FDA Approves Rinvoq (upadacitinib), an Oral JAK Inhibitor for the Treatment of Moderate to Severe Rheumatoid Arthritis

In continuation of my update on Rinvoq (upadacitinib)

AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved Rinvoq (upadacitinib), a 15 mg, once-daily oral Janus kinase (JAK) inhibitor, for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX-IR).1 Rinvoq is expected to be available in the U.S. in late August 2019.

The FDA approval of Rinvoq is supported by data from the SELECT program, one of the largest registrational Phase 3 programs in RA with approximately 4,400 patients evaluated across all treatment arms in five studies.2-6 The studies include assessments of efficacy, safety and tolerability across a variety of RA patients, including those who failed or were intolerant to biologic disease-modifying anti-rheumatic drugs and who were naïve or inadequate responders to methotrexate. Rinvoq is not indicated for methotrexate-naïve patients.

"Despite the availability of multiple treatment options with varying mechanisms of action, many patients still do not achieve clinical remission or low disease activity—the primary treatment goals for rheumatoid arthritis," said Roy M. Fleischmann, M.D., primary investigator for SELECT-COMPARE and clinical professor at the University of Texas Southwestern Medical Center at Dallas. "With this FDA approval, Rinvoq has the potential to help additional people living with RA achieve remission who have not yet reached this goal."

Across the SELECT Phase 3 studies, Rinvoq met all primary and ranked secondary endpoints. The primary endpoints include:

• In SELECT-EARLY, 52 percent of MTX-naïve patients treated with Rinvoq 15 mg achieved ACR50 vs 28 percent treated with MTX at week 121
• In SELECT-MONOTHERAPY, 68 percent of MTX-IR patients treated with Rinvoq 15 mg achieved ACR20 vs 41 percent treated with continued MTX at week 141
• In SELECT-COMPARE, 71 percent of MTX-IR patients treated with Rinvoq 15 mg plus MTX achieved ACR20 vs 36 percent treated with placebo plus MTX at week 121
• In SELECT-NEXT, 64 percent of csDMARD-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 36 percent treated with placebo plus csDMARDs at week 121
• In SELECT-BEYOND, 65 percent of biologic-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 28 percent treated with placebo plus csDMARDs at week 121

"The discovery and development of Rinvoq is indicative of AbbVie's long-standing commitment to advancing the science for people living with immune-mediated conditions," said Michael Severino, M.D., vice chairman and president, AbbVie. "Today's FDA approval marks an important milestone in our pursuit to deliver innovative medicines that advance care for people living with rheumatoid arthritis."

Clinical Remission

Patients taking Rinvoq achieved clinical remission, a state characterized by almost no disease activity and symptoms, even without methotrexate.2-3,6 Approximately 30 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 in SELECT-COMPARE and week 14 in SELECT-MONOTHERAPY compared to six percent with placebo plus methotrexate and eight percent with methotrexate, respectively.1 In SELECT-EARLY, 36 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 compared to 14 percent with methotrexate.1 

Durable remission rates were observed up to week 26. Forty-eight percent of patients treated with Rinvoq alone in SELECT-EARLY and 41 percent of patients treated with Rinvoq plus methotrexate in SELECT-COMPARE achieved clinical remission at weeks 24 and 26, compared to nine percent with placebo plus methotrexate and 18 percent with methotrexate, respectively.1 Analysis at weeks 24 and 26 were not controlled for multiple comparisons.3,10

Radiographic Inhibition

Rinvoq significantly inhibited radiographic progression as measured by the change in modified total Sharp score (mTSS) from baseline compared to methotrexate in SELECT-EARLY (0.14 vs 0.67) and Rinvoq plus methotrexate compared to placebo plus methotrexate in SELECT-COMPARE (0.15 vs 0.78) through weeks 24 and 26, respectively.1 

Safety

The most common side effects associated with Rinvoq include upper respiratory tract infections (common cold, sinus infections), nausea, cough and pyrexia.1 Patients treated with Rinvoq are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.1 Lymphoma and other malignancies have been observed in Rinvoq-treated patients.1 Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions.1 Patients treated with RINVOQ also may be at risk for other serious adverse reactions, including gastrointestinal perforations, neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations, and embryo-fetal toxicity.1 

Ease of Use and Access

Designed to help accommodate the physical limitations of people living with RA, the packaging for Rinvoq includes a bottle cap with a wide, easy-to-grip texture and an embedded tool that punctures the foil liner to simplify medication access. This packaging design was awarded the Arthritis Foundation Ease of Use Commendation.

"Rheumatoid arthritis can have a debilitating impact on the lives of those with the chronic disease, including making it difficult to perform everyday tasks," said Cindy McDaniel, senior vice president, consumer health, Arthritis Foundation. "The Arthritis Foundation is committed to recognizing innovation that can help patients living with rheumatoid arthritis and we are proud to recognize AbbVie with our Ease of Use Commendation for the packaging design of Rinvoq."

AbbVie continues to work closely with key stakeholders to support patient access to Rinvoq, including offering a patient support program and a co-pay card that may reduce out-of-pocket costs to $5 per month for eligible, commercially-insured patients. For those with limited or no health insurance, AbbVie offers myAbbVie Assist, a patient assistance program that provides Rinvoq to qualifying patients.

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

https://www.drugbank.ca/drugs/DB15091

FDA Approves Xenleta (lefamulin) to Treat Community-Acquired Bacterial Pneumonia (CABP)

Nabriva Therapeutics plc (NASDAQ: NBRV), a biopharmaceutical company engaged in the commercialization and development of innovative anti-infective agents to treat serious infections, announced the U.S. Food and Drug Administration (FDA)  approval of Nabriva’s new drug applications for the oral and intravenous (IV) formulations of Xenleta (lefamulin) for the treatment of community-acquired bacterial pneumonia (CABP) in adults. As the first IV and oral antibiotic with a novel mechanism of action approved by the FDA in nearly two decades, Xenleta represents an important new empiric monotherapy treatment option for adults with CABP.

