Allergan Announces FDA Approval of Avycaz (ceftazidime and avibactam) for Pediatric Patients

Allergan plc (NYSE: AGN) announced that the U.S. Food and Drug Administration (FDA) has approved the company's supplemental New Drug Application (sNDA) for Avycaz (ceftazidime and avibactam), expanding the label to include pediatric patients 3 months and older for the treatment of complicated intra-abdominal infections (cIAI) in combination with metronidazole and complicated urinary tract infections (cUTI). This is the first FDA approval of a pediatric indication for cUTI and cIAI in more than a decade.

      

"Difficult-to-treat gram-negative pathogens pose a significant health risk, particularly to the vulnerable and sensitive pediatric patient population with few options for treatment," said David Nicholson, Chief Research & Development Officer at Allergan.  "As resistance rises among the gram-negative pathogens that cause these serious infections, the expanded label for Avycaz provides a safe and effective treatment option now for pediatric patients with cIAI and cUTI. These expanded indications in pediatric patients with infections, including infants and those at a particularly young age, address an unmet need among this vulnerable population and  underscore Allergan's efforts in anti-infective research."

The label expansion was approved based on results from two active-controlled clinical studies evaluating Avycaz in children or infants with cIAI or cUTI, as well as a single-dose pharmacokinetic study. In the cIAI study, the safety and efficacy of Avycaz (in combination with metronidazole) was compared with meropenem. In the cUTI study, Avycaz was compared with cefepime.

Across the trials, 128 pediatric patients 3 months to less than 18 years of age were treated with Avycaz. Overall, the findings from the pediatric studies were similar to the previous determination of safety for Avycaz for the treatment of adult patients with cIAI or cUTI, and no new safety concerns were identified in pediatric patients.

The primary objectives of the studies were to evaluate the safety and tolerability of Avycaz, and they were not powered for a statistical analysis of efficacy. The descriptive efficacy analyses in the pediatric studies were consistent with data from studies in adults with cIAI and cUTI. In the pediatric cIAI study, the clinical cure rate at the test-of-cure (TOC) visit in the intent-to-treat (ITT) population was 91.8% (56/61) in the Avycaz plus metronidazole group and 95.5% (21/22) in the meropenem group. Clinical cure rates for the predominant pathogens, Escherichia coli and Pseudomonas aeruginosa, were 90.5% and 85.7%, respectively for patients treated with Avycaz plus metronidazole, and 92.3% and 88.9%, respectively, for patients treated with meropenem. In the pediatric cUTI study, the combined favorable clinical and microbiological response rate at TOC in the microbiological-ITT population was 72.2% (39/54) in the Avycaz group and 60.9% (14/23) in the cefepime group. The microbiologic response rate for E.coli, the most common uropathogen identified in the study, was 79.6% for patients treated with Avycaz and 59.1% for patients treated with cefepime.

Avycaz was first approved by the FDA in February 2015 for the treatment of cUTI including pyelonephritis, and cIAI in combination with metronidazole, caused by designated susceptible bacteria including certain Enterobacteriaceae and P. aeruginosa, for patients 18 years of age and older. Avycaz was subsequently approved for the treatment of adults with hospital-acquired pneumonia / ventilator-associated pneumonia (HABP/VABP) caused by designated susceptible bacteria in February 2018.

About Avycaz (ceftazidime and avibactam)

Avycaz is a fixed-dose combination antibacterial indicated for the treatment of cIAI (in combination with metronidazole), and cUTI caused by designated susceptible Gram-negative microorganisms in patients 3 months or older. Avycaz is also indicated for the treatment  of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Avycaz consists of a combination of avibactam and ceftazidime.

Avibactam is a first-in-class non-beta-lactam beta-lactamase inhibitor which protects ceftazidime against degradation by certain beta-lactamases. Avibactam does not decrease the activity of ceftazidime against ceftazidime-susceptible organisms. Ceftazadime is a third-generation cephalosporin with a well-established efficacy and safety profile.

Avycaz has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC and certain oxacillinases (OXA). Avycaz also demonstrated in vitro activity against P. aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). Avycaz is not active against bacteria that produce metallo-beta lactamases and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.

