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

[Lucifer]

Biohaven Announces Positive Data from its Exploratory Electroencephalogram (EEG) Biomarker Study of BHV-7000, Completion of Once-Daily Formulation Development, and Plan to Initiate Phase 3 Pivotal Studies

• With target engagement now confirmed in the biomarker EEG study, favorable safety profile demonstrated in Phase 1 studies and development of a once-daily formulation of BHV-7000, Biohaven plans to initiate its Phase 3 program in focal epilepsy before the end of 2023.

Based on the results from the EEG study and preliminary safety profile in SAD/MAD trials, along with PK data from a new once-daily extended-release (ER) formulation, Biohaven plans on exploring three oral doses of BHV-7000 (once daily 25 mg ER, once daily 50 mg ER, and once daily 75 mg ER) in the Phase 3 focal epilepsy program. This dosing approach with a Kv7 activator will allow for assessment of distinct target concentrations over a wide range, above and below projected efficacious EC50 drug concentrations [FIGURE 4], not previously feasible with drugs in this class. No meaningful food effect was observed in the Phase 1 SAD/MAD trial using BHV-7000 in its standard release formulation.

 

[haha ear go eeee]

Biohaven Announces Positive Data from its Exploratory Electroencephalogram (EEG) Biomarker Study of BHV-7000, Completion of Once-Daily Formulation Development, and Plan to Initiate Phase 3 Pivotal Studies

Nice! So what does this mean for the timeline of the release date for BHV-7000?

 

[Lucifer]

Nice! So what does this mean for the timeline of the release date for BHV-7000?

No idea so far. They may announce study completion date once the Phase 3 trial for BHV-7000 starts. I'm hoping the trials for BHV-7000 will be much quicker than XEN1101 but at this time we don't know.

 

[ErikaS]

Now that I have established care with a neurologist, who is the chairman of neurology at one of our biggest local hospitals, and my short trial with Keppra went sideways, next time I meet with him I am going to present Biohaven's Kv7 modulator currently in trials and their expanded access program. I plan to be able to discuss and show the background and research that directly connects dysfunction of the Kv7 potassium channels to DCN hyperactivity, which ultimately triggers tinnitus, how a potassium modulator could be a key role in mitigating tinnitus symptoms, including hyperacusis and noxacusis. I will discuss the off-label use of Retigabine for tinnitus and the significant positive impact it had for many before being pulled. I also have a call scheduled with MyTomorrows to discuss this as well and maybe they can help be an advocate link between my doctor and Biohaven. Thank you to @Christiaan for making me aware of this company!

I know this is such a long shot, but I have the time to try as my current state keeps me debilitated from living my life, working, etc. I haven't seen or heard anyone else on this thread discuss how they have discussed with their doctor to try to request expanded access, but if someone has, please let me know.

 

[Justwaitinchilin]

My doctor requested compassionate use for of BHV-7000 from Biohaven on Wednesday, September 20th.

 

[ErikaS]

My doctor requested compassionate use for of BHV-7000 from Biohaven on Wednesday, September 20th.

Thank you for sharing this, @Justwaitinchilin! I am so hoping for a positive response from Biohaven back to you and your doctor.

Do you know all of the information that your doctor included in the request? Research articles, a write up of your debilitating condition, etc?

Thank you for anything you can share with us.

 

[Justwaitinchilin]

Thank you for sharing this, @Justwaitinchilin! I am so hoping for a positive response from Biohaven back to you and your doctor.

Do you know all of the information that your doctor included in the request? Research articles, a write up of your debilitating condition, etc?

Thank you for anything you can share with us.

She cited all the work done by the many names we all know here, the promising accounts of Ezogabine (aka Retigabine) patients, my hearing tests including tinnitus matching results (65 dB @ 3000-4000 Hz) and everything I've attempted in the past 13 months. She also included an online document signed by Biohaven's CEO that states Knopp Pharmaceuticals was pursuing tinnitus as an indication.

 

[ErikaS]

She cited all the work done by the many names we all know here, the promising accounts of Ezogabine (aka Retigabine) patients, my hearing tests including tinnitus matching results (65 dB @ 3000-4000 Hz) and everything I've attempted in the past 13 months. She also included an online document signed by Biohaven's CEO that states Knopp Pharmaceuticals was pursuing tinnitus as an indication.

