Fialuridine looked safe in animals — 5 of 15 patients died, 2 needed transplants

Fialuridine (FIAU) was a nucleoside analogue developed by Oclassen Pharmaceuticals and Eli Lilly as a treatment for chronic hepatitis B. Preclinical testing in mice, rats, dogs, and monkeys showed no significant toxicity. The drug was approved for a Phase II trial in 1993, with 24 patients enrolled for a six-month course. The first nine weeks showed promising results — viral levels dropped and no serious side effects were observed.

After approximately 13 weeks of treatment, patients began developing severe symptoms: lactic acidosis, liver failure, pancreatitis, and peripheral neuropathy. Of the 15 patients who had completed or were still on treatment, 7 developed hepatic failure. Five died from acute liver failure, and two others were saved only by emergency liver transplants. The toxicity was delayed, cumulative, and catastrophic — once symptoms appeared, the damage was irreversible.

An FDA investigation concluded that the adverse effects could not have been predicted from animal studies or earlier Phase I data. The cause was species-selective mitochondrial toxicity: humans have a nucleoside transporter (hENT-1) that concentrates FIAU inside mitochondria, while other species do not. The drug was never marketed. The FIAU disaster became a landmark case in drug safety, permanently changing how mitochondrial toxicity is evaluated in preclinical drug development.