In general, its about the same as Pandemic with two players. You have the advantage of a lot less happening between your turns, so you are better able to predict and react to the state of the board. And if you get players with strong abilities, you'll be able to use them more times during a game.
The downside is that you lack versatility in being able to have lots of special powers that can be applied to different situations, you can't have presence in as many places on the board, and you have a lot less cards in hand collectively, so you need to be careful about how you go for cures. Also, the Dispatcher role in particular is significantly weakened with fewer players.
There are elements that come up in Legacy that amplify each of these, but nothing that dramatically changes them. I would say that I typically find games with fewer players slightly easier, but Legacy has some elements that auto-correct the difficulty so it shouldn't be a problem.