“Today’s approval of Xenleta is a significant breakthrough in the collective fight against the growing threat of antimicrobial resistance and provides a desperately needed IV and oral empiric monotherapy treatment option for adults with CABP,” said Ted Schroeder, chief executive officer of Nabriva Therapeutics. “We are especially proud of this approval because Xenleta was discovered in our labs over a decade ago and the entire development program was designed and executed by our dedicated and passionate team. We are indebted to the patients and researchers who collaborated with us and are excited to bring to patients and healthcare providers a novel, short course, empiric monotherapy treatment option for CABP. Xenleta has a mechanism of action that is different than other approved antibiotics, resulting in a low propensity for the development of resistance, as well as a lack of cross-resistance with the beta-lactam, fluoroquinolone, glycopeptide, macrolide, and tetracycline antibiotic classes. Xenleta has a targeted in vitro spectrum of activity against the most common causative Gram-positive, Gram-negative and atypical pathogens associated with CABP, which aligns with the principles of antimicrobial stewardship.”

“The gravity of antimicrobial resistance cannot be overstated, particularly in the context of treating pneumonia,” said Julio Ramirez, MD, FACP, Professor of Medicine, and Chief within the Division of Infectious Diseases, University of Louisville School of Medicine. “As an infectious disease specialist who treats CABP patients in the hospital setting, I am grateful to have both a new IV and oral option that gives me confidence that my patients will continue to receive appropriate therapy once they are discharged from the hospital.”

Xenleta is available for oral (600 mg every 12 hours) and IV (150 mg every 12 hours) administration with a short 5-to-7 day course of therapy. Clinicians can initiate patients on IV or oral therapy, allowing for potential avoidance of hospitalization, or can transition from IV to oral therapy, which may expedite discharge from the hospital. Currently, the median length of stay for patients with pneumonia is 3-to-4 days, resulting in approximately $17 billion in hospital costs per year in the United States. The opportunity to avoid a hospital admission or to discharge a patient earlier on oral therapy benefits patients and may result in significant savings to the health system.

Both the IV and oral formulations of Xenleta were granted Qualified Infectious Disease Product (QIDP) and Fast Track designation by the FDA. The FDA approval was based on a clinical development program supported by a robust data package, including two pivotal, Phase 3 trials (known as LEAP 1 and LEAP 2) that evaluated the safety and efficacy of IV and oral Xenleta compared to moxifloxacin in the treatment of adults with CABP. LEAP 1 was designed to evaluate 5-to-7 days of IV/oral therapy of Xenleta versus 7-days of IV/oral moxifloxacin, with or without linezolid, with both treatment groups having the option to switch from IV to oral administration after 3-days. LEAP 2 evaluated 5-days of oral Xenleta versus 7-days of oral moxifloxacin. LEAP 1 showed comparable efficacy with moxifloxacin, with or without linezolid, while LEAP 2 showed comparable efficacy with moxifloxacin, with two fewer days of therapy. Xenleta was generally well tolerated in both LEAP 1 and LEAP 2.

“Emergency departments across the country treat hundreds of thousands of patients with CABP each year. Many of these patients, especially elderly patients with comorbidities, are admitted solely because of the lack of an effective and well-tolerated oral treatment option” said Philip Giordano, MD, Vice Chairman of Emergency Medicine at the Orlando Regional Medical Center. “With a new oral antibiotic option that has been shown to be as effective as a respiratory fluoroquinolone, possessing a favorable side effect profile, we can consider sending more patients home directly from the emergency department and avoid costly hospitalizations, which is good for both patient care and the health system.”

Pneumonia is an infection of the lung that can be serious and fatal, especially among older adult patients with comorbidities. There are approximately five million cases of pneumonia in the U.S. each year, and pneumonia is the fifth leading cause of hospitalization and one of the leading causes of infection-related death. Streptococcus pneumoniae is the most common cause of bacterial pneumonia in the U.S. According to recent data from the SENTRY Antimicrobial Surveillance Program, in the U.S., approximately 30 to 60 percent of S. pneumoniae, depending on region, are macrolide resistant. In addition to macrolides, fluoroquinolones are another common treatment option for CABP. This broad-spectrum class is an effective option, however fluoroquinolones carry boxed warnings for several significant safety concerns.

Nabriva expects Xenleta will be available through major U.S. specialty distributors in mid-September 2019. Xenleta will have a wholesale acquisition (WAC) price of $205 per IV patient treatment day and $275 per oral patient treatment day.

“Offering clinicians and patients a new treatment option for CABP that addresses the urgent and growing threat of antimicrobial resistance is our top priority. With that in mind, our team has been working hard to make Xenleta available in the weeks ahead to ensure that patients with CABP who can benefit from this new treatment option can access it,” said Schroeder.

About Xenleta

Xenleta (lefamulin) is a first-in-class semi-synthetic pleuromutilin antibiotic for systemic administration in humans discovered and developed by the Nabriva Therapeutics team. It is designed to inhibit the synthesis of bacterial protein, which is required for bacteria to grow. Xenleta’s binding occurs with high affinity, high specificity and at molecular sites that are different than other antibiotic classes. Based on results from its two global, Phase 3 clinical trials, Nabriva Therapeutics believes Xenleta is well-positioned for use as a first-line monotherapy for the treatment of CABP due to its novel mechanism of action, targeted spectrum of activity, resistance profile, achievement of substantial drug concentration in lung tissue and fluid, availability of oral and IV formulations and a generally well-tolerated safety profile. Nabriva Therapeutics believes XENLETA represents a potentially important new treatment option for the approximately five million adults in the United States diagnosed with pneumonia each year.

