in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands and feet. Amyloid deposits can also affect the functioning of the heart, kidneys, eyes and gastrointestinal tract. Treatment options have generally focused on symptom management.

Onpattro is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.

“There has been a long-standing need for a treatment for hereditary transthyretin-mediated amyloidosis polyneuropathy. This unique targeted therapy offers these patients an innovative treatment for their symptoms that directly affects the underlying basis of this disease,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.

The efficacy of Onpattro was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.

The most common adverse reactions reported by patients treated with Onpattro are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea (difficulty breathing) and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). Onpattro leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.

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

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

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FDA Approves Onpattro (patisiran) Targeted RNA-based Therapy for Polyneuropathy Caused by hATTR

FDA Approves Annovera (segesterone acetate and ethinyl estradiol) Vaginal Contraceptive System

In continuation of my update on ethinyl estradiol

         

Segesterone acetate       

                                

                                                                              Ethinylestradiol 

The Population Council, a global nonprofit research organization, announced it has received U.S. Food and Drug Administration (FDA) approval for Annovera (segesterone acetate and ethinyl estradiol vaginal system), the first and only contraceptive that provides an entire year of protection against unintended pregnancy while fully under a woman's control. The approval marks an important step toward expanding contraceptive options for women.

Annovera is the first in a new class of contraceptives. It is a soft, reusable, flexible silicone ring (2 ¼ inches diameter) that can be inserted and removed by a woman herself. Left in place for 21 days and removed for 7 days each cycle, it is indicated to prevent pregnancy for up to a year and does not require refrigeration, which is particularly important for distribution and use in low-resource settings. Annovera has not been adequately evaluated in women with a body mass index (BMI) greater than 29 kg/m2.

"Nearly half of all pregnancies in the U.S. are unintended, which can increase health risks for mom and baby," said Population Council President, Julia Bunting. "For more than 60 years, the Population Council has been at the vanguard of global efforts to develop innovative family planning methods that meet women's needs. Having a single contraceptive system that provides a full year of protection while under a woman's control could be a game-changer for some women."

According to the Center for Disease Control, more than 43 million women in the U.S. are at risk of unintended pregnancy. Women with unintended pregnancies are less likely to receive proper prenatal care; are more likely to have premature and low-birth-weight infants; and have increased physical and mental health risks. Providing women with a range of contraceptive options that better meet their family planning needs helps reduce unintended pregnancy and improves outcomes.

"I am delighted to have Annovera as a new family planning option for women who want greater choice, convenience and control," said Anita Nelson, M.D., professor and chair, Obstetrics and Gynecology Western University Health Sciences and a principal investigator of the Phase 3 trials. "The Population Council has been a leader in creatively and collectively addressing women's contraceptive needs. It is exciting they are continuing to help empower women with another contraceptive choice."

The FDA approval of Annovera is based in part on data from 17 clinical trials, including two pivotal Phase 3 safety and efficacy trials. The Phase 3 program enrolled a total of 2,308 women across 27 study sites in the United States, Latin America, Europe, and Australia. Women in the trials were between 18 and 40 years of age and were instructed to use the system over 13 menstrual cycles, or one full year. The Primary Endpoint Pearl Index was 2.98. The data show that Annovera is 97.3% effective in preventing pregnancy when used as directed. Annovera offers a similar risk profile to other combined hormonal contraceptives, including a boxed warning related to increased cardiovascular risk when used while smoking.

In formulating Annovera, researchers at the Population Council's Center for Biomedical Research combined a new progestin (segesterone acetate) with a widely used estrogen (ethinyl estradiol) to develop a single product that can inhibit ovulation for an entire year. A sub-set study of women in the Phase 3 clinical trials ranked Annovera highly in terms of convenience, ease of use and comfort. Nearly 9 in 10 women (89%) surveyed were satisfied with it as a method of contraception. Most participants surveyed experienced no change in sexual pleasure or frequency of sexual intercourse.

