Line 6 Helix Native + Cubase 10.5 suddenly doesn't work anymore.

Just checked and Helix Native is working fine here. Have you updated to 10.5.20? FYI we encourage folks to put their DAW config in their signatures to avoid having to ask for basic info all the time.

Do you have any other software you can check out Helix on, even older versions of Cubase like 10.0 or 9.5.

What options do you select when using Safe Mode?