Frequency Therapeutics — Hearing Loss Regeneration

Are you sure about removing the eardrum and drilling the hole with laser? According to study information, the drug is administrated via intra-labyrinthine infusion and so more like syringe needle injection. While still invasive, but recovery time should be much shorter with not much side effects due to delivery method at least.

And even if it involves lifting the eardrum and drilling a hole, it’s still not the end of the world, as it’s pretty much what’s done during stapedectomy.

 

CEO of Frequency Therapeutics salary is almost $1M per year, so not so difficult to have operating costs in millions…

 

Yes, that is how they do it.

 

Thanks for the clarification.

I know my mind is going, reassuring it's not totally gone.

 

Maybe the ones with Meniere's?

 

I am out of the loop.

Has Frequency's hearing restoration drug project gone awry?
Have they yet to publish any positive results?

 

Good point.

 

Hello everyone,

I haven't had a Tinnitus Talk account beforehand, but I was following this thread, and I was a bit disturbed by all the negativity that just spread after the release of this document with partial results from the clinical trial, so I decided to create an account and post my opinion here.
So, after a not-very-careful reading of that document, I only see encouraging results. Let me explain...

1. The first thing I noticed is that, for ALL the patients that received the drug, the dose seems to be the same, but in different volumes (0.05 mL and 0.2 mL). What I mean is that those who received the 0.2 mL injection hadn't had more of the drug, but more of the vehicle substance, to increase the volume (probably in the eventuality that a higher volume would diffuse better in the cochlea). I say this because they state: "[...] similar results were obtained with both dose volumes. This is consistent with published work showing drug delivery to the cochlea depends more on the concentration of the drug than the volume of injection."
So, if I'm right, the actual drug dose was <0.05 mL, so a really, really small dose.

2. In my opinion, even with that small dose, the results are simply spectacular. Keep in mind that the drug first reaches the high-frequency region of the cochlea; then, have a quick look at the patients' health profiles. Also, keep in mind that the audiometry scores were recorded only up to 8 kHz, so the really high frequencies were not included. Let's get to the patients profiles and word recognition (WR) scores: there were a few with mild SNHL and a few with moderate to moderately-severe SNHL. Those with mild SNHL probably had good WR scores already and good hearing up to 4-8 kHz, so leave those out. Six had worse SNHL *and* were also treated. Out of those six, four had statistically significant improvements in WR. If you look at the numbers, they got approx. 100% improvement (some even more!). That's a damn good improvement for a very small dose in a safety study! [I would kill for 100% improvement in word recognition.]
And if you look at the aggregated results -- treated vs. placebo --, there's a 30% improvement. For me, that's more than acceptable.
They even stated that four of those six worse-SNHL-guys had a 10 dB improvement at 8 kHz and, if that's not due to chance, it's also spectacular.

3. It might be possible that not all the drug reaches the target supporting cells, especially since the dose was so small.

Maybe there would be more things to say, but I'll stop here.

To sum up, these results are exactly how I would expect them to be. You won't see a +50 dB improvement in audiometry scores at 0-8 kHz with less than 0.05 mL of the drug.
I have some hopes with this company and their drug. Just don't get too stressed and wait for the Phase 2 results.

Have a good day, guys!

 

Yes, CGF-166 involved some surgery. There was this video with the first patient to receive the drug:

Gene Therapy To Restore Hearing Loss - Nov 2014

Afterwards, it seemed that the drug actually improved balance more than it improved hearing (at least for that patient).
One interesting fact is that the study for CGF-166 was initially planned to end in 2021, but now, if you look on clinicaltrials.gov, it is planned to end in October this year. Something happened...

 

Thanks for posting John Queen, welcome to the forum.

I needed a boost, cheers for that.

 

LE: There would be a second possibility with the dose -- that the concentration was kept fixed (e.g., 0.1%) and volume was increased, with similar results. This would mean that, indeed, the drug quantity increased, but you would obtain similar results at a certain concentration even if you increase the volume. If you ask me, this situation would be a bit counterintuitive, but it's not impossible. It's not clear, for me at least, from that document or from what can be found on clinicaltrials.gov, what exactly have they done: did they give the same drug quantity to everyone or did they keep the concentration fixed and increased the volume... but either way, the drug quantity is small, and I expect much better results in Phase 2.

I hope they will provide further clarifications when they officially post the results from the study. Or, if anyone here has more information about this, please share it...

 

I am going to design a DIY kit. I just have to figure out how to aim the laser after I cut out my eardrum.

 

The YouTube video will definitely go viral.

 

By the way, in early 2020 we should have the results from Audion's REGAIN trial, and that one is in Phase 2 and has a similar mechanism of action as FX-322, so we will have an indicator for FX-322's efficiency. However, FX-322 should be much, much better.

The drug used in the REGAIN study is aimed at directly transforming supporting cells into hair cells, so you actually lose supporting cells as you regenerate hair cells, while FX-322 first divides the supporting cells, and then induces transformation, so you don't lose supporting cells. It's a much clever approach.

 

Probably more clever but not necessarily more effective... We will see

 

I don't think it is negativity to be disappointed when a hearing loss drug has no impact on audiogram.

Your reasoning is pretty much based on that the dose used in the safety studies was "really really small". I thought that the purpose of phase 1 was to determine maximum dose with accepted safety profile. It would be kind of strange to get a safety approval for x and then in the following phase inject 10x.

