New drugs in preclinical and early stage clinical development in the treatment of heart failure

2018 ◽  
Vol 28 (1) ◽  
pp. 51-71 ◽  
Author(s):  
Juan Tamargo ◽  
Ricardo Caballero ◽  
Eva Delpón
Keyword(s):  
Heart Failure ◽  
Early Stage ◽  
Clinical Development ◽  
New Drugs

scholarly journals EU FP7 research funding for an orphan drug (Orfadin®) and vaccine (Hep C) development: a success and a failure?

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
L. Schmidt ◽  
O. Sehic ◽  
C. Wild
Keyword(s):  
Hepatitis C ◽  
Late Stage ◽  
Research Funding ◽  
Early Stage ◽  
Basic Research ◽  
Pharmaceutical Products ◽  
Clinical Development ◽  
Clinical Indication ◽  
Market Authorisation ◽  
Risk Capital

Abstract Background We considered the extent of the contribution of publicly funded research to the late-stage clinical development of pharmaceuticals and medicinal products, based on the European Commission (EC) FP7 research funding programme. Using two EC FP7-HEALTH case study examples—representing two types of outcomes—we then estimated wider public and charitable research funding contributions. Methods Using the publicly available database of FP7-HEALTH funded projects, we identified awards relating to late-stage clinical development according to the systematic application of inclusion and exclusion criteria, classified them according to product type and clinical indication, and calculated total EC funding amounts. We then identified two case studies representing extreme outcomes: failure to proceed with the product (hepatitis C vaccine) and successful market authorisation (Orfadin® for alkaptonuria). Total public and philanthropic research funding contributions to these products were then estimated using publicly available information on funding. Results 12.3% (120/977) of all EC FP7-HEALTH awards related to the funding of late-stage clinical research, totalling € 686,871,399. Pharmaceutical products and vaccines together accounted for 84% of these late-stage clinical development research awards and 70% of its funding. The hepatitis C vaccine received total European Community (FP7 and its predecessor, EC Framework VI) funding of €13,183,813; total public and charitable research funding for this product development was estimated at € 77,060,102. The industry sponsor does not consider further development of this product viable; this now represents public risk investment. FP7 funding for the late-stage development of Orfadin® for alkaptonuria was so important that the trials it funded formed the basis for market authorisation, but it is not clear whether the price of the treatment (over €20,000 per patient per year) adequately reflects the substantial public funding contribution. Conclusions Public and charitable research funding plays an essential role, not just in early stage basic research, but also in the late-stage clinical development of products prior to market authorisation. In addition, it provides risk capital for failed products. Within this context, we consider further discussions about a public return on investment and its reflection in pricing policies and decisions justified.

New Drugs for Heart Failure: What is the Evidence in Older Patients?

2021 ◽  
Author(s):  
Francesco Orso ◽  
Andrea Herbst ◽  
Alessandra Pratesi ◽  
Francesco Fattirolli ◽  
Andrea Ungar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Older Patients ◽  
New Drugs

Abstract 065: Cardiac Fibrosis and Heart Failure Caused by DsRed Tetramers Involves the Induction of Tissue Inhibitor of Metalloproteinase-1

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Tsung-Hsien Chen ◽  
Shan-Wen Liu ◽  
Mei-Ru Chen ◽  
Kurt M Lin
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Fluorescent Protein ◽  
Early Stage ◽  
Transglutaminase 2 ◽  
Underlying Mechanism ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Cardiac Tissues ◽  
Cardiac Symptoms

Whereas aggregation of intracellular proteins was linked to the initiation of cardiac myopathy, the sequence of participating events, including myocyte apoptosis, autophagy, necrosis and fibrosis as the underlying mechanisms leading to heart failure, was not clear. Green fluorescent protein (GFP) and its derivatives induced cardiac dysfunction in mice when expressed in high quantity; however, the mechanism underlying the aggregation of fluorescent protein leading to heart failure remains unexplored.We created a transgenic mouse with switchable expression of the GFP monomer or the expression of DsRed, a red fluorescent protein (RFP) tetramer that tends to aggregate into a large protein complex. GFP mice were free of cardiac symptoms; in contrast, RFP mice with homozygous DsRed alleles developed myocyte necrosis, carditis, ventricular hypertrophy and fibrosis, left atrium thrombosis, dilated heart failure and death at the age of approximately five months. The hemizygote mice displayed similar symptoms at a later age. The expression of the microtubule-associated protein 1 light chain 3 cleaved isoform II (LC3 II) and transglutaminase 2, and the expression of many myopathy- and fibrosis-related genes were significantly induced in the hearts of two-month-old RFP mice. Together with the findings of increased autophagosomes, lysosomes and dysfunctional mitochondria, these results suggest a marked induction of myocyte autophagy and fibrosis as the main underlying mechanism of heart failure in RFP mice. Interestingly, apoptosis was not elevated in RFP hearts. One of the most up-regulated genes in the early stage RFP heart was the tissue inhibitor of matrix metalloproteinases type 1 (TIMP-1), corroborating the role of TIMP-1 in cardiac remodeling and anti-apoptotic activity. The heart-origin of the morbidity in RFP mice was confirmed by expressing DsRed tetramers specifically in cardiac tissues, and the same phenotypes as in RFP mice were observed. In summary, in cardiac myocytes under the stress of protein aggregation, strong induction of TIMP-1 and down-regulation of MMP activity may play a significant role in enhancing the synthesis of extracellular matrix, resulting in fibrosis and heart failure.

