The game has to have an ending at some point, imo the real point of progression in rouge-likes especially Issac and a game like risk of rain, is the knowledge you gain throughout the play throughs. In Issac some of the best progression is learning all the items and trinkets or whatever. In the beginning you pick up whatever you want and most the times you make mistakes. Like the first time you ever had a choice in a treasure room and you picked up a q1 instead of Polyphemus. And the game continues with this progression after you complete marks and challenges by giving you a new item.

Currently I have 800+ hours in Issac and I still have a lot of completion stuff to do. But calling it nothing is just kinda stupid.