Telemetric long-term assessment of autonomic function in experimental heart failure.

Despite medical advances in the treatment of heart failure (HF), mortality remains high. It has been shown that alterations of the autonomic-nervous-system (ANS) are associated with HF progression and increased mortality. Preclinical models are required to evaluate the effectiveness of novel treatments modulating the autonomic imbalance.

Critical path activities in clinical trial setup and conduct: How to avoid bottlenecks and accelerate clinical trials.

Most clinical trials are delayed due to scientific and/or operational challenges. Any effort to minimize delays can generate value for patients and sponsors. This article reviews critical path process steps commonly identified by practitioners, such as during protocol development, site contracting, or patient recruitment.

Reasons for supply side driven drug shortages - A mixed-methods study on first-level, higher-level, and root causes from the perspective of marketing authorization holders.

Background: Drug shortages impact multiple stakeholders and are detrimental to patient safety. Additionally, drug shortages are an extensive financial burden. In Germany, drug shortages, according to data from the federal ministry for drug and medical products (BfArM), have been increasing by 18% between 2018 and 2021.

Predictive validity in drug discovery: what it is, why it matters and how to improve it.

Successful drug discovery is like finding oases of safety and efficacy in chemical and biological deserts. Screens in disease models, and other decision tools used in drug research and development (R&D), point towards oases when they score therapeutic candidates in a way that correlates with clinical utility in humans. Otherwise, they probably lead in the wrong direction.

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC.

Background: Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential.

Methods: We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung.

"Digital biomarkers" in preclinical heart failure models - a further step towards improved translational research.

Innovations in the development of novel heart failure therapies are essential to further increase the predictive value of early research findings. Animal models are still playing a pivotal role in 'translational research'. In recent years, the transferability from animal studies has been more and more critically discussed due to persistent high attrition rates in clinical trials.

Healthcare Providers' Knowledge of Value-Based Care in Germany: An Adapted, Mixed-Methods Approach.

Background: Value-Based Care (VBC) is being discussed to provide better outcomes to patients, with an aim to reimburse healthcare providers (HCPs) based on the quality of care they deliver. Little is known about German HCPs' knowledge of VBC. This study aims to investigate the knowledge of HCPs of VBC and to identify potential needs for further education toward implementation of VBC in Germany.

A novel approach for quantification of the future unmet medical need in right ventricular dysfunction.

Although 'unmet medical need' (UMN) is an increasingly used term in the healthcare sector instrumental to the approximate value of drug discovery projects relevant to portfolio management, no standardized approach exists for its quantification. Especially in diseases with different comorbidities, high patient heterogeneity, and incomplete epidemiological data, it is difficult to judge the need for new therapies. The approach presented here combines an expert assessment of key UMN indicators related to the individual patient with a literature search to collect epidemiological data describing the corresponding patient population with its underlying heterogeneity.

Perspective of German medical faculties on digitization in the healthcare sector and its influence on the curriculum.

The German healthcare sector is in the process of being disrupted by digitization. Universities are asked to reflect on the consequences and develop strategies to prepare their medical students for a digitalized health care sector. The current state of research does not systematically record the associated activities of individual medical faculties in Germany.

sGC stimulation lowers elevated blood pressure in a new canine model of resistant hypertension.

Therapy-resistant hypertension is a serious medical problem, causing end-organ damage, stroke, and heart failure if untreated. Since the standard of care fails in resistant hypertension patients, there is still a substantial unmet medical need for effective therapies. Active stimulation of soluble guanylyl cyclase via novel soluble guanylyl cyclase stimulators might provide an effective treatment option.

Utilizing machine learning to improve clinical trial design for acute respiratory distress syndrome.

Heterogeneous patient populations, complex pharmacology and low recruitment rates in the Intensive Care Unit (ICU) have led to the failure of many clinical trials. Recently, machine learning (ML) emerged as a new technology to process and identify big data relationships, enabling a new era in clinical trial design. In this study, we designed a ML model for predictively stratifying acute respiratory distress syndrome (ARDS) patients, ultimately reducing the required number of patients by increasing statistical power through cohort homogeneity.

