Prof. Thanos Tzounopoulos Receives $2 Million Grant

Exactly and are we really or is everything in tinnitus research mostly at a standstill at this point aside from Auricle?

 

Well Dr Shore’s research is potentially (please, please, please ) a game changer and that study concludes in a couple months.

 

As a newbie to tinnitus who lives in Pittsburgh, I got a little carried away and contacted Prof. Thanos Tzounopoulos directly last month. He reported that they are still in the preclinical stage, and said that “when clinical trials start, we will post it at phrc.pitt.edu”.

 

Hi @Barb S, 2 months in here and please don’t feel you are ever going too far by being proactive. A lot of members here appreciate that, any new information is always helpful.

 

Quick summary. There are a couple of things advancing so rapidly it is hard to quantify.

1. Computer Processing Power. Even discounting Quantum Computing (I think Quantum Supremacy will be reached in this timeframe), the likes of Intel have stated publicly that they will reached Zetascale supercomputing power by 2027. Their current supercomputer Aurora does 1-2 Exaflops. Zetascale is 1,000 Exaflops. That is an unreal leap, however as stated above Quantum Supremacy could bring many multiples of that.

2. AIs and AGIs they will thrive and develop at such an unimaginable scale based on the available computing power. AIs will solve tinnitus for us. I have no doubt. Plus many more complex conditions.

3. Brain mapping and brain interfaces. Our understanding of the human brain is improving every day. We are learning more about it, but with the assistance of AI our understanding is about to take a giant leap forward. Brain interfaces are rapidly developing. Synchron recently achieved a tetraplegic being able to tweet by ‘thought alone’. Their tech works, it has been proven. Neuralink is the one to watch as it has the most capital by far. It recently achieved a new brain machine latency record of approximately how long it is taking to write this text. Allied with a better understanding of the brain I think they will sort a whole host of medical issues. Also there is huge advances in TMS. See Stanford’s recent depression breakthrough. Severe refractory depression was treated with five days of intense TMS. 80% of participants achieved complete remission after these days. That is unbelievable when you consider the main treatment for depression, SSRI’s, is 25-30-year-old tech, with only an approx 30% success rate with a whole host of side effects. These kinds of leaps will be made with tinnitus soon. I am optimistic.

Finally, I think, given all the above, that Susan Shore, and other researchers are going to be too late to the game.

One of the main reasons I fear for these start-ups (Auricle) etc is that it will only take a breakthrough overnight to completely undermine your company. Shore’s tech is already outdated, yet will probably be an interim treatment until we have ‘the cure.’

To keep this on topic, I believe Pittsburgh is wasting its time with a drug treatment that looks like it won’t be available before 2030. Do they even realise that there is an efficient reformulation of Retigabine coming on the market before 2024/2025? XEN-1101 is that more potent, more selective Potassium channel modulator than Trobalt, with a minimal side effect profile vs placebo.

Given that the Professor Tzounopoulos didn’t know about FDA ‘Fast Track’ makes me think he is not aware of Xenon Pharma and their progress. XEN-1101 will enter Phase 3 this year after FDA Phase 2 meeting in mid year and is also being trialled in a Phase 2 study for depression.

We should have XEN-1101 by 2025 at the latest.

 

Too little too late imho. Can you share his email address as I’d love to ask him about his knowledge of XEN-1101? I was disappointed he wasn’t quizzed about it in the Tinnitus Talk Podcast interview.

 

Wow thank you @Padraigh Griffin, this is an excellent summary especially for a newbie like me who has had difficulty keeping up with all the research info on this forum.

Would tinnitus be off-label use for XEN-1101 or have they explored this in trials?

Very happy to hear you see TMS as still a viable treatment for tinnitus since there’s such a mixed opinion on here at least as far as what I’ve been able to gleam. I will have to look into that Stanford study.

Thanks again for taking the time. This insight really helps!

 

You forget that XEN-1101 might be a 80,000€/year drug that has to prescribed off label (good luck without insurance in the USA...)

Even with insurances in the EU I doubt all insurance companies will cover such an expense off label use.

