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

[Lucifer]

Pfizer was already a pharmaceutical giant before COVID-19.

That may be the case but the COVID-19 vaccine would have put Pfizer in front of the driver seat and made the company much more well known.

There shouldn't be any issues getting BHV-7000 approved in other countries at the same time. XEN1101, on the other hand, may face more delays with releasing it out in other countries since I don't believe Xenon Pharmaceuticals has any drugs out in the market.

Since Pfizer's Biohaven are doing pivotal Phase 2/3 next starting 2H 2023, I wonder if it's going to be quick like Pfizer's COVID-19 vaccine.

 

[Alue]

That's a very interesting detail you highlighted here. There's a significant difference between this drug and XEN1101/Trobalt, and that is that the latter also affect GABA receptors. As many users' testimonials have highlighted, GABA-affecting substances (benzos, alcohol...) seem to help with certain forms of tinnitus. Could it be that Trobalt's benefit for tinnitus sufferers lied not in its Kv7 modulating properties but rather in its effect on GABA? If that was the case, then that could mean that XEN1101 would be the winner for us.

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.

 

[Lucifer]

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 remember seeing your previous post that it also helped with your hyperacusis.

When you stopped taking Trobalt, did the hyperacusis return to its previous level or stayed at the reduced level?

I wonder what Kv potassium channel is related to hyperacusis/noxacusis. I'm hoping it's related to Kv 7.2/7.3. If it's Kv 7.4, we will have to wait even longer for XEN1101.

 

[Nick47]

The effect from Trobalt was profound.

How long after onset did you start treatment with Retigabine?

Was your tinnitus noise induced?

 

[haha ear go eeee]

I remember seeing your previous post that it also helped with your hyperacusis.

When you stopped taking Trobalt, did the hyperacusis return to its previous level or stayed at the reduced level?

I wonder what Kv potassium channel is related to hyperacusis/noxacusis. I'm hoping it's related to Kv 7.2/7.3. If it's Kv 7.4, we will have to wait even longer for XEN1101.

Have you thought of taking high consistent dosages of CBD isolate or Epidiolex? It opens those two channels at that dosage. I might try it because it seems like the safest medication to try first. I honestly don't want to wait until XEN1101 comes out before trying a potassium opener, especially since I'm not entirely sure if it'll help me or not.

 

[Lucifer]

Have you thought of taking high consistent dosages of CBD isolate or Epidiolex? It opens those two channels at that dosage. I might try it because it seems like the safest medication to try first. I honestly don't want to wait until XEN1101 comes out before trying a potassium opener, especially since I'm not entirely sure if it'll help me or not.

I haven't tried.

Would BHV-7000 and XEN1101 be more potent in opening up Kv7.2/7.3 potassium channels compared to CBD?

 

[haha ear go eeee]

Would BHV-7000 and XEN1101 be more potent in opening up Kv7.2/7.3 potassium channels compared to CBD?

I'm not sure, I would assume so though!

 

[Nick47]

Would BHV-7000 and XEN1101 be more potent in opening up Kv7.2/7.3 potassium channels compared to CBD?

I would think a lot more potent. I don't think the CBD route is going anywhere. It was worth investigating though.

 

[Lucifer]

I would think a lot more potent. I don't think the CBD route is going anywhere. It was worth investigating though.

What do you think of mixing Dr. Shore's device with these anti-epilepsy drugs such as BHV-7000 and XEN-1101? Do you reckon taking these drugs to bring the tinnitus down to a 1/10, then using Dr. Shore's device to get rid of the tinnitus permanently without having to continue taking these drugs?

 

[haha ear go eeee]

I would think a lot more potent. I don't think the CBD route is going anywhere. It was worth investigating though.

Why do you think that? I might try it and post my experience with it on here if I get worse. I'm curious to see if it'll help both forms of pain hyperacusis (inner ear and middle).

 

[Lucifer]

Do you believe that with BHV-7000 & XEN-1101 being more potent in opening up the Kv 7.2/7.3 potassium channels that those who suffer from hyperacusis/noxacusis don't have to take it permanently?

Do you believe that improvements in hyperacusis/noxacusis remain even after stopping taking the medication? I'm hoping the potassium channels remain open to the point where we can experience permanent improvements instead of going back to the previous level of hyperacusis/noxacusis after stopping taking the medication.

 

[Nick47]

What do you think of mixing Dr. Shore's device with these anti-epilepsy drugs such as BHV-7000 and XEN-1101? Do you reckon taking these drugs to bring the tinnitus down to a 1/10, then using Dr. Shore's device to get rid of the tinnitus permanently without having to continue taking these drugs?

