Shionogi Announces Acceptance of NDA for Naldemedine for the Treatment of Opioid-Induced Constipation

Shionogi announced that the New Drug Application (NDA) submitted in the U.S. for naldemedine, a once-daily, oral 0.2 mg tablet, has been accepted for review. In the U.S., the proposed indication is for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain (CNCP). The target action date under the Prescription Drug User Fee Act (PDUFA) is March 23, 2017. The company also submitted an NDA in Japan on March 30, 2016 for the proposed indication of the treatment of OIC in adult patients.

Naldemedine is an investigational peripherally-acting mu-opioid receptor antagonist (PAMORA) being studied in the US for the treatment of OIC in adult patients with CNCP. Opioid-induced constipation is characterized by any of the following: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency after initiating opioid therapy.

"If approved, naldemedine will offer a new therapeutic option for chronic non-cancer pain patients living with opioid-induced constipation, a common and often debilitating condition," said Dr. John Keller, President and CEO, Shionogi Inc. "Shionogi is committed to developing new treatments to improve the lives of patients around the world. We look forward to working with U.S. and Japanese health authorities to bring naldemedine to market for their respective indications."

The NDA submissions include data supporting the efficacy and safety of naldemedine from the Phase III COMPOSE program.

About COMPOSE

The COMPOSE program is a global comprehensive development program comprised of seven clinical studies being conducted in patients with OIC and cancer or chronic non-cancer pain.

COMPOSE I and II were 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. Both studies were designed to evaluate the efficacy and safety of naldemedine therapy versus placebo in patients on opioid therapy for at least three months and on a stable dose of opioids for at least four weeks, and who experience chronic non-cancer pain accompanied by OIC. The sample population for COMPOSE I and II included 547 and 553 patients, respectively.

Shionogi previously announced that naldemedine met its primary and key secondary endpoints in COMPOSE I, II and IV. COMPOSE IV was conducted in Japan.

In the studies, a bowel movement occurring within 24 hours after rescue laxative therapy was not considered a spontaneous bowel movement (SBM).

About Opioid-Induced Constipation (OIC)

Opioid-induced constipation (OIC) is characterized by any of the following after initiating opioid therapy: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency.1 Approximately half of all chronic non-cancer pain patients who have OIC are dissatisfied with laxatives.2 Managing OIC and its clinical consequences places a significant burden on the healthcare system and the patient.

Shionogi Announces Acceptance of NDA for Naldemedine for the Treatment of Opioid-Induced Constipation

FDA Issues Complete Response Letter for Apadaz New Drug Application

KemPharm, Inc.  a clinical-stage specialty pharmaceutical company engaged in the discovery and development of proprietary prodrugs,  announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for Apadaz™ (benzhydrocodone and acetaminophen), KemPharm’s investigational abuse-deterrent product candidate for the short-term management of acute pain.

 benzhydrocodone         acetaminophen

The FDA issues CRLs to indicate that the Agency considers the review cycle for an application is complete and that the application is not ready for approval in its present form. Included in the CRL is guidance that describes all specific deficiencies that the FDA has identified in the application. When possible, the FDA recommends actions that the applicant may take to place the application in condition for approval.

“After last week’s amendment request, a Complete Response Letter from the FDA was received for the Apadaz NDA,” said Travis C. Mickle, Ph.D., President and CEO of KemPharm. “We are currently evaluating the points raised in the CRL and intend to request an End of Review meeting with the Agency to determine the pathway forward for Apadaz.”

Allergan Announces FDA Acceptance of NDA Filing for Oxymetazoline HCI Cream 1.0%

Allergan plc  announced that the New Drug Application (NDA) filing for oxymetazoline HCl cream 1.0%, an investigational topical prescription product for the treatment of persistent facial erythema (redness) associated with rosacea in adults, has been accepted by the U.S. Food and Drug Administration (FDA) for standard review. Allergan expects the Prescription Drug User Fee Act (PDUFA) date to be in the first half of 2017.

