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

Pain Therapeutics Announces Feedback from Recent Meeting With FDA on Remoxy

     

In continuation of my update on Remoxy ER (oxycodone)

Pain Therapeutics, Inc. (Nasdaq: PTIE), a clinical-stage drug development company, today announced feedback from a meeting held January 31, 2019 with the U.S. Food and Drug Administration (FDA) regarding the drug candidate, Remoxy ER.  Remoxy is the trade name for a new type of abuse-deterrent, extended-release gel formulation of oxycodone (CII) with physical/chemical properties intended to deter abuse.  As previously disclosed, we requested this meeting to resolve disagreement around comments and conclusions made by FDA in 2018 during a regulatory review of a New Drug Application (NDA) for Remoxy.

During this meeting, we learned that i) FDA denies making math errors, material mistakes or misrepresentations during a June 2018 Advisory Committee Meeting for Remoxy, despite clear evidence to the contrary; ii) comparator data is irrelevant for the evaluation of abuse-deterrent properties, despite FDA written guidance which explicitly states the opposite; and (ii) that we would need to rely on the Freedom of Information Act to access additional data generated by FDA with Remoxy.  As a result of our recent meeting with FDA, we believe we are no closer today to product approval than we were over a year ago.

“Remoxy remains an odyssey without a homecoming,” said Remi Barbier, President & CEO of Pain Therapeutics. “We had hoped for a fair, neutral and impartial review of the Remoxy data. Instead, we walked out of this meeting feeling a bit disoriented by FDA’s lack of transparency, clarity or helpfulness.  It’s a rare occasion when two parties can’t agree on simple math.  We can’t work with shambolic regulations.  This is not how you win support for innovation.”

Historically, the lead candidate in our pipeline has been Remoxy, an analgesic drug that we conceived, patented, developed and tested in collaboration with corporate and academic partners.  Over the years, we have conducted a successful clinical development program for Remoxy, including a large, well-controlled pivotal Phase III efficacy study whose primary endpoints met statistical significance (p<0.05).  The clinical safety or analgesic efficacy of Remoxy for its intended purpose is not in question. Its abuse-deterrent properties, however, are subject of a difference of opinion.  Abuse deterrence refers to properties that are embedded into an opioid formulation to prevent certain common methods of abuse. During the long development history of Remoxy, we generated nearly 9,000 unique data points in over 50 studies at a cost in excess of $100 million.  Studies were designed in consultation with FDA and conducted by independent labs.  Collectively, we believe these studies adequately characterize Remoxy’s abuse-deterrent properties. In particular, we demonstrated that the two currently marketed extended-release oxycodone products -- OxyContin® and Xtampza® -- which both benefit from abuse-deterrent label claims, can both be defeated for purposes of abuse in under a minute using common household items.  In contrast, Remoxy requires a significant investment of time, effort and equipment to defeat, and even then, results in less release of oxycodone.  During our recent meeting with FDA we were informed they believe Remoxy capsules lack abuse deterrence via the injection route of abuse because “oxycodone can be extracted from the product”, regardless of how much time, effort, frustration or equipment is required to so do. We are unable to follow the logic by which a drug product should never release drug. More generally, as the regulatory requirements for Remoxy have changed frequently and suddenly over time, we have experienced significant delays and have incurred unanticipated expenses related to the overall Remoxy development program.

-more-

We believe innovative products such as Remoxy can serve a meaningful social purpose and, potentially, may save lives during the worst drug crisis in American history.  By necessity, however, we rely on reasonably predictive regulatory pathways to guide our product candidates through development in preparation for commercialization.  We also rely on principles of good governance, in which similar drugs receive similar regulatory treatment under rules that are clear, publicized, and evenly applied.  In our experience with Remoxy, the regulatory environment around abuse-deterrence lacks these essential qualities.

There are procedures in place at the FDA and other government agencies to help promote a fair resolution of disputes.  Such procedures can be complex and may not be rapid, predictable or even viable.  Going forward, we will generally be silent regarding our plans or future expectations for Remoxy, unless a significant material event occurs that compels us to update our public disclosures around this product candidate.

https://www.drugbank.ca/drugs/DB00497

https://medlineplus.gov/druginfo/meds/a682132.html

Pain Therapeutics Announces Feedback from Recent Meeting With FDA on Remoxy

FDA Grants Priority Review for Daiichi Sankyo’s New Drug Application for CSF1R Inhibitor Pexidartinib for Treatment of Patients with TGCT, a Rare, Debilitating Tumor

  

Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced that the U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) and granted Priority Review for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery.  TGCT, also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a non-malignant tumor of the joint or tendon sheath, which can be locally aggressive and debilitating in some patients. There are no currently approved systemic therapies for TGCT.

