Audion Therapeutics Trial

Well, here's the first specific information that I am aware of on Audion's clinical trial: http://www.isrctn.com/ISRCTN59733689

Like the Genvec trial, it is a Phase 1/2 trial which is why they talked about starting Phase 1 and Phase 2 in 2017 (though in one place they say it starts in 2016 and ends in 2017). The "intention to publish" date is January 2020. As is standard, part (phase) 1 is the safety trial and part (phase) 2 is efficacy. There is no placebo.

They are using the Notch inhibitor LY3056480. I have not found any information about this drug yet. As expected, the hypothesis is "LY3056480 may induce transdifferentiation of supporting cells into inner-ear hair cells and lead to a subsequent improvement of hearing in patients with sensorineural hearing loss (SNHL)." Thus, if this works it will directly transform supporting cells into hair cells.

Planned enrollment is 62.

Part 1 will be a series of 3 injections. It looks like they are starting at 25 micrograms, and the first people will get 3 injections at that level. Like Genvec they are using "ascending dose cohorts". So there will be a cohort (of unknown size at this point) at 25, then cohorts at 125, 200, and 250 micrograms. They are looking for the "Maximum Tolerated Dose". (It is not clear how they are determining this.)

In the second part (phase) participants are randomized to receive either the MTD or one dose below that. The idea is to look at efficacy at the MTD but to also look for a dose-response effect - is there a bigger effect at MTD compared to one dose below? (The highest tolerated dose may not be the most effective.) It looks like part 2 is another series of injections: "Injections are delivered in the same process as the first part of the study."

What isn't clear is whether the Part 1 participants also participate in Part 2 or if the Part 2 participants are new. It would make sense that the Part 2 participants would be new, but the Plain English Summary says "If participants find their maximum tolerated dose (MTD) then they are enrolled in the second part of the study." This suggests a patient specific MTD and that the same people are in both parts. We will have to see when more information becomes available.

Inclusion criteria:

1. Male or female between 18 and 80 years of age
2. A primary complaint of hearing loss of ˂ 10 years in duration, the history suggesting this hearing-loss to be of age-related, noise-induced or idiopathic origin
3. A bilateral, symmetrical (<15 dBHL difference) SNHL with a pure-tone average threshold across the frequencies 0.5, 1, 2, 4 and 8 kHz of between 25 and 60 dBHL with 2 or more frequencies less than 60 dBHL

Exclusion criteria:

1. Presenting with a primary complaint of tinnitus
2. A ‘true’ air-bone gap >15 dBHL in 3 or more contiguous frequencies between 0.5, 1, 2, 4 kHz
3. History of suspected or diagnosed genetic cause of hearing loss
4. Suspected or known diagnosis of inner ear pathology, congenital hearing loss, fluctuating hearing loss, Ménière’s disease, or secondary endolymphatic hydrops, perilymph fistula, cochlear barotrauma, autoimmune hearing loss, radiation-induced hearing loss, retro-cochlear lesion
5. Evidence of acute or chronic otitis media or otitis externa on examination; or a history of middle ear pathology and/or surgery
6. Any therapy known as ototoxic within 12 months of screening

 

Exclusion #1 isn't going to make it easy to understand the effect of the drug on T sufferers... I guess maybe T isn't someones primary complaint, but they could still have T.

 

I think that is right. This is first and foremost a trial about hearing loss, but tinnitus is one of the secondary outcome measures. What is a little odd is that the primary outcome measure for part 2 is "efficacy of local treatment", but change in hearing is a secondary outcome. I would have thought that change in hearing would have been the way to measure efficacy.

Primary outcome measures
Part 1:
1. Occurrence and severity of procedure related local and systemic AEs are measured using clinical examinations, laboratory tests and patient interviews at visit one, two and three
2. Occurrence of systemic AEs as measured by potentially clinically significant changes by ECG, vital signs, physical examinations and laboratory tests at visit one, two and three
3. Occurrence of surgical and injection sites reactions in and around the treated ear as assessed by otomicroscopy at visit one, two and three
4. Safety of the treatment is assessed using changes in hearing, facial nerve function and balance at visit one, two and three

Part 2:
Efficacy of local treatment is measured if an optimal dose is found in part 1.

Secondary outcome measures
1. Change in hearing is measured using Pure Tone Audiometry (PTA) (dBHL) at baseline and week 12
2. Balance is measured using several balance tests at visit one, two, and three
3. Tinnitus measured using a questionnaire at visit one, two and three

 

@Aaron123 - yes I hope we'll have some data to figure out, if any, correlation between hearing changes (hopefully for the better) and tinnitus (hopefully for the better too).

