Clinical holds are lost battles in the war against drug attrition. The process of drug development critically revolves around the FDA’s Investigational New Drug (IND) application, which is the document required to start testing the drug in humans. Any safety, efficacy or even administrative uncertainty can result in a “clinical hold,” pausing human testing and costing companies millions of dollars.
Recently, Mersana Therapeutics got hit with a hold for their small molecule cancer drug. Mersana is part of the cresting of the antibody-drug-conjogate (ADC) wave. Their products are drugs with known targets (in this case the Her-2-neu oncogene in cancer), where the company seeks to build a better mousetrap by hitching a poison/drug onto the antibody targeting the target. The theory is that it should be just as safe as the parent approved drug/antibody, but more focused on the tissues and locations of interest in the body. Unfortunately, this also means that those tissues and locations may be more susceptible to damage. That’s what the hold was about: a patient with liver disease died. Could the ADC-based concentration of the drug cell killing action have occured in the liver, and could this put patients with liver disease at specific risk? This is what’s known as a tissue-specific adverse effect, if this interpretation is true.
As a reminder of how bad a hold is, the stock dropped on the news, and also dropped again when the hold was lifted! In this case, a relatively minor change was made to address the problem, probably to screen out patients with liver disease. The hold lasted only two months, which is about as good an outcome as you could hope for in a hold. But as evidence of how nasty ANY hold is, the stock tanked on the hold and tanked again on its removal. A hold is a stink that just doesn’t go away.
As with most stinks, its better to prevent them in the first place than remove them once they appear. Could this have been avoided? Well, because of this hold was potentially a tissue specific (liver) effect, if it had been predicted up front, those patients could have been screened out in the trials exclusion criteria up front. So yes, Mersana’s millions could have been saved, IF red flags for tissue-specific adverse effects could have been evaluated up front. GeneCentrix's profiler seeks to identify exactly this kind of effect up front.