Dapagliflozin (FARXIGA): Reduction in Albuminuria Cannot Be Predicted by Clinical Characteristics

MedicalResearch.com Interview with:

Dr-Danilo Verge.png

Dr. Verge

Danilo Verge MD MBA
Vice President, CVRM Global Medical Affairs
AstraZeneca

MedicalResearch.com: What is the background for this study?

Response: Dapagliflozin, an SGLT2 inhibitor (sodium-glucose co-transporter 2), has been shown to improve glycemic control by decreasing glucose reabsorption in the kidneys and inducing urinary glucose clearance. SGLT2 inhibitors have also been shown to be effective in lowering albuminuria and stabilizing eGFR (estimated glomerular filtration rate). The effect of dapagliflozin on UACR (urine albumin-to-creatinine ratio) has been shown to vary among patients.

The objective of this post-hoc analysis, based on the pooled data from 11 randomized, placebo-controlled clinical trials, was to assess baseline characteristics and concurrent changes in cardiovascular (CV) risk markers associated with UACR response to dapagliflozin.

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Real-World Dosing of RAASi are Associated With Risk of Adverse Events in CKD

MedicalResearch.com Interview with:

Lei Qin

Lei Qin

Lei Qin MS
Director, Health Economics and Payer Analytics
AstraZeneca

MedicalResearch.com: What is the background for this study?

Response: Renin-angiotensin-aldosterone system inhibitors (RAASi) are guideline-recommended therapies for patients with chronic kidney disease (CKD), but are commonly prescribed at suboptimal doses, which has been associated with worsening clinical outcomes. The objective of our study was to estimate the real-world associations between RAASi dose and adverse clinical outcomes in patients prescribed RAASi therapies with new-onset CKD in the UK.

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LOKELMA (Sodium zirconium cyclosilicate) for Elevated Potassium: Results of the HARMONIZE GLOBAL Study

MedicalResearch.com Interview with:

Rahul Agrawal MD PhD VP, Global Medicines Leader AstraZeneca

Dr. Agrawal

Rahul Agrawal MD PhD
VP, Global Medicines Leader
AstraZeneca

MedicalResearch.com: What is the background for this study?  

About the study: HARMONIZE Global is a Phase III, randomized, multicenter, double-blind, placebo-controlled trial involving 267 patients with hyperkalemia (mean potassium levels greater than 5.0 mEq/L) in 47 study locations across the Asia Pacific region, which will support registration in Japan, Taiwan, Korea and Russia.

Study design: The trial design of HARMONIZE Global is similar to HARMONIZE (NCT02088073) but evaluated two doses of LOKELMATM (sodium zirconium cyclosilicate) instead of three, as well as patients in different geographical regions. Continue reading

FDA Approves Dupixent: Only Self-Administered Biologic for Moderate-to-Severe Asthma

MedicalResearch.com Interview with:
RegeneronNeil Graham,  M.B.B.S., M.D., M.P.H
VP of Immunology & Inflammation
Regeneron

MedicalResearch.com: What is the background for this announcement? 

Response: Patients with moderate-to-severe asthma often have uncontrolled, persistent symptoms despite standard-of-care therapy that may make them suitable for treatment with a biologic therapy. They live with coughing, wheezing and difficulty breathing, and are at risk of severe asthma attacks that may require emergency room visits or hospitalizations. [i],[ii] Oral corticosteroids can provide relief for severe, short-term symptoms. However, their chronic use is limited to the most severe patients due to the potential for serious side effects. [iii],[iv]

A particular type of inflammation contributes to the cause of uncontrolled symptoms in multiple inflammatory diseases such as asthma and atopic dermatitis.[v] Dupixent is a medicine that inhibits the overactive signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13), two key proteins that contribute to this type of inflammation. This inhibits cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE; however, the mechanism of action of Dupixent in asthma has not been definitively established. Continue reading

FDA Approves Single Dose XOFLUZA™ For Uncomplicated Flu

MedicalResearch.com Interview with:

Mark D. Eisner, MD, MPH Vice President, Product Development Immunology Infectious Disease and Ophthalmology Genentech 

Dr. Mark Eisner

Mark D. Eisner, MD, MPH
Vice PresidentProduct Development Immunology, Infectious Disease and Ophthalmology Genentech

Dr. Eisner discusses the announcement that the FDA has approved XOFLUZA™ (baloxavir marboxil) for the treatment of acute, uncomplicated influenza.

MedicalResearch.com: What is the background for this announcement?

Response: Each year, an estimated 3-11 percent of the U.S. population gets the flu, and it can be very serious, resulting in hospitalization or even death. Since 2010, the Centers for Disease Control and Prevention (CDC) estimates that the flu has resulted annually in 9.2 to 35.6 million illnesses, 140,000 to 900,000 hospitalizations and 12,000 to 80,000 deaths. The severity of last year’s flu season underscores the need for new medical options beyond currently available antivirals.