Ceftazidime and avibactam is being jointly developed with Pfizer. Allergan holds the rights to commercialize ceftazidime and avibactam in North America under the brand name Avycaz, while Pfizer holds the rights to commercialize the combination in the rest of the world under the brand 

Ref : https://www.drugbank.ca/drugs/DB00438

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

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

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

Harmony Biosciences Announces File Acceptance Of Its New Drug Application For Pitolisant

   Harmony Biosciences, LLC (Harmony), announced that the U.S. Food and Drug Administration (FDA) has accepted for filing the New Drug Application (NDA) for its investigational product, pitolisant, and has granted Priority Review for this NDA. Pitolisant is a first-in-class molecule with a novel mechanism of action; it is a potent and highly selective histamine 3 (H₃) receptor antagonist/inverse agonist for the potential treatment of excessive daytime sleepiness (EDS) and/or cataplexy in adult patients with narcolepsy. A Priority Review designation by the FDA indicates that, if approved, pitolisant would provide a significant improvement in the safety or effectiveness of the treatment of EDS and/or cataplexy in adult patients with narcolepsy when compared to existing treatments. Harmony’s goal is to obtain FDA approval to market pitolisant in the U.S. in 2019.

“The impact of narcolepsy can be significant and severely disruptive to everyday life for up to 200,000 Americans living with this disorder,” said John C. Jacobs, President and CEO at Harmony. “This is an important step for patients and for our company, whose mission is to develop novel treatment options for people living with rare and orphan diseases.”

“Pitolisant offers a novel approach to the treatment of both EDS and cataplexy in patients with narcolepsy, for which there have been no new treatment options in over 15 years,” said Jeffrey M. Dayno, M.D., Chief Medical Officer at Harmony. “We look forward to working with the FDA during its review of the pitolisant NDA, with our hope of being able to offer this new treatment option to help address an important unmet medical need for people living with narcolepsy.”

The NDA submission is based on results from the clinical development program in narcolepsy, which included over 300 patients, some of whom were treated for up to five years. It also included safety data in over 1500 patients across multiple patient populations.

About Pitolisant

Pitolisant is an investigational medication in the U.S. that is not approved by the FDA. It was granted orphan designation for the treatment of narcolepsy, Fast Track designation for the treatment of excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy, and Breakthrough Therapy designation for the treatment of cataplexy in patients with narcolepsy. Pitolisant, a first-in-class medication, is a potent and highly selective histamine 3 (H₃) receptor antagonist/inverse agonist; it enhances the activity of histaminergic neurons in the brain that function to improve a patient’s wakefulness and inhibit attacks of cataplexy. It was designed and developed by Bioprojet, who has marketed the product in Europe since its approval by the European Medicines Agency in 2016. Harmony’s goal is to obtain FDA approval to market this new medication in the U.S. in 2019. If approved, pitolisant would represent the first new therapy in the U.S. in over 15 years for the treatment of both EDS and cataplexy in adult patients with narcolepsy.

Alkermes and Biogen Announce U.S. Food and Drug Administration Acceptance of Diroximel Fumarate New Drug Application for Multiple Sclerosis

   

Alkermes plc (Nasdaq: ALKS) and Biogen Inc. (Nasdaq: BIIB)  announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for diroximel fumarate (BIIB098), a novel oral fumarate in development for the treatment of relapsing forms of multiple sclerosis (MS). The NDA has been assigned a PDUFA (Prescription Drug User Fee Act) target action date in the fourth quarter of 2019. If approved, Biogen intends to market diroximel fumarate under the brand name VUMERITY™, which has been conditionally accepted by the FDA and will be confirmed upon approval.

“The NDA filing acceptance for diroximel fumarate further demonstrates the productive collaboration between Alkermes and Biogen and brings us closer to our shared goal of offering a new therapeutic option for people with MS,” said Craig Hopkinson, M.D., chief medical officer and senior vice president, medicines development and medical affairs at Alkermes. “We believe diroximel fumarate has the potential to be a meaningful new offering for patients with MS, and we look forward to continued engagement with the FDA throughout the review process.”

“For more than two decades Biogen has been at the forefront of delivering new medicines to MS patients,” said Michael Ehlers, M.D., Ph.D., executive vice president, research and development at Biogen. “We are encouraged by the FDA’s acceptance of the NDA for diroximel fumarate, which we believe could help elevate the treatment of this complex and often debilitating disease.”

Alkermes is seeking approval of diroximel fumarate under the 505(b)(2) regulatory pathway, referencing Biogen’s dimethyl fumarate data. The NDA submission includes data from EVOLVE-MS-1, a Phase 3, open-label, two-year safety study in relapsing-remitting MS (RRMS) patients. It is hypothesized that the distinct chemical structure of diroximel fumarate may impact its gastrointestinal (GI) tolerability. Alkermes is conducting EVOLVE-MS-2, a head-to-head GI tolerability study versus dimethyl fumarate, with results expected later this year.

About the Diroximel Fumarate Clinical Development Program

The key components of the clinical development program of diroximel fumarate include the EVOLVE-MS-1 study, a Phase 3, open-label, two-year safety study in relapsing-remitting MS (RRMS) patients, along with pharmacokinetic bridging studies comparing diroximel fumarate and dimethyl fumarate. In addition, Alkermes is conducting the EVOLVE-MS-2 study in patients with RRMS, a five-week, head-to-head gastrointestinal (GI) tolerability study versus dimethyl fumarate.

