Depopulation Bomb: Two, in eldraeic pre-history: the asteroid impact preceding the Winter of Nightmares, which wiped out almost everyone, and the Gray Wasting, a Precursor bioweapon that got out of its bottle a couple of hundred thousand years later and only managed to kill one-half to two-thirds of everyone. There are also some ruined planets out there to remind everyone that this is not a local phenomenon, either.
In the modern era, this is why people are encouraged to be careful with their bio/nanoweapons, because it’s frighteningly easy to create one of these by accident.
So what stopped the Grey Wasting?
Same as the Black Death, or many other pandemics: once you kill enough people, you burn out because you no longer have the hosts you need to spread.