scholarly journals New Drugs for Acute Heart Failure

2012 ◽  
Vol 7 (1) ◽  
pp. 35-38
Author(s):  
Mohammad Salman ◽  
Syed Allahsan ◽  
Manzoor Mahmood ◽  
Md Khairul Anam ◽  
Shahed Mohammad Anwar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renal Failure ◽  
Acute Heart Failure ◽  
Health Problem ◽  
Standard Therapy ◽  
New Drugs ◽  
European Medicines Agency ◽  
Major Health Problem ◽  
Major Health ◽  
Long Time

Acute heart failure is a major health problem responsible for several million hospitalizations worldwide each year. Standard therapy has not changed for long time and includes diuretics and variable use of vasodilators or inotropes. Recently Nesiritide and Levosimendan are two drugs for the treatment of acute heart failure which have been approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMEA), respectively. There was little concern that Nesiritide can worsen the renal failure but recent trials had abolished this concern. DOI: http://dx.doi.org/10.3329/uhj.v7i1.10208 UHJ 2011; 7(1): 35-38

scholarly journals AUTOREGULATION OF BRAIN CIRCULATION IN PROGRESSING CARDIAC FAILURE AND ITS RELATION TO THE APPEARANCE OF SEIZURE READINESS

2016 ◽  
Vol 15 (2) ◽  
pp. 86-93
Author(s):  
M.L. Mamalyga ◽  
◽  
L.M. Mamalyga ◽  
Keyword(s):  
Heart Failure ◽  
Blood Flow ◽  
Cardiac Failure ◽  
Early Stage ◽  
Brain Circulation ◽  
Brain Disorders ◽  
Compression Tests ◽  
Cardiac Decompensation ◽  
Severe Stage ◽  
Basilar Arteries

On the early stage of cardiac decompensation, the blood flow in common carotid and basilar arteries does not change, however the seizure readiness (SR) of animals increases. The preserved reaction on hypercapnic and compression tests allows us to stipulate that the increased SR is not related to the circulatory brain disorders. Progressive aggravation of cardiac failure (CF) leads to the severe stage of decompensation accompanied by decreased blood flow in common carotid and basilar arteries, as well as increases SR. At the same time the metabolic cascade of autoregulation is areactive and myogenic is significantly decreased. Ineffective operation of heart in different stages of heart failure shows not the same effect or backup possibilities for cerebral hemodynamic autoregulation affecting the formation and aggravation of SR. The increased SR in cardiac failure is not always caused by brain ischemia.

scholarly journals Diagnosis, treatment, and follow-up of heart failure patients by general practitioners: A Delphi consensus statement

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244485
Author(s):  
Caroline Verhestraeten ◽  
Gijs Weijers ◽  
Daphne Debleu ◽  
Agnieszka Ciarka ◽  
Marc Goethals ◽  
...  
Keyword(s):  
Heart Failure ◽  
General Practitioner ◽  
General Practitioners ◽  
Early Stage ◽  
Blood Analysis ◽  
Care Process ◽  
Delphi Panel ◽  
Delphi Consensus ◽  
Heart Failure Patients

Aims Creation of an algorithm that includes the most important parameters (history, clinical parameters, and anamnesis) that can be linked to heart failure, helping general practitioners in recognizing heart failure in an early stage and in a better follow-up of the patients. Methods and results The algorithm was created using a consensus-based Delphi panel technique with fifteen general practitioners and seven cardiologists from Belgium. The method comprises three iterations with general statements on diagnosis, referral and treatment, and follow-up. Consensus was obtained for the majority of statements related to diagnosis, referral, and follow-up, whereas a lack of consensus was seen for treatment statements. Based on the statements with good and perfect consensus, an algorithm for general practitioners was assembled, helping them in diagnoses and follow-up of heart failure patients. The diagnosis should be based on three essential pillars, i.e. medical history, anamnesis and clinical examination. In case of suspected heart failure, blood analysis, including the measurement of NT-proBNP levels, can already be performed by the general practitioner followed by referral to the cardiologist who is then responsible for proper diagnosis and initiation of treatment. Afterwards, a multidisciplinary health care process between the cardiologist and the general practitioner is crucial with an important role for the general practitioner who has a key role in the up-titration of heart failure medication, down-titration of the dose of diuretics and to assure drug compliance. Conclusions Based on the consensus levels of statements in a Delphi panel setting, an algorithm is created to help general practitioners in the diagnosis and follow-up of heart failure patients.