About Diroximel Fumarate

Diroximel fumarate (BIIB098) is a novel oral fumarate candidate in development for the treatment of relapsing forms of MS. Diroximel fumarate is designed to rapidly convert to monomethyl fumarate in the body and may have the potential to offer differentiated GI tolerability due to its chemical structure as compared to dimethyl fumarate.

Alkermes and Biogen Announce U.S. Food and Drug Administration Acceptance of Diroximel Fumarate New Drug Application for Multiple Sclerosis

Bayer Completes Rolling Submission of NDA for Investigational Drug Darolutamide for the Treatment of Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

   

Bayer  announced the completion of the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the investigational drug darolutamide. The submission, which was initiated in December 2018, is based on data from the Phase III ARAMIS trial in men with non-metastatic castration-resistant prostate cancer (nmCRPC).1 These data were recently presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in San Francisco and published simultaneously in The New England Journal of Medicine.

"We are grateful to the patients, their families and the clinical investigators who have made this important study possible," said Scott Z. Fields, M.D., senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division. "The NDA submission is a key milestone bringing us closer to providing darolutamide as a potential treatment option for men with nmCRPC."

Bayer has been granted Fast Track designation by the FDA for darolutamide in men with nmCRPC. Bayer is also in discussions with other health authorities regarding a submission of darolutamide. The compound is being developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

About the ARAMIS Trial

The ARAMIS trial is a randomized, Phase III, multi-center, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral darolutamide in patients with nmCRPC who are currently being treated with androgen deprivation therapy (ADT) as standard of care and are at high risk for developing metastatic disease. 1,509 patients were randomized in a 2:1 ratio to receive 600 mg of darolutamide twice a day or placebo along with ADT.

The primary endpoint of this trial is metastasis-free survival (MFS) defined as time between randomization and evidence of metastasis or death. The secondary endpoints of this trial are overall survival (OS), time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first symptomatic skeletal event (SSE), and characterization of the safety and tolerability of darolutamide.

About Darolutamide

Darolutamide is an investigational, non-steroidal androgen receptor antagonist with a chemical structure that binds to the receptor and exhibits antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. A Phase 3 study in metastatic hormone-sensitive prostate cancer (ARASENS) is ongoing. Information about these trials can be found at www.clinicaltrials.gov.

Darolutamide is not approved by the U.S. FDA, the European Medicines Agency or any other health authority.

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

FDA Approves Lonsurf (trifluridine/tipiracil) for Adult Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

In continuation of my update on Lonsurf

Taiho Oncology, Inc.  announced that the United States Food and Drug Administration (FDA) has approved Lonsurf as a treatment for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

“The approval of Lonsurf represents a significant milestone for patients living with advanced gastric or GEJ adenocarcinoma who have limited effective treatment options after standard treatment options have failed,” said Timothy Whitten, President and Chief Executive Officer, Taiho Oncology, Inc. “We thank all the patients and physicians who helped make this possible through their participation in Lonsurf clinical trials.”

The approval for Lonsurf follows an FDA Priority Review designation and is based on data from a global, randomized, Phase III TAGS trial evaluating Lonsurf plus best supportive care (BSC) versus placebo plus BSC in patients with previously treated advanced gastric cancer or GEJ adenocarcinoma following progression or intolerance to previous lines of standard therapy. The trial met its primary and secondary endpoints demonstrating prolonged overall survival (OS) with Lonsurf versus placebo, and a safety profile consistent with prior experience with this drug. Full results from the TAGS trial were presented at the European Society of Medical Oncology (ESMO) 2018 Congress with a simultaneous publication in The Lancet Oncology.1

“Effective treatments for patients with heavily pretreated advanced gastric and GEJ cancer are limited,” said Martin Birkhofer, MD, Senior Vice President and Chief Medical Officer, Taiho Oncology, Inc. “By improving survival, Lonsurf may provide a significant impact on the lives of these patients.”

This approval expands the current indication for Lonsurf in the United States, where it is currently approved for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with standard chemotherapy, based on results obtained in the RECOURSE trial.

Ref : https://en.wikipedia.org/wiki/Trifluridine/tipiracil

FDA Approves Gloperba (colchicine) for Prophylaxis of Adult Gout Flares

ROMEG Therapeutics, an innovative drug development company focused on alternative formulations to better meet clinical and patient needs,  announced that the U.S. Food and Drug Administration (FDA) approved Gloperba (colchicine) Oral Solution, 0.6 mg/5 mL for prophylaxis of gout flares in adults. Gloperba is the first liquid formulation of colchicine approved by the FDA for the prophylaxis of gout flares.