In LEAP 1 and LEAP 2 (pooled), the median age of patients treated with Xenleta was 61 (range 19-97) years; 42% of patients were 65 years or older and 18% of patients were 75 years or older. In both trials, approximately half of Xenleta-treated patients had impaired renal function and the most common other comorbidities included hypertension, asthma/COPD and diabetes mellitus. These baseline characteristics were broadly representative of the adult patient population with CABP. 

In LEAP 1, Xenleta demonstrated non-inferiority compared to moxifloxacin, with or without linezolid, for the FDA primary endpoint of early clinical response (ECR) assessed 72 to 120 hours following initiation of therapy in the intent to treat (ITT) patient population (ECR rate = 87.3% for Xenleta and 90.2% for moxifloxacin, with or without linezolid; treatment difference -2.9 [95% confidence interval (CI) -8.5, 2.8]). In LEAP 2, 5-days of oral Xenleta also demonstrated non-inferiority to 7-days of oral moxifloxacin for the ECR endpoint in the ITT population (ECR rate = 90.8% for Xenleta and 90.8% moxifloxacin; treatment difference 0.1 [95% confidence interval (CI) -4.4, 4.5]). Importantly, high-risk patients 65 years and older achieved a similar ECR rate as those less than 65 years of age. The most common adverse reactions in patients receiving Xenleta in LEAP 1 (IV and oral) were administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, and headache in LEAP 1, and in LEAP 2 (oral only) diarrhea, nausea, vomiting and hepatic enzyme elevation. Few discontinuations due to adverse reactions were reported (3.3% in both treatment arms) and the 28-day mortality was low and balanced between treatment groups [8 patients (1.2%)] and [7 patients (1.1%)] for Xenleta and comparator, respectively from pooled data for LEAP 1 and LEAP 2.   

https://www.drugbank.ca/drugs/DB12825

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

FDA Approves Rozlytrek (entrectinib) for People With ROS1-Positive, Metastatic Non-Small Cell Lung Cancer and NTRK Gene Fusion-Positive Solid Tumors

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY),  announced  the U.S. Food and Drug Administration (FDA) has approval of  Rozlytrek (entrectinib) for the treatment of adults with ROS1-positive, metastatic non-small cell lung cancer (NSCLC). The FDA has also granted accelerated approval to Rozlytrek for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy.

These approvals are based on results from the integrated analysis of the pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the Phase I/II STARTRK-NG study. In the integrated analysis, Rozlytrek was studied in several solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers. In ROS1-positive, metastatic NSCLC, Rozlytrek shrank tumors in 78% of people with the disease (overall response rate [ORR]; N=51) and the duration of response (DoR) ranged from 1.8 to 36.8+ months (N=40 out of 51). Rozlytrek also shrank tumors in more than half of people with NTRK gene fusion-positive, locally advanced or metastatic solid tumors (ORR=57%; N=54), and objective responses were observed across 10 tumor types (DoR ranged from 2.8 to 26.0+ months; N=31 out of 54). Objective responses to Rozlytrek were seen in people with central nervous system (CNS) metastases at baseline.

“Rozlytrek’s FDA approval for two rare types of cancer is an important advance for patients, combining a targeted medicine and genomic testing to bring this new treatment option to patients who are waiting,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “Rozlytrek is the first FDA-approved treatment that selectively targets both ROS1 and NTRK fusions, and, importantly, has also shown responses in these rare cancer types that have spread to the brain.”

“The identification of actionable biomarkers like ROS1 has brought about significant progress in the treatment of lung cancer. This approval brings further hope to people with this rare type of the disease,” said Janet Freeman-Daily, co-founder of The ROS1ders, a group of patients and caregivers affected by ROS1-positive lung cancer. “Up to 40% of people with ROS1-positive non-small cell lung cancer have tumors that have spread to the brain, so now there is a new treatment option for those patients.”

The most common adverse reactions (≥20 percent) with Rozlytrek were fatigue, constipation, altered sense of taste (dysgeusia), swelling (edema), dizziness, diarrhea, nausea, nervous system disorders (dysesthesia), shortness of breath (dyspnea), muscle pain (myalgia), cognitive impairment, increased weight, cough, vomiting, fever (pyrexia), joint pain (arthralgia) and vision disorders.

The FDA’s Accelerated Approval Program allows conditional approval of a medicine that fills an unmet medical need for a serious or life-threatening disease or condition. The accelerated approval of Rozlytrek for NTRK gene fusion-positive solid tumors is based on tumor response rate and durability of response, and continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Biomarker testing for ROS1 in NSCLC and NTRK gene fusions across all solid tumors is the only way to identify people who are eligible for treatment with Rozlytrek. Genentech is leveraging its expertise in developing personalized medicines and advanced diagnostics, in conjunction with Foundation Medicine, to help identify people with ROS1 and NTRK gene fusions. Foundation Medicine will submit Foundation®One CDx to the FDA for approval as a companion diagnostic for Rozlytrek. An FDA-approved companion diagnostic for Rozlytrek is not available at this time.

Rozlytrek is now available in the United States for adults and children 12 years of age and older. For those who qualify, Genentech offers patient assistance programs for people prescribed Rozlytrek by their doctor through Genentech Access Solutions. Please contact Genentech Access Solutions at (866) 422-2377 or visit http://www.Genentech-Access.comfor more information.

About the Integrated Analysis

This approval is based on an integrated analysis including data from 51 people with ROS1-positive NSCLC and 54 people with locally advanced or metastatic NTRK gene fusion-positive solid tumors (10 tumor types, >19 histopathologies) from the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials. This approval is also based on data from the Phase I/II STARTRK-NG study in pediatric patients. The studies enrolled people across 15 countries and more than 150 clinical trial sites. Safety was assessed from an integrated analysis of 355 people across these four trials.