That is great information, thank you. Sounds a lot like the information I am collecting myself to give to my doctor.

Is your doctor an ENT or Neurologist? Also, would you mind sharing the link to that signed document that stated Knopp Pharmaceuticals was pursuing tinnitus?

Thank you so much.

 

[Justwaitinchilin]

Is your doctor an ENT or Neurologist? Also, would you mind sharing the link to that signed document that stated Knopp Pharmaceuticals was pursuing tinnitus?

She's a Neurologist.

Link regarding Knopp Pharmaceuticals:

https://ir.biohaven.com/static-files/88ee0514-2c7e-4deb-90f7-cb4a6ec460cc

Read page 6.

 

[ErikaS]

I have read over both this and the XEN1101 thread.

Is there a potential scenario that reactivity/sound sensitive aspect of tinnitus could be mitigated with these drugs? I know some put it under the umbrella of hyperacusis. I have not experienced loudness hyperacusis, only the most sensitive/reactive tinnitus. I need this sh*t to lessen just as much as I need the tinnitus to lessen.

 

[ErikaS]

I spoke with my Neurologist quickly this morning. He said he would definitely request expanded access for BHV-7000 on my behalf, but was a little concerned about their response since they are not doing a formal clinical trial with the drug for tinnitus. I told him I have that concern too, but I have 6-7 research articles that support the potential breakthrough this drug could be for those with tinnitus, anecdotal accounts/evidence with Retigabine use, along with the document that @Justwaitinchilin was so kind to provide that states Knopp Pharmaceuticals had plans to run a tinnitus trial.

So, my next call is to chat with MyTomorrows to see if they would add extra value or support that would ultimately sway Biohaven to consider and grant the expanded access.

 

[Jonno02]

I spoke with my Neurologist quickly this morning. He said he would definitely request expanded access for BHV-7000 on my behalf, but was a little concerned about their response since they are not doing a formal clinical trial with the drug for tinnitus. I told him I have that concern too, but I have 6-7 research articles that support the potential breakthrough this drug could be for those with tinnitus, anecdotal accounts/evidence with Retigabine use, along with the document that @Justwaitinchilin was so kind to provide that states Knopp Pharmaceuticals had plans to run a tinnitus trial.

So, my next call is to chat with MyTomorrows to see if they would add extra value or support that would ultimately sway Biohaven to consider and grant the expanded access.

I really hope for the best here. I'm always empathetic when I read your posts. Your level of suffering seems absolute torture and I genuinely hope you can find some relief soon.

 

[InNeedOfHelp]

I spoke with my Neurologist quickly this morning. He said he would definitely request expanded access for BHV-7000 on my behalf, but was a little concerned about their response since they are not doing a formal clinical trial with the drug for tinnitus. I told him I have that concern too, but I have 6-7 research articles that support the potential breakthrough this drug could be for those with tinnitus, anecdotal accounts/evidence with Retigabine use, along with the document that @Justwaitinchilin was so kind to provide that states Knopp Pharmaceuticals had plans to run a tinnitus trial.

So, my next call is to chat with MyTomorrows to see if they would add extra value or support that would ultimately sway Biohaven to consider and grant the expanded access.

I strongly suggest to use pain as criteria instead of tinnitus (or hyperacusis with pain). Compassionate use is only for the indication being trialed (because they cannot guarantee safety or efficacy for other conditions). Pain is one of the trial conditions.

Compassionate use and off-label at the same time is not existent as far as I know.

 

[ErikaS]

I really hope for the best here. I'm always empathetic when I read your posts. Your level of suffering seems absolute torture and I genuinely hope you can find some relief soon.

I so appreciate your kind words. All of my tinnitus sounds are reactive/sound sensitive. My most debilitating swings anywhere from 13 kHz and 16 kHz, and when this one is aggravated by sound, it's like I have electric power running through my ears, it's not just a sound, it's an actual awful feeling because it's so high frequency. Then all my other sounds are mid range tones, beeps, electric siren swirls of some kind of nature that can all go up in higher range frequencies when spiked by noise, and sometimes some vibrations in the ears. I would say about 5-6 sounds total.