Xenon is obviously not interested in tinnitus, so I'd give Tzounopoulos a fair chance and he is definitely not wasting his time...!

 

Who doesn’t have health insurance in the US?

Xenon talked about treating tinnitus in their presentations.

 

A question I sent to Professor Tzounopoulos that remains unanswered. I'd love to get a response.

 

I've now contacted four researchers from the Pittsburgh Hearing Centre via email looking for their comments on XEN1101 and its potential as a tinnitus treatment. I have also asked how it differs from their existing lab compound.

Unfortunately I have yet to receive a response. If anyone has a contact it would be greatly appreciated.

Pity it wasn't asked in the Tinnitus Talk Podcast interview.

 

I too worry about pricing, but the focal epilepsy market is quite big and the existing competitors for treatment are generic like Carbamazapine, Topiramate, Pregabalin, etc. It won't be an expensive drug imho.

XEN496 could definitely be an expensive drug as it is a niche market.

 

This would something important to figure out, would we have to take his drug for a lifetime, or just for a couple of months?

On another note, I recently stumbled upon the supplement Quercetin and its supposed Kv7 modulation properties:

"Quercetin potentiated KCNQ1/KCNE1, KCNQ2/3 and KCNQ4 currents but, unusually, not KCNQ5. Strikingly, quercetin augmented both activation and inactivation of KCNQ1, via a unique KCNQ activation mechanism involving sites atop the voltage sensor and in the pore. The findings uncover a novel potential molecular basis for therapeutic effects of quercetin-rich foods and a new chemical space for atypical modes of KCNQ channel modulation" (source).

I really want to understand if and how the mechanisms of Quercetin differ from those of Retigabine and similar anticonvulsant drugs. Could Quercetin help in a similar way with tinnitus and hyperacusis? Only a few people on this forum have actually taken this supplement.

 

I personally follow a diet high in Quercetin - lots of oranges, lemons, blueberries, onions, apples every day twice a day, as part of eating very healthily to maybe fix tinnitus. I've been doing that for over 10 months and I haven't seen any improvement.

Even though my tinnitus is mild, I even observed small worsenings, but maybe it's just the physical course of it and it doesn't get affected by the diet anyway. I don't know if taking a Quercetin supplement would be different though.

 

@DimLeb, thanks for answering. Let's hope your tinnitus gets better again.

It seems like Quercetin does not work so well for a lot of people on here. Maybe if one would take like a really high dose of Quercetin the effects would be more noticeable.

I don't know if this would answer your question, but the compound Prof. Tzounopoulos and his team uses is RL648_81. Don't know if you checked it out already but you can read more about it here.

Prof. Tzounopoulos conducted a study with this compound on mice last year. The conclusion of the study reads:

"The most important finding of our study is the wide time-window after noise exposure within which RL-81 can reduce the percentage of mice that show tinnitus. In previous reports, retigabine was administered 30 min and up to 4 days after the acoustic trauma/ hearing loss, and tinnitus was assessed by deficiencies in the gap detection reflex 7 days after noise exposure (Li et al. 2013, 2015). Patients, on the other hand, may not seek treatment immediately after the sudden onset of tinnitus. Therefore, it is crucial that the critical window during which KCNQ potentiation is effective against tinnitus is delineated in a validated animal model. Here, we validated and used an operant animal model of tinnitus, and showed that application of RL-81 even 7 days after noise exposure reduced the percentage of mice that showed tinnitus. Whereas 7 days is the minimum therapeutic window, it is optimistic for future clinical trials. However, more studies are needed to evaluate the full extent of this therapeutic window. Moreover, the duration of the therapeutic benefit following transient administration of RL-81, and whether RL-81 can mitigate tinnitus when assessed months after noise trauma remain to be determined. Finally, given that this potential treatment strategy might be feasible for military personnel exposed to extremely loud sounds, such as blast exposure, assessment of RL-81 in a blast-induced animal model of tinnitus could be beneficial. Evaluation of these parameters will be useful for selecting the most appropriate target population for subsequent clinical trials to assess RL-81 as a tinnitus treatment strategy" (pp. 136-137)

Marinos, L., Kouvaros, S., Bizup, B., Hambach, B., Wipf, P., & Tzounopoulos, T. (2021). Transient delivery of a kcnq2/3-specific channel activator 1 week after noise trauma mitigates noise-induced tinnitus. Journal of the Association for Research in Otolaryngology, 22(2), 127–139.​

I could not figure out which compound XEN-1101 was.