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

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

FDA Approves EluRyng (etonogestrel/ethinyl estradiol vaginal ring), the First Generic NuvaRing

Amneal Pharmaceuticals, Inc. (NYSE: AMRX) (“Amneal” or the “Company”) announced that it has received Abbreviated New Drug Application (ANDA) approval from the U.S. Food and Drug Administration (FDA) for EluRyng™ (etonogestrel/Ethinyl estradiol vaginal ring), the first generic version of NuvaRing®. Amneal has initiated commercialization activities for EluRyng, which is being manufactured internally and launching today.

We are pleased to announce FDA approval of EluRyng, one of 15 new, complex products we expect to launch over the next 18 to 24 months,” said Chirag and Chintu Patel, Co-Chief Executive Officers. “This milestone underscores Amneal’s deep scientific and regulatory capabilities and our ability to overcome significant barriers to entry, including complex formulation development and specialized manufacturing requirements. In addition, EluRyng adds a differentiated, complex dosage form to our portfolio, and bringing this product to market reflects our commitment to improving affordable access to complex drug products. Looking ahead, we remain enthusiastic about the additional high-value opportunities in our pipeline that are designed to improve the lives of patients and drive meaningful growth and value-creation for our shareholders and other stakeholders in 2020 and beyond.”

According to IQVIA™, a leading healthcare data and analytics provider, NuvaRing U.S. annual sales for the 12 months ended October 31, 2019 were approximately $976 million.
About Amneal

Amneal Pharmaceuticals, Inc. (NYSE: AMRX), headquartered in Bridgewater, NJ, is a fully-integrated pharmaceutical company focused on the development, manufacture and distribution of generic and specialty drug products. The Company has manufacturing operations in North America, Asia, and Europe, working together to bring high-quality medicines to patients primarily within the United States.

Amneal has an extensive portfolio of more than 300 generic medicines and is expanding its portfolio to include complex dosage forms, including biosimilars, in a broad range of therapeutic areas. The Company also markets a portfolio of branded pharmaceutical products through its Specialty segment focused principally on the central nervous system and endocrine disorders. For more information, visit www.amneal.com.

https://www.webmd.com/drugs/2/drug-63403/etonogestrel-ethinyl-estradiol-vaginal/details

FDA Approves Nourianz (istradefylline) as an Add-On Drug to Treat Off Episodes in Adults with Parkinson’s Disease

Kyowa Kirin Co., Ltd., (Kyowa Kirin, TYO: 4151) announced the U.S. Food and Drug Administration (FDA) has granted approval for Nourianz (istradefylline) for use as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “OFF” episodes.

“We are proud that Nourianz is now ready to help adult patients with Parkinson’s disease in the US,” said Tomohiro Sudo, Head of Global Product Management Office of Kyowa Kirin. “We believe that Nourianz could be an important contributor to improve treatment outcomes. We will keep working to bring the product to patients globally.”

“Kyowa Kirin has a commitment to global health and well-being by creating new value through the pursuit of advances in life sciences and technology particularly in oncology, nephrology, immunology, and the central nervous system,” said Tom Stratford, President of Kyowa Kirin USA Holdings, Inc. “Today's FDA approval of Nourianz is an important milestone and provides US patients with a novel non-dopaminergic once-a-day oral treatment option to be used in conjunction with levodopa/carbidopa for Parkinson’s disease.”

“Today’s approval is the culmination of decades of perseverance in exploring the science and clinical effects of istradefylline and inhibition of adenosine A2A receptor signaling in people with Parkinson’s disease,” said Jeffrey S. Humphrey, MD, Chief Development Officer of Kyowa Kirin Pharmaceutical Development, Inc. “In clinical studies, istradefylline, used as adjunctive treatment to levodopa/carbidopa in adult patients with PD experiencing 'OFF' episodes, was associated with a decrease in OFF Time and increase in ON Time without troublesome dyskinesia. We are grateful for the FDA approval and for the many dedicated scientists and patients whose participation in our research programs has resulted in a new treatment option for Parkinson's disease.”

“Istradefylline is an Adenosine A2A receptor antagonist, and is a novel non-dopaminergic pharmacologic approach to treating OFF episodes for people living with PD,” said Dr. Stuart Isaacson, MD, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida. “Based on data from four clinical studies, istradefylline taken as an adjunct to levodopa significantly improved OFF time and demonstrated a well-tolerated safety profile. Istradefylline represents an important new treatment option for patients with Parkinson's disease who experience 'OFF' episodes.”

The FDA approval of Nourianz is based on findings from randomized, multi-center, double-blind, placebo-controlled trials in patients with PD taking a stable dose of levodopa/carbidopa with or without other PD medications.

The Kyowa Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

Please see Nourianz indication and Important Safety Information below.

Indication

Nourianz (istradefylline) is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes.

Important Safety Information

Warnings and Precautions

Dyskinesia: Nourianz in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical trials, 1% of patients treated with either Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared to 0% for placebo.

FDA Approves Katerzia (amlodipine) Oral Suspension for Pediatric Patients 6 Years of Age and Older

In continuation of my update on amlodipine

Azurity Pharmaceuticals, a specialty pharmaceutical company that makes safe, high-quality treatments for patients requiring customized formulations for their care, announced  that the U.S. Food and Drug Administration (FDA) has approved Katerzia (amlodipine) Oral Suspension, 1 mg/mL, the first and only FDA-approved amlodipine oral suspension. Katerzia is indicated for the treatment of hypertension (high blood pressure) in adults and pediatric patients 6 years of age and older and coronary artery disease in adults.

“We are pleased to announce the FDA approval of Katerzia”, said Neal Muni, MD, MSPH, President and Chief Executive Officer of Azurity Pharmaceuticals. “The addition of Katerzia complements our existing pediatric hypertension portfolio and will strengthen the overall offering from Azurity. It is also our first product approval since CutisPharma and Silvergate Pharmaceuticals came together to make Azurity Pharmaceuticals, making this a truly exciting time.”

