It seems like an obvious concept: Let's say you are developing a drug that works by inhibiting, say, phosphodiesterase-4 (PDE-4) to treat depression (fictional). You have collected immense molecular, cellular, animal and clinical data supporting and validating PDE-4 as a drug target for depression. You’ve determined that your drug inhibits this enzyme with picomolar affinity and inhibits it in cells and improves depression related behavior in animals. All good right? Well, believe it or not, GeneCentrix’s tools are the only ones in existence that can easily tell you with a simple “google-like” search, whether PDE-4 is significantly over-expressed in the tissues of the brain associated with mood, such as the hypothalamus. Remarkably, just about no one actually checks this during development of their drug. Is it important? You tell us. Seems obvious that it is.
Well, part of the problem is that even with certain tools, and even acknowledging the immense promise of incorporating tissue specificity into drug development, the question remains: How do you deliver the drug preferentially to the target tissue? And what evidence is there that this actually reduces drug attrition?
Well, tissue targeting of drugs has been extensively developed for oncology purposes, where cancer cell markers are central to the drug development process, but outside of oncology, there has been little creative thought. Except for one tissue: the eye. Several first-in-class drugs have been approved for direct injection into eye tissues, including the first ever gene therapy. The approval of such complex drugs via tissue targeting seems to support the idea that tissue-targeted development and delivery reduces drug attrition.
Now Clearside Biomedical’s drug for uveitis reveals the ups and downs. The treatment showed a remarkable 0% response rate in placebo patients while 40% responded to the injection, with minimal side effects beyond the difficulty of administration. That’s the kind of efficacy one dreams about that basically takes drug attrition due to inefficacy or adverse events off the table. However, with great power comes great responsibility: Bringing wacky drugs on-line by direct injection into tissues is precedent-setting in more ways than one, and manufacturing of wacky drugs is one of those other ways that the FDA pays close attention to. Clearside had their approval delayed due to manufacturing issues.
Still, process engineering is an order of magnitude or more less risky than trying to fix lack of efficacy or eliminate an adverse effect. So Clearside’s story, as well as a large number of similar ones for eye-infused drugs, seem to be building to the conclusion that, like biologics, tissue-targeted drugs offer the dream scenario of low drug attrition.