 

What is nice is that you don't need to have very severe hearing loss to enter the trial, so we can expect those kind of criteria for other trials like Frequency Tx. Plus it will be easier to find participants.

 

Thank you Aaron for sharing, very good finding! This will be exciting, finally there is a movement in the industry.

 

What will be interesting is how the brain will respond to the regained hearing and how this will affect tinnitus.

 

I would have thought that age related hearing loss usually takes more than 10 years to be "discovered" by the patient.

 

Are you eligible to participate to the trial ?

 

Me personally?
I have asymmetrical hearing loss of > 15 dB
So if I understand the inclusion criteria correct, no.

 

Too bad...

 

I'm applying! I can't seem to find information whether having an cochlear implant excludes you from the trial?

 

And I do have sensorineural hearing loss from birth. Been deaf/ hard of hearing 28 years.

 

Not to get you down but reading the criteria you need bilateral loss with <15dB difference between ears and to be honest you will probably not have any hearing left after removing your implant...

If I were you I'd wait for frequency TX trial because if you do this one you may not have supporting cells left

 

Unfortunately, that will likely disqualify you:

 

I just went back to the link and read it carefully

Won't I be eligible for my left ear which has severe hearing loss. (Right side has implant, left hearing aid)

 

Thats what worries me. The frequency TX trial requires supporting cells. Anyway, that will be held in the USA. I live in the UK. But there is hope there will be something for hearing loss in the 5-10 years

 

I am wondering if participants are allowed to discuss their results (good or bad) from the treatment prior to Audion releasing their findings.
Anyone have any insight?

 

I am a little bit puzzled by these inclusion criteria.
I think many people with hearing loss will easily have a bilateral, symmetrical SNHL of more than 15 dB.
15 dB is not a lot. Especially if you have to take +/- 5 dB correction into account.
People with hearing loss I know very often have one "bad" ear.
Am I mistaken and do most people with (noise induced) hearing loss fall within these criteria?

 

It is about the difference between two ears. There must not be a difference of more than 15dB between the right and left ear, as that would make your hearing loss asymmetrical. Example; if you have a hearing loss of 20dB in the left ear at 2kHz, but in the right ear one of 40dB at 2kHz, you will be excluded from this trial as the difference between two ears at a certain frequency is more than 15dB.

So you can have a "bad" ear, as long as it doesn't exceed a 15dB difference compared to the other ear.

 

According to the criteria it seems that their primary target is the age-related HL

 

I should be eligible... If I don't tell them my T is awful, lol. But the supporting cells thing is a concern.

+ Frequency won't accept someone who just did another trial before.

Edit : not eligible, I don't live in Germany, Greece or UK...

 

Yes that is what I understand. But this 15 dB difference is minimal. Because of that, many people will not be eligible, I think.

If that is so, I do not completely understand this <10 years. Most people that are diagnosed with age related hearing loss will have this longer than 10 years before diagnosis.
Also this should indicate that there is a clear understanding (and diagnostic tool) between NIHL and age related hearing loss.
I always understood that age related hearing loss is similar to NIHL.
Wear and tear of the hair cells.

 

When are they going to start the trials? On the other hand ... so many different molecules are developing for the recovery of the ear? Or are they all with a similar structure?

 

Its really good they target mild-moderate hearing loss, it also means they target to regenerate outer hair cells which are harder to regenerate. Looking forward for results

 

Yes that is a good point. < 60-70 dB is outer hair cells.

 

I didn't know that. Is there research showing that milder hearing loss is all outer hair cell damage, with all inner hair cells intact?

 

I guess that a loss of OHCs would lead to hearing loss of approximately 50 dB. Having normal hearing level of 10 dB at a certain frequency, one would have 60 dB at that frequency if appropriate OHCs are lost.

 

Something similar I read to.
I read 60 dB, and also 40 dB.
I also read that some researchers expect that problems with inner hear cells and/or connections can give tinnitus.
Not problems with outer hair cells.
We all hope we will know more ASAP (-;

I did a search. This was one of the first articles I found. https://www.ncbi.nlm.nih.gov/pubmed/95382
Quote: "In most instances loss of outer hair cells was substantially greater than that of inner hair cells. In fact, the pattern and location of missing outer hair cells on the basilar membrane were most often correlated with threshold shifts of 50 dB or less. Generally inner hair cell loss was observed when the threshold shift was greater than 50 dB."
So perhaps 50 dB is the number and not 60-70 dB. So I also lost inner hair cells )-;

 

Hi. Is there any updates in this tria?