“Existing therapies do not adequately address the physician’s need to adjust dosages of colchicine to manage the toxicity profile for patients with renal and liver impairments, side effects, common drug-to-drug interactions, and age-related health disorders. The approval of Gloperba addresses a significant unmet and underserved medical need.”

“Gloperba represents an important advancement for patients who are experiencing the recurring, painful effects of gout,” said Naomi Vishnupad, Ph.D., Chief Scientific Officer of ROMEG Therapeutics. “Existing therapies do not adequately address the physician’s need to adjust dosages of colchicine to manage the toxicity profile for patients with renal and liver impairments, side effects, common drug-to-drug interactions, and age-related health disorders. The approval of Gloperba addresses a significant unmet and underserved medical need.”

Gout is a form of arthritis affecting an estimated 8.7 million people in the United States. The current U.S. market for colchicine products is approximately $800 million. The disease is caused by elevated levels of uric acid in the bloodstream, and symptoms from the buildup of uric acid crystals in the joints include sudden, severe attacks of pain, swelling and redness, frequently at the base of the big toe. Gout can become chronic if left untreated.

Physicians have used colchicine to treat gout for decades, but they are often required to adjust the dose or interrupt treatment to address drug interactions or health conditions such as when patients are undergoing kidney dialysis. Compared with currently available capsule and tablet formulations of colchicine, the Gloperba oral solution allows physicians to easily make dosage adjustments for their patients. Gloperba is also beneficial for patients who cannot swallow solid doses or pills. About 15 percent of elderly patients have difficulty swallowing and therefore require liquid formulations.

Gloperba will be available at chain, independent and speciality pharmacies, long-term care facilities, and hospitals across the U.S. in summer 2019.

Ref: https://www.rxlist.com/gloperba-drug.htm#indications

AbbVie Announces New Drug Application Accepted for Priority Review by FDA for Upadacitinib for Treatment of Moderate to Severe Rheumatoid Arthritis

  

In continuation of my update on upadacitinib 

AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, has announced that the U.S. Food and Drug Administration (FDA) has accepted for priority review its New Drug Application (NDA) for upadacitinib for the treatment of adult patients with moderate to severe rheumatoid arthritis. Upadacitinib is an investigational once-daily oral JAK1-selective inhibitor being studied for multiple immune-mediated diseases.1-13 AbbVie anticipates a regulatory decision in Q3 2019.

The NDA is supported by data from the global upadacitinib SELECT Phase 3 rheumatoid arthritis program evaluating more than 4,000 patients with moderate to severe rheumatoid arthritis across five of six Phase 3 studies.3-7 In all SELECT Phase 3 studies, upadacitinib met all primary and ranked secondary endpoints. The most frequent serious adverse events were infections.3-7 Top-line results from these clinical studies were previously announced.

Upadacitinib is also under review by the European Medicines Agency for the treatment of adult patients with moderate to severe rheumatoid arthritis.

About the SELECT Study Program 

The robust SELECT Phase 3 rheumatoid arthritis program evaluates more than 4,900 patients with moderate to severe rheumatoid arthritis in six studies, five of which support regulatory submission for upadacitinib. The studies include assessments of efficacy, safety and tolerability across a broad range of rheumatoid arthritis patients. Key measures of efficacy evaluated include ACR responses, Disease Activity Score (DAS28-CRP) and inhibition of radiographic progression. More information on these trials can be found at www.clinicaltrials.gov (NCT02706847, NCT03086343, NCT02629159, NCT02706873, NCT02706951, NCT02675426).

About Upadacitinib

Discovered and developed by AbbVie, upadacitinib is an investigational oral, small molecule JAK1-selective inhibitor being studied for moderate to severe rheumatoid arthritis and other immune-mediated diseases.1-2 The FDA granted priority review for AbbVie's NDA for moderate to severe rheumatoid arthritis in Q1 2019. Phase 3 trials of upadacitinib in atopic dermatitis, psoriatic arthritis, Crohn's disease, and ulcerative colitis are ongoing and it is also being investigated to treat ankylosing spondylitis.9-13Upadacitinib is not approved and its safety and efficacy have not been evaluated by regulatory authorities.

Gilead Announces Topline Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)

Gilead Sciences, Inc. (Nasdaq: GILD) announced that STELLAR-4, a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib, an investigational, once-daily, oral inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in patients with compensated cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH), did not meet the pre-specified week 48 primary endpoint of a ≥ 1-stage histologic improvement in fibrosis without worsening of NASH.

