I'm going to over simplify this a bit here because it actually involves quite a bit of biochemical but the gist is that different oral and systemic drugs have different volume of distributions (Vd):
https://en.wikipedia.org/wiki/Volume_of_distribution
(Which is basically an equation for how well it leaves blood and goes into tissues).
Drugs with a higher Vd need a lower dose to get in the "nooks and crannies".
Related is peak plasma levels. That's why IV antibiotics cause way more damage than oral antibiotics.
Liver and kidney metabolism is a factor too but that's a whole extra layer of complication that depends on both health state and Cytochrome genes.
There is also a blood cochlear layer (just like a blood brain barrier) which has specialized endothelial cells that try to "keep out" blood substances so the cochlea is a more protected site.
Very few drugs can get around this hurdle systematically unless they are given in large or prolonged quantities or have excellent cochlear penetrance (typically small, not overly polar molecules).
Ebselen (Sound Pharmaceuticals' drug) can circumvent these oral limitations and Hough Ear Institute's drug can be given in massive quantities (and is systemically very safe--Ebselen might be too but doesn't have to be given in as high a dose).
Anyway, back to Frequency Therapeutics...
Frequency Therapeutics' drug can cause systemic effects in rats (cancer) in the very high oral doses needed to reach the cochlea. You can use lower doses and reach a much higher concentration of drug in target tissues (because it's not diluted in the plasma and other tissues) if you make essentially a "topical" like you have with IT drugs.
Frequency Therapeutics has shown in their German perilymph study that they do reach the cochlea with intratympanic injection. They believe that with frequent repeat dosing, they will reach further than the phase 1 dose did.
Repeat dosing or extended release results in much better penetrance and higher peak tissue levels. As an aside, otherwise OTO-104 (Otonomy's phase 3 extended release Dexamethasone drug) would be pointless as IT Dexamethasone is already available.
Btw, Frequency Therapeutics have also done pharmacological assessment in phase 1 and noted it did not reach high levels systemically after IT injection (which makes it much much safer than oral for their drug).