Reformulated Retigabine (Trobalt): BHV-7000, a Kv7.2 Modulator by Biohaven (Pfizer)

[yeezysqueezy]

Thank you so much for letting us know you attempted to request compassionate use for noxacusis pain.

I agree with what you're saying as far as not offering compassionate use for any reason at this time. That's what I got out of their response to the other member. So, if that is the case, they should not be advertising Early Access at all right now. How do you dangle that on the website to people suffering if its not really being offered yet?

Yeah, it's frustrating to get our hopes up. If I were them, I would have a note on the expanded access page saying which drugs are or are not possible to get access to at this time. It would also save them a lot of emails.

I think our best bet is to eventually get expanded access under pain, MDD, or both once the trials are further along.

 

[Christiaan]

Hi @Markku and @Hazel,

Concerning the old topic in which members of Tinnitus Talk used Trobalt (Retigabine), I'd like to know if you were able to summarise the success rate at the time? Taking into account the type of cause of tinnitus with or without pain hyperacusis (sound trauma, for no reason, ototoxicity...).

After all, as I've read through this whole thread, there were improvements, no improvements, and worsenings. There were even people who felt better on a low dose and worse on a higher dose, or vice versa.

I'm asking you this question because there's a lot of speculation about this drug that could help us, without really knowing whether the success rate was high or low.

Thank you very much.

You can find the results of Retigabine on page 5 (table 2).

 

[Josh59]

You can find the results of Retigabine on page 5 (table 2).

Thank you Christiaan.

I don't want to misinterpret the results. Could someone tell me whether, on the whole, Retigabine was satisfactory in terms of reducing tinnitus or whether it was insufficient?

Participants which used therapy N: 53
Big improvement N: 15
Small improvement N: 18
No change N: 16
Made me slightly worse N: 2
Made me a lot worse N: 2

 

[lolkas]

You can find the results of Retigabine on page 5 (table 2).

If I am reading it right, the majority saw improvements, very little worsening overall and we don't really know what these worsening are from anyways (could be something else).

Trying to correlate epilepsy with tinnitus, and if the drug takes about equal time to work on both epilepsy and tinnitus, then perhaps the number of people with improvements will increase significantly. Obviously this is with the assumption that XEN1101 will work on tinnitus as well.

 

[Nick47]

Well, roughly speaking, we can conclude 30% got a clinically significant improvement. Enough of an improvement to rule out the placebo effect. The issue is the doses were all over the place, so interpreting these results is difficult.

 

[DebInAustralia]

That was not true for me. I've tried all sorts of medications and Trobalt was the only one that silenced my tinnitus (while on it). Alcohol makes my tinnitus worse, Gabapentin helps me sleep but does not lower my tinnitus. The effect from Trobalt was profound.

I think this is the way to go. Attempting to access these medications is proactive and, if successful, may open up a window of insight.

I do think emphasis should be on pain or what the indications of the medication are.

Good luck to all who apply!

I presume international patients would be excluded from compassionate use?

 

[Christiaan]

I presume international patients would be excluded from compassionate use?

There have been precedents of US-based pharmaceutical companies that offered global Expanded Access Programs, for example:

Case Study: Expanded Access Program for Non-Small-Cell Lung Cancer (NSCLC)

MyTomorrows was presented with an opportunity to expand a relationship with an already established client, a US-based biopharmaceutical company ("the company") with a primary focus in oncology to provide support for a new Expanded Access program initiative. The company is developing a tyrosine kinase inhibitor for the treatment of non-small cell lung carcinoma and other solid tumors. This treatment is being investigated in a Phase 2 Clinical Trial. The company set up Clinical Trial sites in 14 countries around the world. They requested guidance and expertise for Expanded Access Program management and execution in Israel, India, Canada, Argentina, New Zealand, Italy, France, Sweden, United Kingdom, Switzerland, Austria, Denmark, and Belgium.

Leveraging regulatory and Expanded Access expertise to treat more patients

MyTomorrows was recognized by the company for its expertise in managing global Expanded Access Programs that provides streamlined, efficient delivery and management of the program for them and their stakeholders. Our strong existing client relationship and MyTomorrows' ability to deliver strategic guidance and program design led to this successful partnership. This provided the company the opportunity to engage with the broader disease community while allowing them to remain focused on their clinical development program.