A Priority Review designation is granted by the FDA to drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. Under Priority Review, the FDA aims to take action on an application within six months, as compared to ten months under standard review. The FDA has designated August 3, 2019 as the PDUFA Action date for this application. 

On January 31, 2019, the American Society of Clinical Oncology (ASCO) recognized “Progress in Treating Rare Cancers” as the “Advance of the Year”, and selected pexidartinib as one of five significant advancements in rare disease treatment, calling it the first promising investigational therapy for TGCT.

The NDA is based on results of the pivotal phase 3 ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT. Results of the phase 3 ENLIVEN study were presented during an oral presentation at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.

“We are pleased to announce that the FDA has accepted our application for pexidartinib with Priority Review designation, potentially bringing a treatment option to patients for whom there is no approved therapy,” said Dale Shuster, Ph.D., Executive Director, Global Oncology R&D, Daiichi Sankyo. “Current treatment options for TGCT are largely limited to surgery, but for some patients the disease is debilitating and not amenable to improvement with surgery. We are committed to working with the FDA to potentially bring pexidartinib to carefully-selected patients as soon as possible.”

“We are excited about the first-in-class potential of pexidartinib, another targeted therapy discovered by Plexxikon,” said Gideon Bollag, Ph.D., Chief Executive Officer of Plexxikon Inc., Daiichi Sankyo’s small molecule structure-guided R&D center in Berkeley, CA and a member of the Daiichi Sankyo Group. “Our drug discovery process uses structural data and a specialized scaffold-like screening library to identify and optimize novel drug candidates.”

ENLIVEN is a pivotal, double-blind, randomized, global multi-center phase 3 study that evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness and measures of pain reduction.

The ENLIVEN study met its primary endpoint of overall response rate. In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3X ULN: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

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

Zogenix Submits New Drug Application to U.S. Food & Drug Administration for Fintepla for the Treatment of Dravet Syndrome

     

Zogenix, Inc. (NASDAQ:ZGNX), a global pharmaceutical company developing rare disease therapies,  announced it has completed its rolling submission of a New Drug Application (NDA) to the U.S. Food & Drug Administration (FDA) and submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Fintepla (ZX008, low-dose fenfluramine) for the treatment of seizures associated with Dravet syndrome. Dravet syndrome is an intractable and difficult-to-treat epilepsy that begins in infancy and is associated with frequent, severe, and potentially life-threatening seizures, developmental delay, and cognitive impairment.

Both applications are based on data from two pivotal Phase 3 trials in Dravet syndrome and an interim analysis from an ongoing open-label extension study, which included 232 patients treated for up to 21 months.

“Our concurrent submissions to the FDA and EMA are the culmination of four years’ effort for Zogenix, our investigators, and the families who participated in the ZX008 clinical trial program,” said Stephen J. Farr, President and Chief Executive Officer of Zogenix. “We are honored to have partnered with such dedicated people to develop a potential new treatment for this rare and often catastrophic disease and look forward to working closely with the FDA and EMA during the review process.”

Zogenix is also investigating Fintepla in Lennox-Gastaut syndrome, another rare childhood-onset epilepsy, for which a Phase 3 trial is ongoing.

About Dravet Syndrome

Dravet syndrome is a rare form of intractable (treatment-resistant) epilepsy that begins in infancy and is associated with frequent, severe, and potentially life-threatening seizures, developmental delay, cognitive impairment, and an elevated risk of sudden unexplained death in epilepsy (SUDEP).i,ii  Early estimates on the incidence of Dravet syndrome ranged from one in 20,000 to one in 40,000; however more recent research suggests the incidence may be as frequent as one in 15,700.iii The disease also has an impact on the entire family, often resulting in substantial financial, physical, psychosocial and emotional burdens. 

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

Zogenix Submits New Drug Application to U.S. Food & Drug Administration for Fintepla for the Treatment of Dravet Syndrome

Latest anti-retroviral drug therapies offer powerful solution for HIV infection-associated frailty

In continuation of my update on anti-retroviral drug

 reatment of the HIV/AIDS epidemic has seen remarkable advancements with the advent of the latest anti-retroviral drug therapy and powerful tools to test for drug resistance, making the infection almost "undetectable" in patients who strictly comply with their medication therapy, a just-published perspective article by a clinical team at the University of Arizona College of Medicine - Tucson points out.

