Bristol’s nuc, INX189, crashed not long after the compound was acquired through a $2.5 billion buyout of Inhibitex as a result of heart failure in one patient. Now the FDA has called for a partial clinical hold on a similar compound made by Idenix out of caution. IDIX stock has dropped about 30% today.
Toxicity is a known issue with nucs and has killed many programs. Merck had a potent adenosine analog, MK0608 dropped in Phase 1, two cytidines- RG1626 from Roche and NM107 from Idenix were also discontinued. Work was also halted on Tibotec’s TMC649128 and another Roche compound, RG7348.
More recently, we have seen the failure of Pharmasset’s PSI-938 due to liver issues and of course, INX189 because of cardio.
There do not appear to be any common themes, toxicities range across various nucleoside analogs and prodrugs, striking multiple organs systems- gastrointestinal, haematological, liver, cardio. The only certainty is that without in-human studies, one can only guess as to the safety of a drug. So while INX189 is structurally similar to IDX184, there can be no direct link to toxicity.
Notably, both INX189 and MK0608 showed signs of toxicity in preclinical studies- effects that later bore out in the clinic. It appears investigators chose efficacy over safety at a very steep price.
Idenix’s IDX184 appears to have a fairly clean safety profile; although the preclinical toxicity profile has not been released to the public, there have been no issues in the clinic. Nevertheless, it appeared partners have shyed away. A previously announced plan to partner IDX184 midyear is well past due.
This will be the second clinical halt on IDX184. Will it still be relevant by the time the FDA lifts the halt? I find it unlikely. This is a another huge setback for the compound.