As a result of this initiative, patients were able to receive the investigational drug where they would not have had any other treatment options. Furthermore, the program allowed the company to provide treatment for patients in countries with Clinical Trial sites, while also providing an avenue for other patients around the world. The successful program execution broadened physician experience with the company's treatment, allowing for additional insights and future Expanded Access considerations.

 

[Josh59]

With regards to pain hyperacusis, how could a drug such as BHV-7000 (Biohaven) improve it?

The most likely hypothesis for pain hyperacusis is a degeneration of the cochlear nerve fibres in the inner ear.

The opening of potassium channels would be in the cochlear nucleus, which is different from the inner ear.

 

[Nick47]

I spent a few hours going over the Trobalt thread. It seems at least 50% got significant reductions in tinnitus. Some even at 50 mg doses, but many needed 200-300 mg.

Rather than Dirk De Ridder paying 25€ for 50 g of Psilocybin, he should buy these pills and run 20-patient trials. Some of his 'ideas' seem obscure.

 

[StoneInFocus]

I spent a few hours going over the Trobalt thread. It seems at least 50% got significant reductions in tinnitus. Some even at 50 mg doses, but many needed 200-300 mg.

Rather than Dirk De Ridder paying 25€ for 50 g of Psilocybin, he should buy these pills and run 20-patient trials. Some of his 'ideas' seem obscure.

Do you think BHV-7000 will yield the same results as Retigabine?

I also think it's not possible for a doctor to prescribe discontinued drugs.

 

[Nick47]

Do you think BHV-7000 will yield the same results as Retigabine?

I also think it's not possible for a doctor to prescribe discontinued drugs.

I desperately hope so. No, I mean he's paying 25,000€ for 25 mg of MDMA or whatever. Why not put in an offer to Biohaven or Xenon Pharmaceuticals and run clinical trials. They could do an open label trial comparing them to each other + placebo group.

 

[grate_biff]

The most likely hypothesis for pain hyperacusis is a degeneration of the cochlear nerve fibres in the inner ear.

The opening of potassium channels would be in the cochlear nucleus, which is different from the inner ear.

Pain signals has to travel broh.
We want to intercept them on their way and/or modulate the brain's (DCN) reaction to signals.

So simple, yet so hard.

 

[StoneInFocus]

The opening of potassium channels would be in the cochlear nucleus.

Why do you think so?

 

[Josh59]

Why do you think so?

I have read here that these channels are located in the cochlear nucleus.

If I'm wrong, please correct me.

 

[StoneInFocus]

I have read here that these channels are located in the cochlear nucleus.

If I'm wrong, please correct me.

You are correct, but potassium channels are expressed on all cells of the body.

The voltage gated KCNQ family is expressed in both the peripheral and the central nervous system.

 

[BB23]

I have read here that these channels are located in the cochlear nucleus.

If I'm wrong, please correct me.

For our needs (the elimination of tinnitus), the channels in the DCN need to be opened. But these channels do not solely exist in DCN, they are all over the various parts of the brain. Even Prof. Thanos Tzounopoulos says in one of his videos that you can target what channels to open but you can't just open the ones in one specific region of the brain, all corresponding channels in different regions of the brain will be opened. I'm not sure what channel to mess with when it comes to pain hyperacusis.

Attached is a chart that shows where these Kv7 channels are located.

 

[Nick47]

Attached is a chart that shows where these Kv7 channels are located.

This is what worries me. Kv7.4 is expressed in the inner ear. I think Retigabine acted on Kv7.2 - Kv7.5.

 

[zoid]

I spent a few hours going over the Trobalt thread. It seems at least 50% got significant reductions in tinnitus. Some even at 50 mg doses, but many needed 200-300 mg.

Rather than Dirk De Ridder paying 25€ for 50 g of Psilocybin, he should buy these pills and run 20-patient trials. Some of his 'ideas' seem obscure.

Your post triggered me.

I don't know if I posted it at the time, but I also took Retigabine for a while. I can well remember the first night I took it. I woke up in the night, and I really had complete silence. I woke up my girlfriend and yelled like a maniac, it works, it works, and even went outside to experience the silence. (I was in pretty bad shape at the time and felt so much relief at that moment).

After that, I had ups and downs with Retigabine as well. I did feel like it helped my hyperacusis a lot in a short time. I could throw the cutlery in the drawer again without hurting my ears.

And my tinnitus was definitely lower while taking it, and maybe the overall level dropped permanently.

Eventually I stopped taking it because I started having side effects. And I feel like I got visual snow and eye floaters from it.

But anyway, to my anecdotal evidence, yes, Retigabine, for some, very definitely affects tinnitus and hyperacusis.

By the way, I can live well with my tinnitus and hyperacusis these days after 9 years. It has played a smaller and smaller role in my life over the years. Although every now and then I still check Tinnitus Talk to see if there is a treatment for it.

 

[ploughna]

This is what worries me. Kv7.4 is expressed in the inner ear. I think Retigabine acted on Kv7.2 - Kv7.5.

But hasn't Tzounopoulos concluded that Kv7.2 and Kv7.3 were the specific ones to go after?

One concern I have with his work though is that it was focused on acute tinnitus cases (does a few weeks of tinnitus in a mouse translate to chronic tinnitus in a human?)

 

[yeezysqueezy]

Your post triggered me.

I don't know if I posted it at the time, but I also took Retigabine for a while. I can well remember the first night I took it. I woke up in the night, and I really had complete silence. I woke up my girlfriend and yelled like a maniac, it works, it works, and even went outside to experience the silence. (I was in pretty bad shape at the time and felt so much relief at that moment).

After that, I had ups and downs with Retigabine as well. I did feel like it helped my hyperacusis a lot in a short time. I could throw the cutlery in the drawer again without hurting my ears.

And my tinnitus was definitely lower while taking it, and maybe the overall level dropped permanently.

Eventually I stopped taking it because I started having side effects. And I feel like I got visual snow and eye floaters from it.

But anyway, to my anecdotal evidence, yes, Retigabine, for some, very definitely affects tinnitus and hyperacusis.

By the way, I can live well with my tinnitus and hyperacusis these days after 9 years. It has played a smaller and smaller role in my life over the years. Although every now and then I still check Tinnitus Talk to see if there is a treatment for it.

Glad you're doing better. Did you have loudness hyperacusis, pain hyperacusis, or both? And how long were you on Retigabine before you started to notice visual snow/eye floaters? Thanks for dropping in and telling us your experience!

 

[zoid]

Glad you're doing better. Did you have loudness hyperacusis, pain hyperacusis, or both? And how long were you on Retigabine before you started to notice visual snow/eye floaters? Thanks for dropping in and telling us your experience!

I have loudness and pain hyperacusis. I think I took Retigabine for max two months, and took quite a high dose at the end. During the time taking it, I already started seeing some strange "blips" in my vision. But the whole floater/visual snow thingy started a month or two after stopping taking it. I don't know for sure if it's related. However, it doesn't bother me anymore at all. Much less annoying than tinnitus and hyperacusis (for me).

 

[Diego LR]

Your post triggered me.

I don't know if I posted it at the time, but I also took Retigabine for a while. I can well remember the first night I took it. I woke up in the night, and I really had complete silence. I woke up my girlfriend and yelled like a maniac, it works, it works, and even went outside to experience the silence. (I was in pretty bad shape at the time and felt so much relief at that moment).

After that, I had ups and downs with Retigabine as well. I did feel like it helped my hyperacusis a lot in a short time. I could throw the cutlery in the drawer again without hurting my ears.

And my tinnitus was definitely lower while taking it, and maybe the overall level dropped permanently.

Eventually I stopped taking it because I started having side effects. And I feel like I got visual snow and eye floaters from it.

But anyway, to my anecdotal evidence, yes, Retigabine, for some, very definitely affects tinnitus and hyperacusis.

By the way, I can live well with my tinnitus and hyperacusis these days after 9 years. It has played a smaller and smaller role in my life over the years. Although every now and then I still check Tinnitus Talk to see if there is a treatment for it.

Hello,

Glad to hear your story. Can you tell us a bit more about how you are managing your tinnitus & hyperacusis these days? How could I make my tinnitus & hyperacusis to play a less important role in my life?

 

[Nick47]

Your post triggered me.

I don't know if I posted it at the time, but I also took Retigabine for a while. I can well remember the first night I took it. I woke up in the night, and I really had complete silence. I woke up my girlfriend and yelled like a maniac, it works, it works, and even went outside to experience the silence. (I was in pretty bad shape at the time and felt so much relief at that moment).

