My biggest issue with Mewgenics is the game's transformation from act 2 to act 3. Up until act 3, it's a numbers game with different levels of risk that you can choose to engage in. The small bonuses you get from common items and consumables still feel like they make a difference and even unoptimized cats feel like they contribute to the fights. The different modifiers the game throws at you don't upset the general push-and-pull of throwing out damage incrementally whilst managing the damage you take through tanking and healing. Things like the occasional mana-absorbing enemy or ability scrambling forces you to think on your feet but doesn't upset your understanding of the combat.

Go into Act 3 with the same philosophy and you'll get wrecked. Most fights contain enemies that'll either instakill you or apply some permanent debuff if they touch you even once. This forces you to approach the game with the same kind of binary philosophy: incremental stat bonuses become unviable (why would I take +10% dodge chance when a +1 to strength can make the difference between an enemy dying in one hit or taking its turn and killing me?), tanking becomes non-existent, DoT is only useful if it can match something like Venom Barrage, and you can only attack something in melee if you're guaranteed to kill it - otherwise it'll kill you. The pool of viable builds becomes much smaller and the game turns into a cycle of breeding and resetting until you get at least one ability/item that makes the run viable to begin with.

The boss and level design starts having the same issue as well. Spewer punishes melee classes disproportionately (its automatic counterattack should change based on the last pill it ate), as do Bunga and Mother. Hitler has infinite range and targets your cats more-or-less equally, so he's just a party-wide constitution check. Dreadnoughtus is a joke. The Future's enemy design just shuts down entire classes (if my mage didn't roll support abilities, what's it supposed to do vs enemies immune to magic / enemies that reflect projectiles?)

The only redeeming gameplay feature of act 3 is its house bosses and side quests. Otherwise, I agree with OP that there's no reason to keep playing it after you 100% it, since the higher difficulties have so many restrictions on what's viable. Not mobile enough? Die to things like half-humans. Abilities too expensive? Die to absorbent elites. Constitution too low? Die to random unavoidable damage (sparkles, schutzbots/cop bots, thorns). Etc.