"While rosacea is a common chronic skin condition that affects more than 16 million people in the U.S. alone1, there is a significant unmet need in effective, FDA-approved treatments for the condition," said David Nicholson, Chief R&D Officer, Allergan. "The NDA filing of oxymetazoline speaks to our strong commitment to ongoing innovation of our medical dermatology portfolio, and we look forward to bringing a new treatment option to patients with rosacea."

About Oxymetazoline

Oxymetazoline is a sympathomimetic agonist that is selective for the α1A-adrenoceptor over other α1-adrenoceptors and non-selective for the α2-adrenoceptors. As such, oxymetazoline is a potent vasoconstrictor of the cutaneous microvasculature. The NDA submission for oxymetazoline HCL cream 1.0% was based on data collected from two phase 3 pivotal clinical trials of a 29-day treatment duration and a 1-year open label clinical trial. These studies enrolled male and female patients ≥ 18 years of age with moderate to severe persistent facial erythema associated with rosacea.

AstraZeneca Receives Complete Response Letter from FDA for Sodium Zirconium Cyclosilicate (ZS-9) for Hyperkalemia

AstraZeneca today announced that the US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for sodium zirconium cyclosilicate (ZS-9), the investigational medicine being developed for the treatment of hyperkalemia (high potassium level in the blood serum) by ZS Pharma, a wholly-owned subsidiary of AstraZeneca.

The CRL refers to observations arising from a pre-approval manufacturing inspection. The FDA also acknowledged receipt of recently-submitted data which it has yet to review. The CRL does not require the generation of new clinical data. AstraZeneca and ZS Pharma are evaluating the      (see structure of  ZS-9 (sodium zirconium cyclosilicate) content of the CRL and will work closely with the FDA to determine the appropriate next steps for the NDA.AstraZeneca remains committed to the development of sodium zirconium cyclosilicate as a treatment option for patients with hyperkalemia. Interactions are ongoing with other health authorities in the European Union and Australia, where sodium zirconium cyclosilicate is currently under separate regulatory review.

About Sodium Zirconium Cyclosilicate (ZS-9) for Oral Suspension

Sodium zirconium cyclosilicate (ZS-9) is an insoluble, non-absorbed compound with a structure that was designed to preferentially trap potassium ions. The unique potassium selectivity of sodium zirconium cyclosilicate enables high in-vitro binding capacity for potassium ions even in the presence of other competing ions. Sodium zirconium cyclosilicate has been studied in three double-blind, placebo controlled trials and in one ongoing 12 month open label clinical trial in patients with hyperkalemia which represents over 1,600 patients treated. Sodium zirconium cyclosilicate is an investigational product that is not currently approved for any indication in any market.

About Hyperkalemia

Hyperkalemia (high potassium levels > 5.0 mEq/L in the blood serum) occurs in 23-47% of patients with advanced chronic kidney disease and/or chronic heart failure, and may lead to cardiac arrest and death (mortality of up to 30% in patients with severe hyperkalemia if not treated rapidly). Treatment with common heart medicines (RAAS inhibitors) can also be responsible for increases in hyperkalemia. Current therapeutic options are limited, leaving high unmet medical need.

Lexicon Announces FDA Priority Review of NDA for Telotristat Etiprate for the Treatment of Carcinoid Syndrome

Lexicon Pharmaceuticals, Inc.  announced that the U.S. Food and Drug Administration has accepted for filing the New Drug Application for telotristat etiprate, an oral drug for the treatment of carcinoid syndrome. The FDA has granted a Priority Review of the NDA filing and set a Prescription Drug User Fee Act (“PDUFA”) target action date of November 30, 2016.

“The granting of priority review by the FDA underscores the need for improving the lives of the patients and caregivers who live with carcinoid syndrome on a daily basis,” said Lexicon President and Chief Executive Officer, Lonnel Coats. “If approved, telotristat etiprate would be the only approved therapy for patients who are no longer able to control their carcinoid syndrome with the current standard of care alone.”