Well, we don't know if they are effective for tinnitus/hyperacusis. I think most treatment plans in the future will involve a combination of treatments. At least where good doctors are involved.

Why do you think that?

It has been around for years and I would expect we would know by now if it was beneficial.

 

[haha ear go eeee]

It has been around for years and I would expect we would know by now if it was beneficial.

I mean, I don't believe anyone's tried a high (25mg a day) consistent dosage of CBD isolate except for @StoneInFocus on here. To actually open the potassium channels a meaningful amount, something like Epidiolex or the equivalent dosage in CBD isolate could help people's symptoms. You just have to avoid even trace amounts of THC like the plague because it could spike tinnitus.

 

[Nick47]

I mean, I don't believe anyone's tried a high (25mg a day) consistent dosage of CBD isolate except for @StoneInFocus on here. To actually open the potassium channels a meaningful amount, something like Epidiolex or the equivalent dosage in CBD isolate could help people's symptoms. You just have to avoid even trace amounts of THC like the plague because it could spike tinnitus.

CBD has been around for decades with millions and millions of people using it. We would know.

 

[haha ear go eeee]

CBD has been around for decades with millions and millions of people using it. We would know.

Have you tried that dosage or higher consistently for yourself? Because it was just recently discovered last year that it opens the two potassium channels involved in tinnitus and hyperacusis.

 

[Nick47]

Have you tried that dosage or higher consistently for yourself? Because it was just recently discovered last year that it opens the two potassium channels involved in tinnitus and hyperacusis.

I wouldn't try CBD myself. @StoneInFocus gave it a go and his research and rationale for it was solid. I prefer not needing any medication either but what do you do. If XEN1011 or something comes onto market and is effective for some of us, many would jump at the chance of medication. In fact a survey said most tinnitus patients want a pill. If that pill is Gabapentin, XEN1101, Clonazepam or whatever and it's effective with a few minor side effects, then get on with it until we have better treatment options.

CBD has been around for decades in different forms. I don't have any expectations in its usefulness.

I don't think any supplement or CBD product will be beneficial. Add laser therapy, sound therapy and many other cons to the list.

It's brain surgery, invasive electrical stimulation, implants or drugs that will provide the best treatments with some lesser benefits from Auricle or non-invasive electrical stimulation.

 

[Lucifer]

@grate_biff, did Biohaven reply to your email? Any idea when they might start the pivotal Phase 2/3 and how long that trial will take?

Reading some of the Trobalt user experiences, @Juan Carlos mentioned that his tinnitus went up a bit after stopping Trobalt but it was still at a reduced level compared to before Trobalt and he also said that his hyperacusis was gone.

So with these drugs, such as BHV-7000 and XEN1101, being more potent at Kv 7.2/7.3 potassium channels, there's a good chance that these improvements in tinnitus and hyperacusis/noxacusis will stay even after you stop taking them. We might only need to take these drugs for a few months or a year or two.

The most important pages on the presentation slides.

It shows a clear indication what potassium channels affect which part of the body. I believe Kv7.2/7.3 will be the most important for getting rid of tinnitus and hyperacusis/noxacusis. Kv7.4 might be important but we won't know until BHV-7000 comes out. I'm hoping tinnitus and hyperacusis/noxacusis isn't related to Kv7.4 as we would have to wait even longer for XEN1101 to come out.

How do they know BHV-7000 is more potent than XEN1101? BHV-7000 was tested up to 100 mg and multiple doses up to 40 mg, whereas XEN1101 only tested 15 mg, 20 mg and 25 mg. How are they calculating the potency between the two?

 

[lapidus]

I'm curious about BHV-2100, their drug for chronic pain disorders and if that would have any effect on noxacusis. It's still only in preclinical though.

 

[Nick47]

It shows a clear indication what potassium channels affect which part of the body. I believe Kv7.2/7.3 will be the most important for getting rid of tinnitus and hyperacusis/noxacusis. Kv7.4 might be important but we won't know until BHV-7000 comes out. I'm hoping tinnitus and hyperacusis/noxacusis isn't related to Kv7.4 as we would have to wait even longer for XEN1101 to come out.

That's a great clear illustration. Yes, I'm also not ruling out Kv7.1 and Kv7.4 as being involved. It's my main concern. Yes, I know there is literature from Thanos Tzounopoulos on Kv7.2 and Kv7.3 in the cochlear nucleus, which is clearly involved, but with Retigabine acting broadly, I have my suspicions.

I have also been heavily swayed by Peter McNaughton's work in the UK on HCN2 inhibitors shutting off tinnitus in Guinea Pigs recently. These HCN2 channels are in the auditory nerve and the Organ of Corti. This points to tinnitus generation starting as a peripheral phenomenon that then alters cell firing in the Cochlear Nucleus. Will it translate to humans? Who knows. Dr. Shore's research did.

