GoKawiilPhysician Michael Hayden (right) is frustrated by the slow pace of drug development.Credit: Christopher Morris/Redux Pictures for Nature
For scientists who are involved in drug discovery, failure is part of the job. Less than 15% of drug candidates make it to market from the laboratory. Most drugs don’t get through clinical trials because they aren’t effective enough or have unmanageable side effects.
Each step in drug development typically takes one to three years and has a high risk of failure1. The probability of moving on from phase I trials, which are often the first test of a substance’s effect on humans, is about 64%. Phase II tests safety, dose and efficacy; just over half of candidates don’t make it past this stage. Phase III, the largest of the three, aims to obtain enough data for drugs to be approved by review boards such as the European Medicines Agency and the US Food and Drug Administration. More than 40% of candidates that reach this stage come to the end of the road here.
These failure rates also don’t take preclinical work into account. Before a drug makes it into trials, scientists can spend a good five years identifying and validating its mechanism of action, as well as testing its toxicity, activity and solubility. Most therapeutics don’t clear those hurdles, and even those that make it all the way through the clinical-trial process can still fail because they are too expensive or toxic for real-world use.
Three scientists who have faced obstacles during the various clinical-trial phases reflect on the implications of failure and how they have moved forwards.
Failing phase I
As someone who works on a type of motor neuron disease called amyotrophic lateral sclerosis (ALS), neurologist Jeffrey Rothstein has seen his share of missteps. He chairs the scientific advisory board of the Network of Excellence for ALS, an international group comprised of 160 medical institutions, and provides advice to companies that are developing therapeutics for neurodegenerative diseases. He has therefore come across firms that don’t have the money to do sufficient research ahead of phase I trials, and others that don’t know whether their drugs will reach their intended targets in the brain.
Nature Spotlight: Drug discovery
In 2021, when Rothstein became principal investigator of a trial for a gene therapy called BIIB078, he felt prepared. The therapy was created by biotechnology company Ionis Pharmaceuticals and licensed to another biotech firm, Biogen, both based in Carlsbad, California, for clinical trials. Several genetic and environmental risk factors have been linked to ALS, and BIIB078, a short, synthetic, single-stranded nucleic acid, was designed to target one such factor, a mutation in a gene called C9orf72. “We had a really complete data package,” Rothstein says. “It was safe in mice; it was not toxic to human brain cells. It did what it’s supposed to do and everything about it was working.”
To his surprise, BIIB078 failed in a phase I clinical trial. It increased blood levels of a protein associated with neurodegeneration compared with placebo, and there was no improvement in clinical outcomes such as muscle strength or respiratory and physical function2. “This was 180 degrees opposite of all the preclinical research we had done, and we had not predicted this at all,” Rothstein says.
... continue reading