Author Interviews, Cancer Research, Prostate Cancer / 01.10.2020

MedicalResearch.com Interview with: Maha Hussain, MD, FACP, FASCO Genevieve Teuton Professor of MedicineDivision of Hem/Onc Deputy Director Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine MedicalResearch.com: What is the background for this study? Response: PROfound is an open-label international Phase III clinical trial which evaluated the efficacy and safety of Olaparib (Lynparza) versus enzalumatide or abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on prior treatment with NHA treatments (abiraterone and prednisone or enzalutamide) and have a qualifying tumor mutation in BRCA1/2, ATM or one of the other genes involved in the HRR pathway. The trial design included 2 cohorts; Cohort A included patients with BRCA1,2 or ATM and Cohort 2 included patients with 12 other HRR genes. (more…)
ASCO, Author Interviews, Cancer Research, Journal Clinical Oncology / 10.04.2020

MedicalResearch.com Interview with: Matthew Galsky, MD Icahn School of Medicine at Mount Sinai New York, NY MedicalResearch.com: What is the background for this study? Would you explain what is meant by switch maintenance immunotherapy? Response: For decades, platinum-based chemotherapy has been standard first-line treatment for metastatic urothelial (bladder) cancer. The standard approach to first-line chemotherapy is to administered approximately 6 cycles of treatment (in the absence of disease progression or prohibitive side effects), and then to stop treatment and monitor. Unfortunately, virtually all patients with metastatic disease will experience disease progression after stopping chemotherapy. However, we know that if we just continue the same platinum-based chemotherapy until progression of cancer (rather than stopping after ~6 cycles), the side effects continue to accumulate but the benefits plateau. Approximately 5 years ago, the first new systemic therapies were approved to treatment metastatic urothelial cancer in decades, immune checkpoint inhibitors (PD-1 or PD-L1 inhibitors). In fact, 5 PD-1/PD-L1 inhibitors have been approved by the FDA for the treatment of patients with metastatic urothelial cancer progressing despite prior platinum-based chemotherapy. Given that these drugs are non-cross resistant with chemotherapy in at least a subset of patients (i.e., they can provide benefit even when chemotherapy is no longer working), and because they are well tolerated by a large proportion of patients, a logical question is rather than waiting until cancer progresses after stopping first-line chemotherapy, what if we started immunotherapy immediately. Switch maintenance refers to switching from chemotherapy to a different class of drug (e.g., immunotherapy) and maintenance refers to trying to "maintain" the response achieved with initial chemotherapy. (more…)
Author Interviews, Hospital Acquired, Infections, Merck / 16.04.2019

MedicalResearch.com Interview with: Elizabeth Rhee, MD Executive Director, Infectious Disease Clinical Research Merck Research Laboratories MedicalResearch.com: What is the background for this study? Would you briefly explain the condition of ventilated nosocomial pneumonias? Dr. Rhee: Nosocomial pneumonia (NP) is a lung infection that occurs during a hospital stay. NP is often serious, and is associated with high mortality. It is one of the most common health-care associated infections in both the U.S. and Europe, accounting for over 20% of such cases. Gram-negative bacteria, mainly Pseudomonas aeruginosa (PSA) and Enterobacteriaceae, are frequent causes of nosocomial pneumonia. Limited options currently exist for the management of NP caused by Gram-negative pathogens. This is concerning because rates of resistance to Gram-negative bacteria are growing, and they are becoming increasingly difficult to treat. Forms of nosocomial pneumonia include hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and ventilated HAP. High rates of death (ranging from 20% to more than 50%) are especially associated with ventilated HAP. Pseudomonas aeruginosa, a Gram-negative bacterium, is the most common cause of HAP/VAP in both the U.S. and Europe. Patients with NP are often critically ill, requiring ventilator support and time in intensive care, and it was important to look at this population as we explore new options for the treatment of NP. Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin/beta-lactamase inhibitor combination with broad in vitro activity against Gram-negative pathogens, including multi-drug resistant (MDR) P. aeruginosa and many extended-spectrum beta-lactamase (ESBL) producers. It is FDA approved for complicated intra-abdominal and urinary tract infections in adults at 1.5g (1g ceftolozane/0.5g tazobactam) q8h. C/T is currently being studied at an investigational new dose of 3g (2g/1g) q8h, for the treatment of ventilated nosocomial pneumonia, in the ASPECT-NP Phase 3 trial. (more…)
Alzheimer's - Dementia, Author Interviews, Merck, NEJM / 10.04.2019

