Prevalence of the disease - if it only impacts 1/100 million, going to be hard to ever find sufficient patient population to test and recoup your investment.

Existing quality of treatments - if there are already efficacious drugs on the market - how sure are you that this new therapy will be best in class? Only being as good as the status quo is not an ideal competitive position. Conversely, if there is an unmet need because a disease is so lethal/debilitating, regulatory agencies can give latitude in approvals.

Likelihood patient compliance - if it is the most effective drug in the world, but requires intravenous infusion six times a day - nobody is going to adhere to that. GLP drugs are effective, but there is a needle-phobia that is preventing patients getting on board with the idea. Which is why there is an arms race for the first company to develop an oral version.

Toxicity - all chemicals are poisonous. Yet some have a lower therapeutic window than others. If you drug does what it should, but if you take 2x as much and it gives you a heart arrhythmia that is going to be a tough approval for anything but the most deadly conditions.