Ebrietas at least seems somewhat sinister. She's cooperating with the Choir and providing them with her blood to experiment on attempts at ascension with despite the fact it seems to involve insane levels of human suffering. I think it was implied her main motivation is loneliness, which isn't a great reason to work with mad scientists who turn people into mewling mutants.
Anyway, Yharnam was still functioning as a city at the time I want to use, a weird blood obsessed city with secret police who hunted werewolves, but still a city. The aftermath of the burning of Old Yharnam would probably be something to end on, with the focus being on a steadily increasing level of paranoia in the city, ever more and stronger beasts appearing each night, inter faction politics within the workshop and the church itself leading up to the workshop being disbanded and Gerhman disappearing.
So right now I'm thinking a D100 system, two 'corruption' tracks, one for Beasthood and one for Insight, with the latter reducing the former as it rises but revealing more Great One nonsense to the character, and Beasthood encouraging indiscriminate slaughter in exchange for raw power. Though most of the beasthood themed stuff is post burning, so maybe won't bother.
Basic ideas for character options atm is a few backgrounds, former Bergenwyrth scholars who followed Laurence, older and frailer but know more of the truth behind things, Yharnam hunters recruited specifically for the workshop from the church as the sort of normal generalists, and foreign hunters as the specialists in odd equipment.
Then options for the workshop covenants and badges, Powder Kegs as gun specialists, Saw Hunters as beast killers, Crows as hunter killers and so on.
I could easily work gun parrying in as a reaction option, a less reliable dodge skill that gives lots of damage on the next attack on the target.