Decibel Therapeutics

[patorjk]

They sure are taking their time to report the interim results on their otoprotective drug, Q2 is almost over.

I'm starting to think the study had poor results. They have 3 more days to release the results before 2Q ends. It wouldn't make any sense to release good results right before a long holiday weekend. It's only 20 patients, so I can't imagine it would take a long time to process, especially since they announced months ago that the results would happen in 2Q. Then again, they seem to have moved on from this drug when they switched to specializing in gene therapy, so maybe it's just not a priority.

I believe their plan is to sell it to another company to raise capital (after Phase 1 is done).

 

[AxEars]

They sure are taking their time to report the interim results on their otoprotective drug, Q2 is almost over.

Next earnings date is estimated between August 8th and 12th

Q2 ends Thursday. There's always time in between the quarter ending and the release date for the reports to be filed and audited prior to being released to the public.

 

[Nobody19]

We were all wrong, fortunately!

Results are looking pretty good, actually:

87% of patients who experienced ototoxicity in their placebo-treated ear were protected from ototoxicity in their DB-020-treated ear

Key findings:

• DB-020 was generally well tolerated, with no significant safety issues observed.
• DB-020, administered prior to cisplatin, had no apparent effect on systemic cisplatin levels.
• 13 of 17 (76.5%) patients experienced cisplatin-induced ototoxicity in the placebo ear after the first cycle of cisplatin; 15 of 17 (88.2%) patients experienced cisplatin-induced ototoxicity in the placebo ear by the last evaluable test.
  • Placebo-treated ears lost approximately 30dB on average from baseline in high frequencies, shifting patients from normal or slight hearing loss to moderate hearing loss (two hearing loss categories) on average.
• In the 15 patients who experienced ototoxicity in the placebo ear by the last evaluable test, DB-020 protected 13 (87%) from ototoxicity in their DB-020-treated ear.
  • 8 of 15 (53.3%) were completely protected, and 5 of 15 (33.3%) were partially protected. (Complete protection was defined as no change in hearing from baseline in the ear that received DB-020 according to the ASHA ototoxicity criteria in the clinically assessed range.)
  • Ears treated with DB-020 lost approximately 8dB on average from baseline.
• DB-020 reduced cisplatin-induced loss of speech audibility by 80% as measured by the Speech Intelligibility Index, suggesting treatment with DB-020 may reduce the risk of needing assistive hearing devices after receiving cisplatin.

Decibel Therapeutics Reports Positive Data from Interim Analysis of Ongoing Phase 1b Clinical Trial of DB-020 in Patients Receiving Cisplatin Chemotherapy

 

[patorjk]

I'm starting to think the study had poor results. They have 3 more days to release the results before 2Q ends. It wouldn't make any sense to release good results right before a long holiday weekend. It's only 20 patients, so I can't imagine it would take a long time to process, especially since they announced months ago that the results would happen in 2Q. Then again, they seem to have moved on from this drug when they switched to specializing in gene therapy, so maybe it's just not a priority.

I believe their plan is to sell it to another company to raise capital (after Phase 1 is done).

I spoke too soon, they released positive results this morning:

Decibel Therapeutics Reports Positive Data from Interim Analysis of Ongoing Phase 1b Clinical Trial of DB-020 in Patients Receiving Cisplatin Chemotherapy

Still a bit strange to wait so long, though maybe it took them a while to process all the data.

 

[Nobody19]

I spoke too soon, they released positive results this morning:

Decibel Therapeutics Reports Positive Data from Interim Analysis of Ongoing Phase 1b Clinical Trial of DB-020 in Patients Receiving Cisplatin Chemotherapy

Still a bit strange to wait so long, though maybe it took them a while to process all the data.

As long as the results are good!

 

[Joeseph Stope]

As long as the results are good!

Well it's some sort of progress. Protection from the side-effects of necessary pharmaceuticals.

But for alleviating tinnitus/hyperacusis and restoring hearing loss, I guess we'll have to wait a bit.

 

[Nick47]

It's just great to see positive results in the hearing field and they are very significant.

So is it August for OTO-313 and FX-322? FX-345 later this year and Susan Shore device early 2023?

 

[patorjk]

It's just great to see positive results in the hearing field and they are very significant.