XOFLUZA was granted Priority Review in June 2018 based on results from the Phase III CAPSTONE-1 study of a single dose of XOFLUZA compared with placebo or oseltamivir 75 mg, twice daily for five days, in otherwise healthy people with the flu, as well as results from a placebo-controlled Phase II study in otherwise healthy people with the flu.

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Less Smoking Linked to Lower Antibody Levels in Modern Rheumatoid Arthritis Patients

MedicalResearch.com Interview with:

Pr Gilles Boire, M.D., M. ScService de rhumatologie Département de médecine Faculté de médecine et des sciences de la santé Université de Sherbrooke

Prof. Boire

Pr Gilles Boire, M.D., M. ScService de rhumatologie
Département de médecine
Faculté de médecine et des sciences de la santé
Université de Sherbrooke

MedicalResearch.com: What is the background for this study?

Response: Rheumatoid arthritis (RA) patients are heterogeneous at initial presentation, in response to treatments and according to their outcomes. No clinical features and very few biomarkers, except autoantibodies such as anti-Cyclic Citrullinated Peptides/Proteins (CCP), identify patients with divergent prognostic trajectories.

To help improve early prognostic classification, we initiated 20 years ago the single center longitudinal observational Early Undifferentiated PolyArthritis (EUPA) study of consecutive patients presenting with recent-onset inflammatory polyarthritis, 90% of which fulfill classification criteria for RA at baseline. Our registry includes 739 very early RA patients (median symptom duration 3.6 months), rapidly treated to joint remission (i.e. 0/66 swollen joint) and followed over 5 years. Each patient visit is linked to biosamples and to sequential radiographs scored according to the modified Sharp/van der Heijde method. As we had the clinical impression that clinical features of recruited patients were evolving, we compared patients from 3 periods (1998-2004; 2005-2010; 2011-2017).  Continue reading

Single Dose Baloxavir marboxil (Xofluza) Has Potential To Improve Treatment of High-Risk Flu

MedicalResearch.com Interview with:

Mark D. Eisner, MD, MPH Vice President, Product Development Immunology Infectious Disease and Ophthalmology Genentech 

Dr. Eisner

Mark D. Eisner, MD, MPH
Vice President, Product Development Immunology
Infectious Disease and Ophthalmology
Genentech 

MedicalResearch.com: What is the background for this study?

Response: CAPSTONE-2 is a Phase III multicenter, randomized, double-blind study that evaluated the efficacy and safety of a single dose of baloxavir marboxil compared with placebo and oseltamivir in people 12 years and older who are at a high risk of complications from the flu. The Centers for Disease Control and Prevention (CDC) defines people at high risk for serious flu complications to include adults 65 years of age or older, or those who have conditions such as asthma, chronic lung disease, morbid obesity or heart disease.

A total of 2,184 participants enrolled in the study and were randomly assigned to receive a single, oral dose of 40 mg or 80 mg of baloxavir marboxil (according to body weight), placebo or 75 mg of oseltamivir twice daily for five days. The primary objective of the study evaluated the efficacy of a single dose of baloxavir marboxil compared with placebo by measuring the time to improvement of influenza symptoms. Key secondary endpoints compared outcomes in baloxavir marboxil versus placebo or oseltamivir – these included time to resolution of fever, time to cessation of viral shedding, infectious virus detection in swabs of the nose and throat, prescription of antibiotics and influenza-related complications.

Genentech announced initial results from the study on July 16, 2018 but the full data was presented for the first time during a late-breaking oral presentation at the annual IDWeek meeting in San Francisco, CA on October 6, 2018.

Baloxavir marboxil is a first-in-class, single-dose investigational oral medicine with a novel proposed mechanism of action designed to target the influenza A and B viruses, including oseltamivir-resistant strains and avian strains (e.g. H7N9, H5N1). Baloxavir marboxil is the first potential influenza treatment to demonstrate a clinically meaningful benefit for people highly vulnerable to serious influenza complications in clinical trials.

The FDA accepted a New Drug Application (NDA) and granted Priority Review to baloxavir marboxil as a single-dose, oral treatment for acute, uncomplicated influenza in people 12 years and older. The NDA was based on results from the Phase III CAPSTONE-1 study of a single dose of baloxavir marboxil compared with placebo or oseltamivir 75 mg, twice daily for five days, in otherwise healthy people with the flu. Results from a placebo-controlled Phase II study in otherwise healthy people with the flu were included as supporting data in the NDA. The FDA is expected to make a decision on approval by December 24, 2018. Continue reading

Topical Minocycline Foam for Moderate-to-Severe Acne Meets Phase 3 Study Endpoints

MedicalResearch.com Interview with:
foamixDavid Domzalski
CEO

Foamix Pharmaceuticals

MedicalResearch.com: What is the background for this study?  How does FMX101 differ from other treatment for acne, ie benzoyl peroxide, topical clindamycin etc? 