 

In the study of 877 enrolled patients who received study drug, 14.4 percent of patients treated with selonsertib 18 mg (p=0.56 vs. placebo) and 12.5 percent of patients treated with selonsertib 6 mg (p=1.00) achieved a ≥ 1-stage improvement in fibrosis according to the NASH Clinical Research Network (CRN) classification without worsening of NASH after 48 weeks of treatment, compared with 12.8 percent of patients who received placebo. Selonsertib was generally well-tolerated and safety results were consistent with prior studies.

“While we are disappointed that the STELLAR-4 study did not achieve its primary endpoint, we remain committed to advancing therapies for patients with advanced fibrosis due to NASH, where there is a significant unmet need for effective and well-tolerated treatments. Gilead has a long-term commitment and proven track record of addressing significant challenges in the field of liver diseases. Data from this large study of patients with compensated cirrhosis due to NASH, including the extensive set of biomarkers collected, will further advance our understanding of the disease and inform our broader NASH development programs,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead. “We are grateful to the patients and investigators who participated in the STELLAR-4 study, and we now await the upcoming results from the Phase 3 STELLAR-3 trial of selonsertib in patients with bridging fibrosis (F3) due to NASH and the Phase 2 ATLAS combination trial of selonsertib, cilofexor (GS-9674) and firsocostat (GS-0976) in patients with advanced fibrosis due to NASH later this year.”

Further in-depth analysis of the findings is ongoing and the data will be submitted to an upcoming scientific conference. Gilead will work with the Data Monitoring Committee and investigators to conclude the STELLAR-4 study in a manner consistent with the best interests of each patient.

Selonsertib, cilofexor and firsocostat, alone or in combination, are investigational compounds and are not approved by the U.S. Food & Drug Administration (FDA) or any other regulatory authority. Safety and efficacy have not been established for these agents.

About Selonsertib and the STELLAR-4 Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

The STELLAR-4 study is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib in patients with compensated cirrhosis (F4) due to NASH. Eligible adults ages 18 to 70 years were randomized and received selonsertib 18 mg (n=354), selonsertib 6 mg (n=351) or placebo (n=172) for up to 240 weeks. Either selonsertib or placebo is being administered orally once daily. The primary endpoints of the study are a composite of the proportion of patients who achieve a ≥ 1-stage improvement in fibrosis according to the NASH CRN classification without worsening of NASH at week 48 and event-free survival at week 240 as assessed by time to the first clinical event. Further information about the clinical study can be found at www.clinicaltrials.gov.

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

Theravance Biopharma Announces First Patient Dosed in Registrational Phase 3 Study of Ampreloxetine (TD-9855) for the Treatment of Symptomatic Neurogenic Orthostatic Hypotension

 Theravance Biopharma, Inc. (NASDAQ: TBPH) ("Theravance Biopharma" or the "Company")  announced dosing of the first patient in a registrational Phase 3 clinical trial of ampreloxetine (TD-9855) in patients with symptomatic neurogenic orthostatic hypotension (nOH). Ampreloxetine is an investigational, once-daily norepinephrine reuptake inhibitor (NRI) in development for the treatment of patients with symptomatic nOH.

The Phase 3 study is a four-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety and tolerability of ampreloxetine in approximately 188 patients with symptomatic nOH caused by primary autonomic failure associated with multiple system atrophy (MSA), Parkinson's disease (PD) and pure autonomic failure (PAF). Patients will be randomized to receive a single 10 mg dose of ampreloxetine or placebo once daily for four weeks. The primary endpoint of the study is change from baseline in dizziness severity, as measured by Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 (OHSA #1, a measure of dizziness, lightheadedness or the sensation of being about to black out) at four weeks for ampreloxetine as compared to placebo. The study will evaluate additional efficacy assessments, as well as safety and tolerability measures.

"Given the limitations of currently available therapeutic options, we recognize a significant opportunity exists for a potentially safe and durable treatment for nOH. Positive four-week results achieved in our Phase 2 study provide the basis for advancing ampreloxetine into this registrational Phase 3 program," said Brett Haumann, MD, chief medical officer at Theravance Biopharma. "We are pleased to begin 2019 with this milestone, and in the near term we also anticipate dosing the first patient in the Phase 2b/3 study of TD-1473, our gut-selective JAK inhibitor, in patients with ulcerative colitis."