Carcinoid syndrome is a rare disease affecting thousands of cancer patients with metastatic neuroendocrine tumors (mNETs) that have spread to the liver and other organs from the gastrointestinal tract. The condition is characterized by frequent and debilitating diarrhea that often prevents patients from leading active, predictable lives, as well as facial flushing, abdominal pain, fatigue and, over time, heart valve damage.

About Telotristat Etiprate

Discovered using Lexicon’s unique approach to gene science, telotristat etiprate is the first investigational drug in clinical studies to target tryptophan hydroxylase, an enzyme that triggers the excess serotonin production within mNET cells that leads to carcinoid syndrome. While existing treatments for carcinoid syndrome work to reduce the release of serotonin outside tumor cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells. By specifically inhibiting serotonin production, telotristat etiprate seeks to control this important driver of carcinoid syndrome and, in turn, provide patients with more control over their disease.

Telotristat etiprate has received Fast Track and Orphan Drug designation from the U.S. Food and Drug Administration.

Lexicon retains rights to market telotristat etiprate in the U.S. and Japan, and is building the in-house commercial infrastructure to serve the U.S. market. Lexicon has a license and collaboration agreement with Ipsen to commercialize telotristat etiprate in Europe and other countries outside the U.S. and Japan.

Radius Announces FDA Acceptance for Filing of NDA for for the Treatment of Postmenopausal Women with Osteoporosis

Radius Health, Inc. ), a science-driven biopharmaceutical company that is committed to developing innovative therapeutics in the areas of osteoporosis, oncology and endocrine diseases, announced that its New Drug Application (NDA) for abaloparatide—SC has been accepted for filing by the U.S. Food and Drug Administration (FDA). The acceptance of the NDA reflects the FDA's determination that the application is sufficiently complete to permit a substantive review.

"The FDA's acceptance for filing of our abaloparatide-SC NDA is a major milestone for Radius and we look forward to continuing to work with the FDA as they review our application," said Robert E. Ward, President and CEO of Radius Health. "Given the high unmet medical need in osteoporosis, we believe that abaloparatide-SC, if approved, has the potential to become a promising new treatment option for the approximately 10 million postmenopausal women with osteoporosis, many of whom remain untreated."

The NDA is supported by data from the entire abaloparatide-SC development program, including the results from the 18-month Phase 3 ACTIVE trial in 2,463 postmenopausal women with osteoporosis and the first six months of the ACTIVExtend trial in 1,139 of the ACTIVE participants. Positive results for abaloparatide-SC treatment groups from the ACTIVE and ACTIVExtend trials have met the primary and secondary endpoints essential for submission of the NDA, including the primary endpoint of reduction of vertebral fractures as well as key endpoints of reduction of nonvertebral, clinical, and major osteoporotic fractures. In these and the other trials submitted in the NDA, abaloparatide-SC administered at a dose of 80 mcg daily was generally safe and well tolerated in postmenopausal women with osteoporosis.

As previously reported, Radius submitted a Centralised Marketing Authorisation Application (MAA) for abaloparatide-SC in the European Union on November 17, 2015, which was validated by the European Medicines Agency (EMA) in December 2015, and is currently undergoing active regulatory assessment by the Committee for Medicinal Products for Human Use of the EMA (CHMP). The EMA has granted Radius an additional 3-month extension to the procedural timetable for response in the ongoing MAA assessment. As a result of this extension to the procedural timetable, the Company now anticipates that the CHMP may adopt an Opinion regarding the MAA in late 2016 or in 2017.

Abaloparatide-SC is an investigational treatment for postmenopausal women with osteoporosis and its safety and efficacy have not been established.

Teva Announces FDA Approval of ProAir RespiClick (albuterol sulfate) Inhalation Powder for Pediatric Asthma Patients Ages 4 to 11

Teva Pharmaceutical Industries Ltd.,  announced  that the U.S. Food and Drug Administration (FDA) has approved ProAir RespiClick (albuterol sulfate) Inhalation Powder for the treatment or prevention of bronchospasm in children 4 to 11 years of age with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm (EIB).