With all of this said, I know other cases are worse than me. I do not have loudness hyperacusis or noxacusis. My heart absolutely shatters for those folks, and I wish some of them would get their doctor to try to access this drug for them, but I also understand that it takes time, energy, etc. when many are just surviving each day. Thank you though again for your words, the support here is amazing.

I strongly suggest to use pain as criteria instead of tinnitus (or hyperacusis with pain). Compassionate use is only for the indication being trialed (because they cannot guarantee safety or efficacy for other conditions). Pain is one of the trial conditions.

Compassionate use and off-label at the same time is not existent as far as I know.

I really appreciate your input here, @InNeedOfHelp. I may have my doctor put in "painful sound reactivity/hyperacusis with severe multi-sound tinnitus."

My intention is not to put myself under the noxacusis category as I do not want to upset anyone with true noxacusis, but my reactivity can get so bad and my frequencies are so high that it does cause debilitating discomfort and "pain" in my ears and head due to severity of the reactivity and at the ultra high Hz it is radiating at.

Again, thank you for this feedback.

 

[Nick47]

I really appreciate your input here, @InNeedOfHelp. I may have my doctor put in "painful sound reactivity/hyperacusis with severe multi-sound tinnitus."

My intention is not to put myself under the noxacusis category as I do not want to upset anyone with true noxacusis, but my reactivity can get so bad and my frequencies are so high that it does cause debilitating discomfort and "pain" in my ears and head due to severity of the reactivity and at the ultra high Hz it is radiating at.

Again, thank you for this feedback.

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!

 

[Josh59]

Hello,

I'd like to ask you a few questions to try and understand a bit more about the functions of potassium channels and BHV-7000.

I see in the thread that DCN is linked to potassium channels. Is that correct? In other words, is there a dysfunction in the cochlear nucleus where potassium channels are also located? Or are these potassium channels located in another area of the brain?

I see mentions of Kv7 (Kv7.2/Kv7.3) and KCNQ2/3. Are they the same thing?

Does the compassionate use request to try BHV-7000 for tinnitus require you to live in the United States?

These biotechs are working on epilepsy and mood disorders. Does this mean that tinnitus can increase or worsen as a result of nervous tension, for example?

Finally, I see that we're talking about Phase 3. Whether it's Biohaven or Xenon Pharmaceuticals, and let's say the clinical trial results are positive, as it's a drug and not a device like Auricle, how many years would we have to wait before it's marketed worldwide?

 

[SarahMLFlemmer]

Hello,

I'd like to ask you a few questions to try and understand a bit more about the functions of potassium channels and BHV-7000.

I see in the thread that DCN is linked to potassium channels. Is that correct? In other words, is there a dysfunction in the cochlear nucleus where potassium channels are also located? Or are these potassium channels located in another area of the brain?

I see mentions of Kv7 (Kv7.2/Kv7.3) and KCNQ2/3. Are they the same thing?

Does the compassionate use request to try BHV-7000 for tinnitus require you to live in the United States?

These biotechs are working on epilepsy and mood disorders. Does this mean that tinnitus can increase or worsen as a result of nervous tension, for example?

Finally, I see that we're talking about Phase 3. Whether it's Biohaven or Xenon Pharmaceuticals, and let's say the clinical trial results are positive, as it's a drug and not a device like Auricle, how many years would we have to wait before it's marketed worldwide?

I'm just worried about the side effects as my tinnitus was medication induced.

 

[just1morething]

I'm just worried about the side effects as my tinnitus was medication induced.

The original Retigabine (Trobalt) had severe side effects that could affect your eyes and possibly your heart. That's why it was discontinued. I don't think a reformulated version is available that is safe at this time. They should also discontinue Accutane if it can damage your inner ear and cause severe tinnitus. I wonder what percentage of people that took Accutane developed tinnitus?

 

[Kleiner]

The original Retigabine (Trobalt) had severe side effects that could affect your eyes and possibly your heart. That's why it was discontinued. I don't think a reformulated version is available that is safe at this time.

And some money consideration, to be honest.