Katerzia offers a ready-to-use (simply shake) oral suspension for children 6 years of age and older that require or prefer an oral liquid option of amlodipine. Appropriate dosing for children is now simple, safe, and effective, while providing the assurance of quality as an FDA-approved product. Katerzia will be readily available through an extensive network of pharmacies and a qualified mail order service. For additional information on Katerzia, please email media@azurity.com.

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

Turalio (Pexidartinib) Approved to Treat Tenosynovial Giant Cell Tumor

In continuation of my update on pexidartinib 

Turalio (pexidartinib) capsules have been approved to treat adults with symptomatic tenosynovial giant cell tumor (TGCT), the U.S. Food and Drug Administration announced.

The drug was approved for patients with TGCT with severe morbidity or functional limitations that has not improved with surgery. Turalio is only available through the Risk Evaluation and Mitigation Strategy Program.

Approval was based on data from a multicenter international clinical trial of 120 patients. After 25 weeks, patients who received Turalio had a statistically significant improvement in overall response rate (ORR) to an ORR of 38 percent versus no response in patients who received placebo. Fifteen percent of patients had a complete response and 23 percent had a partial response. Among patients followed for a minimum of six months following initial response, 22 of 23 patients maintained their response for six months or longer; all 13 patients who initially responded and were followed for a minimum of 12 months maintained their response for 12 months or longer.

Commonly reported side effects include lactate dehydrogenase, increased aspartate aminotransferase, loss of hair color, increased alanine aminotransferase, and increased cholesterol. Side effects also include neutropenia, increased alkaline phosphatase, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, and decreased phosphate. A Boxed Warning on the prescription information for Turalio warns about the risk for serious and potentially fatal liver injury and advises health care professionals to monitor patients' liver tests before and during treatment and to alter or discontinue use of the drug if liver tests are abnormal.

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

FDA Approves Gadavist (gadobutrol) Contrast Agent for Use in Cardiac MR in Adult Patients with Known or Suspected Coronary Artery Disease

In continuation of my update on Gadavist (gadobutrol)

Bayer announced today the U.S. Food and Drug Administration (FDA) has approved Gadavist (gadobutrol) injection for use in cardiac magnetic resonance (MR) imaging to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD). Gadavist is now the first and only contrast agent FDA approved for use in cardiac MR – an important diagnostic tool for patients with CAD.

"Gadobutrol-enhanced cardiac MR demonstrated efficacy in a large global multicenter clinical trial," said Daniel S. Berman, MD, FACC, Chief of Cardiac Imaging and Nuclear Cardiology at the Cedars-Sinai Heart Institute and the S. Mark Taper Foundation Imaging Center. "The FDA approval is a landmark for making this validated, non-invasive method available to healthcare professionals to evaluate their patients for the most common form of heart disease in the world."

The approval was based on two multinational, non-randomized, blinded-read Phase 3 studies of almost 1,000 adults with suspected or known CAD based on signs and symptoms. Nearly 800 of those patients were evaluated for efficacy. First approved in 2011, cardiac MR is now the fourth FDA approved indication for Gadavist.2

The Society for Cardiovascular Magnetic Resonance recognizes cardiac MR as a non-invasive tool that provides relevant and actionable information to healthcare professionals.3

"We now have an approved contrast agent for use in cardiac MR to assess perfusion and late gadolinium enhancement in less than one hour," said Scott Flamm, MD, MBA, Head of Cardiovascular Imaging, Cleveland Clinic. "A Gadavist-enhanced cardiac MR is a key diagnostic tool, providing additional important clinical information, which can help physicians manage their patients with known or suspected CAD."

A disease that affects approximately 16.5 million Americans, CAD develops when the major blood vessels that supply the heart with blood, oxygen and nutrients (coronary arteries) become damaged or diseased.1,5 Cholesterol-containing deposits (plaque) in the arteries and inflammation are usually the cause of CAD. When plaque builds up, it narrows the coronary arteries, decreasing blood flow to the heart. Eventually, the decreased blood flow may cause chest pain (angina), shortness of breath, or other coronary artery disease signs and symptoms. A complete blockage can cause a heart attack.4

"This latest FDA approval represents another first from Bayer, as Gadavist is the first and only contrast agent approved for cardiac MR," said Dennis Durmis, SVP and Head of Americas Region at Bayer Radiology. "Not only does this approval add to our existing indications for Gadavist, expanding scientific knowledge, but also underscores our dedication to research and provides radiologists and cardiologists with another diagnostic option as they manage their patients with known or suspected CAD."

About Gadavist

Gadavist (gadobutrol) injection was first approved in the U.S. in 2011 for intravenous use in magnetic resonance (MR) imaging in adults and children (2 years of age and older) to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system. Gadavist was further approved in the U.S. in 2014 for MR of the breast in adult patients to assess the presence and extent of malignant breast disease and for pediatric patients less than 2 years of age, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system. In 2016, it was approved in the U.S. for use with magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients including term neonates.

Gadavist, also known as Gadovist® and Gadovist® 1.0 in other regions, is the U.S. brand name of the aqueous 1.0M solution of gadobutrol, a gadolinium (Gd)-based extracellular contrast agent for MRI with a macrocyclic structure. The safety profile of Gadavist has been established in clinical trials involving 7,713 patients (including 184 pediatric patients ages 0-17). The safety and effectiveness of Gadavist have not been established in preterm neonates for any indication or in pediatric patients of any age for use with MR to assess the presence and extent of malignant breast disease, or for use in cardiac MR to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (CAD). Please see Important Safety Information, including Boxed Warning below.