After that, I had ups and downs with Retigabine as well. I did feel like it helped my hyperacusis a lot in a short time. I could throw the cutlery in the drawer again without hurting my ears.

And my tinnitus was definitely lower while taking it, and maybe the overall level dropped permanently.

Eventually I stopped taking it because I started having side effects. And I feel like I got visual snow and eye floaters from it.

But anyway, to my anecdotal evidence, yes, Retigabine, for some, very definitely affects tinnitus and hyperacusis.

By the way, I can live well with my tinnitus and hyperacusis these days after 9 years. It has played a smaller and smaller role in my life over the years. Although every now and then I still check Tinnitus Talk to see if there is a treatment for it.

Thanks for coming back and providing your insights. I've just read through your user experiences. Did your tinnitus react and get louder to external sound?

The hopes on these potassium channel openers like XEN1011 and BHV-7000 come from people like yourself, who are brave and willing to try things.

 

[BB23]

I have loudness and pain hyperacusis. I think I took Retigabine for max two months, and took quite a high dose at the end. During the time taking it, I already started seeing some strange "blips" in my vision. But the whole floater/visual snow thingy started a month or two after stopping taking it. I don't know for sure if it's related. However, it doesn't bother me anymore at all. Much less annoying than tinnitus and hyperacusis (for me).

Did you go cold turkey or did you taper off the Retigabine slowly?

Did your visual snow get better or stay the same all these years? Is it just static or did it give you the full blown visual snow syndrome with other symptoms?

I wonder why some people ended up with visual snow on Retigabine.

Was it because it had GABAergic properties, because it sporadically opens many channels all at once, or was it due to some other toxicity issue, like direct damage to the optical nerve or something...

 

[StoneInFocus]

I have loudness and pain hyperacusis. I think I took Retigabine for max two months, and took quite a high dose at the end. During the time taking it, I already started seeing some strange "blips" in my vision. But the whole floater/visual snow thingy started a month or two after stopping taking it. I don't know for sure if it's related. However, it doesn't bother me anymore at all. Much less annoying than tinnitus and hyperacusis (for me).

Hey, thanks for sharing.

Did you notice any permanent improvements in your tinnitus & hyperacusis after quitting Retigabine?

 

[Nick47]

Just skimming through this paper from 2015. It mentions the HCN channels as being important which adds credence to the work of Professor Peter McNaughton on HCN2 blockers. It talks about a dual approach of opening Kv7.2/3 and blocking HCN activity.

Again a mice study on acute tinnitus.

We really need our charities, the Brai3n Clinic or some health board to sponsor a trial. Frustrating for these compounds to exist, but not tested, whilst we suffer.

 

[BB23]

Just skimming through this paper from 2015. It mentions the HCN channels as being important which adds credence to the work of Professor Peter McNaughton on HCN2 blockers. It talks about a dual approach of opening Kv7.2/3 and blocking HCN activity.

Again a mice study on acute tinnitus.

We really need our charities, the Brai3n Clinic or some health board to sponsor a trial. Frustrating for these compounds to exist, but not tested, whilst we suffer.

From the paper:

"our results suggest that increases in KCNQ2/3 channel activity promote a decrease in fusiform cell HCN channel activity and resilience to tinnitus."

Just having potassium channel openers would be enough based on this, although if we could have both Kv7 openers and HCN blockers, it would be a better approach.

However, I'm feeling a little worried now since your paper also says "although DCN is not essential for the maintenance of tinnitus, it is indispensable for the induction of tinnitus." And goes on to mention which areas of the auditory brain might be involved in the maintenance of tinnitus. I read Prof. Thanos Tzounopoulos's papers and listened to his interviews again for the millionth time, he says when previous researchers ablated the DCN 3 months after exposure, meaning after it became chronic, tinnitus remained, but when the ablation was done during exposure, tinnitus wasn't established! And the mechanisms of potassium channels and whatnot that we know are about the acute phase of tinnitus generated in DCN before it establishes itself in the brain, turning into a disorder. I don't think the interviewers asked relevant questions in regards to chronic tinnitus at all, he just talked science related stuff and the interviewers were overwhelmed and didn't realize he wasn't talking about chronic tinnitus at all. He said he believes it will bring relief to 'central tinnitus', which is long lasting tinnitus. But through what mechanism, he didn't say.