Again, Retigabine indeed has heavy side effects but these mainly concerned high doses in the long-term. It's not poison.

A reformulation halving the side effects would be, in my opinion, already acceptable.

 

[ErikaS]

I'm just worried about the side effects as my tinnitus was medication induced.

The original Retigabine (Trobalt) had severe side effects that could affect your eyes and possibly your heart. That's why it was discontinued. I don't think a reformulated version is available that is safe at this time. They should also discontinue Accutane if it can damage your inner ear and cause severe tinnitus. I wonder what percentage of people that took Accutane developed tinnitus?

A lot of questions and speculations about XEN1101 and BHV-7000 can be answered by reading the threads, the links provided, and some simple searches. Biohaven has come out with a very safe side effect profile. Their first clinical trial consisted of healthy individuals who experienced minimal to no side effects. That's the point of both of these drugs, they are more potent than Trobalt, but much more selective to Kv7.2/7.3 channels and their side effect profiles are MUCH safer than Trobalt, most likely because of their selectivity to specific channels and not all. A key reason Biohaven is doing a Phase 2/3 at the same time is because they are that confident in their product, and they have already proven it is safe. They also know it is a rat race with Xenon Pharmaceuticals.

Hello,

I'd like to ask you a few questions to try and understand a bit more about the functions of potassium channels and BHV-7000.

I see in the thread that DCN is linked to potassium channels. Is that correct? In other words, is there a dysfunction in the cochlear nucleus where potassium channels are also located? Or are these potassium channels located in another area of the brain?

I see mentions of Kv7 (Kv7.2/Kv7.3) and KCNQ2/3. Are they the same thing?

Does the compassionate use request to try BHV-7000 for tinnitus require you to live in the United States?

These biotechs are working on epilepsy and mood disorders. Does this mean that tinnitus can increase or worsen as a result of nervous tension, for example?

Finally, I see that we're talking about Phase 3. Whether it's Biohaven or Xenon Pharmaceuticals, and let's say the clinical trial results are positive, as it's a drug and not a device like Auricle, how many years would we have to wait before it's marketed worldwide?

A lot of your questions are in the threads, but I will answer what I can quickly.

1) The potassium channels are located in cell membranes, so they are part of the cell. These cells are in our brains, mainly in brainstem (where dorsal cochlear nucleus is), and are also found in hippocampus, cortex, and thalamus. We focus in on the DCN because studies show that this a very important part of the auditory pathway/system, and further, Dr. Shore has stated and shown in research that that this is main area where tinnitus arises. When someone experiences noise-induced tinnitus or tinnitus that originates from cochlear hair cell damage, the potassium channels in the cells dysfunction/close/decrease in activity, which leads to hyperexcitability of fusiform cells sending incorrect signals through the auditory pathway, creating tinnitus. I will attach an article that I specifically like that goes into this more.

2) Kv7.2/Kv7.3 and KCNQ2/3 are essentially the same thing.

3) I can't answer your question about compassionate use and needing to be in the USA. However, I don't believe @Christiaan lives in the USA and he has a call with MyTomorrows to discuss Biohaven's expanded use program.

4) I don't know what this question is really asking. Can tinnitus get worse from tension and stress? Yes.

5) No one can say when these drugs would become available, but the good news is we have two companies in a race to release this novel, first ever selective Kv7 channel modulator. I forget if either company has a Fast Track designation with the FDA, but that would only speed things up. I would hope in 3-4 years one of the drugs is available, but again, this just a hope.

 

[Justwaitinchilin]

Below is the answer to my doctor's request for compassionate use of BHV-7000:

Thank you for your email message and your interest in expanded access use of BHV-7000. I am one of the team members at Biohaven that facilitates expanded access requests. I have reviewed your questions and your expanded access request with our Program and Medical Leads, however, at this time Biohaven is unable to offer expanded access to treat your patient. Although there is potential to treat tinnitus as you mentioned below, at this time we have limited clinical data, safety data, and/or rationale to offer expanded access for patients.

Biohaven is working diligently on our KV7 platform and its development. We are committed to our research of novel therapies for people suffering from neurological and neuropsychiatric diseases, and rare disorders. As our program develops and we are able to collect and analyze efficacy and safety data we may be able to offer expanded access once we are further along in our clinical development stages.