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

FDA Approves Nouress (cysteine hydrochloride) Injection for Treating Neonate Patients Requiring Total Parenteral Nutrition (TPN)

Avadel Pharmaceuticals plc (Nasdaq: AVDL) announced today that the U.S. Food and Drug Administration (FDA) has approved Nouress (AV001), a cysteine hydrochloride injection, a critical drug for treating neonatal patients requiring total parenteral nutrition (TPN).

In addition, Avadel announced today that the United States Patent and Trademark Office (USPTO) recently issued United States Patent No. 10,493,051 covering cysteine solutions, including the approved Nouress product. This patent is listed in the Orange Book for Nouress and is set to expire in March of 2039. Avadel has additional U.S. patent applications pending for Nouress.

“We are pleased to receive FDA approval for Nouress, which validates our strategy of developing innovative medicines for patients,” said Greg Divis, Chief Executive Officer of Avadel. “Nouress is the fourth FDA approved product in our sterile injectable hospital business. The cash flow generated by this legacy business is supporting the clinical development costs from our lead program, FT218, which is currently expected to announce topline data from the pivotal Phase 3 REST-ON trial in the second quarter of 2020. We believe that as a once-nightly formulated sodium oxybate, FT218, if approved by the FDA, has the potential to take a significant share of the twice-nightly sodium oxybate market, which is currently valued at an estimated annualized rate of $1.7 billion.”

Avadel is currently evaluating the timing and process for a commercial launch of Nouress in the United States. In this regard, a competitor received FDA approval earlier this year for its cysteine hydrochloride injection and more recently was granted a U.S. patent, which Avadel is assessing along with other market factors. 

Due to a historical lack of reliable supply, U.S. markets previously imported cysteine hydrochloride injection from Canada under special FDA rules allowing shortage drugs to be sourced abroad if no domestic supplies are available. With FDA approvals of Nouress and another U.S. company’s cysteine hydrochloride injection earlier this year, Avadel expects domestic supply of cysteine hydrochloride injection will be sufficient to support the entire U.S. market, which, under FDA regulations, should preclude further import or U.S. marketing of unapproved cysteine hydrochloride injection products.  Under these potential market conditions, the U.S. annual market for cysteine hydrochloride could be greater than $50 million. 

https://pubchem.ncbi.nlm.nih.gov/compound/L-Cysteine-hydrochloride

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

https://www.drugbank.ca/salts/DBSALT001754









FDA Approves Nouress (cysteine hydrochloride) Injection for Treating Neonate Patients Requiring Total Parenteral Nutrition (TPN)

FDA Approves Otezla (apremilast) for the Treatment of Oral Ulcers Associated with Behçet’s Disease

In continuation of my update on Otezla (apremilast) 

Celgene Corporation today announced that the U.S. Food and Drug Administration (FDA) has approved Otezla (apremilast) 30 mg twice daily (BID) for the treatment of adult patients with oral ulcers associated with Behçet’s Disease. Otezla, an oral, selective inhibitor of phosphodiesterase 4 (PDE4), is the first and only approved treatment option for oral ulcers associated with Behçet’s Disease, a rare, chronic, multisystem inflammatory disease that is difficult to treat.

“Oral ulcers are a recurring and debilitating manifestation that affects nearlyeveryone living with Behçet’s Disease,and have an important negative impact on the quality of life for these patients,” said Yusuf Yazici, M.D., Clinical Associate Professor, Department of Medicine, New York University Langone Health. “In the clinical trial, Otezla demonstrated improvements in measures of oral ulcers at week 12. Otezla has the potential to be a needed treatment option for U.S. patients and their physicians, who previously had limited options available.”

Behçet’s Disease, also known as Behçet’s Syndrome, affects approximately 5 in 100,000 people in the U.S. Oral ulcers, the most common manifestation of Behçet’s Disease occurring in more than 98% of patients, can be painful, disabling and negatively affect quality of life.3

“We are excited to provide the first and only FDA-approved treatment for oral ulcers associated with Behçet’s Disease,” said Terrie Curran, President, Celgene Inflammation & Immunology. “This approval is a reflection of Celgene’s commitment to research in areas of high unmet need, including rare diseases such as Behçet’s Disease. We remain dedicated to further studying Otezla and its role in inflammatory conditions.”

The FDA approval was based on efficacy and safety results from the randomized, placebo-controlled, double-blind Phase 3 RELIEF™ study evaluating Otezla in 207 adult patients with Behçet’s Disease with active oral ulcers who were previously treated with at least one nonbiologic medication and were candidates for systemic therapy. Results showed Otezla 30 mg BID resulted in a 42.7 point reduction from baseline in the pain of oral ulcers as measured by the visual analog scale (VAS) at week 12, compared with an 18.7 point reduction with placebo. The proportion of patients achieving an oral ulcer complete response (oral ulcer-free) at week 12 was 52.9% in the Otezla arm and 22.3% in the placebo arm. The proportion of patients achieving oral ulcer complete response by week 6 and who remained oral ulcer-free for at least six additional weeks during the 12-week treatment phase was 29.8% in the Otezla arm and 4.9% in the placebo arm. The daily average number of oral ulcers during the 12-week treatment phase was 1.5 in the Otezla arm and 2.6 in the placebo arm (based on oral ulcer counts measured at baseline and at weeks 1, 2, 4, 6, 8, 10 and 12).

“Behçet’s Disease is a chronic inflammatory disease in which patients present with symptoms such as oral ulcers that can have a significant impact on daily life,” said Mirta Avila Santos, M.D., Executive Director, American Behçet’s Disease Association. “Today’s approval for Otezla marks an important milestone for people with Behçet’s Disease who have been eagerly waiting for treatment options for their oral ulcers.”

