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Clot twist

Just when you thought you were out, they pull you back in. We in the business obsess over the “valley of death” and the drug development milestones around it at early and preclinical stages of drug development, but danger also lies beyond our horizon.

Normally, when we hear about small molecule drug discovery progression, we are told it starts from target identification and goes to target validation, to assay development, to high-throughput screening, to hit validation, to hit-to-lead-optimization, to lead optimization, to preclinical efficacy and safety testing, to clinical safety testing, to clinical efficacy testing, to FDA approval. The story almost always ends with FDA approval and a “ka-ching” sound. (You had me at “positive top line results!")

Now we know better. The Vioxx failure nearly crippled Merck, and it's not an isolated incident. Just this month, Pfizer was hit with a safety signal for a blockbuster drug. Their rheumatoid arthritis drug Xeljanz (tofacitinib) was linked to life-threatening pulmonary emboli. As with Vioxx, the unexpected adverse event identified post-surveillance is tissue-specific: In Vioxx’ case, it was the heart; for Xeljanz, it's the vasculature. It remains to be seen if Pfizer’s cold sweat turns into a Vioxx-sized calamity, but one of the really difficult things about post-marketing adverse effects is that they are very difficult to handicap for risk, since they are due to the rather quirky system of voluntary post-marketing surveillance.

The industry is hard at work developing and using tissue-specific bioassay systems to predict adverse effects early, such as the hERG patch clamp system and iPSCs and organoids for seizure activity. We at GeneCentrix believe that this issue can be additionally and broadly addressed through novel computational tools. Try them, and stay tuned for our next generation this year.

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