Stem Cell Studies Create More Questions Than Answers
In the last year, exciting breakthroughs in cellular research have crossed the newswires with increasing regularity. The potential of novel treatment modalities, as well as insight into the genesis of numerous pathologies is quite compelling. Within nonclinical safety assessment, scientists are assessing the value of stem cell in vitro assays for predicting drug-induced toxicity.
The following data suggests against relying solely on pure in vitro assays, including stem cell based paradigms and focused ion channel studies, for early decision making and compound selection. This is especially true in the prediction of cardiovascular safety.
In 2008, our laboratories interrogated over 120 discrete compounds in the isolated perfused heart for their potential to interact with cardiac function. A majority of these studies were conducted in response to direct evidence of ion channel blockade (for example, IKr [hERG] antagonism) or as part of a standard testing funnel within the individual Sponsor’s safety assessment function.
Although we had extensive anecdotal experience that would ultimately validate the outcome, upon analysis of the data we are able to state that pure in vitro assays will not accurately predict the full integrative cardiac effects of many late Discovery compounds or preclinical development candidates. In fact, these assays often introduce uncertainty into the testing funnel due to their lack of complexity.
For example, in the data set below note that approximately 50% of test articles had appreciable effect on PR interval (atrial to ventricular conduction) – a parameter not even capable of interrogation in these cellular-based assays.
These ‘non-QT related’ findings can be as looming of a roadblock as lengthening of repolarization. The pharmacists’ shelf carries a number of compounds that are known for PR prolongation, most notably the recent anti-virals such as rotinavir and more seasoned medicines like the tricyclic antidepressants. An August 2009 Journal of the American Medical Association study has demonstrated that even slight PR interval prolongation is associated with an increase in atrial fibrillation and all-cause mortality.
Of additional interest, only 20% of the compounds showed potential liability for QT interval prolongation. Given the impetus for conducting these assays, this suggests a high propensity for false positivity with interrogation of IKr anatagonism alone.
This scenario has been played out in project team meetings countless times. “We have a ‘hit’ in the ion channel assay, why does the isolated heart [or in vivo assay] not translate?”
This reasoning is folly; we’ve lost our way in the quest for faster, cheaper methods to get a clinical candidate. Far fewer of our colleagues ask the related, more appropriate question; “We have a clean signal in the whole heart [or in vivo] approach, why is there a signal in the ion channel assay?” The answer is, of course, identical in both scenarios. However, the latter approach demonstrates a more reasonable grasp on the science behind the conduct of the assays.
The integrative approach is infinitely more complicated than a single ion channel or cell type. The more reasonable paradigm limits the sometimes misleading influence of relying entirely on these simple assays. They have a role in the testing funnel. However, without complementary interrogation, compounds not likely to have a clinical effect risk being unnecessarily de-prioritized.
Regards,
Dr. Michael Gralinski, CorDynamics CEO