So is it August for OTO-313 and FX-322? FX-345 later this year and Susan Shore device early 2023?

Yeah, August for OTO-313, then in the months after that results for higher dose OTO-313 and OTO-413. FX-322 results will be late this year or early next year. FX-345 hasn't even started trials, though their goal is to start a Phase 1b trial in the second half of this year.

As an aside, I came across a company called Fennec Pharmaceuticals whose whole goal is a create a drug to reduce cisplatin-induced ototoxicity (same thing as DB-020, OTO-510, and one of Ting Therapeutics' drugs). It's further along than DB-020, though patients get that drug intravenously rather than a shot to the ear.

Fennec may be one to keep an eye on. Even though their focus is just 1 drug, I like they're concerned about ototoxicity.

 

[Nick47]

Yeah, August for OTO-313, then in the months after that results for higher dose OTO-313 and OTO-413. FX-322 results will be late this year or early next year. FX-345 hasn't even started trials, though their goal is to start a Phase 1b trial in the second half of this year.

As an aside, I came across a company called Fennec Pharmaceuticals whose whole goal is a create a drug to reduce cisplatin-induced ototoxicity (same thing as DB-020, OTO-510, and one of Ting Therapeutics' drugs). It's further along than DB-020, though patients get that drug intravenously rather than a shot to the ear.

Fennec may be one to keep an eye on. Even though their focus is just 1 drug, I like they're concerned about ototoxicity.

I had not heard of Fennec. Thanks for clarifying.

 

[Jurger]

Otoprotective drugs are interesting to me as a hearing loss patient, because they can provide insights with regards to getting drugs into the inner ear. One of my concerns is that intratympanic injections have significant drawbacks in terms of getting drugs deep and long enough in the cochlea to have an effective, predictable healing effect.

 

[addot]

Always nice to hear positive results! Thank you @Nobody19 and @patorjk for staying on top of all these developments and sharing them with us. I am also very grateful to everyone who participated in this trial. Given how well DB-020 worked, I find it a little sad that participants only got shots in one ear as opposed to both. I know this is the nature of placebo-controlled trials, I'm just grateful for their participation and their sacrifice.

I do wish there was more news about Decibel's synapse regeneration treatment. It seems like it's been stuck in the discovery phase for quite a while...

As an aside, I came across a company called Fennec Pharmaceuticals whose whole goal is a create a drug to reduce cisplatin-induced ototoxicity (same thing as DB-020, OTO-510, and one of Ting Therapeutics' drugs). It's further along than DB-020, though patients get that drug intravenously rather than a shot to the ear.

Your mention of Ting Therapeutics made me think of something: Ting claims that some of their drugs might also protect against noise-induced hearing loss. I wondered if this was the case for DB-020 and PEDMARK (Fennec's drug). Both of them are formulations of sodium thiosulfate. It doesn't seem like it: even though sodium thiosulfate is an anti-oxidant, apparently its main mechanism is binding to the cisplatin that builds in the cochlea during chemotherapy and flushing it out of the body, which obviously wouldn't do much for NIHL.

 

[reggie green]

Their stock is on fire, so it must be good news!

 

[AxEars]

I'd like to point out that this company traded 10.5 million shares between June 29th and 30th two weeks ago. Its average is 85 thousand. So the volume of shares traded was 123 times its average.

Good lord.

 

[SmallRonnie]

These guys are researching at least 6 drugs for hearing loss, not including the one currently in clinical trials. Looks hopeful but they are a very long way off getting to market.

 

[Stenis]

Decibel Therapeutics Announces Submission of Investigational New Drug (IND) Application for Lead Gene Therapy Candidate DB-OTO

This announcement came today. Not sure if DB-OTO is based on DB-020.

 

[Nick47]

Decibel Therapeutics Announces Submission of Investigational New Drug (IND) Application for Lead Gene Therapy Candidate DB-OTO

This announcement came today. Not sure if DB-OTO is based on DB-020.

I saw this yesterday. It's for those with certain congenital gene mutations.

 

[Stenis]

I saw this yesterday. It's for those with certain congenital gene mutations.

OK, so this wouldn't help us with tinnitus?

 

[Nick47]

OK, so this wouldn't help us with tinnitus?