Theravance Biopharma previously announced positive four-week results from a Phase 2 clinical trial of ampreloxetine in patients with nOH. Findings showed that a majority of patients enrolled in the study's single ascending dose portion demonstrated durable improvements in nOH symptom severity as measured by OHSA #1. Patients treated in the extension phase of the study showed a mean symptom improvement of 2.4 points at four weeks. Importantly, mean symptom improvement was greatest (3.8 points) in nOH patients who reported dizziness symptoms (OHSA #1 > 4) at baseline, a pre-defined regulatory and clinical threshold that will be used to enroll patients in Phase 3. Additionally, ampreloxetine consistently increased systolic blood pressure (SBP), including clinically meaningful increases in standing SBP at the three-minute assessment at all time points on all weekly clinic visits. There were no drug-related serious adverse events reported, and ampreloxetine was generally well tolerated in the study.

http://www.dcchemicals.com/product_show-DC11076.html

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Theravance Biopharma Announces First Patient Dosed in Registrational Phase 3 Study of Ampreloxetine (TD-9855) for the Treatment of Symptomatic Neurogenic Orthostatic Hypotension 

FDA Orphan Drug Designation to Amplyx Pharmaceuticals for APX001 for Treatment of Cryptococcosis

Amplyx Pharmaceuticals, a company developing first-in-class products for life-threatening infections, announced  that the U.S. Food and Drug Administration (FDA) Office of Orphan Product Development has granted orphan drug designation to APX001, the company’s lead drug candidate, for treatment of cryptococcosis.

Orphan drug designation qualifies APX001 for seven years of market exclusivity in the U.S. upon FDA approval of a new drug application (NDA) for the orphan designated indications. APX001 had previously received orphan drug designation for the treatment of invasive candidiasis, invasive aspergillosis, coccidioidomycosis, and rare mold infections caused by Scedosporium spp., Fusarium spp., and Mucorales fungi (including Mucor spp., and Rhizopus spp.). In addition to orphan designations, FDA had previously granted Qualified Infectious Disease Product (QIDP) designation for APX001 for treatment of cryptococcosis, invasive candidiasis, invasive aspergillosis, and coccidioidomycosis. QIDP provides significant development incentives including eligibility for Fast Track designation, priority review and when combined with orphan drug designation, a total of twelve years of marketing exclusivity.

“Orphan and QIDP designations highlight the potential for APX001 to address unmet needs of patients with rare, life-threatening infections,” said Ciara Kennedy, Ph.D., President and Chief Executive Officer of Amplyx. “And with the FDA’s recent addition of cryptococcal meningitis to its list of neglected tropical diseases, Amplyx has the potential to obtain a valuable Tropical Disease Priority Review Voucher from the FDA, creating additional value for Amplyx and its stakeholders.”

Cryptococcosis is an infectious disease of the lungs or central nervous system (the brain or spinal cord) caused by the fungus Cryptococcus (either Cryptococcus neoformans or Cryptococcus gattii), which is typically found in the environment and inhaled. Brain infections due to the fungus Cryptococcus are called cryptococcal meningitis. Infection is most often seen in people with a weakened immune system, including those who are infected with HIV/AIDS, take high doses of corticosteroid medicines, have had an organ transplant, are receiving immune suppressing therapies for cancer or other diseases, or have Hodgkin’s disease.

“While antiretroviral therapy has successfully extended the lifespan of HIV patients, cryptococcal meningitis remains a leading cause of death in HIV patients, particularly in low and middle-income countries,” said Michael Hodges, MD, Chief Medical Officer of Amplyx. “The standard therapy of intravenous amphotericin B plus flucytosine requires inpatient hospitalization and has been known to cause significant side effects including anemia and kidney toxicity. APX001, Amplyx’s first-in-class antifungal agent, in combination with fluconazole, has the potential to be a transformational life-saving, once daily, all oral treatment for cryptococcal meningitis.”

http://www.probechem.com/products_APX001.aspx

Researchers find clues that depression may speed brain aging

In continuation of my updates on depression and its causes

Memory and thinking skills naturally slow with age but now scientists are peeking inside living brains to tell if depression might worsen that decline—and finding some worrisome clues. Depression has long been linked to certain cognitive problems, and depression late in life even may be a risk factor for the development of Alzheimer's. Yet how depression might harm cognition isn't clear.

One possibility: Brain cells communicate by firing messages across connections called synapses. Generally, good cognition is linked to more and stronger synapses. With cognitive impairment, those junctions gradually shrink and die off. But until recently, scientists could count synapses only in brain tissue collected after death.

Yale University scientists used a new technique to scan the brains of living people—and discovered that patients with depression had a lower density of synapses than healthy people the same age.

The lower the density, the more severe the depression symptoms, particularly problems with attention and loss of interest in previously pleasurable activities, Yale neuroscientist Irina Esterlis said Thursday at a meeting of the American Association for the Advancement of Science. She wasn't studying just seniors but a range of ages including people too young for any cognitive changes to be obvious outside of a brain scan—on the theory that early damage can build up.

"We think depression might be accelerating the normal aging," she said.

Her studies so far are small. To prove if depression really worsens that decline would require tracking synaptic density in larger numbers of people as they get older, to see if and how it fluctuates over time in those with and without depression, cautioned Jovier Evans, a staff scientist at the National Institute on Mental Health.

