Broad lessons from negative trials in rare diseases

Negative trials are often perceived as setbacks, but they can be among the most instructive and essential for recalibrating assumptions in rapidly evolving fields such as gene therapy. 1 Negative trials can prompt a cautious re-evaluation of surrogate endpoints, trial design, timing of intervention, and the interpretation of early-phase data, including reliance on historical controls. In The Lancet Neurology , Francesco Muntoni and colleagues report the negative results of the CIFFREO study, 2 a large, randomised, double-blind, placebo-controlled, phase 3 trial evaluating fordadistrogene movaparvovec, an adeno-associated virus 9 (AAV9)-based mini-dystrophin gene therapy, in ambulant boys with Duchenne muscular dystrophy. Despite robust and widespread mini-dystrophin expression and a marked biological signal, the trial did not show any functional benefit on the North Star Ambulatory Assessment or any other endpoint at 52 weeks. CIFFREO provides several important lessons that extend well beyond this specific gene therapy and even beyond Duchenne muscular dystrophy.