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" ... Extreme clinical phenotypes caused by rare genetic variations have been the basis of some of the most exciting drug targets in today’s pharmaceutical pipeline: PCSK9 in cholesterol, sclerostin in bone diseases, Nav1.7 for pain. The rare gene signatures underlying these programs can provide a big boost to the confidence in rationale (CIR) for working on novel drug approaches, especially those that have no clinical precedent for pharmacologic intervention. ... "
" ... So why didn't Amgen see this risk in their genetic data? According to Kristin Neese, an Amgen spokeswoman, the DeCode approach showed that patients with sclerostin mutations were very fracture-resistant, with high bone mineral density. But there weren't enough patients to provide insight on safety. That's in contrast to genetic mutations in PCSK9 or ASGR1, which both protect against heart attacks, where there were enough individuals with a single copy of the mutation to know they live longer than age-matched controls. ... "