ProAir RespiClick was approved by the FDA for use in patients 12 years of age and older in March 2015 and remains the only breath-activated, multi-dose, dry powder, short-acting beta-agonist (SABA) inhaler available in the U.S.

Flexion Therapeutics Receives Positive Guidance from FDA on NDA Submission for Zilretta for Osteoarthritis of the Knee

Flexion Therapeutics, Inc. announces that yesterday it received written responses from the U.S. Food & Drug Administration (FDA) to questions the company had submitted in advance of a pre-NDA meeting regarding Flexion's lead product candidate, Zilretta (also known as FX006). The FDA clearly indicates in its responses that the safety and efficacy data from the registration program for Zilretta are "acceptable to support filing of an NDA submission." Based on this positive FDA feedback, the in-person pre-NDA meeting has become unnecessary and the FDA responses will serve as the official meeting minutes.

Michael Clayman, M.D., President and Chief Executive Officer of Flexion, stated, "The endorsement from the FDA for the Zilretta NDA submission represents a major milestone in the development of this drug candidate and brings us one step closer to making it available to the many millions of knee osteoarthritis (OA) patients who lack good pain-relief options. We intend to submit the NDA in the fourth quarter of this year."

Allergan Receives FDA Approval of Teflaro (ceftaroline fosamil) for Pediatric Patients

Allergan plc, a leading global pharmaceutical company,  announced the U.S. Food and Drug Administration (FDA) has approved the company's supplemental New Drug Application (sNDA) for Teflaro (ceftaroline fosamil), granting new indications for pediatric patients 2 months of age to less than 18 years of age with acute bacterial skin and skin structure infections (ABSSSI), including infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and community-acquired bacterial pneumonia (CABP) caused by Streptococcus pneumoniae and other designated susceptible bacteria.

"The impact of ABSSSI and CABP among children is significant, as these infections often require hospitalization and are met with limited pediatric treatment options, particularly as resistance increases among the pathogens that cause these infections," said David Nicholson, Chief R&D Officer, Allergan. "These new indications are yet another testament to our ongoing research and development in anti-infectives to address the evolving challenges of serious infections. Importantly, it allows us to educate physicians on the data they need to prescribe Teflaro to appropriate pediatric patients in need of an option that is safe and effective against some of the most difficult-to-treat pathogens in ABSSSI and CABP."

ABSSSI and CABP are common causes of healthcare visits and hospitalizations among children. Studies show more than 70,000 hospitalizations for ABSSSI occur among children per year – a rate that has more than doubled over the past 13 years.1 A study conducted by the Centers for Disease Control and Prevention (CDC) also found children younger than 5 years of age accounted for 70 percent of children hospitalized for community-acquired pneumonia.

These new indications were approved based on results from clinical studies evaluating TEFLARO in pediatric patients (2 months to less than 18 years of age), including one active-controlled study in ABSSSI and two active-controlled studies in CABP. In the ABSSSI active-controlled study, the efficacy and safety of Teflaro was compared with vancomycin or cefazolin (each with optional aztreonam). In the CABP studies, Teflaro was compared with ceftriaxone. Use of Teflaro in pediatric patients 2 months to less than 18 years of age is supported by evidence from adequate and well-controlled studies of Teflaro in adults, as well as additional pharmacokinetic and safety data from pediatric trials.

The primary objective of the pediatric ABSSSI and CABP studies was to evaluate the safety and tolerability of Teflaro. These studies were not powered for comparative inferential efficacy analysis, and no efficacy endpoints were identified as primary.

To evaluate the treatment effect of Teflaro in the ABSSSI pediatric trial, an analysis was conducted in 159 patients with ABSSSI in the Modified Intent-to-Treat (MITT) population. This analysis evaluated responder rates based on achieving both cessation of lesion spread and absence of fever on Study Day 3. Patients treated with Teflaro showed a higher response at Study Day 3 versus the comparator group, with clinical response achieved in 80.4 percent (86/107) of patients treated with Teflaro and 75 percent (39/52) of patients in the comparator group, with a treatment difference of 5.4 percent (95 percent Confidence Interval [CI] -7.8, 20.3). Clinical cure rates at the test of cure (TOC) visit (8 to 15 days after the end of therapy) for the ABSSSI pediatric trial were 94.4 percent (101/107) for patients treated with Teflaro and 86.5 percent (45/52) for the comparator, with a treatment difference of 7.9 (95 percent CI -1.2, 20.2).