Response: This study measures the safety and efficacy of a topical foam formulation of the antibiotic minocycline, for the treatment of moderate-to-severe acne.

Minocycline is one of the most commonly used products for the treatment of acne, but is currently only available in an oral dosage form.

Significant side effects are associated with oral minocycline, including GI upset, photosensitivity, headaches, dizziness, and other potential effects on the CNS.  In addition to the side effects associated with oral minocycline, many currently available topical acne medications contain ingredients which can be drying and irritating to the skin.  These side effects can be frustrating to patients and potentially impact overall compliance to their treatment regimen.  The study addresses important unmet needs in dermatology to determine whether providing patients with a topical dosage form of minocycline may have potential advantages over existing products.

In our first two Phase 3 clinical studies, >95% of facial local tolerability signs and symptoms were classified as “none” or “mild,” including dryness, erythema and itching.  Also, our topical minocycline foam, FMX101, is a natural triglyceride-based vehicle that does not contain ingredients that serve as  primary irritants or surfactants.  We believe that FMX101, if approved, would be the first topical minocycline available for the treatment of acne and provide a novel and much needed treatment option for patients who suffer from the physical and psycho-social effects of acne. Continue reading

New Antibiotic Combination IMI/REL Can Treat Resistant Infection With Less Kidney Toxicity

MedicalResearch.com Interview with:

Michelle Hoffman Brown Associate Principal Scientist at Merck Merck

Michelle Brown

Michelle Hoffman Brown
Associate Principal Scientist
Merck

MedicalResearch.com: What is the background for this study? What are the kidney risks of using colistin to treat carbapenem-resistant bacterial infections?

Response: Gram-negative pathogens are responsible for half of all healthcare-associated infections and their ability to resist traditional antibiotics makes them more dangerous for seriously ill patients in a healthcare setting. The need for new approaches to treat these pathogens is essential and this trial aimed to evaluate the efficacy and safety of imipenem/relebactam (IMI/REL) for the treatment of these challenging infections.

Nephrotoxicity is a common complication of colistin-based therapy and is the potential adverse experience of greatest concern to prescribing clinicians, limiting its use to treat carbapenem-resistant bacterial infections. Relebactam is a novel β-lactamase inhibitor that restores imipenem activity against many imipenem-non-susceptible strains of Gram-negative pathogens. In the Phase 3 RESTORE-IMI 1 study (NCT02452047), IMI/REL was shown to be as effective as, but better tolerated than, colistin plus imipenem, including as demonstrated by a lower incidence of treatment-emergent nephrotoxicity (prespecified secondary endpoint). This analysis looked at additional renal safety data from the RESTORE-IMI 1 trial.  Continue reading

Retrotope Expands Compassionate Use Access to RT001 for Amyotrophic Lateral Sclerosis

MedicalResearch.com Interview with:
RetrotopeRobert J Molinari, Ph.D.

President and CEO
Retrotope, Inc.

 

MedicalResearch.com: What is the background for this study?
How does RT001 differ from other treatments for neurodegenerative diseases? 

Response: Lipid peroxidation in critical cell and mitochondrial membranes represents a common pathway of cell death in many neurodegenerative diseases, regardless of the initiating trigger of original damage, e.g. aberrant gene expression, misfolded proteins such as tau and amyloid, environmental insults, etc. This hypothesis was supported by work showing that stabilizing lipids (using virtually indistinguishable isotopic variants of the original dietary molecules) was able to mitigate disease-related cell dysfunction, and reverse disease in a variety of animal models, and more recently, in human patients enrolled in clinical trials.

It has been known for decades that lipid peroxidation detritus of oxidized membrane fats are present in most all diseases of degeneration and aging, including Alzheimer’s disease, Parkinson’s disease, atherosclerosis, ALS, Huntington’s, and fatal inborn genetic errors resulting in neurodegenerative diseases (among others). The hypothesis that controlling such oxidation could provide therapeutic benefit was abandoned when numerous formal trials of classical antioxidants, e.g. Co-enzyme Q, Vitamin E, and others failed to provide meaningful benefit. We believed that the antioxidant mechanism used to attempt control of the membrane oxidation was flawed, but that the target itself was correct. Indeed, by using a new class of oral drugs that are lipids fortified against damage at the key susceptible bonds, we observed reduction in lipid peroxidation damage that halted, and even reversed neurodegenerative disease progression. Dosed in amounts and forms similar to omega 3 and 6 supplements, these drugs exhibited profound disease modification across a broad range of diseases in animal models, placebo controlled- and open label- human trials. Continue reading

How Much Do Clinical Trials For New Medications Really Cost?

