Got the email from Lutron that the Audio Pico remote will work with either S1 or S2. But NOT both at the same time. So if you do a split system, you will have to choose which version to control.
I would imagine this will be the same limitation every control system runs into. Split systems will have to make a choice.

Likely, one would have the Pico's near the controlled units or the Pico will target a certain unit. In this case only some of the Pico's in a split system would need to be reprogrammed.

Crestron has a webinar today on the S2 changes. Will report back later today.