This one comes out of the past, but it is about a fear as old as time . . . or at least as old as Merck, namely that testing in animals does little to predict efficacy or safety in humans. Actually, check that. It is actually the rule rather than the exception: Testing in animals DOES NOT predict much in humans. But we in the biz keep hoping, right? (What else are we gonna do?)
Well, it's not so bad (health wise–it's pretty bad for business though!) if animals fail to predict efficacy in humans. The trial will fail, but hey, at least no one got hurt, right? But the now-defunct TeGenero company suffered the worst case scenario back in 2006. Their drug was called Theralizumab or TGN1412 and was an agonist of the CD28 immune system receptor on T-cells, expected to target these cells in leukemia and rheumatoid arthritis. Testing in preclinical animals, including monkeys, was superficially unremarkable. And then all six of the first human subjects to get TGN1412 experienced a massive cytokine storm minutes after receiving the drug, resulting in massive fluid shifts in their bodies, essentially meaning that their skin swelled up enormously and their whole bodies experienced poison ivy at the same time. Fortunately, because of the acute nature of the reaction, all were immediately hospitalized and survived, but they basically ballooned up to enormous size including their heads, one subject lost fingers and toes and all likely experience immune dysfunction from then on. Graphically and acutely, it was probably the worst drug trial failure on record, and it immediatly bankrupted the company.
Interestingly, the cause of this massive failure was not found to be incompetence or falsification of results or anything sinister. Instead, it turned out to be biological activity in human tissues that was not exhibited by the animal species. In other words it was mechanistic and natural, not human error. But then the true scientific reason was finally determined: the CD28 target protein receptor for the drug was not expressed on monkey T-cell tissue, but was liberally expressed on human T-cells. In retrospect, that seems almost incompetent. Common sense would dictate that one should evaluate the expression of your drug target in tissues of the human body and probably in the animal tissues you are testing too. Common sense would lead to the expectation that everybody does that for every drug being developed, right? Wrong. Almost nobody does it. But now that the TGN1412 disaster happened, everybody does it NOW right? Uuuuuhhhh . . . well, how shall we put this . . . I know, lets accentuate the positive: Genecentrix is all about incorporating tissue-specific drug target expression data into the drug discovery and development process!