Peptides, proteins, and the risks of cardiac arrythmias: A CDER study suggests that the human Thorough QT study is not needed for products comprised of naturally occurring amino acids
CDER research is helping to inform how peptide and protein therapeutics that are not monoclonal antibodies should be regulated.
Background and scientific challenge
The most common mechanism of drug-induced QT prolongation[1] and the associated rare, but potentially life-threatening, cardiac arrhythmia Torsade de Pointes (TdP) is the direct block of hERG channels in the heart by small molecules. Therefore, the current regulatory guidelines for assessing the risk of QT prolongation - the International Council for Harmonization (ICH) S7B for nonclinical and ICH E14 for clinical - focus on identifying direct hERG channel block-mediated QTCc prolongation. ICH S7B recommends testing the ability of the new molecule to block hERG channels in cells and to prolong the QT interval in non-rodent species. ICH E14 details the clinical method, including the human Thorough QT study, to determine whether and to what extent a new molecule would prolong the QT interval in humans. The testing paradigm has been successful in that since the implementation of both guidelines, no new drugs with unanticipated QT prolongation or TdP risk are known to have entered the market.
ICH S7B and E14 were developed based on data from small molecules. These are typically less than 1 kDa[2] in molecular mass and can easily cross the cell’s outer membrane to block hERG channels directly from inside the cell. Large protein therapeutics, notably monoclonal antibodies (mAbs), have become mainstays in the treatment of many chronic diseases. FDA-approved mAbs range from 50 to 155 kDa, much larger than small molecule drugs, and do not cross the cell membrane. Thus, mAbs are unlikely to directly block hERG channels, and are generally not required to undergo hERG testing or be evaluated in Thorough QT studies (unless there are nonclinical or clinical data suggesting that a specific mAb has the potential to cause arrhythmia).
In between small molecules and mAbs are therapeutics of intermediate size, including peptide and protein products[3] whose role in the treatment of diverse diseases has also grown rapidly in recent decades. However, whether these molecules have the potential to block hERG channels (e.g.,small molecules) and should undergo Thorough QT assessment was unclear.
How CDER researchers addressed this challenge
CDER investigators reviewed data in applications and regulatory reviews pertaining to peptide and protein products (excluding mAbs). They evaluated the results from clinical and nonclinical studies that characterized treatment effects on the QT interval in humans and animals, respectively, as well as data from the in vitro hERG assay and the ventricular repolarization assay, both of which measure treatment effects on the activity of hERG channels. By comparing the nonclinical and clinical results, they were able to understand the risk of hERG block-mediated-QT prolongation for the peptide and protein products.
Some key results of the CDER study
- Clinical QT prolongation was observed for some peptides and proteins. However, QT prolongation was not dose-proportional (i.e., the QT interval did not increase with increasing concentration) or was due to poor characterization in the clinical study (imprecision in measurements) making it impossible to exclude the possibility of small QT increases. Of note, hERG channel block-mediated QT prolongation is dose-proportional.
- Results from the hERG assay and the ventricular repolarization assays did not align with the clinical QT results. Amongst the 24 products that had both hERG channel data and clinical QT results,[4] four were observed to prolong the QT interval in the clinical studies. However, none of these products blocked hERG channels in vitro, even at concentrations that far exceeded those tested in humans. One product blocked hERG channels in vitro, but the result was a false negative as the product was associated with a negative clinical QT study. Likewise, twelve products were tested in the in vitro repolarization assays, and one was shown to prolong duration of the heart’s cell action potential. This is a false positive, however, as the product was associated with a negative clinical QT study. Altogether, the data demonstrate that peptide and protein products reviewed did not block hERG channels or act on other targets within the heart cells to alter their electrical behavior.
- Twenty-six products had in vivo QT data from animals and clinical QT data from humans. There was one true positive, meaning the product was positive for in vivo and clinical QT studies. Three products were false negatives and one was a false positive. These were likely due to study design or species difference (i.e., humans vs. animals) in response to treatment.
CDER investigators concluded that the peptides and proteins they reviewed do not block hERG channels directly, and that clinical QT prolongation. when observed. was mediated through mechanisms not related to direct cardiac ion channel interactions. As mentioned above, mAbs are generally not expected to undergo Thorough QT study based of their low likelihood to interact with hERG channels. Based on data and the idea that humans would have evolved to resist nonspecific interactions with naturally occurring amino acids, CDER investigators suggest that the Thorough QT study may not be necessary for peptide and protein products of any size as long as they are comprised of naturally occurring amino acids. Given the rapid advancement in the field of medicinal chemistry, with new chemical modifications resulting in the development of a variety of unnatural and uncommon amino acids aimed at improving molecular stability, target specificity, and membrane penetrance to act on intracellular targets, future studies should continue to collect information to understand whether products with different unnaturally occurring amino acids that are cell permeant carry a hERG liability.
How does this research advance regulatory science?
The current retrospective study found that an important group of therapeutics – peptides and proteins that are not monoclonal antibodies (mAbs) – have a low likelihood of directly blocking hERG channels to induce Torsade de Pointes. Based on data and the idea that humans have evolved to resist nonspecific interactions with naturally occurring amino acids, human Thorough QT studies are unnecessary for products comprised of naturally occurring amino acids unless their potential to cause cardiac arrythmia is suggested by either nonclinical or clinical data.
[1]The QT interval represents the duration of ventricular depolarization and subsequent repolarization and is measured from the beginning of the QRS complex to the end of the T wave.
[2]A kilodalton (1000 daltons) is a commonly used unit of molecular mass. One dalton is equal to one twelfth of the mass of a carbon-12 atom.
[3]FDA defines a protein to be an amino acid polymer composed of more than 40 amino acids in length. By exclusion, a peptide is an amino acid polymer composed of 40 or fewer amino acids in length.
[4]They ranged in size from 0.5 to 60 kilodaltons.
Reference
Wu, Wendy W., Moran Choe, Lars Johannesen, Jose Vicente, Girish Bende, Norman L. Stockbridge, David G. Strauss, and Christine Garnett. "ICH S7B in vitro assays do not address mechanisms of QTC prolongation for peptides and proteins–data in support of not needing dedicated QTC studies." Clinical Pharmacology & Therapeutics 114, no. 6 (2023): 1332-1341.
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