Effects of Riociguat in Treatment-Naïve vs Pretreated Patients With Pulmonary Arterial Hypertension

MedicalResearch.com Interview with:

Prof. Hossein-Ardeschir Ghofrani University of Giessen and Marburg Lung Center Giessen, Germany, and Member of the German Center of Lung Research and Department of Medicine Imperial College London London, UK

Prof. Ghofrani

Prof. Hossein-Ardeschir Ghofrani
University of Giessen and Marburg Lung Center
Giessen, Germany, and
Member of the German Center of Lung Research
and Department of Medicine
Imperial College London
London, UK

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

Response: Pulmonary arterial hypertension (PAH) is characterised by increased pulmonary vascular resistance (increased resistance to blood flow in the pulmonary circulation), which can lead to right heart failure and death. Riociguat is the first of a new class of drugs – the soluble guanylate cyclase stimulators. It has been approved for the treatment of PAH based on the impressive efficacy and safety results from two pivotal Phase III studies: PATENT-1 and its long-term extension phase, PATENT-2. PATENT-1 was a 12-week, double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of riociguat in patients with PAH. Patients who completed PATENT-1 without ongoing riociguat-related serious adverse events (AEs) could enter PATENT-2, in which they received open-label riociguat. PATENT-1 admitted patients whether they were treatment-naïve or already receiving targeted PAH therapies, such as endothelin receptor antagonists (ERAs) and prostanoids. This current analysis compared the safety and efficacy of riociguat between treatment-naïve and pretreated patients in the PATENT-2 long-term extension study.

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Ibalizumab Immunotherapy Decreased Viral Load In Resistant HIV

MedicalResearch.com Interview with:

Brinda Emu MD Assistant Professor of Medicine (Infectious Diseases Yale University New Haven, CT

Dr. Brinda Emu

Brinda Emu MD
Assistant Professor of Medicine (Infectious Diseases
Yale University
New Haven, CT 

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

Response: Ibalizumab is a fully humanized monoclonal antibody that targets the CD4 receptor.  This Phase III registrational study enrolled individuals with HIV infection that harbor high levels of multi-drug resistance, with limited treatment options.  At IDWeek in October, 2016, data was presented that demonstrated patients experienced a significant decrease in viral load after receiving a single loading dose of ibalizumab 2,000 mg intravenously (IV) in addition to their failing antiretroviral therapies (ART) (or no therapy). Seven days after this loading dose, 83% of patients achieved a ≥ 0.5 log10 decrease from baseline compared with 3% during the seven-day control period .These results were statistically significant (p<0.0001).

At CROI, additional data on the Week 24 results from this study are now presented.

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Allergic Rhinitis: Three Years of Immunotherapy Gives Longer Lasting Symptom Control

MedicalResearch.com Interview with:
Stephen R. Durham, MD

Imperial College, London, and Royal Brompton and Harefield Hospitals
NHS Foundation Trust
London, United Kingdom

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

Response: Allergic rhinitis affects 1 in 4 the UK population and may compromise sleep and work/school performance and be associated with bronchial asthma. When nasal steroids and antihistamines do not work or cause side effects, allergen immunotherapy is an alternative. Immunotherapy using high doses of grass pollen allergen as monthly injections or daily tablets under the tongue are highly effective. Treatment for 3 years not only gives sustained improvement on treatment but also long-term benefits and disease remission for at least 2-3 years after stopping treatment.

This single centre study at Imperial College London and Royal Brompton Hospital London included 106 adults with severe Hayfever followed up for 3 years, 2 years on treatment and 1 year after stopping treatment. In this double-blind trial, 3 randomised groups took sublingual immunotherapy, subcutaneous immunotherapy and placebo treatment. 92 completed the trial. Results showed that 2 years treatment with both modalities did not result in persistent benefit at year 3, although the researchers found that both treatments were effective compared to placebo during years 1 and 2.