To evaluate the treatment effect of Teflaro in the CABP trial submitted for this pediatric filing, an analysis was conducted in 143 patients with CABP in the MITT population. This analysis evaluated responder rates at Study Day 4 based on achieving improvement in at least two out of seven symptoms (cough, dyspnea, chest pain, sputum production, chills, feeling of warmth/feverish and exercise intolerance or lethargy), and worsening in none of these symptoms. The clinical response at Study Day 4 was 69.2 percent (74/107) for patients treated with Teflaro and 66.7 percent (24/36) for the comparator, with a treatment difference of 2.5 percent (95 percent CI -13.9, 20.9). Clinical cure rates at TOC were 87.9 percent (94/107) for patients treated with TEFLARO and 88.9 percent (32/36) for the comparator, with a treatment difference of -1.0 (95 percent CI -11.5, 14.1).

Results from the clinical studies in pediatric patients showed that Teflaro demonstrated a safety profile that was compatible with treatment of ABSSSI and CABP at the clinical dosages studied. The safety findings were similar to those seen in the adult studies, and no safety concerns were identified beyond those already known to be cephalosporin class effects.

Teflaro is the first and only cephalosporin indicated in adults and pediatric patients 2 months of age and older for the treatment of ABSSSI and CABP due to designated susceptible pathogens that can be administered by intravenous (IV) infusion in five minutes to one hour.

Allergan Announces FDA Approval of Byvalson (nebivolol and valsartan) for Hypertension

In continuation of my update on nebivolol and valsartan

Allergan plc (NYSE: AGN), a leading global pharmaceutical company,  announced the approval of Byvalson (nebivolol and valsartan) 5 mg/ 80 mg tablets, by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension to lower blood pressure. Byvalson is the first and only fixed-dose combination (FDC) of a beta blocker (BB) and angiotensin II receptor blocker (ARB) available in the U.S.

 nebivolol  Valsartan

"Achieving blood pressure control is critical to reducing the risk of serious and life-threatening cardiovascular events. There remains a need for new therapies, as observed by the nearly half of patients in the U.S. who remain uncontrolled," said David Nicholson, Chief R&D Officer at Allergan. "We are pleased with the FDA approval of Byvalson, which will provide physicians a new fixed dose combination therapy treatment option for patients affected by hypertension."

Hypertension represents a significant public health problem with high prevalence in the U.S. Hypertension often has no warning signs or symptoms and has been associated with serious cardiovascular (CV) risks, such as stroke, heart failure, and myocardial infarction. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the beta-blocker class to which nebivolol principally belongs and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Byvalson.

"The majority of patients with hypertension require two or more medications to achieve their blood pressure goals," said William B White, MD Professor of Medicine and Chief of the Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center at UConn Health in Farmington and immediate past president of the American Society of Hypertension. "Nebivolol and valsartan are used widely in the management of hypertension and are effective drugs. The new fixed-dose combination Byvalson, that includes these 2 therapies, offers reduction of blood pressure through multiple mechanisms of action."

The FDA approval of Byvalson was based on a Phase 3, double-blind, placebo-controlled, dose-escalating, 8-week efficacy and safety study, published in The Lancet, which randomized approximately 4,100 patients with Stage 1 or 2 hypertension. In this pivotal efficacy and safety study, treatment with the FDC of nebivolol and valsartan for 4 weeks demonstrated statistically significant reductions from baseline in diastolic and systolic blood pressure versus either nebivolol alone or valsartan alone. The overall rate of adverse events was similar across treatment groups and placebo during this 4 week period.