Esterlis is planning a larger study to do that. It's delicate research. Volunteers are injected with a radioactive substance that binds to a protein in the vesicles, or storage bins, used by synapses. Then during a PET scan, areas with synapses light up, allowing researchers to see how many are in different regions of the brain.

Esterlis said there are no medications that specifically target the underlying synapse damage.

But other brain experts said the preliminary findings are a reminder of how important it is to treat depression promptly, so people don't spend years suffering.

"If your mood isn't enough to make you go and get treated, then hopefully your cognition is," said Dr. Mary Sano, who directs the Mount Sinai Alzheimer's Disease Research Center in New York and wasn't involved in the new research.

Still, she cautioned that normal cognitive aging is a complicated process that involves other health problems, such as heart disease that slows blood flow in the brain. It might be that depression, rather than worsening synaptic decline, just makes it more obvious, Sano noted.

With depression "at any age, there's a hit on the brain. At an older age the hit may be more visible because there may already be some loss," she explained.

Indeed, another way the brain ages: The blood-brain barrier, which normally protects against infiltration of damaging substances, gradually breaks down, Daniela Kaufer of the University of California, Berkeley, told the AAAS meeting. That triggers inflammation, setting off a cascade that can cause cognitive impairment. Her lab found a specific molecular culprit and is developing, in studies with mice, a way to block the inflammatory damage.

The University of Toronto's Etienne Sibille is developing a compound to target yet another piece of the puzzle, brain receptors that are impaired with both aging and depression. Mouse studies showed it could reverse stress-induced memory loss, he said. Any human testing is at least several years away.

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Researchers find clues that depression may speed brain aging

Statins Help the Heart, No Matter What Your Age

Cholesterol-lowering statins are already known to help cut heart risks for seniors and the middle-aged. Now, research confirms the meds can also help people aged 75 and older.

"Statin therapy has been shown to prevent cardiovascular disease in a wide range of people, but there has been uncertainty about its efficacy and safety among older people," said lead investigator Anthony Keech. He's a professor of medicine, cardiology and epidemiology at the University of Sydney in Australia.

He and colleagues at the University of Oxford in England analyzed the findings of 28 large clinical trials of statins. The trials involved nearly 187,000 people in six age groups: younger than 55; 55 to 60; 60 to 65; 65 to 70; 70 to 75; and older than 75.

"Our study summarized all the available evidence from major trials to help clarify this issue. We found that there were significant reductions in major vascular events in each of the six age groups considered, including patients [who were] aged over 75 at the start of treatment," Keech said in an Oxford news release.

Major vascular events included heart attack, stroke and procedures to clear clogged arteries.

"Statin therapy appears to be just as effective in people aged over 75 years as it is in younger people," study co-investigator Jordan Fulcher said in the news release. Fulcher is a cardiovascular research fellow at the University of Sydney.

"We have definitive evidence that statins benefit older people who have suffered a heart attack or stroke. Fewer healthy older people were represented in these trials, so more information in this group of people would help confirm the same benefits that we see in our overall trials population," he said.

Fulcher noted that a new randomized trial in Australia is exploring whether statins prolong disability-free survival in a healthy population.

The risk of heart attacks and strokes rises sharply with age, yet statins are not used as widely in older people as they should be, study co-investigator Colin Baigent said in the news release. He's director of Oxford's Medical Research Council Population Health Research Unit.

"Since the risk of heart attack and stroke increases with age, the potential benefits are likely to be even greater for older people," he said.

"Therefore, there is a need to ensure that patients at risk of cardiovascular disease due to their age are offered statin therapy where there is good reason to believe that it will be beneficial," Baigent said.

Anyone with concerns about whether statin therapy is right for them should discuss it with their health care provider, he added.

Sunovion Receives Complete Response Letter from FDA for Apomorphine Sublingual Film (APL-130277)

 Sunovion Pharmaceuticals Inc. (Sunovion) announced today that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) for the New Drug Application (NDA) for apomorphine sublingual film (APL-130277) to treat OFF episodes (the re-emergence or worsening of Parkinson’s symptoms otherwise controlled by medications) experienced by people living with Parkinson’s disease (PD).

Upon review of the application, the FDA determined that it was unable to approve the apomorphine sublingual film NDA in its present form. The Agency requested additional information and analyses, but no new clinical studies are required.

“OFF episodes are a common and challenging part of Parkinson’s disease with few existing treatment options,” said Antony Loebel, M.D., Executive Vice President and Chief Medical Officer at Sunovion, Head of Global Clinical Development for Sumitomo Dainippon Pharma Group. “Sunovion remains committed to working with the FDA to address its requests so that we can bring apomorphine sublingual film to patients as expeditiously as possible.”

About Apomorphine Sublingual Film (APL-130277)

APL-130277, a novel formulation of apomorphine and a dopamine agonist, is being developed for the on-demand management of OFF episodes associated with Parkinson’s disease (PD). Apomorphine is currently FDA approved for the acute, intermittent treatment of hypomobility, “OFF” episodes (“end-of-dose wearing OFF” and unpredictable “ON/OFF” episodes) associated with advanced PD, and it is currently available in the U.S. as a subcutaneous injection. APL-130277 is intended to rapidly convert people living with PD from the OFF to the ON state and has been studied for treatment of motor OFF episodes up to five times per day and no sooner than two hours from the previous dose. APL-130277 has not been approved by the FDA. In October 2016, Sunovion acquired Cynapsus Therapeutics Inc. along with its product candidate APL-130277. The Michael J. Fox Foundation funded in part two Phase I trials of APL-130277 – a comparative biostudy in healthy volunteers and a dosing study in people with Parkinson's disease.

Alkermes Receives Complete Response Letter From U.S. Food and Drug Administration for ALKS 5461 New Drug Application

In continuation f my update on ALKS 5461

 Alkermes plc (Nasdaq: ALKS) announced that it received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for ALKS 5461 for the adjunctive treatment of major depressive disorder (MDD). 

The CRL states that the FDA is unable to approve the ALKS 5461 NDA in its present form and is requesting additional clinical data to provide substantial evidence of effectiveness of ALKS 5461 for the adjunctive treatment of MDD. Alkermes plans to meet with the FDA to discuss the contents of the CRL and potential next steps for ALKS 5461. This interaction with the Agency will inform whether there is a viable path forward for the ALKS 5461 program.

The NDA submission for ALKS 5461 was based on results from a clinical efficacy and safety package with data from more than 30 clinical trials and more than 1,500 patients with MDD. Throughout the clinical development program, ALKS 5461 demonstrated a consistent profile of antidepressant activity, safety and tolerability in the adjunctive treatment of MDD.

About ALKS 5461

ALKS 5461 is a proprietary, investigational, once-daily oral medicine that acts as an opioid system modulator and represents a novel mechanism of action for the adjunctive treatment of major depressive disorder (MDD) in patients with an inadequate response to standard antidepressant therapies. ALKS 5461 is a fixed-dose combination of buprenorphine, a partial mu-opioid receptor agonist and kappa-opioid receptor antagonist, and samidorphan, a mu-opioid receptor antagonist.

About Major Depressive Disorder (MDD)

According to the DSM-5® (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), major depressive disorder (MDD) is a condition in which patients exhibit depressive symptoms, such as a depressed mood or a loss of interest or pleasure in daily activities consistently for at least a two-week period, and demonstrate impaired social, occupational, educational or other important functioning. An estimated 16.2 million people in the U.S. suffered from MDD in 2016,1 the majority of whom may not adequately respond to initial antidepressant therapy.

https://en.wikipedia.org/wiki/Buprenorphine/samidorphan

Alkermes Receives Complete Response Letter From U.S. Food and Drug Administration for ALKS 5461 New Drug Application

SK Life Science Announces FDA Acceptance of NDA Submission for Cenobamate, an Investigational Antiepileptic Drug

  SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals Co., Ltd., an innovative biopharmaceutical company focused on developing and bringing to market treatments for central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has accepted the filing of its New Drug Application (NDA) for cenobamate. Cenobamate, an investigational antiepileptic drug for the potential treatment of partial-onset seizures in adult patients, is the first molecule discovered and developed from inception through to the submission of an NDA without partnering or out-licensing from a Korean pharmaceutical company. SK life science plans to commercialize cenobamate independently.

The NDA submission is based on data from pivotal trials that evaluated the efficacy and safety of cenobamate. Results from the clinical trial program, which enrolled more than 1,900 patients, have been presented at medical conferences including the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) Annual Meetings.

"The FDA's acceptance of our NDA filing is a critical step toward our goal of introducing a new treatment option for people with uncontrolled epilepsy," said Marc Kamin, M.D., chief medical officer at SK life science. "We look forward to working with the FDA during their review of our data on cenobamate."

Despite the availability and introduction of many new AEDs, overall treatment outcomes for people with epilepsy have not improved in 20 years1 and the CDC states that nearly 60 percent of people with epilepsy are still experiencing seizures, showcasing a great unmet need for patients and their families.2Additionally, while some patients may experience a reduction in seizure frequency with current treatments, they continue to live with seizures.2 The impact of continued seizures can be debilitating and life-altering and the complications of epilepsy can include depression and anxiety, cognitive impairment and SUDEP (sudden unexpected death in epilepsy)

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

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SK Life Science Announces FDA Acceptance of NDA Submission for Cenobamate, an Investigational Antiepileptic Drug