In an interview with Gamereactor, Saints Row design director Scott Phillips confirmed that Saints Row IV is the last of the exisiting saga with the Third Street Saints. Therefore, if the franchise continues past IV, it will most likely move in a new direction.
"We're definitely considering Saints Row IV sort of the end of that saga of this character and the Saints as they are," Phillips said. "So if there's any more future Saints Rows—which you know we always hope there will be, we hope there's fans for future games like that—they will probably continue in a different direction."
Considering the series has made the leader of the gang the President of the United States and then gave him/her insane super powers, it makes sense this is the end. After this kind of insanity, where could it go from here? Space? Mutants? Don't answer that.
Saints Row IV releases on August 20, 2013.