MedicalResearch.com Interview with:

Thomas J Moore Senior Scientist Institute for Safe Medication Practices Lecturer, Department of Epidemiology and Biostatistics The George Washington University Milken Institute of Public Health Alexandria, VA 22314

Thomas J Moore

Thomas J Moore AB
Senior Scientist Institute for Safe Medication Practices
Lecturer, Department of Epidemiology and Biostatistics
The George Washington University
Milken Institute of Public Health
Alexandria, VA 22314

MedicalResearch.com: What is the background for this study? What are the main findings?

  • The study provides realistic cost estimates of pivotal clinical trials that establish drug benefits to support FDA approval of 59 new drugs released for marketing in 2015-2016.
  • The median estimated cost was just $19 million, with half of the 138 trials studied clustered between $12 million and $33 million.
  • The highest cost trials–with estimates up to $345 million–were for new drugs that were similar to drugs already available and already proven in treating serious illnesses. 

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IXORA-S Study Suggest Taltz May Provide Significantly Greater Clearance of Nail Psoriasis

MedicalResearch.com Interview with:

Lotus Mallbris, M.D., Ph.D., Vice president, Immunology Development Lilly Bio-Medicines 

Dr. Mallbris

Lotus Mallbris, M.D., Ph.D.,
Vice president, Immunology Development
Lilly Bio-Medicines 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: By exploring creative clinical approaches and patient-centric pathways to more thoroughly address the key aspects of treating these complex conditions, Lilly is bringing innovation forward in hopes of reducing the burden of dermatologic disease for people around the world.

The results of the IXORA-S study suggest that Taltz may provide significantly greater clearance of nail psoriasis than ustekinumab. This is significant because nail lesions are a common feature of psoriasis. It’s often associated with discomfort, which can lead to functional impairment and distress, further supporting the importance of complete clearance.   Continue reading

Asthma: Add-on Maintenance Treatment with FASENRA (benralizumab) Can Reduce Exacerbations

MedicalResearch.com Interview with:

Tosh Butt, MBA VP Respiratory AstraZeneca

Tosh Butt

Tosh Butt, MBA
VP Respiratory
AstraZeneca

MedicalResearch.com: What is the background for this study? How is benralizumab different from more traditional treatments for asthma?

    • BORA is a randomized, double-blind, parallel-group, Phase III extension, and is one of six Phase III trials in the WINDWARD program in asthma. The current analysis includes results for 1,926 patients from the two placebo controlled exacerbation trials, SIROCCO (48 week) and CALIMA (56 weeks). BORA provides evidence that add on maintenance treatment with FASENRA (benralizumab) resulted in a consistent safety profile over a second year of treatment, with no increase in the frequencies of overall or serious adverse events, and sustained efficacy in terms of reducing asthma exacerbations, and improving lung function and asthma symptoms. The BORA trial results could provide confidence to patients with severe eosinophilic asthma and physicians that the positive outcomes they may be seeing with benralizumab can be maintained over a second year of treatment.
  • FASENRA, a different kind of respiratory biologic, has a strong clinical profile which includes the ability to show lung function improvement after the first dose, the potential to reduce – or even stop – oral steroid use, and the convenience of 8-week dosing (no other respiratory biologic offers this dosing). FASENRA is approved for add-on maintenance treatment of patients with severe asthma ages 12 years and older, and with an eosinophilic phenotype. FASENRA binds directly to the IL-5a receptor on an eosinophil and uniquely attracts natural killer cells to induce apoptosis, or cell death. Other biologics currently available are anti-IL5s – a passive approach that primarily acts to block differentiation and survival of the eosinophil.

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FDA Approves Poteligeo® (mogamulizumab-kpkc) for T-Cell Lymphoma of the Skin

MedicalResearch.com Interview with:

Jeffrey S. Humphrey, MD President of Kyowa Kirin Pharmaceutical Development, Inc

Dr. Humphrey

Jeffrey S. Humphrey, MD
President of Kyowa Kirin Pharmaceutical Development, Inc

MedicalResearch.com: What is the background for this announcement? Would you briefly explain what is meant by Mycosis Fungoides and Sézary Syndrome?

Response: Kyowya Kirin has received FDA approval for Poteligeo (mogamulizumab), based on findings from the MAVORIC trial. Mogamulizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets CC chemokine receptor 4 (CCR4), for the treatment of the most common subtypes of cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF) and Sézary syndrome (SS).