Social media mining in drug development-Fundamentals and use cases.

The incorporation of patients' perspectives into drug discovery and development has become critically important from the viewpoint of accounting for modern-day business dynamics. There is a trend among patients to narrate their disease experiences on social media. The insights gained by analyzing the data pertaining to such social-media posts could be leveraged to support patient-centered drug development.

Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042).

Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress.

Danger in the Valley of Death: how the transition from preclinical research to clinical trials can impact valuations.

In drug development, a crucial step is the transition of a company from preclinical stages to human trials: the so-called 'Valley-of-Death' (VoD) that most efforts do not survive. Here, we analyzed how the valuations of biotech companies in the life science sector change as they cross this valley. Their average valuation increased significantly (87%) when crossing the VoD no later than their fourth funding round.

Cardiac output improvement by pecavaptan: a novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure.

Aims: Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short-term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long-term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre-clinical HF models.

Digital Competencies and Attitudes Toward Digital Adherence Solutions Among Elderly Patients Treated With Novel Anticoagulants: Qualitative Study.

Background: Nonadherence to medication is a driver of morbidity and mortality, and complex medication regimens in patients with chronic diseases foster the problem. Digital technology might help, but despite numerous solutions being developed, none are currently widely used, and acceptance rates remain low, especially among the elderly.

Objective: This study aimed to better understand and operationalize how new digital solutions can be evaluated.

Perception of the Progressing Digitization and Transformation of the German Health Care System Among Experts and the Public: Mixed Methods Study.

Background: Health care systems worldwide are struggling to keep rising costs at bay with only modest outcome improvement among many diseases. Digitization with technologies like Artificial Intelligence or Machine Learning algorithms might address this. Although digital technologies have been successfully applied in clinical studies the effect on the overall health care system so far was limited.

Vascular Protection and Decongestion Without Renin-Angiotensin-Aldosterone System Stimulation Mediated by a Novel Dual-Acting Vasopressin V1a/V2 Receptor Antagonist.

Increased plasma vasopressin levels have been shown to be associated with the progression of congestive heart failure. Vasopressin mediates water retention by renal tubular V2 receptor activation as well as vasoconstriction, cardiac hypertrophy, and fibrosis through V1a receptor activation. Therefore, we developed a novel, dual-acting vasopressin receptor antagonist, BAY 1753011, with almost identical Ki-values of 0.

A proof-of-concept trial of HELIOX with different fractions of helium in a human study modeling upper airway obstruction.

Background: Helium in oxygen (HELIOX) can relieve airway obstruction and lower the work of breathing because it increases the threshold at which turbulent gas flow is induced. Less turbulent and more laminar flow lowers the work of breathing. According to guidelines, the fraction of Helium in HELIOX should be maximized (e.

How soon will digital endpoints become a cornerstone for future drug development?

Digital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late-stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA).

Remote Left Ventricular Hemodynamic Monitoring Using a Novel Intracardiac Sensor.

Background: Heart failure (HF) remains the most common reason for hospital admission in patients aged >65 years. Despite modern drug therapy, mortality and readmission rates for patients hospitalized with HF remain high. This necessitates further research to identify early patients at risk for readmission to limit hospitalization by timely adjustment of medical therapy.

Digital Transformation and Disruption of the Health Care Sector: Internet-Based Observational Study.

Background: Digital innovation, introduced across many industries, is a strong force of transformation. Some industries have seen faster transformation, whereas the health care sector only recently came into focus. A context where digital corporations move into health care, payers strive to keep rising costs at bay, and longer-living patients desire continuously improved quality of care points to a digital and value-based transformation with drastic implications for the health care sector.

New pulmonary hypertension model in conscious dogs to investigate pulmonary-selectivity of acute pharmacological interventions.

Purpose: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal.