RL648_81: Synthesis and Evaluation of Potent KCNQ2/3-specific Channel Activators

[Bobby B]

We know the FDA and the medical community isn't taking tinnitus suffering seriously.

There is no reason to side with the FDA on that one - they will make sure the process takes a very long times and costs so much that most investors will be reluctant to pour money unless they are sure to recoup their investment.

And the other risk here, if during this long time another better epilepsy drug is discovered, with a mode of action not affecting T, we can probably kiss this "official" RL_81 goodbye for good.

Professor T - great name for this btw - spent all this time working on his new molecules.. it would be very sad that this ends up nowhere for all the many reasons that have nothing to do with how it works.

Then we will are back to "live with it" and try those snake-oily sound or T re-training techniques...

 

[attheedgeofscience]

Maybe we should start sending messages of desperation (end of my rope, can't do it anymore...) and obituaries to some of those people to get some attention!

To be (very) honest, I don't think that would change much. "Zooming out" and seeing the big picture, I would like to mention that - on average - 22 US veterans commit suicide. Every day. There is even a specific home page on FB for that (Mission 22):

www.facebook.com/Mi22ion

With such staggering numbers, you would think that a lot would get done to alter that statistic. For sure some of these veterans are - and were - suffering from tinnitus (being the #1 disability suffered by veterans). But even that seems not to get the attention of decision makers. I personally corresponded with the WWP - the most powerful NGO for veterans (and +3M followers on Facebook) and they were not interested in sharing anything related to tinnitus and research on their Facebook page. In fact, tinnitus wasn't even mentioned in their latest survey from members (see attachment).

In retrospect, and with the setbacks seen in terms of clinical trials and long delays with time-to-market, I cannot help but think that my stem cell treatments were the best decision I could ever have made - because the cavalry didn't come to rescue me back in 2013 (and not anytime soon thereafter either).

I should, however, point out that Auris Medical is still a player in the game, and also one dedicated and well managed pharma company (and helpful staff). At some point their AM-102 is due to enter clinical trials (provided all goes well). Indeed, a news feed post was shared on that a little while back:



It remains to be seen which category of patients will be in scope for the trial. But at least, there is potentially one additional drug coming our way.

While the embedded FB-post (on RL-81) I shared in the first message here on this thread now has +200 ratings (all-in-all), the one from Auris Medical, above, has far less. It would be better if the tinnitus community had ensured that the ratings were the other way around.

 

[Mithrandir]

@attheedgeofscience Thanks for your information about Mission 22, that's a sad moment for USA. This country doesn't help those brave guys who worked for it...so sad story ! Disability of vets like T must be one of the most important act from US Army for the guys...

After all your tinnitus journey (through the hell) and with all the knowledges you provide us. Definitely you consider stem cell like the best think you've ever done ? Is it your main advice for T sufferers ? (of course if people have money to go to Asia)

 

[Alue]

To be (very) honest, I don't think that would change much. "Zooming out" and seeing the big picture, I would like to mention that - on average - 22 US veterans commit suicide. Every day. There is even a specific home page on FB for that (Mission 22):

www.facebook.com/Mi22ion

With such staggering numbers, you would think that a lot would get done to alter that statistic. For sure some of these veterans are - and were - suffering from tinnitus (being the #1 disability suffered by veterans). But even that seems not to get the attention of decision makers. I personally corresponded with the WWP - the most powerful NGO for veterans (and +3M followers on Facebook) and they were not interested in sharing anything related to tinnitus and research on their Facebook page. In fact, tinnitus wasn't even mentioned in their latest survey from members (see attachment).

It seems they adopt the "just ignore it, pretend it doesn't exist, and hope it goes away" mantra with tinnitus.

The WWP is a pretty disgraceful NGO when you take a closer look at their spending.

In retrospect, and with the setbacks seen in terms of clinical trials and long delays with time-to-market, I cannot help but think that my stem cell treatments were the best decision I could ever have made - because the cavalry didn't come to rescue me back in 2013 (and not anytime soon thereafter either).

I should, however, point out that Auris Medical is still a player in the game, and also one dedicated and well managed pharma company (and helpful staff). At some point their AM-102 is due to enter clinical trials (provided all goes well). Indeed, a news feed post was shared on that a little while back:

It remains to be seen which category of patients will be in scope for the trial. But at least, there is potentially one additional drug coming our way.

Although I haven't seen the results I had hoped for with AM101 (could be the placebo), the trails have been a positive experience for me, and at least at my site everything has been very professional. I really hope Auris is successful! Even if AM101 doesn't help chronic sufferers, a successful drug coming to market would be huge for the future of tinnitus research.

If AM102 targets more chronic tinnitus, do you think patients that participated in AM101 would still be eligible to sign up for the AM102 trials?

 

[Bertman]

Well we don't own the patent rights to this so why are you even thinking of approval ? That's not the plan here .
We test it and if it works we keep on testing it until they release it then we buy it officially...

A test of how life can be during ten years without hearing tinnitus all the time.

How about that ? Isn't this a worthwhile test to most of us ?

That's what I assumed this thread was all about. Kind of like how people are trialling trobalt on their own but with an experimental drug instead. It's for personal benefit, not to create scientific data; that's what scientists, doctors and researchers are for. More of a try it and see if it works for you kind of thing. If it does then great, if not then keep on keeping on like we are now. As I said earlier though, it is too risky for me at the moment, but who knows, in the future if people say it works then I may have to reconsider. It'd be nice to know if something out there works and have the option of trying it before/if it makes it to market.

 

[linearb]

A misunderstood statistic: 22 military veteran suicides a day (LA Times)

http://www.forbes.com/sites/timwors...c-of-suicide-in-the-us-military/#69acb6641769

But before we conclude that this is happening we do in fact need to check and see whether the rate is odd. Is out of order for the society which people come from. And that's where this story of an epidemic of military suicides rather falls down. The actual suicide rate in the US military seems to be around and about that for the US as a whole. Soldiers and ex-soldiers don't kill themselves in any greater numbers than the average American does.

On the other hand, veterans certainly do have tinnitus at much higher rates than the general population, to the tune of $1 billion a year in disability costs.

 

[Bertman]

While the embedded FB-post (on RL-81) I shared in the first message here on this thread now has +200 ratings (all-in-all), the one from Auris Medical, above, has far less. It would be better if the tinnitus community had ensured that the ratings were the other way around.

I agree with you, but I also understand why it's the way it is. Although we don't know the specifics on whether or not it will work for us chronic T folk, it's easy to associate it with am-101 which doesn't seem to have hope for us longer term T people. So the majority of people on here will likely dismiss it as something with less value to us than it really has. This drug on the other hand seems like it would be able to help chronic T more than an injection into the ear would. (I know this is a very long shot and we shouldn't get too excited over preliminary data like this yet, but that's just the way it appears)

 

[attheedgeofscience]

If AM102 targets more chronic tinnitus, do you think patients that participated in AM101 would still be eligible to sign up for the AM102 trials?

I would have absolutely no opinion on such matters. I would say such a question would either be answered via the inclusion/exclusion criteria when/if the trial of AM-102 commences. Alternatively, there may also be an opportunity to set up a Q&A-session with Auris Medical at some point in the future (they have already done that - very generously - twice in the past). As it happens, I set up the first one back in January/February last year:

https://www.tinnitustalk.com/threads/auris-medical-q-a.8201

If members of this board would like me to investigate that, then, as a minimum, I require the news feed post of AM-102 that I shared earlier on in this thread to reach a minimum of 250 ratings combined (likes/shares/comments).

Alternatively, I know @Michael2013 is looking for ways to become more of an asset with the tinnitus community - so perhaps this could be his first task as an apprentice (i.e. setting up a Q&A-session).

 

[Leo1994]

Researchers at the University of Pittsburgh School of Medicine and Arts & Sciences have designed a more effective version of an FDA-approved epilepsy drug with the potential for fewer side effects, according to a study published on March 22 in Molecular Pharmacology. The experimental agent also could prove to be a treatment for tinnitus and other disorders caused by volatile neural signaling.

Epilepsy, in which erratic firing of nerve signals causes seizures, affects about 1 percent of people worldwide, said senior investigator Thanos Tzounopoulos, Ph.D., Endowed Chair in Auditory Physiology, associate professor of otolaryngology and member of the Auditory Research Group, University of Pittsburgh School of Medicine. Drugs to treat the disorder primarily work by influencing the transport of sodium, potassium and chloride ions across the nerve cell membrane to try to reduce the excitability of the brain cells.

"Unfortunately, these drugs don't work well in nearly a third of patients and there is a great need for better treatments," Dr. Tzounopoulos said. "We have been able to refine an existing medication so that it acts selectively on certain nerve cell membrane transport channels, which should make it more effective."

The available drug is called retigabine, and while it has improved symptoms for some patients, it can also lead to troublesome side effects, including retinal abnormalities, urinary retention and skin discoloration. Dr. Tzounopoulos was part of a study team that evaluated an earlier modification of retigabine, dubbed SF0034, which is being further developed by SciFluor Life Sciences LLC in Cambridge, Mass.

For the current project, Dr. Tzounopoulos and Peter Wipf, Ph.D., Distinguished University Professor of Chemistry at Pitt, rationally redesigned several structural components of retigabine to further increase its potency. Retigabine works by activating all five types of potassium transport channels in the KCNQ category, but only two of the potassium channels, KCNQ2/3, are important for stabilizing the cell membrane of brain cells involved in hyperexcitability-related disorders, such as epilepsy and tinnitus, Dr. Tzounopoulos explained. The new compound, known as RL648_81 ("RL-81"), targets just those channels.

When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects.

The experimental compound could also help people with tinnitus by preventing hyper-excitation of nerve cells in auditory pathways, Dr. Tzounopoulos noted.

"At this point, the new compound is ready to be studied further in animal models of epilepsy and tinnitus and for other preclinical assessments," Dr. Wipf said. "RL-81 appears to have great potential for the treatment of these challenging neurological conditions."

https://www.sciencedaily.com/releases/2016/03/160330102848.htm

 

[Beste]

I think we need to start a petition as TT and help the team behid this study to finish it before 2020! Most of us will be chronic by then and this drugs will not work for us most probably.

 

[Bobby B]

Yeah petition will work ! Maybe the starving children in Africa should also start a petition on the Internet to draw attention .

No one wants to take the risk trying that drug on themselves and no one is willing to pay for tests etc... So you will have to wait until 2020 and beyond

 

[Beste]

Yeah petition will work ! Maybe the starving children in Africa should also start a petition on the Internet to draw attention .

No one wants to take the risk trying that drug on themselves and no one is willing to pay for tests etc... So you will have to wait until 2020 and beyond

Bobby, you know this world is cruel place. Since no one will gain money by helping African children they just refuse to pay more attention to them. It sucks but this is what it is.

This is something different. I read somewhere that Professor said the progress is slow due to financial situations. I think that means if we help the team of retigabine they may finish their works earlier. I think our situation is not as desperate as African children.

 

[Danny Boy]

Bobby, you know this world is cruel place. Since no one will gain money by helping African children they just refuse to pay more attention to them. It sucks but this is what it is.

This is something different. I read somewhere that Professor said the progress is slow due to financial situations. I think that means if we help the team of retigabine they may finish their works earlier. I think our situation is not as desperate as African children.

This drug isn't for tinnitus first, it's for epilepsy first. Therefore, we won't be able to obtain the drug for quite a long time, as it's not even in trials yet. They are trying to find a pharmaceutical company who wants the drug.

Also, people who are on the verge of suicide, because of their tinnitus would beg to differ. If you have super loud tinnitus coupled with hyperacusis and reactive tinnitus, yeah...It's horrible.

Additionally, I would think it's useful to know if the drug actually works for tinnitus on humans, as people are jealous of these mice getting rid of their tinnitus and we can't.

 

[Beste]

This drug isn't for tinnitus first, it's for epilepsy first. Therefore, we won't be able to obtain the drug for quite a long time, as it's not even in trials yet. They are trying to find a pharmaceutical company who wants the drug.

Also, people who are on the verge of suicide, because of their tinnitus would beg to differ. If you have super loud tinnitus coupled with hyperacusis and reactive tinnitus, yeah...It's horrible.

Additionally, I would think it's useful to know if the drug actually works for tinnitus on humans, as people are jealous of these mice getting rid of their tinnitus and we can't.

Yes. I'm one of those people.

 

[gotyoubynuts]

Yes. I'm one of those people.

You now have hyperacusis and reactive tinnitus as well? What's next?

 

[Beste]

You now have hyperacusis and reactive tinnitus as well? What's next?

I always had hyperacusis and reactive tinnitus. Please first read my old posts! They just used to be mild.

 

[jacob21]

Hi

I read this tread very interesting
Hope Dr Tzounopoulus will find something very soon

I have a question , what is RTG ? is it a drug ?

 

[DebInAustralia]

Rtg = retigabine

 

[lambos]

Has anyone heard anything new with RL-81??..according to the article link below from March 30/2016 RL-81 was ready to be studied further in animal models of epilepsy and tinnitus.

https://www.sciencedaily.com/releases/2016/03/160330102848.htm

 

[valeri]

Has anyone heard anything new with RL-81??..according to the article link below from March 30/2016 RL-81 was ready to be studied further in animal models of epilepsy and tinnitus.

https://www.sciencedaily.com/releases/2016/03/160330102848.htm

At best this drug is at least 10 years away!

 

[lambos]

I sure hope sooner than that but you might be right valeri as its such a slow process with animal and then human testing and lastly the hope of FDA approval...i would love to be part of the human testing of this drug however having said that maybe stem cell is the way to go or another epilepsy drug perhaps.

 

[Jim51042]

Its been over a year since this RL-81 thread was created. I was wondering if anyone has heard any updates? Any updates in the animal research? Is 2020 still the target date for human clinic trials? Thanks.

 

[Jim51042]

Here is a supplier and price of the RL-81. Note I'm not suggesting you try. I've just emailed Prof T to get an update on his progress. If what I've interpreted from the prior posts conversions with Prof T are correct and he is no longer developing this drug then maybe someone on this site knows a university/drug maker who can take up the baton.

http://www.sigmaaldrich.com/catalog/product/sigma/sml1738?lang=en&region=US

 

[Kratos]

If what I've interpreted from the prior posts conversions with Prof T are correct and he is no longer developing this drug

http://www.news.pitt.edu/news/sound-investment-pitt-allergan-collaborate-tinnitus-research

 

[Jim51042]

That answered my question. Thanks.

 

[Tigo]

Can you buy this stuff? Is it for T?

 

[ReyKalinic]

No one knows. I'm going back to pre forum level. It Made me loopy.

 

[Jim51042]

I want to update my earlier post. I have received an email reply from Prof T. He is still working on RL648-81 with the goal of doing clinic studies on people.

 

[acufenero]

I want to update my earlier post. I have received an email reply from Prof T. He is still working on RL648-81 with the goal of doing clinic studies on people.

Good news. I've been on Retigabine some months ago (I still have a full box of 300 mg). It definitely worked for me as it lowers my T for a few hours, but it has too many serious side effects.

 

[Jim51042]

@acufenero how much say from at (8/10 to a 4/10) did RTG reduce your T?