MF and SS may have a profound and severe impact on quality of life, including a patient’s functional, emotional and social well-being, as symptoms may include a scaly red rash or light or dark patches in areas of the body that are not usually exposed to the sun; thin, reddened, eczema-like rash; thickened scaly, red skin (or plaques) or psoriasis-like rash; more advanced disease can include tumors (with significant thickness) on the skin, which may develop ulcers and become infected. Because CTCL manifests in skin lesions, it is often mistaken for other skin conditions (early stage MF and SS can be diagnosed as other skin conditions), which can delay conclusive diagnosis and treatment options.

MF is the most common subtype of CTCL, affecting 50-70% of individuals. In most patients diagnosed with early stage MF, the skin involvement does not progress, but in some patients, it will slowly progress. SS accounts for approximately 3% of CTCL cases and is a more aggressive, leukemic form of CTCL, affecting the blood, skin, lymph nodes and visceral organs

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For Resistant HIV: Phase III Trial of Trogarzo Demonstrates Safety and Efficacy

MedicalResearch.com Interview with:
TaiMed BiologicsStanley Lewis, M.D.

TaiMed Biologics
Irvine, CA 92614


MedicalResearch.com: What is the background for this study?

Response: The phase III clinical trial was conducted to assess the efficacy and safety of Trogarzo™ (ibalizumab-uiyk) injection in patients with multidrug resistant HIV-1. The study design was approved by the FDA. Results obtained were included in the New Drug Application submitted to the FDA which approved Trogarzo™ on March 6, 2018.

The phase III, open-label study, enrolled 40 patients with multidrug-resistant (MDR) HIV-1 in whom multiple antiretroviral therapies had failed. All patients at baseline were experiencing viral failure. After a seven-day control period, patients received an intravenous 2000 mg loading dose of Trogarzo™ which was the only change made to their antiretroviral regimen. Through the 24-week treatment period of the study, patients were given a maintenance dose of 800 mg of Trogarzo™ every two weeks along with an optimized background regimen that included at least one additional fully active agent.

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Crohn’s Disease: Positive Findings from Phase III Study of Antibiotic Combination

MedicalResearch.com Interview with:
RedHill Biopharma LtdMr. Gilead Raday, MPhil, MSc
Chief Operating Officer
RedHill Biopharma Ltd

MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by Crohn’s disease?  How common is it and whom does it affect? 

Response: Crohn’s disease (CD) is a chronic, relapsing inflammatory gastrointestinal disorder characterized by a variety of symptoms, including severe abdominal pain, diarrhea, bleeding, bowel obstruction, fever and weight loss. The underlying cause of Crohn’s is unknown; however, CD is believed to arise secondary to genetic and environmental stimuli. More than 1.5 million people suffer from CD globally and it is prevalent in the U.S., affecting more than 200 people per 100,000.

The current standard of care for Crohn’s disease is limited to anti-inflammatories, immuno-suppressants and biologics that treat auto-immune disorders. These therapies target symptomatic improvement in the inflammation associated with CD, are widely considered to be of limited efficacy in the long term, and are associated with numerous side effects. This speaks to the great unmet need for an effective therapy for this debilitating disease.

Additionally, there is no current therapy that treats the suspected underlying cause of Crohn’s disease. We have developed RHB-104 with the MAP hypothesis in mind, which posits that Crohn’s disease is caused by infection by a bacteria, Mycobacterium avium subspecies paratuberculosis (MAP). This is similar to peptic ulcer disease, a condition that was initially associated with stress, smoking, NSAIDs and other behavioral factors, yet was found to be caused by H. pylori bacterial infection in the 1980s, revolutionizing the field of ulcer treatment. Validation of this theory would revolutionize how Crohn’s disease is viewed and treated by the medical community and RHB-104 is the only therapy in development targeting MAP infection.  Continue reading

HIV: Hopeful Results of Doravirine vs Ritonavir-Boosted Darunavir at 96 Weeks

MedicalResearch.com Interview with:
merck

Kathleen Squires MD
Director, Division of Infectious Diseases
Jefferson University Hospitals and
Ming-Tai Lai, PhD
Senior Principal Scientist, Biology Discover
Merck

 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Dr. Squires: The DRIVE-FORWARD study is a pivotal, randomized, double-blind, Phase 3 study that evaluated the safety and efficacy of doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor (NNRTI) in treatment-naïve adults with HIV-1 infection. Data from week 48 of this trial have previously been presented demonstrating that doravirine met its primary endpoint of non-inferior efficacy compared to ritonavir-boosted darunavir (DRV+r). In addition, at 48 weeks, a secondary endpoint showed that the doravirine-treated group had statistically significant lower levels of fasting LDL-C and non-HDL-C versus the DRV+r group.