Unlikely. Miles away and not meant for tinnitus. Dr. Shore's device (if successful) is closest to market.

 

[CW Dragon]

Otoprotective drugs are interesting to me as a hearing loss patient, because they can provide insights with regards to getting drugs into the inner ear. One of my concerns is that intratympanic injections have significant drawbacks in terms of getting drugs deep and long enough in the cochlea to have an effective, predictable healing effect.

Interesting. Permeability of the round window membrane. Apparently a French suction catheter allowed permeability of the RWM to increase 30x, of course most of the animals (guinea pigs) this suctioning had been performed on had already received a solution of NaCl and other stuff, including benzyl alcohol and mannitol. So basically sterilize middle ear, apply solution to RWM, then suction, then deliver FX-322 or OTO-413 for maximum absorption.

Honestly, I feel that intratympanic injections will be the cure since they don't have to cross the blood brain and blood labyrinth barrier and being diluted/nullified by digestive system.

Permeability of the Round Window Membrane is Influenced by the Composition of Applied Drug Solutions and by Common Surgical Procedures

Makes me wish I had had Walter White (actually Heisenberg) as a chem teacher... that would have gotten me to pay better attention in class... this stuff is so confusing

 

[Brian Newman]

Interesting. Permeability of the round window membrane. Apparently a French suction catheter allowed permeability of the RWM to increase 30x, of course most of the animals (guinea pigs) this suctioning had been performed on had already received a solution of NaCl and other stuff, including benzyl alcohol and mannitol. So basically sterilize middle ear, apply solution to RWM, then suction, then deliver FX-322 or OTO-413 for maximum absorption.

Honestly, I feel that intratympanic injections will be the cure since they don't have to cross the blood brain and blood labyrinth barrier and being diluted/nullified by digestive system.

Permeability of the Round Window Membrane is Influenced by the Composition of Applied Drug Solutions and by Common Surgical Procedures

View attachment 51765

Makes me wish I had had Walter White (actually Heisenberg) as a chem teacher... that would have gotten me to pay better attention in class... this stuff is so confusing

Yeah I do think intratympanic injections will be the way hearing loss gets treated. The companies we are all following are intratympanic injection based.

Not sure about injecting through the actual round window membrane, I read they were doing it for AM-101. You don't want to puncture the round or oval window membrane; that will give you a perilymph fistula. Those are a nightmare. I'm pretty sure I got one and your dizzy all the time, it gives you hyperacusis, distortions, more tinnitus tones, head pressure, all sorts of stuff. I was on forums for that condition and people who have it severe; even years after surgery, you still can't work out, bend over or strain or it re-opens and they have to get surgery again. So pretty much if you get it bad enough no more lifting weights, no straining hard, anything pressure related. Most people heal on their own and it goes away and they go back to normal. Weird stuff.

I think the gel holding medicine on the round window membrane is the best. Let's hope Frequency Therapeutics and Otonomy are not giving us more letdowns.

 

[CW Dragon]

Yeah I do think intratympanic injections will be the way hearing loss gets treated. The companies we are all following are intratympanic injection based.

Not sure about injecting through the actual round window membrane, I read they were doing it for AM-101. You don't want to puncture the round or oval window membrane; that will give you a perilymph fistula. Those are a nightmare. I'm pretty sure I got one and your dizzy all the time, it gives you hyperacusis, distortions, more tinnitus tones, head pressure, all sorts of stuff. I was on forums for that condition and people who have it severe; even years after surgery, you still can't work out, bend over or strain or it re-opens and they have to get surgery again. So pretty much if you get it bad enough no more lifting weights, no straining hard, anything pressure related. Most people heal on their own and it goes away and they go back to normal. Weird stuff.

I think the gel holding medicine on the round window membrane is the best. Let's hope Frequency Therapeutics and Otonomy are not giving us more letdowns.

Yep definitely didn't mean to puncture either membranes. Judging by permeability of it, it seems both high and low molecular weight solutions can penetrate it. BDNF is about 28 kDa. Blood brain barrier only allows less than 400 Da to pass through it seems, probably similar to the blood labyrinth barrier. Those two barriers I think are the main factors preventing regenerative rejuvenations, and why NAC has a lot of success in regards to hearing loss (only 163 Da).