 

[TheFriendlyGhost]

They have a compassionate use program for BHV-7000. They are studying it for pain. I think a lot of people with noxacusis might be able to access it through the compassionate use program.

Has anyone had their physician request compassionate use for BHV-7000? I assume only people in the US can do this.

 

[Lucifer]

That's a great clear illustration. Yes, I'm also not ruling out Kv7.1 and Kv7.4 as being involved. It's my main concern. Yes, I know there is literature from Thanos Tzounopoulos on Kv7.2 and Kv7.3 in the cochlear nucleus, which is clearly involved, but with Retigabine acting broadly, I have my suspicions.

I have also been heavily swayed by Peter McNaughton's work in the UK on HCN2 inhibitors shutting off tinnitus in Guinea Pigs recently. These HCN2 channels are in the auditory nerve and the Organ of Corti. This points to tinnitus generation starting as a peripheral phenomenon that then alters cell firing in the Cochlear Nucleus. Will it translate to humans? Who knows. Dr. Shore's research did.

If the theory of suppressing the type II afferents' response to hair cell damage is true, then it seems hyperacusis/noxacusis is going to be more related to Kv7.2 and Kv7.3 potassium channels. We might not need to worry about Kv7.4 but we won't know how important it might be till BHV-7000 comes out. It's unfortunate that no one is trying to access the Kv7.1 potassium channels.

Do we know what potassium channels were open when using Retigabine and by how much, compared to BHV-7000 and XEN1101?

I've been looking up on what potassium channels were open when using Retigabine (Trobalt) and it was stated that it opens Kv7.2, Kv7.3, Kv7.4 and Kv7.5. It never opens Kv7.1 but who knows.

If we assume that the side effects from Retigabine were caused by Kv7.5 and GABA, that leaves us with Kv7.2, Kv7.3 and Kv7.4. Most likely tinnitus and hyperacusis/noxacusis is related to Kv7.2 and Kv7.3 which BHV-7000 should help but if we also need Kv7.4 to get rid of tinnitus and hyperacusis/noxacusis, then XEN1101 is the drug that we must take.

I wonder how Biohaven recruited patients so fast for their Phase 1 trial for BHV-7000. Do we know whether those patients from Phase 1 can go into the Phase 2/3 pivotal trial or would they have to select new patients who have never taken BHV-7000?

 

[Lucifer]

Biohaven Provides Preliminary EEG Data Update for Kv7 Platform, Regulatory Update on Troriluzole and Other Corporate Updates

For the Phase 2/3 pivotal phase for BHV-7000, they will be using a once daily extended release dose. No mention of when they are starting the pivotal phase.

 

[Nick47]

The press release states that "Biohaven's primary focus will be developing treatments for neurological and rare disorders including epilepsy, pain and mood disorders, obsessive-compulsive disorder, spinocerebellar ataxia and spinal muscular atrophy."

The stock dropped 25% a few days ago. It was due to FDA not approving the drug for spinocerebellar ataxia.

It was mitigated by a successful EEG readout on Phase 1 BHV-7000.

 

[Lucifer]

The stock dropped 25% a few days ago. It was due to FDA not approving the drug for spinocerebellar ataxia.

It was mitigated by a successful EEG readout on Phase 1 BHV-7000.

When I first heard the stock drop by a lot, I thought something bad had happened with BHV-7000.

 

[Lucifer]

We should know by next month who is ahead of releasing these Kv7 potassium channel openers first. Xenon Pharmaceuticals will provide a quarterly update and we may know when the study completion date is.

I just wish these companies were a lot faster in their enrollment.

I really do hope Biohaven starts the pivotal phase for BHV-7000 next month but that seems unlikely since they didn't announce an actual date other than 2H 2023. I would be curious to know how long that trial will take compared to XEN1101.

 

[Alue]

I remember seeing your previous post that it also helped with your hyperacusis.

When you stopped taking Trobalt, did the hyperacusis return to its previous level or stayed at the reduced level?

I wonder what Kv potassium channel is related to hyperacusis/noxacusis. I'm hoping it's related to Kv 7.2/7.3. If it's Kv 7.4, we will have to wait even longer for XEN1101.

I think my hyperacusis was reduced but not fully gone, at least for a couple of years until my tinnitus/hyperacusis got worse from additional noise exposure.

How long after onset did you start treatment with Retigabine?

Was your tinnitus noise induced?

Yes, noise induced. I don't recall, it may have been a year after onset as I did the AM-101 trials shortly after my tinnitus started and waited until I was no longer in a clinical trial before starting Trobalt.

I actually could have done one or the other first, but not both.