The data presented at AIDS 2018 are week 96 data from the DRIVE-FORWARD trial.
At week 96, the doravirine group demonstrated efficacy of 73.1% compared with 66.0% in the DRV+r group, a treatment difference of 7.1% (95% CI: 0.5, 13.7)  Two participants in the DOR treatment group developed genotypic and phenotypic resistance to DOR through 96 weeks of treatment. The rate of discontinuation of therapy due to adverse events was 1.6 percent in the DOR group and 3.4 percent in the DRV+r group.

Doravirine is a late-stage investigational NNRTI for the treatment of HIV-1 infection in treatment-naïve adults and is being evaluated both as a once-daily single-entity tablet in combination with other antiretroviral agents, and as a once-daily fixed-dose combination regimen with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF). Earlier this year, Merck announced that the FDA accepted for review two New Drug Applications (NDAs) for doravirine for the treatment of HIV-1 infection in treatment-naïve adults. The NDAs are based upon the findings at week 48 of two ongoing Phase 3 trials, DRIVE-FORWARD and DRIVE-AHEAD, evaluating the efficacy and safety of doravirine and the fixed-dose combination regimen of DOR/3TC/TDF, respectively. The FDA has set a target action date of October 23, 2018 for both applications.

Dr. Lai: This study aimed to characterize the mutant viruses selected in treatment-naïve participants through week 48 from DRIVE-FORWARD and DRIVE-AHEAD, and to assess the impact of selected mutations on non-nucleoside reverse transcriptase inhibitor (NNRTI) susceptibility and viral fitness. All of the seven doravirine (DOR)-resistant mutants are either partially susceptible or susceptible to etravirine. Mutants containing the F227C substitution were shown to be hypersusceptible to some nucleoside reverse transcriptase inhibitors (NRTIs) such as azidothymidine (AZT), tenofovir (TFV), lamivudine (3TC), and MK-8591. Among the 12 participants who developed efavirenz (EFV) resistance, 9 of the EFV-resistant clinical mutants were susceptible to DOR with fold-change <2.5.

The majority of DOR-selected viruses identified in the treatment-naïve participants in clinical trials to date retain susceptibility to etravirine and hypersensitivity to some NRTIs, with low replication capacity. In addition, the majority of EFV-selected viruses retain susceptibility to DOR.  Continue reading

Medical Textbooks Riddled With Undisclosed Conflicts of Interest

MedicalResearch.com Interview with:

Brian J. Piper, PhD, MS Department of Basic Sciences Geisinger Commonwealth School of Medicine Scranton, PA 18509

Dr. Piper

Brian J. Piper, PhD, MS
Department of Basic Sciences
Geisinger Commonwealth School of Medicine
Scranton, PA 18509

MedicalResearch.com: What is the background for this study?

Response: The authors of this study are biomedical scientists, health care providers and educators who teach medical and pharmacy students. It is a standard practice in reputable medical journals like the New England Journal of Medicine to disclose conflicts of interest (CoI). Reputable sources like the Cochrane Library also disclose CoIs and analyze for their potential impact on the evidence base. Unfortunately, textbooks, which can be highly influential in the training of medical professionals, usually do not disclose their conflicts of interest.

A prior study in this quantitative bioethics area found that more than one-quarter of a team-authored pharmacology textbook, Goodman and Gilman’s Pharmacological Basis of Therapeutics, had an undisclosed patent (PLoS One, 2015; 10: e0133261).  The goal of this investigation was to determine whether there were undisclosed CoIs in textbooks used in the training and as a reference for allopathic physicians, osteopathic physicians, dentists, pharmacists, nurses and other allied healthcare providers.  Continue reading

ORILISSA™ (elagolix) Now Approved for Management of Moderate to Severe Pain Associated with Endometriosis

MedicalResearch.com Interview with:

Dr. Dawn Carlson MD MPH Vice President, General Medicine Development AbbVie 

Dr. Carlson

Dr. Dawn Carlson MD MPH
Vice President, General Medicine Development
AbbVie 

MedicalResearch.com: Please provide some background on this announcement. Would you briefly explain what endometriosis is? Whom does it affect and how does it interfere with quality of life?

Response: Endometriosis is one of the most common gynecologic disorders in the U.S that affects an estimated one in 10 women of reproductive age. It occurs when tissue similar to the lining of the uterus starts growing outside of the uterus, where it doesn’t belong.

The symptoms of endometriosis, including pain with menstrual periods and between periods, and with sexual intercourse, can be debilitating and significantly impact day-to-day activities of women’s lives, personally and professionally. Unfortunately, women with endometriosis can suffer for up to 10 years and visit multiple physicians before receiving a proper diagnosis. Unresolved endometriosis pain results in higher healthcare costs from emergency department visits and repeat surgeries.  Continue reading

Flu: Novel Oral Single Dose Antiviral Baloxavir Marboxil Reduced Symptoms in High Risk Patients

MedicalResearch.com Interview with:

Mark Eisner MD MPH Vice President and Global Head of Respiratory Actemra, ID, and Metabolism Clinical Development at Genentech Professor of Clinical Medicine University of California, San Francisco

Dr. Mark Eisner


Mark Eisner MD MPH

Mark D. Eisner, MD, MPH
Vice President, Product Development Immunology, Infectious Disease, and Ophthalmology
Genentech

 

MedicalResearch.com: What is the background for this study?
Would you briefly explain how 
baloxavir marboxil differs from other flu treatments? 