There appear to be three layers to the RWM, outer epithelium (cells in conjunction with mucus lining), middle connective tissue (fibroblasts, collagen, blood/lymph vessels), and the inner epithelium (cells in conjunction with mesothelial cells). I guess the suctioning from the previous post probably removed a lot of the outer epithelium which is why the permeability went up.

It's also thicker on the sides, so getting the compound on the bullseye and making sure it doesn't run along to the edges for less absorption is important, but then again, just administer more. I could actually see this as lowering the results of clinical trials.

I can't believe I would spend a half hour reading a study on the cochlea. I couldn't picture this a few months ago but then again I've had a few drinks

Permeability of round window membrane and its role for drug delivery: our own findings and literature review

By the way, I saw your audiogram. That OTO-413 will do wonders for you I pray.

 

[Brian Newman]

Yep definitely didn't mean to puncture either membranes. Judging by permeability of it, it seems both high and low molecular weight solutions can penetrate it. BDNF is about 28 kDa. Blood brain barrier only allows less than 400 Da to pass through it seems, probably similar to the blood labyrinth barrier. Those two barriers I think are the main factors preventing regenerative rejuvenations, and why NAC has a lot of success in regards to hearing loss (only 163 Da).

There appear to be three layers to the RWM, outer epithelium (cells in conjunction with mucus lining), middle connective tissue (fibroblasts, collagen, blood/lymph vessels), and the inner epithelium (cells in conjunction with mesothelial cells). I guess the suctioning from the previous post probably removed a lot of the outer epithelium which is why the permeability went up.

It's also thicker on the sides, so getting the compound on the bullseye and making sure it doesn't run along to the edges for less absorption is important, but then again, just administer more. I could actually see this as lowering the results of clinical trials.

I can't believe I would spend a half hour reading a study on the cochlea. I couldn't picture this a few months ago but then again I've had a few drinks

Permeability of round window membrane and its role for drug delivery: our own findings and literature review

By the way, I saw your audiogram. That OTO-413 will do wonders for you I pray.

That's interesting detail! I didn't know there were so many layers to the round window. That all makes sense, the barrier is what makes it hard for drugs to absorb. Crazy complicated.

Let's hope something comes out eventually. I hope OTO-413 is not a bust because, yeah, it would be amazing to try it. I don't even have any missing word score. I wish we had better diagnostics and imaging to see inside the cochlea. That would be groundbreaking. But still few people care about hearing even though it's a main sense. I hope major progress is made this decade. This community deserves it.

 

[patorjk]

I've been doing a deeper dive on this company recently, and I think I've found some interesting stuff. However, I kind of don't know what I'm looking at so I need other people to let me know if this is something to get excited about or if this is a nothing burger. Anyway, last summer, right before Decibel Therapeutics announced their DB-020 results, they filed two very interesting patents:

• Cochlear outer hair cell promoters and uses thereof
• Cochlear inner hair cell promoters and uses thereof

The inner hair cell (IHC) patent has a lot of cancelled claims, but there are no cancelled claims in the outer hair cell one (OHC). To me, this may signal why their current corporate presentation focuses more on OHCs. In the above OHC patent they make some interesting claims:

29. A method of treating a subject having or at risk of developing hearing loss, comprising administering to the subject an effective amount of the nucleic acid vector of any one of claims 1-14 or the composition of claim 15 or 16.

34. A method of promoting OHC regeneration in a subject in need thereof, comprising administering to the subject an effective amount of the nucleic acid vector of any one of claims 1-14 or the composition of claim 15 or 16.

43. The method of any one of claims 29-42, wherein the nucleic acid vector or composition is administered in an amount sufficient to prevent or reduce hearing loss, prevent or reduce tinnitus, delay the development of hearing loss, slow the progression of hearing loss, improve hearing, improve hair cell function, prevent or reduce hair cell damage, prevent or reduce hair cell death, promote or increase hair cell survival, or increase hair cell numbers.​

Am I wrong, or does it sound like they have something here? I would assume since they filed a patent it's important? It's also unclear to me how close to the clinic they are. Maybe this is just to protect some exciting work? Anyone have any thoughts on this? Also of note - there have been no press releases on this stuff.

