Frequency Therapeutics — Hearing Loss Regeneration

On this note, I feel especially bad for veterans who devoted their lives to their country only to be rewarded with things like hearing loss, tinnitus, and PTSD. It's like the fight never ends for them.

 

This is a very good point. I think the average person believes that hearing loss is just a matter of turning up the volume. I also see cochlear implants sometimes being referred to a 'cure' that we already have for hearing loss and it makes me cringe because, as great as the technology is, it in no way replicates natural human hearing.

 

You're absolutely correct. I always just assumed hearing aids were like glasses. They put you right back to normal sight/hearing.

 

Hopefully FX-322 works. The hype is good but if it doesn't work, then I don't know.

 

Hearing aids and CIs are most definitely not the hearing equivalent of eye glasses but that's how it is almost marketed.

 

Then add tinnitus and hyperacusis in the mix as well. Not many people know about these conditions.

 

These tweets are interesting. In Phase I/II, the words in noise improvement participants saw didn't meet the bar for statistical significance (I think there was a ~20% improvement). I wonder if this means that they're expecting better results for this metric in Phase 2a? Surely they would look somewhat foolish putting something like this out there if the coming results didn't reflect what they were talking about.

If they did look at interim results, would they be able to talk to their marketing team about the kinds of materials they wanted to put out into the world? Or would that be off limits?

 

A good marketer would have these items + others in the queue even if they don't use them for a while. It's only off limits if they advertise that the drug does something that they cannot prove. It's not off limits to make stuff that isn't viewed by the public. FX-322 in the Phase 1/2 still showed a clinically meaningful improvement for WIN, just not statistically significant. Either way, I think they're confident, and seeing how the company is being run, they probably have stocked up on more hearing-related marketing assets like the ones we're seeing the past month.

 

From memory, six or eight patients saw a statistically significant improvement, or at least a clinically meaningful improvement. If I remember correctly, all patients saw an improvement of some sort, but not all of them were statistically significant.

However, for reasons explained here before, that shouldn’t be read into too much. The potential ceiling of improvement in some of these patients was likely quite low, meaning that even if the drug did work in those patients, one would not observe a statistically significant improvement, even if an improvement of some kind was actually observed.

 

True. If the drug would show large gains on the audiogram it would be a homerun. There would be no debates, no discussions, and no doubts. I hope they show real gains.

 

No, you're thinking of the word recognition (WR) score - that test is a "words in quiet" test. 4 patients saw statistically significant WR score improvements. I've attached the slide from their presentation which shows the difference between the two tests. A ~30% improvement was seen overall in the Words in Quiet test, while a ~20% improvement overall was seen in the Words in Noise test.



In my post I was referring to the Words in Noise test, which did not achieve statistical significance - but it is the subject of Frequency Therapeutics' tweet. Also of interest is that this type of hearing is supposedly improved by increasing synaptic connections (what OTO-413 does). Though Frequency Therapeutics may be trying to say that new hair cells help too.

 

What are the rules about Frequency Therapeutics taking a peek at data early? Are they at some level actively looking at ongoing results as the study is still underway and double blinded?

 

I do hope that with additional doses of FX-322 it would also improve words in noise. This is probably the most important out of the two.

A month and a half till results come out.

 

I believe that they can look at results in aggregate but are blinded as to what individuals got drug and who didn't.

@Diesel, do you know?

 

Here's how the process works for publicly traded companies running clinical trials:

1. The FDA provides the "approved" data to the company
2. There may be an agreement between the FDA/SEC and the company to release the data within a certain timeframe
3. Generally, a company cannot keep clinical trial data a secret for more than 1 calendar year

The SEC Requires that the data disclosed to the public is:
- Accurate and reliable
- Does not overstate the outcome of the trial
- Does not include unqualified projections
- Does not differ in interpretation from the FDA
- Does disclose negative results (safety, side effects, etc)
- Is filed with the SEC (likely an 8-K filing)

 

Either way, my point stands. I’m on my phone right now, but assuming those slides are from their 19 January presentation, you will see on slide 61, if I recall correctly, that most patients did not have a measurable WR impairment. This would suggest then what I previously said, which is that the ceiling for improvement would be too low to be able to register a statistically significant improvement in the first place, especially given some, if not most of the patients only had mild hearing loss.

If I recall correctly, they were measuring a standard deviation in a x/50 WR test as 3 words. You need at least more than one standard deviation (sometimes two or three or more depending on your test) to deem something as not being able to be explained by chance I.e. is statistically significant. With that in mind, let’s assume for the sake of argument that 2 standard deviations (6 words) were required to observe statistically significant improvement. Given slide 61 says that most patients did not display measurable WR impairment, it wouldn’t be far fetched to say many could have had a score of 45/50 or higher for a quiet WR test pre-trial. If they then scored 50/50 post FX-322, this 5 word improvement would still fall under 2 standard deviations. I’m personally not concerned, and I think this is why frequency did not focus on the mild hearing loss group for Phase 2, because they knew they’d have a better chance of demonstrating statistical significance in the moderate group, even if mild groups do indeed benefit.

