In the middle of the development of Uncharted 4, the Naughty Dog has decide to take a completely new direction in the story which is why the second actor quit because he did not like changes in the project.

Uncharted 4: A Thief’s End initially started with the usual developers crew from Naughty Dog. But when the creative director and writer Amy Hennig left the studio, director’s place in the game creation was taken by Neil Druckmann and Bruce Straley, who, according to unofficial information chose entirely new direction for the project, and a whole new story for the game. That move resulted in two actors losing their engagement in the game.

Uncharted 4 Gets A Whole New Story And Makes Some Actors Angry

Last year, actor Todd Stashwick left the project, claiming that Naughty Dog is doing some strange changes in the game. His example was followed by Alan Tudyk, complaining that the changes that followed  made his contract void and worthless.
About the potential changes in the story, we can only speak in the abstract, because we have not actually seen Uncharted 4 often enough to even catch what the story is about. But in any case we hope that Naughty Dogs know best what they are doing with this great PS4 exclusive.