The most common adverse events observed occurring in ≥10% of patients in the RELIEF trial were diarrhea (41.3% with Otezla; 20.4% for placebo), nausea (19.2% with Otezla; 10.7% for placebo), headache (14.4% with Otezla; 10.7% for placebo) and upper respiratory tract infection (11.5% with Otezla; 4.9% for placebo). The safety profile was consistent with the known safety profile of Otezla.

Otezla is now approved for three indications in the U.S., including the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, adult patients with active psoriatic arthritis and adult patients with oral ulcers associated with Behçet’s Disease. Since its initial FDA approval in 2014, Otezla has been prescribed to more than 250,000 patients with moderate to severe plaque psoriasis or active psoriatic arthritis in the U.S.

Otezla is available in the U.S. and is dispensed through a comprehensive network of specialty pharmacies. For more information about accessing Otezla and patient support services (including reimbursement assistance and 24/7 nurse support), doctors and patients can contact Otezla® SupportPlus™ at 1-844-4OTEZLA (1-844-468-3952) or visit www.OTEZLA.com for more information.

Celgene anticipates a regulatory decision for Otezla in oral ulcers associated with Behçet’s Disease from the Pharmaceuticals and Medical Devices Agency in Japan in the second half of 2019. The Company also submitted a Type II Variation to the Marketing Authorization Application earlier this year seeking approval in the European Union.

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

FDA Approves Accrufer (ferric maltol) for the Treatment of Iron Deficiency in Adults

Shield Therapeutics plc (LSE: STX), a commercial stage, pharmaceutical company with a focus on addressing iron deficiency, announces that the U.S. Food and Drug Administration (FDA) has approved its lead product Accrufer® (Feraccru® in the European Union and Switzerland) for the treatment of iron deficiency in adults.

With this broad label approval Accrufer (as the product will be marketed in the USA) has taken a big step towards exploiting the very large commercial opportunity in the USA, the world’s largest and most attractively reimbursed pharmaceutical market. Market research suggests that the prescription market for iron replacement therapy in the USA is worth over $1.0bn annually. There are between 8 million and 9 million patients in the USA who suffer from iron deficiency anaemia and management estimate potentially two to three times this number require treatment for iron deficiency.

Accrufer’s confirmed efficacy, together with its good tolerability and mode of absorption - by which the body absorbs only as much iron from Accrufer as it needs - means that the product could be the ideal choice for iron deficient patients who cannot tolerate salt-based oral iron alternatives. These features, combined with the noninferiority results from the AEGIS-H2H study announced in March 2019, mean that treatment with Accrufer might remove the need for patients to progress to intravenous iron therapy, leading to a change in the current paradigm for the treatment of iron deficiency anaemia.

Together with its advisors, Shield is in discussions with a number of potential commercial partners for the US opportunity for Accrufer and looks forward to providing updates on these discussions in due course. Feraccru is already approved in both the European Union and Switzerland for the treatment of iron deficiency in adults and commercialisation activities in these territories are progressing well via Shield’s licensing partners.

Carl Sterritt, CEO of Shield Therapeutics: “We are delighted that the FDA has approved the new drug application for our lead asset. This is a further major milestone for the Company which we have worked tirelessly to achieve, and I am very proud to lead the team within Shield that has made this happen. With this broad approval and IP protection out to 2035, Feraccru®/ Accrufer® has a real and very attractive long-term market opportunity to exploit in the USA. We have been pleased with the levels of interest and engagement shown by 3rd parties in commercialising Accrufer® in the USA and we look forward to finalising these discussions and appointing a commercial partner In the world’s most attractive pharmaceutical market,so that more patients with iron deficiency can benefit from treatment with Accrufer® at the earliest opportunity.”

Jackie Mitchell, VP Regulatory Affairs of Shield Therapeutics: “The broad label that the FDA has granted provides a very strong signal as to the tolerability and efficacy profile of Feraccru®/ Accrufer® and provides a novel and convenient treatment alternative to the millions of US patients who routinely suffer with iron deficiency. We believe that this broad approval, together with the recent clinical trial data on Feraccru® that showed it to be non-inferior in treatment effect to Ferinject®/ Injectafer®, the leading IV iron therapy, can lead to a change in the current paradigm for the treatment iron deficiency anaemia

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

FDA Approves Nubeqa (darolutamide) for Men with Non-Metastatic Castration-Resistant Prostate Cancer

The U.S. Food and Drug Administration (FDA) today approved Nubeqa (darolutamide), an androgen receptor inhibitor (ARi), for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). The FDA approval is based on the Phase III ARAMIS trial evaluating Nubeqa plus androgen deprivation therapy (ADT), which demonstrated a highly significant improvement in the primary efficacy endpoint of metastasis-free survival (MFS), with a median of 40.4 months versus 18.4 months for placebo plus ADT (p<0.0001).1 MFS is defined as the time from randomization to the time of first evidence of blinded independent central review (BICR)-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. Nubeqa was approved under the FDA's Priority Review designation, which is reserved for medicines that may provide significant improvements in the safety or effectiveness of the treatment for serious conditions.

"Patients at this stage of prostate cancer typically don't have symptoms of the disease. The overarching goals of treatment in this setting are to delay the spread of prostate cancer and limit the burdensome side effects of therapy," said Matthew Smith, M.D., Ph.D., Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center. "This approval marks an important new option for the prostate cancer community."

In the U.S., over 73,000 men are estimated to be diagnosed with castration-resistant prostate cancer (CRPC) in 2019. About 40 percent of these patients have prostate cancer that has not spread to other parts of the body and is also associated with a rising prostate-specific antigen (PSA) level, despite a castrate testosterone level, which is known as nmCRPC. This is important because about one-third of men with nmCRPC go on to develop metastases within two years.4 PSA monitoring is important to identify patients and help offset undertreatment in men before the disease spreads.