 

[haha ear go eeee]

I think my hyperacusis was reduced but not fully gone, at least for a couple of years until my tinnitus/hyperacusis got worse from additional noise exposure.

Yes, noise induced. I don't recall, it may have been a year after onset as I did the AM-101 trials shortly after my tinnitus started and waited until I was no longer in a clinical trial before starting Trobalt.

I actually could have done one or the other first, but not both.

Sorry if you already answered this, but what type of hyperacusis did you have? Loudness and/or noxacusis? Was it primarily middle ear noxacusis or inner ear noxacusis?

 

[Lucifer]

Any reason why neither BHV-7000 nor XEN1101 have received Breakthrough Therapy status or FDA Fast Track yet? XEN1101 is currently in Phase 3 trial and BHV-7000 will start their Phase 2/3 pivotal trial later this year. Aren't these drugs better in terms of potency, safety and efficacy than the ones currently out in the market?

 

[andrewdaniels]

Any reason why neither BHV-7000 nor XEN1101 have received Breakthrough Therapy status or FDA Fast Track yet? XEN1101 is currently in Phase 3 trial and BHV-7000 will start their Phase 2/3 pivotal trial later this year. Aren't these drugs better in terms of potency, safety and efficacy than the ones currently out in the market?

I also do wonder. Maybe it's because there are a variety of epilepsy drugs on the market? Just none that work on that mechanism from what I can gather.

I'm hopeful the trials will wrap up next year and they can rush to production in 2025. Happy to try it out, as based on the size of their studies, I suspect many of the scarier side effects should be determined before then. I also hope no side effects come out in the larger trial that then cancel the drug.

As a new user here, I was reading through some of the old trial threads and saw how much hope folks had (e.g., Auris Medical, Otonomy, etc.). I am praying this does not follow suit and we get a breakthrough.

 

[Lucifer]

I also do wonder. Maybe it's because there are a variety of epilepsy drugs on the market? Just none that work on that mechanism from what I can gather.

I'm hopeful the trials will wrap up next year and they can rush to production in 2025. Happy to try it out, as based on the size of their studies, I suspect many of the scarier side effects should be determined before then. I also hope no side effects come out in the larger trial that then cancel the drug.

As a new user here, I was reading through some of the old trial threads and saw how much hope folks had (e.g., Auris Medical, Otonomy, etc.). I am praying this does not follow suit and we get a breakthrough.

That seems to be the case. I wonder what the difference is between Trobalt and other anti-epilepsy drugs out in the market. If these new reformulated drugs can get rid of or reduce the amount of seizures in an epilepsy patient, and are safer compared to these current drugs, they should at least receive FDA Fast Track status.

I was a big believer in the hearing regeneration drugs but now I've switched to Kv7 potassium channel openers and VX-548 (for pain) for the time being. Spiral Therapeutics have bought OTO-413 and right now they are investigating it to see if it can be reformulated with their new delivery method. The low dose trial was the one that passed whereas the higher dose trials failed.

FDA: Fast track

Any drug being developed to treat or prevent a condition with no current therapy obviously is directed at an unmet need. If there are available therapies, a fast track drug must show some advantage over available therapy, such as:

• Showing superior effectiveness, effect on serious outcomes or improved effect on serious outcomes
• Avoiding serious side effects of an available therapy
• Improving the diagnosis of a serious condition where early diagnosis results in an improved outcome
• Decreasing a clinical significant toxicity of an available therapy that is common and causes discontinuation of treatment
• Ability to address emerging or anticipated public health need

So potentially BHV-7000 and XEN1101 could receive FDA Fast Track status and possibly Breakthrough Therapy status if they can show their drugs are more potent, safer and more effective as the FDA considers epilepsy to be a serious condition.

I wonder if Xenon Pharmaceuticals and Biohaven have enough data to show that their drugs are more potent, safer and more effective compared to current anti-epilepsy drugs to apply for both FDA Fast Track status and Breakthrough Therapy status. Biohaven's BHV-7000 seems to be the one to have a better chance at getting these two statuses from the FDA due to Pfizer's acquisition and having multiple clinical trials relating to BHV-7000.

@InNeedOfHelp, do you reckon they will start the Phase 2/3 pivotal phase for BHV-7000 after they release the full EEG results from the Phase 1 trials at the end of the year? If that's the case, we might not see them start the pivotal phase until November or December.

How was Retigabine approved in the first place? I'm wondering if BHV-7000 and XEN1101 will suffer the same fate as Retigabine where the severe side effects don't show in the trials but years later after it has been approved.

It's going to be a shame if it ends up helping tinnitus and hyperacusis/noxacusis sufferers but then gets pulled due to the severe side effects.