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PCSK9 Inhibition with Alirocumab Increases Removal of LDL Cholesterol

MedicalResearch.com Interview with:
Henry N. Ginsberg, MD

Irving Institute for Clinical and Translational Research
Columbia University
Columbia College of Physicians and Surgeons
New York, NY

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

Response: Previous studies in mice and cells have identified increased hepatic low density lipoprotein (LDL) receptors as the basis for LDL lowering by PCSK9 inhibitors, but there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism, particularly effects on very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) or LDL metabolism.

This study in 18 healthy subjects, found that alirocumab decreased the number of IDL and LDL particles in the circulation, and their associated cholesterol and apoB levels by increasing efficiency of the clearance of IDL and LDL. There were not effects on VLDL metabolism. The increased clearance of IDL meant that less LDL was produced from IDL, which is the precursor of LDL. Thus, the dramatic reductions in LDL cholesterol resulted from both less LDL being produced and more efficient clearance of LDL. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition.

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Imatinib Revolutionizes Treatment of Unresectable/Metastatic GI Stromal Tumors

MedicalResearch.com Interview with:

Michael C. Heinrich, MD Professor of Medicine and Cell and Developmental Biology Oregon Health & Sciences University

Dr. Michael Heinrich

Michael C. Heinrich, MD
Professor of Medicine and Cell and Developmental Biology
Oregon Health & Sciences University

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

Response: Prior to 2000, there were no effective medical treatments for advanced GI stromal tumor and patients faced an average life expectancy of 18 months or less.  In our study of the  long-term treatment results using imatinib (Gleevec),  we found that approximately 7% of patients were still on front-line therapy at 10 years without any evidence of tumor progression.  More importantly, the estimated 10 year survival was 23%.   Progression-free and overall survival rates were significantly higher for patients with KIT exon 11-mutant GIST when compared with patients with KIT exon 9-mutant or “wild-type” GIST (no KIT/PDGFRA mutations).

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Cancer Killed While Preserving A Kidney Transplant

MedicalResearch.com Interview with:

Kenar D. Jhaveri, MD Professor of Medicine Division of Kidney Diseases and Hypertension Hofstra Northwell School of Medicine, 100 Community Drive, Great Neck, NY 11021

Dr. Kenar Jhaveri,

Kenar D. Jhaveri, MD
Professor of Medicine
Division of Kidney Diseases and Hypertension
Hofstra Northwell School of Medicine,
100 Community Drive, Great Neck, NY 11021

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

Response: The immune check point inhibitors are novel anti cancer agents being used rapidly in various cancers. Many cancers don’t allow our natural immune system to attack the cancer. These immunotherapy agents “activate” the immune system to attack the cancer. These agents have been reported to cause multiple end organ side effects as noted by this recent NYT article. We also recently reported the known renal effects of immunotherapy.

In the kidney transplant patient who is on immunosuppressive agents, the physicians need to keep the immune system suppressed to preserve the kidney. When one of these agents are used for a cancer in a kidney transplant patient, prior reports have suggested severe rejection episodes and loss of the transplanted kidney. Our case in the NEJM is the first report of a preventive strategy used to allow for simultaneous treatment of cancer and preventive rejection of the kidney. We used a regimen of steroids and sirolimus( an anti-proliferative agent that is used to treat cancer and also is an immunosuppresant) along with the immunotherapy. The cancer started regressing and the kidney did not reject.

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Vaccine Nanodiscs Can Trigger More Cancer Fighting Immune Cells

MedicalResearch.com Interview with:

James Moon, PhD John Gideon Searle Assistant Professor University of Michigan Dept. of Pharmaceutical Sciences and Biomedical Engineering Biointerfaces Institute Ann Arbor, MI, 48109

Dr. James Moon

James Moon, PhD
John Gideon Searle Assistant Professor
University of Michigan
Dept. of Pharmaceutical Sciences and Biomedical Engineering
Biointerfaces Institute
Ann Arbor, MI, 48109

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

Response: The field of cancer immunotherapy has recently made a breakthrough with the clinical success of immune checkpoint inhibitors, which work by removing the brakes on immunosuppressed T-cells. However, these approaches generally work by augmenting pre-existing T-cell immunity and benefit only a subset of patients. In addition, because the majority of somatic mutations in cancer cells are unique to each patient, cancer immunotherapy may benefit from a personalized approach.