"We know that men with nmCRPC are still in the prime of their lives and are at a critical point in their disease when action needs to be taken," said Howard R. Soule, Ph.D., Executive Vice President and Chief Science Officer, Prostate Cancer Foundation (PCF). "For 26 years, PCF has been focused on research aimed at improving patient outcomes and we welcome the addition of new treatment options that provide men with more choices when working with their doctor to select what's right for them."

"With the approval of Nubeqa, we now have a new therapy that extends MFS and allows physicians greater flexibility to treat men living with nmCRPC," said Robert LaCaze, Member of the Executive Committee of Bayer's Pharmaceuticals Division and Head of the Oncology Strategic Business Unit at Bayer. "Bayer is proud to take this latest step forward in the nmCRPC treatment landscape. Nubeqa is the newest addition to our prostate cancer portfolio and reflects Bayer's commitment to finding treatments for men at different stages along the prostate cancer continuum."

In the ARAMIS trial, both arms showed a 9 percent discontinuation rate due to adverse reactions. The most frequent adverse reactions requiring discontinuation in patients who received Nubeqa included cardiac failure (0.4 percent), and death (0.4 percent).  Adverse reactions occurring more frequently in the Nubeqa arm (≥2 percent over placebo) were fatigue (16 percent versus 11 percent), pain in extremity (6 percent versus 3 percent) and rash (3 percent versus 1 percent). Nubeqa was not studied in women and there is a warning and precaution for embryo-fetal toxicity.

Overall survival (OS) and time to pain progression were additional secondary efficacy endpoints. OS data were not yet mature at the time of final MFS analysis.1 The MFS result was supported by a delay in time to pain progression, defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids, in patients treated with Nubeqa as compared to placebo.1 Pain progression was reported in 28 percent of all patients on study.

Bayer has filed for approval of Nubeqa in the European Union (EU), Japan, and with other health authorities. Nubeqa is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

FDA Approves AirDuo Digihaler (fluticasone propionate and salmeterol) Inhalation Powder for Asthma

In continuation of my update on (fluticasone propionate and salmeterol

   

Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) announced today that the U.S. Food and Drug Administration (FDA) has approved AirDuo® Digihaler™ (fluticasone propionate 113 mcg and salmeterol 14 mcg) Inhalation Powder, a combination therapy digital inhaler with built-in sensors that connects to a companion mobile application to provide information on inhaler use to people with asthma. AirDuo Digihaler is indicated for the treatment of asthma in patients aged 12 years and older. AirDuo Digihaler is not used to relieve sudden breathing problems and won’t replace a rescue inhaler.

“We are thrilled to be able to expand our Digihaler™ portfolio to now include a maintenance treatment,” said Tushar Shah, M.D., Global Head of Specialty Clinical Development at Teva Pharmaceuticals. “With this approval, patients can now track how frequently they are using their inhalers. Granting patients the ability to track their maintenance inhaler use may help inform conversations with their doctors about treatment adherence and proper technique.”

Like ProAir® Digihaler™ (albuterol sulfate 117 mcg) inhalation powder, indicated for the treatment or prevention of bronchospasm in patients aged four years and older with reversible obstructive airway disease, and for prevention of exercise-induced bronchospasm (EIB) in patients four years and older, AirDuo® Digihaler™ contains built-in sensors that detect when the inhaler is used and measure inspiratory flow rates. This data is then sent to a companion mobile app using Bluetooth® Wireless Technology so that patients can review their data over time, and if desired, share it with their healthcare providers. Patients can also schedule reminders on their smartphone to take their AirDuo® Digihaler™ as prescribed.

“Even the most diligent asthma patients may not realize they are not following their treatment regimen, despite their best efforts,” said Dr. Nabeel Farooqui, MD, FAAAAI, FACAAI, Assistant Professor, Department of Medicine, Indiana University School of Medicine. “The ability to now measure their inspiratory flow rates and track their maintenance medication use, as well as the frequency with which they use their inhaler, may provide important data and insights to help inform treatment discussions with physicians. As a doctor, it’s exciting that my patients are able to share this type of information with me.”

The approval of AirDuo Digihaler is based on the review of the supplemental new drug application (sNDA) submitted by Teva to the FDA. AirDuo Digihaler combines a breath-actuated, multi-dose dry powder inhaler with fluticasone propionate, an inhaled corticosteroid (ICS) medicine that may help to decrease inflammation in the lungs, which can lead to breathing problems, and salmeterol, a long acting beta2 adrenergic agonist (LABA), which helps the muscles around the airways in the lungs stay relaxed in order to prevent symptoms. AirDuo Digihaler contains salmeterol. LABA medicines such as salmeterol when used alone increase the risk of hospitalizations and death from asthma problems. AirDuo Digihaler contains an ICS and a LABA. When an ICS and a LABA are used together, there is not a significant increased risk in hospitalizations and death from asthma problems.

AirDuo Digihaler was approved in a low, medium and high dose: 55/14 mcg, 113/14 mcg and 232/14 mcg administered as one inhalation twice daily. As a fixed dose combination asthma therapy containing an ICS and a LABA, AirDuo Digihaler contains the same active ingredients as Advair Diskus, which is also approved in low, medium and high doses: 100/50 mcg, 250/50 mcg and 500/50 mcg.

“For the 25 million Americans living with asthma1, advancements like this one are important and could help patients track their inhaler use and frequency,” said Tonya Winders, President & CEO of the Allergy & Asthma Network. “Allowing patients access to both their rescue and maintenance inhaler use information on their smartphones is a promising step towards potentially fostering greater discussions about asthma management.”

“The approval of AirDuo Digihaler is an important step for Teva and the respiratory community to create a technology platform for use in asthma management along with the previously-approved ProAir Digihaler,” said Sven Dethlefs, Executive Vice President, Global Marketing & Portfolio. “This technology aims at delivering innovations through cloud-based services with the target to provide new insights to guide treatment choices for caregivers to help them improve outcomes for asthma patients.”

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

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