The paper finishes on the following note:

"Combined with the increased chemical stability as a function of the fluorinated backbone structure in RL-81, RL-81 is less likely to exhibit the clinical pathology characteristic of retigabine. Further toxicology assessments and a transition to early clinical evaluation are therefore in progress" (p. 138).​

I think we have very real reasons to be optimistic for this drug.

1. Prof. Tzounopoulos and his team seem to have enough funding for clinical trials.
2. Unlike XEN-1101, RL-81 is actually being tested on animals for tinnitus.
3. If I read the study correctly, RL-81 is more effective at preventing tinnitus from developing in mice after acoustic trauma in comparison to Retigabine.
4. RL-81 will likely have less adverse effects than Retigabine.

 

Thanks for that. I will read your link. It is all interesting. A lot to hope for with any Retigabine reformulation. I’d have liked some comment from Prof. Tzounopoulos or his team on XEN-1101 but have fallen on deaf ears.

 

RL-81 Could Be Promising Drug Candidate for Noise-Induced Tinnitus

 

You should check out this apprehensive article published in March 2021 by Prof. Tzounopoulos, which "thoroughly discuss the current state of human and animal tinnitus research, outline current challenges, and highlight new and exciting research opportunities". While it doesn't discuss XEN-1101, it gives a nice summary of tinnitus drug candidates and their clinical status. It also summarizes "tinnitus-related compounds that have been successful in animal models", including Retigabine.

 

Amazing, thanks. Jesus, why won't the Professor comment on XEN-1101?

He is the most qualified person in the world to give an opinion on it. Surely he knows all about the drug. It is essentially the same compound as his own. Will a pill taken continuously help chronic sufferers or is it all about injecting the compound in the acute phase? So many questions. God the Tinnitus Talk Podcast interview did not get anything for us. Pity.

Putting two and two together, if Dr. Susan Shore can reduce tinnitus by modulating the Fusiform cells in chronic sufferers, then in theory a continuous use of a pill that regulates these Potassium channels SHOULD work but it would be great to get an expert's opinion.

The more I read, the more it is just plain confusing that he won't refer to Xenon Pharmaceuticals.

For example, he refers to the fact that Gateway Biotechnology is currently developing a drug (GW201) to target T-type calcium channels.

I'm just lost for words that there is zero recognition of XEN-1101.

Love the avatar too BTW StoneInFocus. Big fan of Tyler Durden and some of his philosophy

 

Some concerns I’ve seen with how this type of drug might work overtime for some users... see below. Taken from RL-81 thread. A user of Retigabine reported these things...

So my question is will the new potassium channel modulators work indefinitely? Or will some users become tolerant and maybe it will stop working? Maybe you gotta take it a certain way to avoid this dilemma.

User also said that Retigabine worked like a Tylenol basically—takes the “headache” away for a few hours, then you gotta pop another pill when it comes back. So it’d take tinnitus away for a few hours.

 

This may just be down to the fact that it's competition.

 

↓

Did you answer your own question. Maybe he doesn't want to talk about XEN-1101 if his compound competes with it. Or do you expect him to say "I'm working on this compound, it's pre-clinical, you should be aware though that an almost identical drug is already in Phase 3 by someone else..."?!

I'm not qualified to say how similar they are. Surely they are not identical though.

 

True. Of course it is not identical to exactness but it sure contains extemely similar potency levels, selectivity, and probably far less side effect burden from what we know from Xenon's safety study. Yes, competition is a reason but if you write an all encompassing article like the one above it is not ethical in my opinion to leave out the one drug we may have in the next few years. Especially when your entire research focus is on a similar compound.

