The disease is Hutchinson-Gilford Progeria, an ultra-rare condition – occurring in just 1 in 4 million births and characterized by premature aging.

The natural history of progeria is death, usually due to cardiac causes, in the early to mid-teen years. Until recently, there have been no known therapies.

Enter lonafarnib, an obscure little farnesyl transferase inhibitor that has seen some use in hepatitis delta virus infection and is being investigated for its anti-cancer properties.

The primary gene defect in progeria is in lamin A. Lamin A normally gets farnesylated, but the farnesyl part of the protein is subsequently cleaved. In progeria, that cleavage site is rendered inactive, leading to retention of the farnesyl group and accumulation of the altered protein which leads to the progeria phenotype.

Researchers, led by Leslie Gordon, wondered whether inhibiting farnesylation in the first place would make a difference. Lonafarnib does just that.

The first trial of lonafarnib led to promising results – kids treated with the drug had improved weight gain and less skeletal rigidity. But only now was there enough data collected to look at a hard outcome – all-cause mortality.

The researchers compared 63 patients treated with lonafarnib to 63 patients who were not treated with the drug. Again, this wasn’t randomized. I think there’s a good argument here that randomization would be unethical. That said, the researchers matched treated and untreated patients on a variety of factors to minimize bias. And the results were dramatic.