I realized we still don't know the exact science behind why Retigabine worked on some long-term sufferers. Maybe the same potassium channels regulate chronic tinnitus in other parts of the auditory system, or maybe it worked for people with their tinnitus maintained in the DCN, who knows. But none of the papers we read mentioned manipulation of the Kv7 channels in other parts of the brain for chronic tinnitus.

We are heading into uncharted territories with these drugs. If Retigabine was any indication, they will work for some of us, but not all of us and may not bring permanent reduction or elimination we are looking for. We don't even know how it works on chronic tinnitus.

 

[Nick47]

although DCN is not essential for the maintenance of tinnitus, it is indispensable for the induction of tinnitus."

This has come up before. What they found was destroying the DCN did not stop tinnitus, BUT as this is the part of the brain where tinnitus is started, modulating it can still reduce the tinnitus. It's like how auditory nerve is where tinnitus originates from but cutting it probably won't relieve it. However, repairing it (cochlear implant) probably will treat the tinnitus.

 

[Jonno02]

From the paper:

"our results suggest that increases in KCNQ2/3 channel activity promote a decrease in fusiform cell HCN channel activity and resilience to tinnitus."

Just having potassium channel openers would be enough based on this, although if we could have both Kv7 openers and HCN blockers, it would be a better approach.

However, I'm feeling a little worried now since your paper also says "although DCN is not essential for the maintenance of tinnitus, it is indispensable for the induction of tinnitus." And goes on to mention which areas of the auditory brain might be involved in the maintenance of tinnitus. I read Prof. Thanos Tzounopoulos's papers and listened to his interviews again for the millionth time, he says when previous researchers ablated the DCN 3 months after exposure, meaning after it became chronic, tinnitus remained, but when the ablation was done during exposure, tinnitus wasn't established! And the mechanisms of potassium channels and whatnot that we know are about the acute phase of tinnitus generated in DCN before it establishes itself in the brain, turning into a disorder. I don't think the interviewers asked relevant questions in regards to chronic tinnitus at all, he just talked science related stuff and the interviewers were overwhelmed and didn't realize he wasn't talking about chronic tinnitus at all. He said he believes it will bring relief to 'central tinnitus', which is long lasting tinnitus. But through what mechanism, he didn't say.

I realized we still don't know the exact science behind why Retigabine worked on some long-term sufferers. Maybe the same potassium channels regulate chronic tinnitus in other parts of the auditory system, or maybe it worked for people with their tinnitus maintained in the DCN, who knows. But none of the papers we read mentioned manipulation of the Kv7 channels in other parts of the brain for chronic tinnitus.

We are heading into uncharted territories with these drugs. If Retigabine was any indication, they will work for some of us, but not all of us and may not bring permanent reduction or elimination we are looking for. We don't even know how it works on chronic tinnitus.

I kinda believe there isn't much difference between early onset (which will then be chronic) and chronic. It's the same thing, the only difference is time since onset.

If you also think of any tablet - let's use PPIs for acid reflux here. Two people have the same severity of symptoms and Person A is entirely asymptomatic on 20 mg Omeprazole. For Person B Omeprazole did absolutely nothing, but Esomeprazole cures them.

Both of these tablets have exactly the same chemical formula, they're isomers. Except the arrangements of the atoms are ever so slightly different. That small change can completely change the chemical properties and potency of the compound.

Pills and tablets aren't a one-size-fits-all. Once there is a pill that can treat tinnitus and the mechanism is known and proven, that's when things might get really interesting. An isomer might come along that is an incredibly effective treatment.

 

[BB23]

I attached two papers. The first one covers the inferior colliculus, saying that the Kv7 channels (2 and 3) are present there and can be modulated using Retigabine. Great that these drugs will work on at least two different parts of the auditory system. More coverage means more success in terms of a treatment.

The second one is about the role of Kv7 channels in thalamus. The paper highlights the importance of their role in sensory gating (tinnitus?), pain perception, and thalamic dysrhythmia.

→ Electrophysiological and Molecular Analysis of Kv7/KCNQ Potassium Channels in the Inferior Colliculus of Adult Guinea Pig

→ Thalamic Kv7 channels: pharmacological properties and activity control during noxious signal processing