"This approval is a key first step toward introducing this product globally and better meeting the sexual and reproductive health needs of women, men and young people in the U.S. and around the world," said Jim Sailer, executive director, Center for Biomedical Research at the Population Council. "We are grateful to the dozens of researchers who have worked on this product, the donors who have funded its development, and most of all, to the thousands of women who volunteered to participate in clinical trials and made this all possible."

Important public and private donors from around the world have supported the research and development of Annovera, including the United States Agency for International Development (USAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Bill & Melinda Gates Foundation, the Avis and Clifford Barrus Medical Foundation, the World Health Organization (WHO), and the Population Council.

Recently, the Population Council announced a license agreement with TherapeuticsMD, an innovative healthcare company focused exclusively on women's health, to make Annovera available to women in the U.S. Through the license agreement, TherapeuticsMD will provide significantly reduced pricing to federally designated Title X family planning clinics serving lower-income women. TherapeuticsMD currently estimates Annovera will be commercially available as early as the third quarter of 2019 and commercially launched as early as the fourth quarter of 2019 or first quarter of 2020. Proceeds from the license agreement will be reinvested into the Population Council's continued research and development programs. The Population Council is continuing efforts to make Annovera available worldwide, including in low- and middle-income countries where more than 214 million women have an unmet need for contraception.

Annovera will be the sixth contraceptive technology that Population Council researchers have developed to address family planning needs around the world and brought to market through commercialization agreements. We estimate that more than 170 million women worldwide are currently using highly effective contraceptives developed by the Population Council or based on our technologies. Other Population Council-developed contraceptives include: the copper IUD ParaGard®; intrauterine system Mirena®; contraceptive implants Norplant® and Jadelle®; and Progering®, the contraceptive vaginal ring for breastfeeding women.

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

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

FDA Approves Jornay PM (methylphenidate) Extended-Release Capsules for Attention Deficit Hyperactivity Disorder (ADHD)

In continuation of my update on methylphenidate

Ironshore Pharmaceuticals & Development, Inc. (“Ironshore”) a wholly owned subsidiary of Highland Therapeutics Inc. (“Highland”) announced,  that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for Jornay PM (methylphenidate) (formerly known as HLD200) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older. Jornay PM is a novel formulation of methylphenidate which is taken in the evening and has demonstrated improvement in the severity of ADHD symptoms in the early morning and throughout the day. Jornay PM is the first drug utilizing Ironshore’s proprietary drug delivery platform, Delexis®. Ironshore plans to initiate the commercial launch of Jornay PM in the first half of 2019.

According to independent research reports commissioned by Ironshore, control over the symptoms of ADHD during the early morning routine remains a significant concern for parents of children with ADHD. As previously reported in the Journal of Child and Adolescent Psychopharmacology, a majority of surveyed parents of children with ADHD report that the symptoms associated with ADHD in the early morning are described as “moderate” or “severe” during this time period.1

Commenting on the approval, David Lickrish, President & CEO stated, “Some manufacturers have adjusted the ratio of immediate-release and extended-release features in different formulations of methylphenidate to achieve an earlier onset. Our approach to drug development was to start from the desired pharmacokinetic profile and then work to develop a purpose-built technology capable of achieving that profile. I believe that the unique Delexis® drug delivery platform is a disruptive technology that has many applications and opportunities in several therapeutic categories.”

Delexis is a novel and proprietary drug delivery technology that contains two functional film coatings that act synergistically to achieve a unique pharmacokinetic profile. The first layer delays the initial release of drug for up to 10 hours while the second layer helps to control the rate of release of the active pharmaceutical ingredient throughout the day.

Dr. Bev Incledon, Head of Research and Development at Ironshore stated, “Developing a drug using a different delivery technology that will provide an additional option for patients and the physicians who treat them takes time. After 10 years of unrelenting determination, those efforts have finally been rewarded with the approval of Jornay PM. I want to thank and congratulate the many people who helped to make this possible including the formulation scientists, the Research & Development Team, the Investigators and the patients who participated in the clinical trials.”