 

Well, that's what they are doing.

 

You don't normally keep escalating a drug dose until you get the "maximum safe dose". That's something that cannot be known before testing.

The only way you could even get the "maximum safe dose" is by escalating until you literally poisoned some people and then back it down from there.

In animals, this kind of testing results in serious harm and even death (when LD50 is needed) of the lab animal.

If phase 1 drugs were titrated to toxicity, no one in their right mind would ever volunteer for phase 1 (which is usually on healthy volunteers).

There is always a pre-determined dose range for phase 1 testing of any drug, and they test within that range only, focusing on (hopefully) small side effects and then determining pharmacokinetics with bloodwork.

If the drug tests very safe (in this case, Fx-322 had very limited systemic absorption so presumably you would be looking at local cochlea effects), phase 2 is where you escalate dosing to figure out the dosing you need for effectiveness. At that point you see if the effective dose is toxic. If even the "safety test dose" in phase 1 was very toxic, you would stop there.

 

Logic bomb:

So we can't have this drug until it is proven safe. Well, someone has to be the guinea pig, right? The people in these trials know the risks and are allowed to undergo the treatment, so.............

Why can't we sign a consent form and try it out too? Do the rest of you realize how ass backwards all of this is? They could answer the question about tinnitus so much faster. Oh, Lord.

 

There are actually people working on changing the status quo. Per Janet Woodcock at the FDA (she's written a lot about this recently), the "bottom 1%" of reckless drug companies kind of ruined it for everyone and the regulations are written around them more or less.

She said what now happens is since it costs 100s of millions to get a drug through FDA trials and the drug company has to recoup costs and also make it worth it for investors, this means increasingly insurance finds ways to not pay for expensive drugs and access is limited. There are many people on the inside saying it's a "broken system" and working to fix it.

In the meantime, I would just like to see "right to try" expanded to non terminal but seriously quality of life affecting illness. It wouldn't be a bad idea to start a petition and involve many chronic illness groups.

 

Like the ATA?

 

What you are essentially saying is that safety is far from confirmed.

 

Yes, both safety and efficacy are not fully confirmed until all phases of the trial are complete.

 

In phase 2A they will test the effect of up to 4 injections over a time period. No mention of the dose though. Might by the high dose tried the previous phase. So there is a new element of risk and safety will still be checked but will not be the purpose of the tests. That is what I make of it!

 

The question is does Frequency Therapeutics truly believe in FX-322? The IPO value of the business would be at least 10 times higher after completion of successful phase 2 so from financial perspective it doesn’t make sense to IPO it on the verge of a presumed breakthrough. Current owners have deep pockets and they could easily finance phase 2 without an IPO. Development would be faster without all the burden that comes from added regulations and requirements of a public listing.

However, it is easy to see why they want to IPO the business now as there are so many uncertainties. No credible sign of efficacy, true safety remains untested as they need to increase dosing substantially in the next phase and drug delivery is an issue as they claim the drug did not reach inner cochlea. Positive part is that following their development is quite interesting and with public listing they are required to provide more information and more frequently to the public.

 

Wayyy too much pessimism in this thread, people think that just because there wasn't an immediate improvement in audiograms means the drug isn't effective. This conclusion is not sound.

Let's say the average audiogram test has a variation of 15%, and then let's say the dose given (a small dose in a safety trial) increases hearing capability by 5%. In this scenario, the drug works and improved hearing, but you cannot statistically come to the conclusion that the drug works.

These people know what they are doing, give them some credit, have optimism and let's wait for more information and further testing before you come to conclusions.

On another note, I have been following CGF-166 for a while now and I can safely say it is garbage, don't even bother researching it.

Additionally, WSJ just posted an article on hearing loss drug research, posted below.

Cures for Hearing Loss May Be Found in New Drugs

 

Did I miss that claim? Any source? Or is it our speculation?

 

IPOing now gives more value to investors since the increased value of the stock would be "priced in" after phase 2.

It's counterintuitive, but you may get a lot more funding by getting a wave of speculative investors now and a second wave of more conservative after phase 2. It's not that unusual for biotech startups to IPO at this early stage, some make it to market with a successful drug and some don't. I am not aware of a single biotech (even with very successful outcomes) that increased 10x value after phase 2 but it might in the time from phase 1 to FDA approval. Did you have an example in mind?

There is no reason to believe that Frequency doesn't believe in the drug based on IPO timing imo and there is certainly evidence that Astellas does believe in it.

Can you explain why you think an IPO would slow development?

 

What if most of our tinnitus cases are from loss of the hair cells and SGNs but our varying symptoms, loudness, etc are due to where nerves disconnect from lack of input and reconnect?

For instance, my tinnitus can be modulated without moving at all and watching things move on a screen. Wouldn't that mean that some of my nerves in my brainstem dealing with hearing have formed new connections with parts of my visual system?

 

It's probably even more complicated than that; in some studies, loudness and distress seem to arise from disparate, but related and highly connected brain regions. IIRC, gray matter deficits in the right anterior insula, caused reliably worse distress ratings among people who had been matched for volume ratings. On that note -- long-term meditators show increased gray matter density in this same brain region, which once again provides an interesting but uncorroborated mechanism by which cognitive practices may literally retrain the brain at a physical level to handle the tinnitus signal better.