Lead author Stephen A. Klotz, MD, professor in the Division of Infectious Diseases in the UA Department of Medicine, adds that in the past, HIV/AIDS patients often suffered from extreme frailty, in effect, often "aging 10 to 15 years" in appearance and function.

But the article, HIV Infection-Associated Frailty: The Solution for Now is Antiretroviral Drugs, published Feb. 25, 2019 in the Journal of the International Association of AIDS Care Providers, notes frailty related to HIV infection is "rapidly becoming a specter of the past." Further, thanks to the new treatments, disfiguring lipodystrophy (changes in body fat that affect some patients) is "a grim historical footnote to the HIV epidemic" in the United States," the authors add.

"We have shown that years of anti-retroviral therapy can return patients to a non-frail state. In addition, prolonged anti-retroviral therapy restores cellular function and numbers of cells adversely affected by HIV," Dr. Klotz says. "Recently we demonstrated a marked improvement in aging markers in HIV patients on long-term anti-retroviral drug therapy."

The team also has employed another major advancement in the treatment of HIV/AIDS: A "Frailty Meter," developed by Bijan Najafi, PhD, MSc, then a professor in the UA Department of Surgery and director of the Consortium on Advanced Motion Performance.

The device now allows clinicians to measure HIV/AIDS patients' frailty in a matter of seconds - whereas in the past frailty measurements often required several clinic visits.

The Frailty Meter detects frailty through a small, Bluetooth-supported motion sensor that attaches to the subject's wrist. In about 20 seconds, it measures subjects' elbow flexes (similar to arm curls) to accurately determine their frailty. (Dr. Najafi now is a professor of surgery and director of clinical research, Division of Vascular Surgery, Baylor College of Medicine.)

Another major clinical advancement is the ability today to cure the hepatitis C virus infection, which in the past commonly was associated with HIV/AIDS infection, Dr. Klotz points out. "So this other viral scourge is decreasing in prevalence, not only in the general public, but in our HIV patients as well."

Remarkably, today, patients with HIV take a single anti-retroviral pill (which contains three medications) once a day, "with virtually no side effects," Dr. Klotz says, noting in the early 1980s, patients might have taken nearly 20 pills a day, with many suffering severe side effects.

In related research led by co-authors Nicole Bradley, PhD, a postdoctoral research associate in the UA Department of Immunobiology and Nafees Ahmad, PhD, professor in the UA Department of Immunobiology and a member of the UA Cancer Center, the team also is studying specific immune aging markers in HIV patients "and once again is finding improvement in infected patients on continuous long-term anti-retroviral therapy," according to the article.

Co-author Shannon Smith, MBA, manages the Petersen Clinics, part of the UA Department of Medicine's Division of Infectious Diseases. In collaboration with Banner - University Medicine, Petersen Clinics provides clinical care for people living with, or at risk for, HIV. The program provides outpatient care at affordable prices for HIV-infected adults, plus testing, education and counseling services to patients and their families. The program provides biomedical interventions for people at risk for HIV, including Pre-Exposure Prophylaxis (PrEP) and Non-Occupational Post-Exposure Prophylaxis (nPEP), Smith says. The Petersen Clinics uses a multi-disciplinary team approach to provide patients comprehensive HIV specialty care and is comprised of infectious disease specialists, pharmacists, clinical coordinators, medical case managers and early interventionists.

"We're very proud of the scope of services we provide," Smith says. "We're very creative in ensuring our patients and families obtain the care they need."

Ref : https://opa.uahs.arizona.edu/newsroom/news/2019/latest-anti-retroviral-drug-regimens-provide-lazarus-effect-hiv-patients

Latest anti-retroviral drug therapies offer powerful solution for HIV infection-associated frailty

FDA Advisory Committee Recommends Approval of Spravato (esketamine) Nasal Spray for Adults with Treatment-Resistant Depression

  

 The Janssen Pharmaceutical Companies of Johnson & Johnson  announced that the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee jointly voted (14 yes, 2 no, 1 abstain) that data support the favorable benefit-risk profile of Spravato (esketamine) nasal spray CIII for adults living with treatment-resistant depression. Spravato is an investigational prescription treatment that is thought to work differently than currently approved therapies for major depressive disorder (MDD). Janssen announced on September 4, 2018 that it submitted a New Drug Application (NDA) to the FDA for the approval of Spravato.1 If approved, Spravato would provide the first new mechanism of action in 30 years to treat this debilitating mental illness.2,3

“We are pleased with the advisory committees’ vote and their recommendation to approve Spravato as a potential therapy for adults living with treatment-resistant depression,” said Husseini K. Manji, M.D., Global Head, Neuroscience Therapeutic Area, Janssen Research & Development, LLC. “Our comprehensive research program for esketamine nasal spray supports a positive benefit-risk profile for adults with treatment-resistant depression.”