The effectiveness of Jornay PM was established in two separate Pivotal Phase III, multicenter, randomized, double-blind, placebo-controlled studies conducted in a total of 278 pediatric patients aged 6 to 12 years with a diagnosis of ADHD per DSM-5 criteria. In addition to the traditional scales that assess efficacy in ADHD clinical trials such as the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale and the ADHD Rating Scale (ADHD-RS-IV), Ironshore’s pivotal trials assessed Jornay PM’s efficacy in the early morning period using the morning subscale of the Parent Rating of Evening and Morning Behavior-Revised (PREMB-R AM) scale and the Before School Functioning Questionnaire (BSFQ).

In Study 1, improvement in ADHD manifestations in a classroom setting was demonstrated by the primary endpoint, an average of all post-dosed SKAMP combined scores measured during a 12-hour period (8:00 a.m. to 8:00 p.m.), and improvement in ADHD manifestations in the early morning was demonstrated by the secondary endpoint, PREMB-R AM.

In Study 2, improvement in ADHD manifestations throughout the day was demonstrated by the primary endpoint, ADHD-RS-IV, and improvement in ADHD manifestations before school was demonstrated by the secondary endpoint, the BSFQ, which is intended to assess early morning before school activities from the time the child awakens and some behaviors not specific to early morning.

Commenting on the approval, Dr. Randy Sallee, Chief Medical Officer at Ironshore stated, “Many parents of children with ADHD note that the early morning routine is often one of the most chaotic times of the day. The idea of dosing the medication the night before was our moon-shot solution to meeting this need. The approval of Jornay PM is a welcome treatment option for healthcare providers, patients and their caregivers that may affect the way physicians think about ADHD treatment going forward.”

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

Plant-derived substance could offer new option for treatment of obesity

A plant-derived substance widely used in traditional Chinese medicine has demonstrated promising weight loss effects. The findings of a study conducted by scientists at the Helmholtz Zentrum München, a partner of the German Center for Diabetes Research (DZD), have now been published in the journal 'Diabetes'. If this substance called Celastrol also proves effective in clinical trials, it could offer a new option for the treatment of obesity.

According to the guidelines for the prevention and treatment of obesity issued by the German Association for the Study of Obesity (DAG), patients should aim to lose between five and ten percent of their body weight per year depending on their body mass index. However, despite the huge amount of dietary and lifestyle choices available, only few people reach their weight loss goal. "Yet, breaking through this 'magical barrier' is so important, as it leads to an improvement in metabolism and accompanying metabolic diseases such as type 2 diabetes," explains Dr. Paul Pfluger, last author and head of the current study.

He and his team in the Neurobiology of Diabetes department at the Helmholtz Zentrum München have now succeeded in contributing to the development of new anti-obesity drugs by demonstrating that Celastrol leads to significant weight loss and also to an improvement in diabetes in obese mice.

Compound 'switches on' sensation of fullness

The researchers were able to prove that Celastrol activates specific satiety centers in the brain which play a key role in controlling body weight. Katrin Pfuhlmann, PhD student and first author of the study, explains the effect: "Celastrol reactivates the body's own mechanisms for controlling weight that would otherwise be switched off in obese individuals. Normally those affected lose that feeling of fullness because the respective hormone - leptin - no longer has any effect. Celastrol, the compound we examined, restores leptin sensitivity and thus the sense of satiety."

The researchers in fact observed a significant change in eating habits among overweight animals. "The administration of Celastrol resulted in a much lower intake of food," reports Paul Pfluger. "Correspondingly, we observed an average loss of about ten percent in body weight within one week."