Response: CAPSTONE-2 is a Phase III multicenter, randomized, double-blind study that evaluated a single dose of baloxavir marboxil compared with placebo and oseltamivir in people 12 years and older who are at a high risk of complications from the flu. The high risk inclusion criteria in CAPSTONE-2 were aligned with the Centers for Disease Control and Prevention (CDC), which defines people at high risk for serious flu complications to include adults 65 years of age or older, or those who have conditions such as asthma, chronic lung disease, diabetes or heart disease. For these people, flu can lead to hospitalization or even death. Participants enrolled in the study were randomly assigned to receive a single dose of 40 mg or 80 mg of baloxavir marboxil (according to body weight), placebo or 75 mg of oseltamivir twice a day for five days.

The FDA recently accepted a New Drug Application (NDA) and granted Priority Review to baloxavir marboxil as a single-dose, oral treatment for acute, uncomplicated influenza in people 12 years and older. The NDA was based on results from the Phase III CAPSTONE-1 study of a single dose of baloxavir marboxil compared with placebo or oseltamivir 75 mg, twice daily for five days, in otherwise healthy people with the flu. Results from a placebo-controlled Phase II study in otherwise healthy people with the flu were included as supporting data in the NDA. The FDA is expected to make a decision on approval by December 24, 2018.

Baloxavir marboxil is a first-in-class, single-dose investigational oral medicine with a novel proposed mechanism of action designed to target the influenza A and B viruses, including oseltamivir-resistant strains and avian strains (H7N9, H5N1). Unlike other currently available antiviral treatments, baloxavir marboxil is the first in a new class of antivirals designed to inhibit the cap-dependent endonuclease protein within the flu virus, which is essential for viral replication. By inhibiting this protein, baloxavir marboxil prevents viral replication earlier in the flu virus life cycle. Continue reading

Lupus: Phase 2 Trial of Baricitinib Improved Signs and Symptoms

MedicalResearch.com Interview with:

Daniel J. Wallace M.D., FACP, MACR Associate Director, Rheumatology Fellowship Program Board of Governors, Cedars-Sinai Medical Center Professor of Medicine, Cedars-Sinai Medical Center David Geffen School of Medicine Center at UCLA In affiliation with Attune Health  Beverly Hills, Ca 90211

Dr. Wallace

Daniel J. Wallace M.D., FACP, MACR
Associate Director, Rheumatology Fellowship Program
Board of Governors, Cedars-Sinai Medical Center
Professor of Medicine, Cedars-Sinai Medical Center
David Geffen School of Medicine Center at UCLA
In affiliation with Attune Health
Beverly Hills, Ca 90211

MedicalResearch.com: What is the background for this study? What are the main findings?

 

Response: This is the first positive study of systemic lupus erythematosus (SLE) using baricitinib,  a small oral molecule that blocks the JAK system.

The human kinome consists of 500 genes and helps regulate cell surface receptor interaction. While agents that inhibit certain pathways are approved for rheumatoid arthritis and certain malignancies, this is the first study of its kind in SLE.

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Diabetes: Switching to Sulfonylureas from Metformin Linked to Increased Side Effects

MedicalResearch.com Interview with:

Samy Suissa, PhD Director, Centre for Clinical Epidemiology, Lady Davis Institute Professor, Departments of Epidemiology and Biostatistics and of Medicine McGill University

Dr. Suissa

Samy Suissa, PhD
Director, Centre for Clinical Epidemiology, Lady Davis Institute
Professor, Departments of Epidemiology and Biostatistics and of Medicine
McGill University 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Sulfonylureas are widely used oral antidiabetic drugs that are recommended as second-line treatments after first-line metformin to treat patients with type 2 diabetes. While their safety has been studied extensively, studies in patients with poorly controlled diabetes in need of pharmacotherapy escalation have been sparse and limited. Our study evaluated whether adding or switching to sulfonylureas after initiating metformin treatment is associated with increased cardiovascular or hypoglycaemic risks, compared with remaining on metformin monotherapy.

Using a large cohort of over 77,000 patients initiating treatment with metformin monotherapy, we found that adding or switching to sulfonylureas is associated with modest increases of 26% in the risk of myocardial infarction and 28% in the risk of death, as well as an over 7-fold major increase in the risk of severe hypoglycaemia leading to hospitalisation.

