Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics

Vargas, Hugo M.; Bass, Alan S.; Breidenbach, Alexander; Feldman, Hal S.; Gintant, Gary A.; Harmer, Alex; Heath, Bronagh; Hoffmann, Peter; Lagrutta, Armando; Leishman, Derek J.; McMahon, Nick; Mittelstadt, Scott W.; Polonchuk, Liudmila; Pugsley, Michael K.; Salata, Joseph J.; Valentin, Jean‐Pierre

doi:10.1016/j.vascn.2008.04.001

Cited by 116 publications

(50 citation statements)

References 32 publications

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“…jpet.aspetjournals.org gion (anti-Kv11.1 pAb; Extra) or the use of an intracellular anti-Kv11.1 pAb to mimic nonspecific extracellular blockade were devoid of any effect on hERG channel function in vitro. These findings with the two pAb reagents demonstrate that large molecules, e.g., antibody type, are unlikely to have nonspecific effects at the hERG channel because such protein therapeutics are engineered to have high specificity for their molecular target/epitope and have little ability to block the hERG channel specifically in contrast with small-moleculelike drugs (Vargas et al, 2008).…”

Section: Bekm-1 Prolongs Qtc Intervals In Isolated Rabbitmentioning

confidence: 87%

BeKm-1, a Peptide Inhibitor of Human ether-a-go-go-Related Gene Potassium Currents, Prolongs QTc Intervals in Isolated Rabbit Heart

Fang²,

Gao³

et al. 2010

J Pharmacol Exp Ther

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Drug-induced cardiac arrhythmia, specifically Torsades de pointes, is associated with QT/QTc interval prolongation, thus prolongation of the QT interval is considered as a biomarker for Torsades de pointes risk (N Engl J Med 350:1013-1022, 2004). Specific inhibition of human ether-a-go-go-related gene (hERG) potassium channels has been recognized as the main mechanism for QT prolongation (Cardiovasc Res 58:32-45, 2003). This mechanism has been demonstrated for a variety of smallmolecule agents, which access the inner pore of the hERG channel preferentially from inside the cell. Peptide inhibitors of hERG, such as BeKm-1, interact with the extracellular amino acid residues close to the external pore region of the channel. In this study, the isolated rabbit heart was used to assess whether BeKm-1 could induce QTc prolongation like dofetilide and N- [4-[[1-[2-(6-methyl-2-pyridinyl) ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide (E-4031). Five hearts were perfused with 10 and 100 nM BeKm-1 sequentially. ECG parameters and left ventricular contractility were measured with spontaneously beating hearts. Both concentrations of BeKm-1 prolonged QTc intervals significantly and concentration-dependently (4.7 and 16.3% at 10 and 100 nM, respectively). When evaluated for their inhibitory effect in a hERG functional assay, BeKm-1, dofetilide, and E-4031 caused QTc prolongation at concentrations that caused significant hERG channel inhibition. Lastly, two polyclonal anti-hERG antibodies were also assessed in the hERG channel assay and found to be devoid of any inhibitory effect. These results indicated that the isolated rabbit heart assay can be used to measure QTc changes caused by specific hERG inhibition by peptides that specifically block the external pore region of the channel.

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Section: Bekm-1 Prolongs Qtc Intervals In Isolated Rabbitmentioning

confidence: 87%

BeKm-1, a Peptide Inhibitor of Human ether-a-go-go-Related Gene Potassium Currents, Prolongs QTc Intervals in Isolated Rabbit Heart

Fang²,

Gao³

et al. 2010

J Pharmacol Exp Ther

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“…As more and more small-molecule pharmaceutical companies enter the biopharmaceutical realm, the need for clarity around the differences between safety testing for the two classes of pharmaceuticals increases. It is hoped that the high-level discussion provided within this Review will help to address, at least in part, this (Vargas et al, 2008) • Conducted pre-FIH and relevant endpoints may be integrated in the design of toxicity studies (ICH S6). The conduct of separate dedicated studies may be necessary when there is a specific cause for concern…”

Section: Discussionmentioning

confidence: 99%

Overview of the nonclinical quality and toxicology testing for recombinant biopharmaceuticals produced in mammalian cells

Lebrec

Narayanan

Nims

2010

J of Applied Toxicology

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Biopharmaceuticals represent significant advances in therapeutic approaches for unmet medical needs, and increasingly, traditional pharmaceutical firms have been incorporating biotechnology capabilities into their product portfolios. There are some differences in the overall safety testing paradigms for small molecules and biopharmaceuticals, this safety testing including both quality and toxicology aspects. These differences are associated with both the manufacturing processes involved and the molecules themselves. For example, for biopharmaceuticals, living cells represent the factories for synthesizing complex molecular entities. As a result of this, safety testing for this class of drugs includes adventitious agent testing (e.g. viral, mycoplasma, transmissible spongiform encephalopathy agents) not normally needed for small molecules. Also, strategies for nonclinical toxicology testing of biopharmaceuticals differ from the paradigms used for small molecules and often need to be defined on a case-by-case basis, primarily taking into consideration species cross-reactivity attributes of the molecule of interest. Certain studies required for small molecules are not applicable to most biopharmaceuticals (i.e. genotoxicity testing, testing for interactions with the hERG channel). This manuscript provides an overview of both the quality and nonclinical toxicology testing for these mammalian-cell-derived products, two elements pivotal to the overall nonclinical assessment of the safety of these biopharmaceutical products.

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“…nonhuman primates). Development of large biologic molecules has provided an impetus to explore gathering more functional CV data from repeat-dose in vivo general toxicity studies (Vargas et al, 2008).…”

Section: Traditional Paradigmsmentioning

confidence: 99%

Integrated and translational nonclinical in vivo cardiovascular risk assessment: Gaps and opportunities

Berridge

Hoffmann

Turk

et al. 2013

Regulatory Toxicology and Pharmacology

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Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics

Cited by 116 publications

References 32 publications

BeKm-1, a Peptide Inhibitor of Human ether-a-go-go-Related Gene Potassium Currents, Prolongs QTc Intervals in Isolated Rabbit Heart

BeKm-1, a Peptide Inhibitor of Human ether-a-go-go-Related Gene Potassium Currents, Prolongs QTc Intervals in Isolated Rabbit Heart

Overview of the nonclinical quality and toxicology testing for recombinant biopharmaceuticals produced in mammalian cells

Integrated and translational nonclinical in vivo cardiovascular risk assessment: Gaps and opportunities

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