The committees based their support on the safety and efficacy data from five Phase 3 studies in patients with treatment-resistant depression: three short-term studies; one maintenance of effect study; and one long-term safety study. In addition, the Spravato research program provided supportive data from three Phase 2 studies and 19 Phase 1 studies in patients with treatment-resistant depression and healthy volunteers. Data from both a short-term Phase 3 study and a long-term Phase 3 study demonstrated that esketamine nasal spray plus a newly initiated oral antidepressant provided statistically significant, clinically meaningful, rapid, and sustained improvement of depressive symptoms in this difficult-to-treat population.4,5 All the patients who participated in the Phase 3 studies received esketamine or placebo in addition to a newly initiated oral antidepressant at the start of the treatment phase.

The long-term safety study showed that esketamine was generally tolerable, with no new safety signals with dosing up to 52 weeks compared to data from short-term (4-week) studies.6 Discontinuation rates due to esketamine-related adverse events were low and occurred typically in the first weeks. Most treatment-emergent adverse events, including dissociative symptoms, dizziness/vertigo, increased blood pressure, and sedation, occurred shortly after dosing while patients were under the supervision of a health care professional, were transient, and resolved the same day. In addition to the comprehensive clinical research program, the company proposed a robust Risk Evaluation and Mitigation Strategy (REMS).

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

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FDA Advisory Committee Recommends Approval of Spravato (esketamine) Nasal Spray for Adults with Treatment-Resistant Depression

FDA Approves Wixela Inhub (fluticasone propionate and salmeterol inhalation powder, USP), First Generic of Advair Diskus

In continuation of my updates on fluticasone propionate & salmeterol

              

Mylan N.V. (NASDAQ: MYL)  announced the U.S. Food and Drug Administration (FDA) approval of Wixela Inhub (fluticasone propionate and salmeterol inhalation powder, USP), the first generic of Advair Diskus.

Wixela Inhub will launch in the second half of February incorporating the latest safety information required by FDA earlier this month, which prompted an amendment to the label for certain inhaled corticosteroids, including Advair Diskus and any generic versions. Wixela Inhub will be available in the 100 mcg/50 mcg, 250 mcg/50 mcg and 500 mcg/50 mcg strengths for asthma patients and the 250 mcg/50 mcg strength for COPD patients.

Mylan CEO Heather Bresch commented, "Mylan remains steadfast in its efforts to expand patient access to medicines, and the FDA approval of Wixela Inhub reinforces our commitment to provide patients greater choice and lower-cost alternatives. This milestone represents the culmination of an extensive research and development program and Mylan's more than $700 million of investment. We're proud of our Wixela Inhub team, who worked tirelessly and in close collaboration with the FDA to bring this important medicine to market and add it to our growing global portfolio of more than 700 respiratory products. As one of the leading providers of prescription medicines in the U.S., we continue to execute on our mission and do our part to reduce costs for patients and identify pathways that help increase sustainability for the U.S. healthcare system overall."

Wixela Inhub is indicated for the twice daily treatment of asthma in patients age 4 and older not adequately controlled on long-term asthma control medications or whose disease warrants initiation of treatment with both inhaled corticosteroids and long-acting beta agonists; maintenance treatment of COPD; and the reduction of COPD exacerbations in patients with a history of exacerbations. It is not indicated for the relief of acute bronchospasm.

Mylan President Rajiv Malik added, "We're pleased to offer the first FDA-approved generic of Advair Diskus, one of the leading treatments for asthma and COPD management today. We've long been confident in the science around this product and are proud of the dedication of our scientific teams to bring Wixela Inhub to market. This complex product required a rigorous research and development program spanning over a decade and close collaboration with FDA to define the regulatory pathway. We also are proud to manufacture Wixela Inhub in our own state-of-the-art plant. This approval reinforces our ongoing commitment to increase access to more affordable treatment options for patients."

