[A high-G maneuvering vehicle traveling at mach 20 would certainly be a very, very, challenging target.]
The vehicle is 50 miles or higher during the transit phase. The air is so thin that it offers just enough resistance to allow maneuvering wedges to function.
The vehicle must shed velocity when it re-enters the atmosphere in its' terminal approach. Otherwise it would break up in the lower elevations where the air is denser.
The re-entry phase is a point of vulnerability for such weapons.