The extent to which the findings will be validated in humans remains unclear, the authors say, but Dr. Pfluger expresses confidence. "Since the satiety hormone leptin has an almost identical effect in humans and mice, Celastrol has great potential," he says. While Celastrol will not replace the changes in eating habits and lifestyle that are necessary in order to lose weight, it could support patients in their efforts to achieve permanent weight loss. "Relevant clinical trials are currently taking place in the United States, and we eagerly await the initial results," Dr. Pfluger concludes.

Ref : https://www.helmholtz-muenchen.de/en/news/latest-news/press-information-news/article/44932/index.html

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

FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

In continuation of my update on lenvatinib

Woodcliff Lake, NJ and Kenilworth, announced today that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor Lenvima (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT (Study 304), where Lenvima demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

“Unresectable hepatocellular carcinoma is an extremely difficult-to-treat cancer, with no new first-line systemic therapy options for more than a decade,” said Dr. Ghassan Abou-Alfa, medical oncologist, Memorial Sloan Kettering Cancer Center. “REFLECT is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC. The efficacy and safety data from REFLECT are important findings for oncologists and others in the multidisciplinary teams who treat liver cancer, as well as for our patients who are affected by it.”

Adverse reactions, some of which can be serious or fatal, may occur with Lenvima, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the severity of the adverse reaction, Lenvima should be monitored, withheld or discontinued. Based on its mechanism of action and data from animal reproduction studies, Lenvima can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see “Important Safety Information” below.

REFLECT showed that Lenvima achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with Lenvima experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted when 351 events had occurred in the Lenvima arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, Lenvima showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

• Median PFS was doubled with Lenvima compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with Lenvima versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77) per RECIST 1.1.
• Lenvima showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with Lenvima versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
  • Per mRECIST: Treatment with Lenvima resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with Lenvima resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
  • Per RECIST 1.1: Treatment with Lenvima resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with Lenvima resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib

In addition, median time to progression (TTP) was doubled with Lenvima compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with Lenvima versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

In REFLECT, the most common adverse reactions (≥20%) observed in patients treated with Lenvima were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism and nausea. The most common serious adverse reactions (≥2%) reported in patients treated with Lenvima were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%).

The most common adverse reactions (≥20%) observed in patients who received sorafenib were palmar-plantar erythrodysesthesia syndrome, diarrhea, fatigue, hypertension, abdominal pain, decreased appetite, rash, decreased weight and arthralgia/myalgia. The most common serious adverse reactions (≥2%) reported in patients who received sorafenib were ascites (2%) and abdominal pain (2%).

It is also important to note that the dose for Lenvima for patients with unresectable HCC is based on the patient’s weight (12 mg for patients weighing 60 kilograms or more, 8 mg for patients weighing less than 60 kilograms); the recommended dosage and dose adjustments are described in the full prescribing information.

“Eisai strives to be a leading global R&D-based pharmaceutical company, driven by our human health care (hhc) mission to improve the lives of patients and their loved ones,” said Shaji Procida, President and Chief Operating Officer, Eisai Inc., and Commercial Head of the Oncology Business Group, Americas at Eisai. “That purpose is what has propelled us toward this win for patients with unresectable hepatocellular carcinoma. Our goal is to bring monumental solutions to patients and health care providers, changing expectations for the oncology landscape, and we look forward to continuing this work in our ongoing collaboration with Merck.”

“We are pleased by the FDA approval of Lenvima as it marks an important advancement in the treatment of unresectable hepatocellular carcinoma,” said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. “With our shared mission to find solutions for difficult-to-treat cancers, we look forward to working with Eisai to help bring this needed option to patients and physicians.”

Lenvima, a kinase inhibitor, was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In May 2016, Lenvima was approved in the U.S. in combination with everolimus, for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Under the collaboration, Eisai and Merck initiated co-commercialization activities for Lenvima in the U.S. in June 2018. Since the initial launch, more than 10,000 patients were treated with Lenvima, which is approved in more than 50 countries worldwide.

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FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)