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Vandetanib Had Antitumor Activity In RET-rearranged NSC Lung Cancer

MedicalResearch.com Interview with:
Dr Kiyotaka Yoh

Department of Thoracic Oncology
National Cancer Center Hospital East
Kashiwa, Japan

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

Response: LURET is multicenter, single-arm, phase II study to evaluate the efficacy and safety of vandetanib as RET inhibitor in patients with advanced RET-rearranged non-small-cell lung cancer (NSCLC). In 2012, RET rearrangements were identified as rare oncogenic alterations for NSCLC.

Among 17 eligible patients included in primary analysis, the objective response rate was 53% (95% CI 28–77), which met the primary endpoint. At the data cutoff, median progression-free survival was 4.7 months (95% CI 2.8–8.5). Overall, vandetanib was tolerated, with an adverse event profile similar to those seen in previous large population studies of vandetanib in patients with unselected NSCLC.

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First-line ribociclib + letrozole in patients with de novo HR+, HER2- Advanced Breast Cancer

MedicalResearch.com Interview with:

Joyce O'Shaughnessy, MD Co-Chair, Breast Cancer Research Texas Oncology-Baylor Charles A. Sammons Cancer Center

Dr. Joyce O’Shaughnessy

Joyce O’Shaughnessy, MD
Co-Chair, Breast Cancer Research
Texas Oncology-Baylor Charles A. Sammons Cancer Center

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

Response: The MONALEESA-2 trial is a Phase III, randomized, double-blind, international study of LEE011 in combination with letrozole vs. letrozole alone, in postmenopausal women with HR+/HER2- advanced breast cancer who had received no prior systemic therapy for advanced disease.

Because de novo disease has not been previously treated with systemic treatment for early-stage breast cancer, tumors may exhibit a different disease biology, which could result in varied responses compared to patients who experience recurrence of their initial breast cancer. We analyzed a pre-defined subgroup of women with de novo HR+/HER2- advanced breast cancer to better understand the response of LEE011 plus letrozole in this patient population.

In the de novo advanced breast cancer patient sub-group, progression free survival was significantly prolonged; LEE011 plus letrozole reduced the risk of disease progression or death by 55% over letrozole alone (HR=0.448 [95% CI: 0.267–0.750]). The 12-month PFS rate was 82% in the LEE011 plus letrozole arm compared to 66% with letrozole alone.

Most adverse events were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and reduction. The most common all-grade adverse events (≥30% of patients with de novo advanced breast cancer) in the LEE011 plus letrozole arm were neutropenia (70.2%), nausea (48.2%), fatigue (42.1%), alopecia (39.5%), and leukopenia (31.6%).

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Pembrolizumab Found to Be Cost-Effective in Advanced Melanoma

MedicalResearch.com Interview with:

Herbert H F Loong MBBS(HK), PDipMDPath(HK), MRCP(UK), FHKCP, FHKAM(Medicine) Specialist in Medical Oncology Clinical Assistant Professor, Department of Clinical Oncology Deputy Medical Director, Phase 1 Clinical Trials Centre The Chinese University of Hong Kong Prince of Wales Hospital Hong Kong SAR

Dr. Herbert Loong

Herbert H F Loong
MBBS(HK), PDipMDPath(HK), MRCP(UK), FHKCP, FHKAM(Medicine)
Specialist in Medical Oncology
Clinical Assistant Professor, Department of Clinical Oncology
Deputy Medical Director, Phase 1 Clinical Trials Centre
The Chinese University of Hong Kong
Prince of Wales Hospital
Hong Kong SAR

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

Response: Advanced melanoma have previously been known to be a disease with a dismal prognosis. Over the last few years, clinical trials data and real-world clinical experience of checkpoint inhibitors have significantly changed the treatment landscape for advanced melanoma patients. This was first demonstrated with the Anti-CTLA4 Ab Ipilimumab, and more recently with the Anti-PD1 Ab pembrolizumab. Whilst we have seen dramatic improvements in disease control with the use of these agents, the high costs of these drugs may be prohibitive to the average patient who has to pay out-of-pocket and potentially may place significant burdens on healthcare systems. There is a need to rationally assess the cost-effectiveness of these new agents, specifically addressing the potential benefits to the individual patient and to society, whilst balancing the costs that such a treatment may entail.