Edit: when I said frequency were not focusing on mild groups, I didn’t mean excluding. They are simply extending to moderately severe.

Edit 2: Ok, I realise I am still confusing the two tests, but it isn’t obvious to me as to why one can’t extend the same logic from quiet WR to word in noise. The ceiling may indeed be higher for word in noise in mild groups (it is for moderate/severe), although this is not immediately obvious to me, and the improvements observed may still be below the number of standard deviations required. This would also be consistent with the less strong p value, if i recall correctly, compared to the quiet WR test. As for possible explanations as to why, a mild hearing loss group may still have a low ceiling for improvement. Alternatively, the dosage schedule may have not been high enough to reach some critical frequencies. Phase 2 will answer this question. And of course, it’s possible that given FX-322’s hands are tied in regrowing synapses only where an OHC has lost its respective synapse, it’s possible that a word in noise test is likely to see greater gains from a synaptopathy drug, such as OTO-413, as you have alluded to.

For the record I’m in bed on my phone about to sleep lol, so will come back on this again tomorrow with more clarity.

 

From what I have read, they can do an interim analysis. Interims are bulk snapshots of data with no identifying of individuals or day-0 assessments. It all comes down to the agreement between the company, SEC, and FDA.

I think it's highly likely that Frequency Therapeutics did an assessment in April/May when they were running into a recruiting slowdown due to COVID-19. What they had to do was go the FDA and probably SEC to get approval for a specific blinded interim analysis. From there, they probably saw some results that were trending in a significant direction, but were advised by the FDA that they should continue the trial by completing full recruiting. Somewhere in there, it's possible the SEC & FDA granted Frequency Therapeutics a waver to keep the interim analysis sealed.

It's likely that if they did some kind of interim analysis that was kept sealed in 2020, they would have to disclose it either in their 10-K or by May of 2021.

 

The DOSE GROUP when compared to the PLACEBO GROUP indicated a P-Value of 0.01. Note that they're using % of improvement to compare the two groups. So, someone going from 45-50 words correct still improved by 11%. Looking at the chart, it looks like the placebo group improved around -5% - 5% on average; but the dose group improved anywhere from 15% to 100%. Statistical significance also would be achieved by aggregating the improvements over time. As we see in the WR chart, that first 15-days, everyone that got the drug probably saw that slope of improvement; and then stayed there.

The 3-word variation is used to establish the baseline for clinically meaningful improvements. And as usual, it's a flawed measurement. A patient going from 16 words to 21 isn't clinically meaningful, but would lend to the statistically significant category as a 31% improvement.

 

I disagree. Audiogram is wayyy more important to me, I have moderate/severe high frequency loss (-70 dB @ 4000 Hz) and I only usually miss one or two words with my bad ear.

 

Honestly, the borders will be back open well before FX-322 is actually on the market, if it makes it that far.

Push comes to shove, I'm sure folks on here will advocate for you.

 

I thought the results would be released in March?

 

The only reason why I said speech in noise was more important than word scores in quiet settings is that you will more likely to have noise around you most of the time when you're working in the office and outside. If you can't hear your co-workers talking to you while there's noise around the office then you won't be able to do the job.

There is also a theory that speech in noise (synapses) is what causes people to have hyperacusis so if FX-322 shows that with additional doses it helps word scores in quiet and with noise then it will be good for the both of us.

 

They are. However, they have stated that it would likely be near the end of March but they could possibly release them earlier in the month.

 

I have a delivery method question. Since it's only being injected just past the ear drum, what causes it to enter the round window? Does a lot of the medication go to waste by not entering?

 

It would be nice if they found another delivery method and could avoid ear drum injection.

 

I started following Frequency Therapeutics about 8 months ago in hope rather than expectation... I've continued to follow and more recently happened upon this thread, thanks to all that have contributed and clarified and sometimes argued mostly constructively...

When I look at the clinical data (to date) and the recent soundbites from the company it's actually quite exciting, I have no expectation but surely with this and other trials ongoing there is true hope for a treatment that can make a difference to so many lives.

My GP told me the difference between a treatment and a cure is like the difference between a journey and a destination.

My bags are packed and I'm good to go.

 

Expectations for the timing of the upcoming Day-90 release:

Frequency Therapeutics owes a Q4/2020 Press Release in February; which typically includes an outlook for 2021. It's highly likely that in that PR, they'll specify a date in March where they will disclose the 90-day Phase-2A Interim results in a webcast or in a PDF, or both, that they'll then file with the SEC.

I do not think it will be an unexpected release. It would be beneficial to set a specific date in March.

If I could speculate, they may only need to give a week's notice.

 

According to Google Trends, more and more people are searching "tinnitus". Maybe COVID-19 and increased time in solitude are doing it, or the earbud generation is cumulatively acquiring more damage. I'm not saying this is a good thing, but the silver lining would be more research and funding.

 

That's probably just me searching tinnitus every 5 minutes on Google to see if they have a cure lol.

 

This is exactly what I thought it was, and exactly how I ended up in this mess.