Please feel free to contact me for updates on expanded access use. I will also keep your contact information on file and provide any updates to you on expanded access use. Future updates about our clinical program for KV7 can be found on Biohaven's website: https://www.biohaven.com/pipeline/

Please let me know if you have any additional questions at this time.

Kind regards,
Kelly

Kelly Sweeney
Associate Director, Clinical and Data Operations
c: +1 314.799.1696
e: kelly.sweeney@biohavenpharma.com
w: biohavenpharma.com
a: 215 Church Street , New Haven , CT , 06510

 

[ErikaS]

Below is the answer to my doctor's request for compassionate use of BHV-7000:

This literally breaks my heart, @Justwaitinchilin. I am so sorry that they have denied your doctor's request. I'm wondering if I should even have my doctor send in the request, possibly just so they have yet another one asking for tinnitus and if at some point they decide to allow it? Ugh, I don't know, what a let down.

 

[Jonno02]

Unfortunately for us, tinnitus is seen as just a 'nuisance, deal with it' at worst from those that don't suffer with it. Boils my blood.

 

[Justwaitinchilin]

This literally breaks my heart, @Justwaitinchilin. I am so sorry that they have denied your doctor's request. I'm wondering if I should even have my doctor send in the request, possibly just so they have yet another one asking for tinnitus and if at some point they decide to allow it? Ugh, I don't know, what a let down.

You should definitely submit your request. Strength in numbers.

 

[lolkas]

Unfortunately for us, tinnitus is seen as just a 'nuisance, deal with it' at worst from those that don't suffer with it. Boils my blood.

This definitely sucks but I was sure of them denying the request (unfortunately).

They are definitely not planning on trialing this on anything BUT what they know this will work on. Even if they have people with tinnitus in the trial being treated for epilepsy and they report positive effect on the tinnitus - they would still most likely deny this until drug is approved by FDA. Simply because they don't want potential risks negatively affecting their stock.

 

[Joey72]

This literally breaks my heart, @Justwaitinchilin. I am so sorry that they have denied your doctor's request. I'm wondering if I should even have my doctor send in the request, possibly just so they have yet another one asking for tinnitus and if at some point they decide to allow it? Ugh, I don't know, what a let down.

Go for it.

 

[InNeedOfHelp]

This literally breaks my heart, @Justwaitinchilin. I am so sorry that they have denied your doctor's request. I'm wondering if I should even have my doctor send in the request, possibly just so they have yet another one asking for tinnitus and if at some point they decide to allow it? Ugh, I don't know, what a let down.

As I said, there is insufficient data and safety information available for compassionate use of tinnitus. They will not accept off-label for compassionate use.

Pain and MDD (treatment resistant depression) is the way to go. You'll have to make sure that your doctor emphasizes major depression and pain as symptoms from your severe reactive and painful tinnitus. And make sure to say that you have tried all possible medications to treat your depression (SSRIs and TCAs).

There is no point in not trying. You just need to fit the criteria of what is currently under trial (bipolar disorder includes severe depression if I'm not mistaken).

@Justwaitinchilin got his answer quite fast. Good luck to you.

I work at an pharmaceutical API manufacturing site and I am very well aware on production processes of APIs. Any legal exposure or publicity in general is a strong no. It's not about them not being compassionate about tinnitus. They can get sued if something happens to a patient after prescribing Phase 1 medicine (which is very premature) for an off-label purpose. Building a manufacturing site costs literally 100s of millions of euros. The doses that are manufactured for trials are extremely small quantities made on lab scale and therefore very costly as there is no actual manufacturing cycle in place.

 

[Josh59]

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.

 

[yeezysqueezy]

I've already tried requesting compassionate use for noxacusis pain. I agree there is no way they will offer it for tinnitus when they're not currently trialing for tinnitus. They're not offering compassionate use for any reasons due to the stage of development.

 

[ErikaS]

I've already tried requesting compassionate use for noxacusis pain. I agree there is no way they will offer it for tinnitus when they're not currently trialing for tinnitus. They're not offering compassionate use for any reasons due to the stage of development.

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?