Best way to get a Leopon is to breed to a first generation Leopon, which gives a 10% chance. Next best chance is a 2nd generation Leopon, which gives a 5% chance. If there is a specific mutation you want, the best way to get it is to either buy it or to breed an existing lioness with the mutation and feed her a lion scrotum, which will give her a 25% chance of passing the mutation.

Mutations and RNG in general, is complex and unpredictable. The item that has the greatest chance of generating a new mutation would be a GMO Cow, but they are expensive, and you could still end up with nothing. You could do a ton of CRBs like myself, but I've done several hundred without a valuable mutation to show. However, just by normal breeding I've bred two lethals. At the end of the day, all these things have a relatively low chance so it will all be a statistical numbers game to try and find success.

All the things you stated (low fertility, CRB, lion meat) do increase the chance of a mutation, however, it is important to keep in mind roll order of mutation items. Due to this, I'm not a big fan of using multiple items for breeding. Here is roll order:
Leopon OR Overgrown Fur OR Tigon† ➜ Patches/Piebald† ➜ GMO Cow/Lion Meat ➜ Cotton Root Bark ➜ Fertility/Natural Chance ➜ Lion Scrotum ➜ Primal ➜ Dorsal Fur† ➜ Tigon Boost* ➜ Mukombero ➜ Dorsal Fur Guarantee*

Currently, it is my belief that the best most economic way to get a new mutation is mass breeding CRBs with a king with a primal Mutation, due to primal Mutation rolling after cotton root bark and natural chance.

If you have any questions feel free to ask me.

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