He should be called out on that. That is very poor form if competition is the reason. He certainly should have been asked about XEN-1101 in the Tinnitus Talk Podcast interview. Why was he not?

I guess we won't really know. From my reading of the horrible thread on Trobalt it was side effects that were the main problem. This is not Trobalt thank God.

It would be nice to get the Professor's opinion. Is he working on a pill or is it IV for acute? Must watch the video again.

 

I just read through the thread “My Trobalt Blog” and it’s unfortunately underwhelming. This forum has a trove of threads from the past where we can study what people had to say about Trobalt. A user documented their use of the medication several years ago and it’s disappointing to see that it didn’t work.

Why is it that some people didn’t have much success with the drug, but others did? I’ve been a supporter of XEN-1101 and RL-81, and the formulation of similar drugs, because of the great success stories. But sometimes I worry about whether they’ll deliver effectively for some.

I guess the takeaway here is that there’s a good chance it’ll help a lot of sufferers, based off what we saw with Trobalt, but undoubtedly it won’t help everyone. It won’t be a magic pill for all. But for some, perhaps it will. And that’s hope.

Maybe with tinnitus being as variable as it is (cause-wise), a potassium channel modulator just won’t work for some. But shouldn’t it theoretically work for all sufferers, regardless of the cause, due to the mechanism at work with the medication? If the auditory problem lies in the DCN (where an acoustic trauma or ototoxic reaction disrupts the potassium channels), then why did some report no success with Trobalt? Really weird. Tinnitus, being the enigmatic POS that it is, does not give up its secrets easily. I just hope we find a “cure” or reliable treatment soon.

 

Just listened to the Tinnitus Talk Podcast interview again. He really is a good guy and knows this area inside out. The theory is that if it works for epilepsy on a pill basis, it might work for tinnitus, but it hasn't of course, as we all know, been tested in humans for its efficacy for tinnitus.

He really is missing his deadlines massively though. There should have been news on a Phase 1 ages ago and it is hard to work out what is happening. Sure COVID-19 delayed it but he is still massively behind, plus not commenting on XEN-1101 is bad form. Not even acknowledging its existence is just weird and a tad unethical in my opinion, especially when writing an article on current research.

It is also hard to imagine how Professor Tzounopoulos and his team + Chemist from Pittsburgh University will come up with a better reformulation than Xenon Pharmaceuticals.

Xenon Pharmaceuticals spent $75.5M on R&D last year and have $545M in cash. Pittsburgh's largest grant from DoD was $2M in comparison.

I guess there might be something in the science that makes it more specific to tinnitus, but from my very basic understanding this is not the case. The reformulation targets the same KNCQ channels and has the same mechanism of action.

It would be great to get an update from Professor Tzounopoulos or even another Tinnitus Talk Podcast interview.

 

I am not so sure about that, why do you think so?

All we know is that Retigabine, XEN-1101 and RL-81 work on certain KCNQ channels.

I could not find any information on the chemical structure of XEN-1101, but it could be entirely different from that of RL-81, meaning they probably have different potency, different toxicology profile etc.

Also, XEN-1101 has never been tested for tinnitus before. Prof. Tzounopoulos is also an otolaryngologist, not a molecular biologist, so maybe he really just does not know.

Love to see another FC fan on Tinnitus Talk. I suppose I've broken rule number 1, but so be it.

 

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

Dunno about that. I'd venture a guess that a molecular biologist would be looking at things from the bottom up approach and an (deep breath) otolaryngologist would be looking at things from the top down.

Of course we here are all tinnitus experts. It's we who hear the noise, after all.

 

You are right, I've made an error. Prof. Tzounopoulos has studied molecular biology. What I meant to say is that he is not a medicinal chemist. But maybe that is not what you meant by that post.

 

It's clear that you know more about Prof. Tzounopoulos than I do. I even have trouble spelling his name. But whether he's an otolaryngologist, a molecular biologist or a medicinal chemist, it's a sign of progress when the different professions interact and compare notes and results and what-not.

 

He’s working with a chemist.