From all of my other digging it looks like the company is focused on DB-020, DB-OTO (hearing loss due to OTOF gene), and AAV.103 (congenital hearing loss). The CEO recently went to JPM2023 and presented this slide deck (which makes no mention of hair cell regeneration), and he was completely quiet on Twitter for 3 months until reappearing recently to do some hobnobbing with other JPM2023 attendees.

 

[Joeseph Stope]

The claims are kind of broad, and somewhat all-encompassing.

Some points worth keeping in mind:

Medications geared towards preventing hearing loss and tinnitus would be of benefit to soldiers, firemen, rock musicians etc.

Stuff for alleviating acute tinnitus, well umm... a large percentage of sufferers achieve habituation or manage to get rid of their tinnitus in the first few months anyway, so proving that the medication did the trick, deserves, ahem... statistical scrutiny.

Chronic tinnitus, 12 months or more. Now that's what most of us here are following and praying for a cure.

Just my two cents...

Stope (who has no medical knowledge base)

 

[patorjk]

Decibel Therapeutics announced this morning that they're being acquired by Regeneron. The deal is $4 per share plus $3.5 per share in CVR (contingent value right). According to the agreement the CVR is:

CVR holders would become entitled to receive contingent payments as follows: (i) $2.00 in cash, upon the fifth participant being administered with DB-OTO in a clinical trial on or prior to December 31, 2024 (the DB-OTO Milestone); and (ii) $1.50 in cash, upon (a) the first participant being administered with DB-OTO in a registration enabling trial (as defined in the CVR Agreement) or (b) acceptance for review of a Biologics License Application by the U.S. Food and Drug Administration, a Marketing Authorization Application by the European Medicines Agency or the U.K. Medicines and Healthcare Products Regulatory Agency, or an equivalent application by the applicable national regulatory authority in any of Germany, France, Italy or Spain for DB-OTO, whichever occurs first, on or prior to December 31, 2028; provided the DB-OTO Milestone is achieved on or prior to December 31, 2024. There can be no assurance that any payments will be made with respect to the CVR. The closing of the tender offer will be subject to certain conditions, including the tender of at least a majority of the outstanding shares of Decibel common stock and other customary closing conditions. Upon the successful completion of the tender offer, Regeneron will acquire all shares not acquired in the tender through a second-step merger for the same consideration per share paid in the tender offer. The transaction is expected to close in the third quarter of 2023.

The first $2 seems pretty likely given that the DB-OTO trial has already started. Hopefully this means some of these larger companies are getting more serious about hearing treatments, it'll be interesting to see if there's some kind of race between Eli Lilly (who acquired and Akouos a few years ago) and Regeneron now that both of them have some skin in the game. Decibel Therapeutics has some interesting patents related to hair cell regeneration, now that a bigger company is in the driver seat I wonder if we'll hear more or less about those.

 

[patorjk]

I decided to dig around and see if there was any news from DB-OTO study and I found this press release from Regeneron that indicated some initial success:

TARRYTOWN, N.Y., Oct. 26, 2023 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced preliminary, positive safety and efficacy results from the first patient (<2 years of age) dosed in the Phase 1/2 CHORD trial investigating otoferlin gene therapy (DB-OTO) in children with profound genetic hearing loss due to mutations of the otoferlin gene.

In the trial, the child received an intracochlear injection of DB-OTO in one ear. At planned follow-ups, the child experienced improvements in auditory responses through week 6 compared to baseline, per auditory brainstem response (ABR) and behavioral (pure tone) audiometry. ABR, a clinically accepted physiologic measure of hearing sensitivity, is often absent in those with classic otoferlin-related hearing loss and was absent in both ears of the child at baseline. There were no concerning safety signals through week 6 following treatment.

A placebo effect for this kind of hearing loss is unlikely, especially for a child that probably doesn't even know what's happening. I think it bodes well for the tech Decibel Therapeutics developed. Their strategy was to tackle small diseases and work their way up, so I imagine it'll be a while before they have something ready for general hearing loss. Still, it's encouraging to see some progress in this general area. On the one hand, I hate the idea of waiting 10 years, but a step forward is a step forward. Hopefully gene therapy bears fruit when it comes to fixing hearing problems.