Frequency Therapeutics — FX-345

Simply because they couldn’t demonstrate a significant audiogram improvement...

 

FX-322 hasn't shown to improve audiogram scores in a significant way. It doesn't penetrate deeply enough to activate progenitors in the cochlea at ranges that are picked up by the standard audiogram (up to 8 kHz). Some speculate that the Inner Hair cells are preferential in growing first, which is how they develop in the womb. An audiogram isn't an effective tool to measure Inner Hair Cell growth, but is for Outer Hair cells.

Inner Hair Cells are more effective for hearing spoken word in quiet and noise. Speaking of, word score is the measurement that seems to show a consistent improvement in a specific subset of SNHL patients treated with FX-322, so it made sense at the time to seek out patients with reduced word scores. Lower word score, more room for improvement.

There are, unfortunately, a lot of problems with the standard testing used in the clinical setting (and at trial sites). They all have a degree of subjectivity to them, and are not objectively sensitive when compared to modern tests, or do not accurately assess the health of the cochlea in its entirety. This is a challenge for any hearing loss treatment that seeks FDA approval.

 

@Diesel, I have a question. What distinguishes FX-345 from FX-322? According to the PowerPoint, FX-345 enables coverage of the entire cochlea so is it just a new form of drug delivery? If it is, why is it a completely different drug?

Furthermore, based on a cursory glance of the PowerPoint, it looks like FX-345 is just a better version of FX-322. But why is that? What about it makes it better than FX-322?

And finally, why make two drugs instead of just replacing FX-322 with FX-345?

 

I am not the forum's favourite hydrocarbon, but I can try to answer this!

Their new GSK3i is supposedly more potent (replacing CHIR99021) and they're possibly using a higher concentration of Valproic Acid, courtesy of using a purified Poloxamer P407 (unpurified P407 will not allow for higher concentrations of Valproic Acid as it will not gel then). More Valproic Acid will allow for a higher penetrance.

With the new drug, they have to do the trials again. FX-322 works, so it makes sense to bring it to market while running trials on FX-345.

 

So FX-345 is, indeed, "FX-322 but better"?

 

Yes, the idea is the same, but it's going to be better.

 

Financial incentive.

 

I assume FX-345 is going to be more expensive than FX-322?

 

Not much is known about FX-345.

 

Look at car manufacturing as an example of this. GM is coming out with a redesigned GMC Canyon/Chevy Colorado for 2023 but why do they continue selling the current 2021 & 2022 models?

 

Are they going to have for FX-345 the same exclusion criteria as FX-322? If your word scores are too good, will you be rejected from the FX-345 trial as well? If this FX-345 meant for people with more hearing loss, you would think they would ease up so more people could get into the trial.

 

I have almost perfect word scores in my ear where I suffered sudden hearing loss.

Improving word scores isn’t going to improve tinnitus. We need audiogram improvement.

 

That's why I am asking. If the exclusion criteria is the same for FX-345, we are fucked.

I am hoping they will open it up for people with more hearing loss and not just base it off of word scores. Or else, I am never going to be accepted into any of their trials. My word scores are just too good, but I have a hard time hearing the beeps.

 

I believe there will be audiogram improvements in the Phase 2b trial especially when they are testing up to 16 kHz compared to 8 kHz for the Phase 1b trial.

 

What does "Formulation enabling evaluation of a range of dose levels" mean?

Does that mean "FX-345 has different types of concentration"?

They have learned in Phase 1b that the effect of a drug is influenced by concentration, not volume.

Is this an achievement of the lesson?

 

How does that make sense? Considering FX-322 (and FX-345) cause the regeneration of progenitor cells, wouldn't a greater coverage cause greater regeneration? Or does the drug cause regeneration even if applied to a smaller or one area?

Furthermore, if they learned this, why aren't they carrying this lesson into FX-322 and experimenting with different concentration levels there too?

 

If you want to change the concentration, it will be a different drug and start over from Phase 1.

You can avoid "redoing" by starting with a group of different concentrations from the beginning.

The difference in the strength of the effect is, for example, 5 dB, 10 dB, 15 dB for improvement at 8 kHz with one injection.

 

But how does that work? Why does it have that effect? Shouldn't something which regenerates progenitor cells go by volume rather than concentration?

 

Concentration makes more sense. It’s a liquid that is diffusing into another liquid. There are volume limitations at the injection site.

 

https://investors.frequencytx.com/static-files/bd82e199-8b2c-4c35-9929-3d7ed4cbcfc2

Please read page 15 of the report.

 

I don't understand.

 

That doesn't explain why higher concentration leads to higher regeneration.

 

https://en.wikipedia.org/wiki/Diffusion

"More drug = more regeneration" isn't the right way to think about it.

The diffusion of the right amount of both molecules to trigger PCA to take place is what they're after. Increase the concentration at the absorption point (cochlea base), more levels of the drug will diffuse more deeply and consistently into the perilymph within the cochlea.

 

So the higher the concentration of the drug, the more it will absorb and regenerate? In other words, even if the site of delivery is in one place, the drug itself will spread throughout the cochlea?

 

That is the theory being tested in the clinical trial.

 

I agree.

And if the improved gel itself penetrates deeper, I think it will be more effective.

 

God, I hope so. We really need some good news. I am so tired of this s*^!

 

That's economics, I suppose.

They have already sunk capital into the fixed costs. Why ignore the remaining set of returns to be gained from selling the older model? As long as the revenue exceeds the variable costs the profits keep coming in.

 

There is a contract that they will be rewarded from Astellas for completion and sale of FX-322.

Furthermore, if FX-322 is successful, I think they can get a good contract for FX-345.

"Frequency is bagging $80 million now, but stands to pick up another $545 million down the line in development and sales milestone payments as well as royalties."

Astellas picks up Frequency's regenerative hearing loss med outside U.S. for $80M

 

FX-345 is not up for grabs as Astellas is already entitled to the rights on it since it is simply an improved version of FX-322 with just a more potent GSK3 inhibitor.