In particular, we found that switching from metformin to sulfonylureas was associated with higher risks of myocardial infarction and death, compared with adding sulfonylureas to metformin.  Continue reading

Two Studies Evaluate Monoclonal Antibody Tralokinumab For Asthma

MedicalResearch.com Interview with:

Reynold A. Panettieri, Jr., M.D. Professor of Medicine, Robert Wood Johnson Medical School Vice Chancellor, Clinical & Translational Science Director, Rutgers Institute for Translational Medicine & Science Emeritus Professor of Medicine, University of Pennsylvania Child Health Institute of New Jersey Rutgers, The State University of New Jersey New Brunswick, NJ  08901

Dr. Panettieri

Reynold A. Panettieri, Jr., M.D.
Professor of Medicine, Robert Wood Johnson Medical School
Vice Chancellor, Clinical & Translational Science
Director, Rutgers Institute for Translational Medicine & Science
Emeritus Professor of Medicine, University of Pennsylvania
Child Health Institute of New Jersey
Rutgers, The State University of New Jersey
New Brunswick, NJ  08901

MedicalResearch.com: What is the background for this study?

Response: Severe asthma is characterized by Type 2 inflammation manifested by increases in IL-13, IL-4 and Il-5 levels in the airways that promotes airway hyperresponsiveness and in part irreversible airway obstruction.  These clinical manifestations profoundly increase asthma morbidity and mortality.

To address an unmet therapeutic need, Tralokinumab was developed as a monoclonal antibody targeting soluble IL-13 with the goal of improving lung function and patient reported outcomes while decreasing annual exacerbation rates.  Stratus 1 and 2 represent two identical randomized, double-blind, placebo-controlled, phase 3 clinical trials in severe asthma.  These international trials enrolled approximately 2000 subjects with severe asthma and examined whether Tralokinumab decreased annualized exacerbation rates (AER) as compared with placebo (primary outcome).

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Dapagliflozin (Farxiga®)Added to Insulin for Type 1 Diabetes May Improve Glycemic Control

MedicalResearch.com Interview with:

Chantal Mathieu, MD, PhD Professor of Medicine Clinical and Experimental Endocrinology Catholic University of Leuven, Belgium

Dr. Mathieu

Chantal Mathieu, MD, PhD
Professor of Medicine
Clinical and Experimental Endocrinology
Catholic University of Leuven, Belgium

MedicalResearch.com: What is the background for this study?

Response: People with type 1 diabetes (T1D) are confronted often with the inability to achieve satisfactory glycemic control, being good HbA1c, but in particular stable glycemic control, avoiding hyperglycemic events, but also hypoglycemic events, despite novel insulins and novel technologies. Moreover, intensive insulin therapy is often associated with weight gain, leading to an increase in overweight and obesity also in people with T1D. All of these issues affect quality of life.

In the DEPICT 2 study we examined the impact of adding a selective SGLT2 inhibitor, dapagliflozin (two doses tested – 5 and 10mg) in a double blinded manner versus placebo to background insulin (MDI or CSII) in people with T1D reaching insufficient glycemic control (HbA1c 7.5-10.5%). Primary endpoint was lowering in HbA1c at 24 weeks and secondary endpoints included insulin dose reduction and weight reduction as well as a composite endpoint of having a HbA1c drop of >=0.5% without severe hypoglycemia. The study ran internationally, with about 1/3 of patients coming from North America, 1/3 from Europe and 1/5 from Asia (Japan).

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Does Preloading With a Nicotine Patch Help Smokers Quit?

MedicalResearch.com Interview with:
“Day 1 of nicotine patch, just stuffed my face with lunch at work and do NOT even want a cigarette” by David Bruce Jr. is licensed under CC BY 2.0Paul Aveyard
Professor of Behavioural Medicine
Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Primary Care Building
Radcliffe Observatory Quarter
Oxford

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Tobacco addiction occurs because of repeated pairings of the act and sensation of smoking with binding of nicotine in the midbrain leading to release of dopamine in the nucleus accumbens. These repeated pairings create associative learning and, when brain nicotine concentrations fall, this produces a compulsion to keep using tobacco. In theory, blocking the actions of nicotine released while smoking ought to reverse this learning. One way to do this is to use a nicotine patch which provides a steady state high concentration of nicotine that desensitises the nicotinic receptors in the midbrain, making them unresponsive to nicotine from a smoked cigarette. This is the theory behind nicotine preloading.

The clinical trial evidence that preloading works is equivocal, with some trials suggesting a very large therapeutic effect and others no benefit at all. In the light of both the promise and the uncertainty, we aimed to complete the largest trial to date of nicotine preloading to examine its effectiveness, safety, and tolerability.

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