Yes, I play Mage The Awakening (one of the core lines in the Chronicles of Darkness) with only one player on a regular basis and while I have never maintained a long term game with exactly two I have neve let having only two of the players being available prevent a session.
The key to playing with very small groups is to tailor the challenges to the characters. This of course is good advice in any game, but with small groups that don't have a broad set of resources to draw from it becomes vital. Most of the challenges they face should be of a kind that can be directly addressed with the skills and powers possessed by the players. If and when you do give them more open ended challenges that their skills are not directly suited for, be willing to follow their lead in making the resources they look for to get around your challenge available.
This is somewhat easier with Mage where the powers given to the characters are very broad and flexible by design, but the general principle works with the entire Chronicles of Darkness.