The research and development program for Wixela Inhub compared all strengths of treatment to Advair Diskus in order to meet the FDA requirements of therapeutic equivalence for a substitutable generic. In the 28-day, randomized, double-blind, placebo-controlled, parallel group study of 1,128 adult asthma patients conducted to evaluate the local (lung) bioequivalence of Wixela Inhub 100 mcg/50 mcg and ADVAIR DISKUS 100 mcg/50 mcg, the two treatments produced equivalent efficacy. Both treatments were safe and well-tolerated with lower numbers of withdrawals due to asthma compared to the placebo group. The study included both naive and current users of Advair Diskus.

"Patients enrolled in clinical trials found Wixela Inhub easy-to-use and highly effective at controlling their asthma in a clinical bioequivalence study. Asthma and respiratory specialists and primary care providers welcome this generic alternative to benefit many patients with asthma and COPD.  We have waited for years for generic inhalers to emerge in respiratory medicine," said Edward Kerwin, MD of Crisor LLC, a division of the Clinical Research Institute located in Medford, Ore. and a Clinical Investigator on the Wixela Inhub clinical program.

Advair Diskus had U.S. sales of $4.2 billion for the 12 months ending November 30, 2018, according to IQVIA.

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

https://www.drugbank.ca/drugs/DB00588

FDA Approves Egaten (triclabendazole) for the Treatment of Fascioliasis, a Neglected Tropical Disease

Novartis announced that the US Food and Drug Administration (FDA) has approved Egaten (triclabendazole) for the treatment of fascioliasis in patients six years of age and older. This makes Egaten the only FDA-approved drug for people with this disease and is expected to facilitate broader access to this important drug not only in the US, but also in affected countries worldwide.

"Novartis has a long-standing commitment to addressing global health challenges and supporting disease elimination efforts, in diseases such as leprosy, malaria and fascioliasis," said Vas Narasimhan, CEO of Novartis. "Today's FDA approval of Egaten is another important milestone that we believe will help further expand access to this one-day treatment, taking us a step closer toward disease elimination."

Fascioliasis, commonly known as liver fluke infestation, is a neglected tropical disease that infects 2.4 million people worldwide[1], with an additional 180 million at risk of infection[2]. It is caused by two species of parasitic flatworms that can infect humans following ingestion of larvae in contaminated water or food.

Egaten is currently the only medicine for fascioliasis recommended by the WHO and is on the WHO Model List of Essential Medicines. It is supplied by WHO during epidemic outbreaks and for periodic use in endemic countries. FDA approval of Egaten is expected to facilitate drug licensing and import to these countries, helping ensure sufficient and prompt availability of the drug when needed. Fascioliasis is recognized by the FDA as a neglected tropical disease, triggering the award of a Priority Review Voucher based upon this approval.

Novartis has been donating Egaten to the WHO since 2005, helping to treat around 2 million fascioliasis patients in more than 30 countries. In 2018, we renewed our agreement with the WHO to extend the drug donation until 2022, expected to reach 300 000 patients per year.

"This FDA decision is welcome news for millions who suffer or are at risk of fascioliasis and removes a major hurdle in expanding treatment to countries where it is most needed," said Dr Mwelecela Malecela, Director of the Department of Control of Neglected Tropical Diseases at the WHO. "We are thankful to Novartis for their sustained decade-long commitment in tackling yet another disease of poverty."

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

PTSD Drug, Prazosin, May Do More Harm Than Good

In continuation of my update on prazosin

A drug used to treat post-traumatic stress disorder (PTSD) may actually be harmful, a new study suggests.

The high blood pressure drug prazosin is sometimes used to treat PTSD-related nightmares and insomnia that can increase suicide risk. But this small study suggests the drug may make nightmares and insomnia worse and not reduce suicidal thoughts in PTSD patients.

"I think we have to view this as not the final word on this, but it raises questions," said study author Dr. W. Vaughn McCall. He's chairman of psychiatry and health behavior at the Medical College of Georgia.

The study included 20 PTSD patients, including two military veterans and several civilian women who had been sexually assaulted. All had active suicidal thoughts, some had previously attempted suicide, and most were taking antidepressants and/or had them prescribed for the study.

For eight weeks, participants took prazosin at bedtime with an aim of preventing nightmares and suicidal thoughts. They were assessed weekly for severity of suicidal thoughts, nightmares, insomnia, depression and PTSD.

The drug "did not seem to do much for suicidal ideation and that was somewhat disappointing, but the thing what was mind-blowing was that it actually worsened nightmares," McCall said in a university news release. "Maybe it's not for everybody."

The unexpected increase in nightmares and insomnia might owe to the severity of a patient's PTSD or the once-a-day dose of prazosin, he said.