MedicalResearch.com Interview with: Michael F. Egan, MDVice President,  NeuroscienceGlobal Clinical DevelopmentMerck Research LaboratoriesNorth Wales, PAMichael F. Egan, MD Vice President,  Neuroscience Global Clinical Development Merck Research Laboratories North Wales, PA  MedicalResearch.com: What is the background for this study?   Response: Alzheimer’s disease (AD) appears to be due to the gradual accumulation of amyloid over many years (the “amyloid hypothesis”). At some point, it is thought that amyloid triggers abnormalities in tau, which then forms deposits within neurons and leads to progressive neurodegeneration. Amyloid is made up of  a small, sticky peptide, Abeta, which is produced when the enzyme BACE cleaves a large protein called APP.  In our trial, we tested whether a potent BACE inhibitor, verubecestat, could slow disease progression in subjects with early AD (or prodromal AD) by blocking formation of Abeta.  A previous trial in subjects with dementia due to AD failed to find evidence of efficacy. One possible reason for this failure is that subjects had too much amyloid in their brain already. (more…)
Author Interviews, Critical Care - Intensive Care - ICUs, Hospital Acquired, Infections, Kidney Disease, Merck / 06.10.2018

MedicalResearch.com Interview with: 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.  (more…)
Author Interviews, HIV, Merck / 02.08.2018

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.  (more…)
Alzheimer's - Dementia, Author Interviews, Merck, NEJM / 02.05.2018

MedicalResearch.com Interview with: Dr. Michael F. Egan MD Merck & Co. North Wales, PA 19454   MedicalResearch.com: What is the background for this study? What are the main findings? Response: A leading theory of Alzheimer's Disease is that it is caused by the buildup of amyloid plaques in the brain. Amyloid is composed of a sticky peptide called Abeta.  Abeta production can be blocked by Inhibiting an enzyme called BACE.  In animal models, BACE inhibtion prevent amyloid accumulation.  We aimed to see if a potent BACE inhibitor would slow clinical decline in Alzheimer's Disease. EPOCH was a Phase 2/3 randomized, placebo-controlled, parallel-group, double-blind study evaluating efficacy and safety of two oral doses of verubecestat an investigational BACE inhibitor, administered once-daily versus placebo in patients with mild-to-moderate AD currently using standard of care treatment. The primary efficacy outcomes of the study are the change from baseline in cognition (assessed using the Alzheimer's Disease Assessment Scale Cognitive Subscale, or ADAS-Cog),  as well as the change from baseline in function (assessed using the Alzheimer's Disease Cooperative Study – Activities of Daily Living, or ADCS-ADL)  after 78 weeks of treatment. Following the recommendation of the external Data Monitoring Committee (eDMC), which assessed overall benefit/risk during  the trial,  the study was stopped early, as there was “virtually no chance of finding a positive clinical effect.” Verubecestat did not reduce cognitive or functional decline in patients with mild-to moderate Alzheimer’s disease and was associated with treatment-related adverse events.  (more…)
Author Interviews, HIV, Merck, Pharmacology / 25.07.2017

MedicalResearch.com Interview with: Dr. Pedro Cahn Chief of the infectious disease unit at Juan A. Fernandez Hospital Buenos Aires, Argentina, and ONCEMRK lead study investigator MedicalResearch.com: What is the background for this study? What are the main findings? The ONCEMRK Phase 3 study was conducted to evaluate the efficacy and safety of once-daily ISENTRESS (raltegravir) HD 1200 mg (given as two 600 mg oral tablets) compared to twice daily raltegravir 400 mg, each in combination therapy with emtricitabine plus tenofovir disoproxil fumarate in previously untreated adults with HIV-1 infection with levels of HIV-1 RNA ≥ 1,000 copies/mL.
  • Week 96 data showed:
    • 5 percent of the 531 patients taking once-daily raltegravir 1200 mg (2 x 600 mg) achieved viral suppression of less than 40 copies/mL of HIV-1 RNA, compared to 80.1 percent of the 266 patients taking twice-daily raltegravir 400 mg, both in combination therapy with emtricitabine plus tenofovir disoproxil fumarate, with a treatment difference of 1.4 percent.
    • Increases in CD4+T-cell counts from baseline were comparable for the two treatment regimens, with an average increase of 261.6 cells/mm3 for once-daily raltegravir (1200 mg) and 262.2 cells/mm3 for twice-daily raltegravir (400 mg).
    • Efficacy was consistent across a variety of patient populations, including those with high viral load at baseline (HIV-1 RNA >100,000 copies/mL).
    • Treatment-emergent viral mutations leading to any drug resistance were detected in less than 1 percent of patients in both treatment arms, with 4/531 (0.8 percent) in the once-daily raltegravir (1200 mg) treatment arm, and 2/266 (0.8 percent) in the twice-daily raltegravir (400 mg) treatment arm through 96 weeks.
    • The rate of discontinuation of therapy due to adverse events through 96 weeks was low (1.3 percent in patients receiving once-daily raltegravir (1200 mg) and 2.3 percent in patients receiving twice-daily raltegravir (400 mg).
(more…)