Sorry, I realize those excerpts in my earlier comment don't really convey what I intended. The paper does talk about about how the various improvements over the years were changes in just a few (or even just one) amino acids in the molecule. It's a large molecule, nearly 6000 daltons (for reference, the limit for what we call small molecules is around 1500 da), so there's been a lot of opportunity for tinkering.

FWIW, the full paper is available at https://sci-hub.tw/10.1056/nejmms1411398