scholarly journals Characteristics and Outcomes of Women Developing Heart Failure After Early Stage Breast Cancer Chemotherapy: A Population-Based Matched Cohort Study

2021 ◽  
Author(s):  
Husam Abdel-Qadir ◽  
Felicia Tai ◽  
Ruth Croxford ◽  
Peter C. Austin ◽  
Eitan Amir ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Heart Failure ◽  
Early Stage ◽  
Sequential Therapy ◽  
Cardiovascular Death ◽  
Population Based ◽  
Emergency Department Visits ◽  
Early Stage Breast Cancer ◽  
Administrative Databases ◽  
Breast Cancer Chemotherapy

Background: The prognosis of heart failure (HF) after early stage breast cancer (EBC) treatment with anthracyclines or trastuzumab is not well-characterized. Methods: Using administrative databases, women diagnosed with HF after receiving anthracyclines or trastuzumab for EBC in Ontario during 2007 to 2017 (the EBC-HF cohort) were categorized by cardiotoxic exposure (anthracycline alone, trastuzumab alone, sequential therapy with both agents) and matched on age with ≤3 cancer-free HF controls to compare baseline characteristics. To study prognosis after HF onset, we conducted a second match on age plus important HF prognostic factors. The cumulative incidence function was used to describe risk of hospitalization or emergency department visits (hospital presentations) for HF and cardiovascular death. Results: A total of 804 women with EBC developed HF after anthracyclines (n=312), trastuzumab (n=112), or sequential therapy (n=380); they had significantly fewer comorbidities than 2411 age-matched HF controls. After the second match, the anthracycline-HF cohort had a similar 5-year incidence of HF hospital presentations (16.5% [95% CI, 12.0%–21.7%]) as controls (17.1% [95% CI, 14.4%–20.1%]); the 5-year incidence was lower than matched controls for the trastuzumab-HF (9.7% [95% CI, 4.7%–16.9%]; controls 16.4% [95% CI, 12.1%–21.3%]; P =0.03) and sequential-HF cohorts (2.7% [95% CI, 1.4%–4.8%]; controls 10.8% [95% CI, 8.9%–13.0%]; P <0.001). At 5 years, the incidence of cardiovascular death was 2.9% (95% CI, 1.2%–5.9%) in the anthracycline-HF cohort vs. 9.5% (95% CI, 6.9%–12.6%) in controls, and 1.7% (0.6%–3.7%) for women developing HF after trastuzumab vs. 4.3% (95% CI, 3.1–5.8%) for controls. Conclusions: Women developing HF after cardiotoxic EBC chemotherapy have fewer comorbidities than cancer-free women with HF; trastuzumab-treated women who develop HF have better prognosis than matched HF controls.

scholarly journals Assessing the Clinical Benefit of Systemic Adjuvant Therapies for Early Breast Cancer

2017 ◽  
Vol 77 (10) ◽  
pp. 1079-1087 ◽  
Author(s):  
Volker Möbus ◽  
Susanne Hell ◽  
Marcus Schmidt
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Clinical Benefit ◽  
Early Stage ◽  
Survival Rates ◽  
Disease Free Survival ◽  
New Drugs ◽  
Early Stage Breast Cancer ◽  
Risk Of Recurrence ◽  
Adjuvant Therapies

AbstractOncologic therapy is currently undergoing significant changes. A number of innovative targeted medications currently in clinical development have raised high expectations. With that in mind, discussions about terms such as “clinical benefit” and “clinical relevance” are highly topical. This also applies to further developments in the field of adjuvant systemic therapies for early-stage breast cancer. As the treatment aim is curative, assessment of the clinical benefit of adjuvant therapies must be largely based on efficacy outcomes. The focus must be on improving disease-free survival rates and lowering the risk of recurrence. Because of the current low mortality rates, statements about overall survival rates are only possible after very long observation periods. Consequently, new drugs in adjuvant therapies should be considered as offering a clinical benefit, if they reduce the risk of recurrence below current low levels of risk. The evidence for established adjuvant therapy standards in early-stage breast cancer can be used as objective criteria for comparison. This review article considers the requirements for clinical benefit of new adjuvant therapies for early breast cancer, based on examples from adjuvant endocrine therapy, adjuvant polychemotherapy and adjuvant anti-HER2 therapy.

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