Lack of pro-arrhythmic potential for the novel soluble guanylate cyclase stimulator vericiguat: results from preclinical studies

Introduction Vericiguat is an orally-administered soluble guanylate cyclase stimulator, developed for the treatment of symptomatic chronic heart failure (HF) in adult patients who have had a previous decompensation event. At the maximum therapeutic dose of 10 mg once daily in patients with HF, the protein-unbound plasma concentrations of vericiguat and its major pharmacologically inactive N-glucuronide metabolite M-1 are approximately 18 nmol/l and 43 nmol/l, respectively. As part of an integrated risk assessment, vericiguat and its M-1 metabolite were characterised electrophysiologically in vivo and in vitro. This was performed according to the International Council for Harmonisation standard S7B guideline and to recent related “best practice” revisions (draft ICH E14/S7B Q&A), being adopted as a result of the Comprehensive In Vitro Proarrhythmia Assay (CIPA) initiative. Purpose To assess the potential for a proarrhythmic risk from vericiguat and its M-1 metabolite in a series of preclinical studies. Methods The potential for proarrhythmic risk was investigated in conscious telemetered dogs and in a series of in vitro electrophysiological studies, including mechanistic ion channel studies, using both generally accepted and CIPA voltage-clamp protocols under conditions simulating normal and diseased physiological states. The ion channels studied were hERG, hNav1.5, hCav1.2, hKvLQT1/minK and hKv4.3. Transfected human embryonic kidney cell lines were used for the hERG, hNav1.5 and hKvLQT1/minK studies; transfected Chinese hamster ovary cell lines were used for the hCav1.2 and hKv4.3 studies. Results In dogs, administration of vericiguat as single oral doses was associated with dose-dependent decreases in arterial blood pressure (consistent with its mode of action) and compensatory increases in heart rate (Table 1). Heart rate-corrected QT (QTc) intervals were not prolonged by vericiguat to a clinically meaningful extent. Neither vericiguat nor its M-1 metabolite inhibited cardiac ion channels (hERG, hNav1.5, hCav1.2, hKvLQT1/minK and hKv4.3) at exposure multiples of >150-fold (Table 2). Conclusion There was no preclinical evidence of proarrhythmic risk from the in vitro (simulating normal and diseased physiological states) and in vivo assessment of vericiguat or its major N-glucuronide metabolite M-1. This integrated risk assessment of non-clinical data supports the conclusion that administration of vericiguat 10 mg once daily in humans is not associated with meaningful QTc prolongation. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding for this research was provided by Bayer AG, Berlin, Germany and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Antiarrhythmic Medication for Atrial Fibrillation (AIM-AF) study: A physician survey of sotalol use and patient monitoring in the EU and USA

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Sanofi Introduction In the recent 2020 European Society of Cardiology (ESC) guidelines, sotalol was downgraded from a Class IA to a llbA recommendation and advised not to be prescribed in patients with specific co-morbidities. All patients given sotalol should also be closely monitored for proarrhythmic risk factors. To date, American guidelines have not changed. Our study sought to understand the use of sotalol in AF patients and monitoring compliance across the USA and in the EU, with regards to the recent ESC guideline change. Method An online physician survey of cardiologists, cardiac electrophysiologists (EPs) and interventional EPs (N = 569) was conducted in the USA, Germany, Italy and the UK. All respondents were actively treating ≥10 AF patients who received drug therapy and/or who had received or were referred for ablation. This survey included topics on AF types and antiarrhythmic drug (AAD) treatment practices in those with AF +/- co-morbidities (including left ventricular hypertrophy [LVH], LV heart failure, and sinus node dysfunction or renal impairment). Results Sotalol was prescribed across all patient sub-groups, with high use in those with hypertension (49% of physicians) and revascularised coronary artery disease (44%). Sotalol use was consistently higher among US respondents than EU clinicians across co-morbidity categories (heart failure with reduced ejection fraction: 25% vs 14% [guideline deviation]; hypertension: 53% vs 44%; valve disease: 33% vs 23%; recent myocardial infarction [MI]: 44% vs 22%; old MI: 52% vs 31%, respectively). Use was also generally higher among EPs compared with cardiologists, but remained low in patients with minimal or no structural heart disease across all groups. Many respondents prescribed sotalol in those with LVH (35%) or renal impairment (22%), despite guidelines advising against this due to proarrhythmia risk. This contrasts with expressed respondent concerns, as 43% cited ventricular proarrythmia risk as a reason for not using sotalol. Although respondents noted concern over such risks, as per the new guidelines, routine monitoring for these factors was not performed as follows: electrocardiograms (ECG) (19% [US: 23%; EU: 15%]), renal function assessment (42% [US: 36%; EU: 50%]) or electrolyte monitoring (48% [US: 49%; EU: 46%]). Respondents reported sotalol is typically initiated in hospital (45% of patients) or in outpatients with intensive ECG monitoring (37%), but is also being started in non-monitored outpatients (19%). Conclusions Although sotalol use among EU clinicians was lower compared with the USA, which may reflect recent ESC guideline changes, the extent of monitoring practices that would indicate avoidance in those with proarrhythmic risk factors was insufficient. The lack of routine monitoring for specific factors, such as renal impairment or electrolytes, and unmonitored outpatient initiation highlights an ongoing need for further education on maximising safety when using AADs. Abstract Figure.

Inflammation as a Risk Factor in Cardiotoxicity: An Important Consideration for Screening During Drug Development

Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K+ channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications’ cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how in silico modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development.

Comprehensive preclinical evaluation of how cardiac safety profiles of potential COVID-19 drugs are modified by disease associated factors.

Background and Purpose: Hydroxychloroquine and chloroquine, alone or in combination with azithromycin, have been proposed as therapies for COVID-19. However, there is currently scant and inconsistent data regarding their proarrhythmic potential in these patients. Moreover, their risk profile in the setting of altered physiological states encountered in patients with COVID-19 (i.e. febrile state, electrolyte imbalances, and/or acidosis) is unknown. Experimental approach: Potency of hERG block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from three separate individuals. Key Results: Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47±0.07 µM and 3.78±0.17 µM respectively, indicating proarrhythmic risk at concentrations effective against SARS-CoV-2 in vitro and proposed in COVID-19 clinical trials. Hypokalaemia and hypermagnesemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs (i.e. reduced proarrhythmic risk), whereas increased temperature decreased potency of chloroquine and hydroxychloroquine but increased potency for azithromycin. In silico simulations across genetically diverse populations predicted that 17% of individuals exhibit action potential durations >500 ms at the highest proposed therapeutic levels, equating to significant QT prolongation. Conclusion and Implications: Significant proarrhythmic risk is predicted for hydroxychloroquine and chloroquine at doses proposed to treat COVID-19. Clinicians should carefully consider the risk of such treatments, and implement long term QT interval monitoring in trials, particularly in patients with electrolyte imbalances.

Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs

Introduction: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals. Methods: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects. Results: Covariate adjusted QT (slope −12.57 ms/°C) and JTpca (−14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca. Conclusion: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.