PTSD patients' nightmares often focus on the trauma that caused their PTSD, he said.

Two patients required emergency inpatient psychiatric care, but there were no suicide attempts or deaths during the study, which was published recently in the Journal of Clinical Psychopharmacology.

Prazosin may help some PSTD patients, but may not be a good choice when suicide is an active concern, according to McCall, who is now seeking input from PTSD experts across the United States

Two larger studies in active and retired military personnel yielded mixed results as well, he noted.

"We need to reconcile how is it that we had 10 years of data saying prazosin is good for nightmares in PTSD, a big study this February indicating it has essentially no [effect] and now a smaller study showing it can worsen some aspects," McCall said. "We need to know what it all means."

The antidepressants sertraline (Zoloft) and paroxetine (Paxil) are the only U.S. Food and Drug Administration-approved PTSD drug therapies, he said, adding that neither is widely effective.

Ref: https://journals.lww.com/psychopharmacology/Abstract/2018/12000/A_Pilot,_Randomized_Clinical_Trial_of_Bedtime.15.aspx

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Animal Study Suggests Ritalin Won't Harm the Heart

    

In continuation of my update on Ritalin 

Ritalin, a widely used stimulant drug to treat attention-deficit/hyperactivity disorder (ADHD), likely poses no risk of heart damage in children, new research in monkeys suggests.

The findings are "very reassuring," said the study's principal investigator, Dr. Steven Lipshultz.

Each year, more than 1.8 million children in the United States take drugs to treat ADHD. Concerns have been raised that Ritalin, Concerta and other forms of methylphenidate could harm children's hearts.

Some studies have reported an increase in sudden cardiac death among children taking methylphenidate or other stimulant drugs for ADHD.

But this new study found that five years of high doses of methylphenidate did not damage the hearts of 30 rhesus monkeys. That length of time is similar to how long children and adults would use the drugs.

"Even high-dose chronic [methylphenidate] stimulant therapy did not result in any evidence of abnormal structures or function in the hearts of the monkeys," said Lipshultz, chair of pediatrics at the University at Buffalo School of Medicine and Biomedical Sciences, in New York.

However, his team cautioned that the results of animal research are not automatically applicable to humans.

One ADHD specialist unconnected to the study agreed.

"The [animal] study cannot be automatically applicable to humans," said Dr. Victor Fornari, who directs child and adolescent psychiatry at Zucker Hillside Hospital in Glen Oaks, N.Y.

Still, the findings "provide compelling evidence of the cardiac safety of this important evidence-based treatment for ADHD," Fornari said.

About 10 percent of U.S. children have been diagnosed with ADHD and related disorders. Up to 70 percent of them take prescription stimulant drugs, so possible heart risks associated with the drugs are a major concern, study author Lipshultz said in a university news release.

The U.S. Food and Drug Administration has ordered some prescription stimulants to carry black box warnings stating that children with underlying heart disease should use these medications with caution.

In Canada, a stimulant drug was removed from the market after it was linked to a small number of sudden cardiac deaths. Sales of the drug later resumed.

"This controversy has persisted without answer," Lipshultz said. "Yet the number of prescriptions for these medications for children with ADHD continues to expand."

Another expert said the new findings should help ease concerns.

The study results "are overall re-assuring in terms of cardiac safety and long-term use of stimulants for ADHD in otherwise healthy individuals," said Dr. Andrew Adesman, chief of developmental and behavioral pediatrics at Cohen Children's Medical Center in New Hyde Park, N.Y.

However, he added that the study "does not address clinical concerns about the safety of stimulants in individuals with certain types of heart disease."

Therefore, "health care providers need to continue to screen children for cardiac problems prior to prescribing stimulant medications like Ritalin, Concerta or Adderall, since there are some individuals who may still be at increased risk for potentially serious heart problems if treated with stimulant medication," Adesman said.

Lipshultz noted that the findings are good news for another type of pediatric patient: young cancer survivors.

"I have cared for children and adolescents who have survived childhood cancer, who now are experiencing severe learning disabilities as a result of their cancer therapies. They become my patients because their hearts have been damaged, an unfortunate effect of the successful treatment of their childhood cancer," he said.

"Current recommendations state that children such as these, with underlying heart disease, should avoid chronic stimulant therapy because of the concern that it could further damage their hearts," he explained. "However, these prescription stimulants often allow these children to do much better with their learning progress."

The new findings suggest that, in many cases, these medications can be prescribed to these children as well, Lipshultz said.