Electrocardiographic assessment for therapeutic proteins—scientific discussion

Rodríguez, I.; Erdman, Andrew R.; Padhi, Desmond; Garnett, Christine; Zhao, Hong; Targum, Shari L.; Balakrishnan, Suchitra; Strnadova, Colette; Viner, Norman; Geiger, Margarethe; Newton‐Cheh, Christopher; Litwin, Jeffrey; Sager, Philip T.; Krucoff, Mitchell W.; Finkle, John K.

doi:10.1016/j.ahj.2010.07.001

Cited by 34 publications

(29 citation statements)

References 29 publications

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“…Since this is the first dedicated QTc study conducted for an ADC to the best of our knowledge, multiple analytes (T‐DM1 conjugate, total trastuzumab, and DM1) were assessed to evaluate the effect of T‐DM1 on QTc interval. According to a white paper published recently by the Cardiac Safety Research Consortium, ADCs may require a TQT study as outlined in the ICH E14 guidelines or a study that incorporates many of the key components of the TQT study if evidence suggests that the small molecule component of the ADC or its metabolites might become systemically available in humans . In addition, for ADCs with target expression in and around the heart, additional consideration should be given to the degree to which the small molecule component and/or its metabolites will be locally bioavailable to cardiac myocytes.…”

Section: Discussionmentioning

confidence: 99%

“…There are several reasons for this difficulty. First, the cytotoxic effects of most anticancer agents preclude their study in healthy volunteers . Second, the ICH E14 guidelines do not specifically address potential QT/QTc effects in biologic therapeutics such as monoclonal antibodies or ADCs.…”

mentioning

confidence: 99%

“…Second, the ICH E14 guidelines do not specifically address potential QT/QTc effects in biologic therapeutics such as monoclonal antibodies or ADCs. Current guidelines were originally developed for small molecule drugs, which differ from monoclonal antibodies and ADCs in their pharmacokinetic and safety profiles . Third, evidence suggests that the QT interval is generally longer in patients with cancer, as a consequence of underlying disease or because of the use of concomitant oncology medications that are known to prolong the QTc interval .…”

mentioning

confidence: 99%

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Effects of Trastuzumab Emtansine (T‐DM1) on QT Interval and Safety of Pertuzumab Plus T‐DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Gupta¹,

Wang²,

Carrothers³

et al. 2013

Clinical Pharm in Drug Dev

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Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in development for human epidermal growth factor receptor 2 (HER2)-positive cancer. Drugs in development are generally tested for their effects on QT interval, prolongation of which is associated with the potentially fatal arrhythmia torsades de pointes. In addition, an association between left ventricular dysfunction and other HER2-directed agents has been documented. This multicenter, phase 2 study, TDM4688g, assessed the safety and pharmacokinetic characteristics of T-DM1 (3.6 mg/kg every 3 weeks) in patients with previously treated HER2-positive metastatic breast cancer, and the safety of pertuzumab plus T-DM1, an anti-HER2 extracellular domain antibody, in patients with early disease progression on T-DM1 alone. The primary end point was the change in QTc interval from baseline to each postbaseline time point, adjusted for heart rate using Fridericia's correction. T-DM1 had no clinically relevant effect on QTc interval. The observed upper limit of the one-sided 95% confidence interval was below the 10-millisecond threshold of safety concern. The safety and efficacy of single-agent T-DM1 was consistent with that observed in previous studies. Pertuzumab plus T-DM1 was generally well tolerated with no new safety signals. These results support further investigation of T-DM1 as a single agent and with pertuzumab.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Effects of Trastuzumab Emtansine (T‐DM1) on QT Interval and Safety of Pertuzumab Plus T‐DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Gupta¹,

Wang²,

Carrothers³

et al. 2013

Clinical Pharm in Drug Dev

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“…Because protein therapeutics are designed to be highly specific, adverse reactions are most commonly a result of exaggerated pharmacology (e.g., from prolonged target inhibition) 25 . Since CGRP is a vasodilator, its inhibition might be expected to translate into increased blood pressure and secondarily increased heart rate.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide

Walter

Alibhoy

Escandón³

et al. 2014

mAbs

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Calcitonin gene-related peptide (CGRP) is a well-validated target for migraine therapy and a known potent systemic vasodilator. LBR-101 is a monoclonal antibody against CGRP in clinical development for the preventive treatment of episodic and chronic migraine. Understanding the hemodynamic and cardiovascular consequences of chronic CGRP inhibition is therefore warranted. Given the conservation in CGRP sequence between monkeys and humans, addressing this question in monkeys is ideal as it allows dosing at super-therapeutic levels. To this end, two independent studies were conducted in monkeys: a single dedicated cardiovascular safety study and a repeat-dose, chronic study, both with electrocardiogram and hemodynamic assessments. LBR-101 was very well tolerated in both studies, with no clinically significant changes noted in any hemodynamic parameter, nor any relevant changes noted in any ECG parameter. In cynomolgus monkeys, cardiovascular and hemodynamic parameters do not appear to be affected by long-term inhibition of CGRP with LBR-101.

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“…27 These platforms provide information on drug-induced effects from cardiac electrophysiology, including cardiac repolarization, 28 conduction defects, and incidence of arrhythmic events. The duration of ventricular depolarization and repolarization is shown as the QT interval on an ECG.…”

Section: Sudden Cardiac Deathmentioning

confidence: 99%

Finding the Rhythm of Sudden Cardiac Death

Sallam

Sager

et al. 2015

Circulation Research

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Sudden Cardiac Death (SCD) is a common cause of death in patients with structural heart disease, genetic mutations or acquired disorders affecting cardiac ion channels. A wide range of platforms exist to model and study disorders associated with SCD. Human clinical studies are cumbersome and are thwarted by the extent of investigation that can be performed on human subjects. Animal models are limited by their degree of homology to human cardiac electrophysiology including ion channel expression. Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single ion channel offering incomplete insight into changes of the action potential profile. Induced pluripotent stem cell derived Cardiomyocytes (iPSC-CMs) resemble, but are not identical, to adult human cardiomyocytes, and provide a new platform for studying arrhythmic disorders leading to SCD. A variety of platforms exist to phenotype cellular models including conventional and automated patch clamp, multi-electrode array, and computational modeling. iPSC-CMs have been used to study Long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and other hereditary cardiac disorders. Although iPSC-CMs are distinct from adult cardiomyocytes, they provide a robust platform to advance the science and clinical care of SCD.

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Electrocardiographic assessment for therapeutic proteins—scientific discussion

Cited by 34 publications

References 29 publications

Effects of Trastuzumab Emtansine (T‐DM1) on QT Interval and Safety of Pertuzumab Plus T‐DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Effects of Trastuzumab Emtansine (T‐DM1) on QT Interval and Safety of Pertuzumab Plus T‐DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide

Finding the Rhythm of Sudden Cardiac Death

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