The assessment of cost-effectiveness of a particular treatment is extremely important in Hong Kong, as this has direct implications on drug reimbursement and accessibility of the particular drug in question at public hospitals in Hong Kong. The aim of the study is to assess the cost-effectiveness of pembrolizumab in patients with advanced melanoma used in the first-line setting in Hong Kong, and comparing it to (1) ipilimumab and (2) cytotoxic chemotherapy. Cytotoxic chemotherapy chosen for comparison were drugs commonly used in the first line setting in Hong Kong, which included dacarbazine, temozolomide and carboplatin+paclitaxel combination. It is important to note that whilst ipilimumab is registered for this indication in Hong Kong, there is no reimbursement of this drug by the Hospital Authority in Hong Kong and patients have to pay out-of-pocket. The cost of ipilimumab and the associated side effects has been prohibitive to most advanced melanoma patients in the public setting.

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Mutliple Sclerosis: Ocrelizumab Lowers Rate of Disease Progression and Disability

MedicalResearch.com Interview with:

Jerry S. Wolinsky, MD Emeritus Professor in Neurology McGovern Medical School part of UTHealth | The University of Texas Health Science Center at Houston Houston’s Health University Department of Neurology Houston, Texas 77030

Dr. Jerry Wolinsky,

Jerry S. Wolinsky, MD
Emeritus Professor in Neurology
McGovern Medical School
The University of Texas Health Science Center at Houston
Houston’s Health University
Department of Neurology
Houston, Texas 77030

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

Response: Multiple sclerosis (MS) clinically is a very heterogeneous disease. It presents in considerably different ways and has a very poorly predictable clinical course. In an attempt to better communicate between experts in the field, there have been multiple attempts to categorize “typical” courses of the disease. How we think about the disease is in part driven by these somewhat artificial categories that lump our patients into those with relapsing forms of the disease (relapsing remitting with or without accumulating clinical disability, and secondary progressive with accumulating disability eventually occurring even in the absence of apparent clinical episodes of the disease), and primary progressive MS, where patients are slowly or sometimes rather rapidly accumulating disability in the absence of prior clinical relapses.

However, the distinctions between multiple sclerosis patients are not always as clear as the definitions would suggest, and it is certain that patients with primary progressive multiple sclerosis sometimes have clinical relapses after years of never having had relapses, and show MRI evidence of having accumulated many lesions in the brain over the course of their disease. Until now, none of the drugs that have shown benefit for relapsing disease have been able to convincingly show clinical benefit for patients with primary progressive disease, and for that matter have shown variable results when attempted in patients categorized as having secondary progressive courses. While some of our currently approved drugs have shown hints of benefit when tried in major clinical trials in primary progressive MS, the results were not been robust enough to seek regulatory approval.

The Oratorio study design was based on lessons learned from prior trials in primary progressive and relapsing forms of MS, as well as the recognition that B cells might play an important role in the immunopathogenesis of disease based on a considerable amount of preclinical work and observations in patients with multiple sclerosis.

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Breast Cancer: PARP Inhibitor Veliparib Has Potential To Enhance Platinum Chemotherapy in Recurrent or Metastatic Disease

MedicalResearch.com Interview with:
Vince Giranda, M.D., PH.D.
Project Director
AbbVie Oncology Development

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

Response: In this Phase 2 study, called BROCADE 2, veliparib combined with the platinum chemotherapy regimen carboplatin and paclitaxel showed positive trends in overall survival (OS) and progression-free survival (PFS), although these were not statistically significant. Importantly there were no meaningful increase in side effects with the addition of veliparib to carboplatin and paclitaxel. The veliparib combination regimen also demonstrated a significantly higher objective response rate.

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