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

@StoneInFocus, is this still your view?

 

No, because I haven't investigated Susan Shore's device enough to say anything sensible about it. I'm a bit out of the loop right now. Anything happen?

 

@StoneInFocus, go to the report posted by @Hazel.

 

Biohaven updated their pipeline for BHV-7000 Kv7.2. They are going to run four trials at once.

- Focal Epilepsy, Phase 1
- KCNQ2-DEE, Phase 1
- Mood Disorders, Phase 1
- Pain Disorders, Phase 1

I don't see the trials yet on ClinicalTrials.gov.

I'm not based in the US so I cannot apply, unfortunately.

 

Thanks for the information! I wonder if hyperacusis / noxacusis sufferers would qualify for the chronic pain study.

 

So no hope for tinnitus?

 

I definitely would not say that - their latest presentation states:

"Broad Potential in Adjacent Indications: Warrants further evaluation in BPD, depression, pain, others".​

So might qualify under 'mood disorders' for the upcoming trials, or one of these other indications such as depression later (and with a bit of luck, maybe tinnitus will appear in the 'others' category). They also have a compassionate use program, so I'd say there are a number of paths to gain access.

Also, interesting to see they claim to have a differentiated formulation to the competition (meaning XEN1101):

"Pursuing Differentiation: Dialing out GABArisk (somnolence, sedation, dizziness) without impacting efficacy"​

See here: https://ir.biohaven.com/static-files/2dfd9a38-a99c-460e-a27b-6b6ca537f4e1

It goes into a lot more detail on the advantages over XEN1101.

 

So basically we are hitching a ride and hoping for a glitch in the matrix.

 

I'm inclined to believe the chances of Kv7 modulators helping with tinnitus are bigger than "a glitch in the matrix", but you're right about us once again having to hitch a ride on something designed primarily for another condition. This seems to be a recurring theme with potential pharmaceutical cures. Until the mechanics behind tinnitus are better understood, it looks like too big of a risk for a pharmaceutical company to pursue treatments specifically for our issues: Otonomy's failure and dissolution is the latest example of that.

 

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.

 

The research seems to point to KCNQ2/3 potassium channels as the primary mechanism. I haven't personally seen much on the GABA aspect but you have a good point. If both drugs make it to market, we may have an opportunity to find out!

Dr. Tzounopoulos' work has verified the action of KCNQ2/3 channels in animal models with RL-81 which is also a highly selective potassium channel activator (no mention of GABA):

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

What I like about BHV-7000 is that it's much more potent and more selective than the others, meaning a much smaller dose for equivalent effect, which means much less potential for undesirable side effects.

And I also like that the Biohaven team have an impressive track record of success, getting product to market quickly with multiple parallel trials, etc. They see themselves in a race to market with Xenon Pharmaceuticals.

EDIT:

On the GABA point above, worth to mention that there are a number of GABA agonist drugs already available that could be taken in combination with BHV-7000 if that turned out to be of any benefit. My money is on the KCNQ2/3 channels being the dominant factor, but the good news is that we'll probably get to find out in the next 1-2 years.

It'd be great if Prof. Tzounopoulos would come back on Tinnitus Talk Podcast for a follow-up interview. How similar is it and is he even still pursuing RL-81 anymore given Xenon Pharmaceuticals and Biohaven are planning a very similar drug? @Padraigh Griffin (RIP) was unsuccessful in getting an answer to this question despite multiple attempts.

 

From their latest investor deck in January - moving quickly:

 

Great news. I hope it happens early in H2!

 

There are five different kinds of KCNQ potassium channels in the body, but only two are important in epilepsy and tinnitus: KCNQ2 and KCNQ3. The problem with Retigabine is that it acts on other KCNQ potassium channels as well. That's why it has so many unwanted side effects.

In terms of the aggressive schedule, well that's what happens when a big pharmaceutical company gets involved in our space. It may be good news for some of us as it has pushed other smaller companies like Xenon Pharmaceuticals to crack on due to competition.

 

BHV-7000 completed its Phase 1 successfully.

Preliminary Safety:

• Single doses up to 100 mg and multiple doses up to 40 mg daily x15 days generally well-tolerated
• Most adverse events mild and resolved spontaneously
• No serious or severe adverse events
• No dose limiting toxicities

​

This means it is moving to the simultaneous Phase 2/3 soon, which is presented in the forward statement. In the deck there is a nice comparison with the safety profile of XEN1101. It is pointing that BHV-7000 has a better safety profile.

Biohaven | TD Cowen 43rd Annual Health Care Conference (PDF)

 

Please let me know if any of you have high expectations for the potassium channel modulators, but had low expectations for FX-322/FX-345 and OTO-413.

It would give me more confidence in your ability to foresee...

 

With biotechs, the odds are stacked against you. 1/10 drugs are successful across the industry as a whole, but it’s even wider with more complex drugs (an example would be Alzheimer’s drugs).

The thing that got me with Frequency Therapeutics was the comment made, I think by Christopher Loose (from Frequency Therapeutics), ‘you can’t squint your ears to hear better’, basically it’s there or it isn’t. Then we found out people lied about their level of hearing loss to get into trials.

We need to QUESTION EVERYTHING.

 

Where does it say that BHV-7000 has completed Phase 1 successfully? The way I read the PowerPoint, Biohaven just gives an update on the study, but the results are not conclusive yet. Also, their website seems to indicate that it's still in Phase 1 as well.

Does anyone know how BHV-7000 is metabolized? It appears that the study did not measure transaminase concentrations. I wonder how harsh it is on the liver.

 

I'm just getting up to speed on these Kv7 modulators. I found a good paper (linked below) describing Kv7.4 modulators for hearing loss/tinnitus. It's my understanding that these reformulated Trobalt drugs, especially BHV-7000, are generally more specific for Kv7.2/7.3. Is it reasonable that these newer drugs might miss out on some efficacy compared to Trobalt (although having fewer side effects) given that they are not binding strongly to Kv7.4 channels? I understand that the Kv7.2 and 7.3 are very important as well.

PDF: Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

 

XEN1101 binds to Kv7.4 somewhat well actually, with a Kv7.4 IC50 of 113nm, vs. an established Kv7.2/3 IC50 of 27nm, which is somewhere around 4x less potent, but if tolerable at large doses, some effect would be observed.

It would be nice though if Acousia Therapeutics' Kv7.4 activator got approved, because then we could really know for sure.

Page 8 of this PDF.

 

Thanks for that information! Great to read.

I also had no idea about Acousia Therapeutics. Seems like they still have a ways to go in terms of clinical trials, but at least they bring added hope for the future. I found a thread on Tinnitus Talk about them but it seems relatively quiet, given how game-changing they could be.

 

Hey all. Does anyone know the differences between the GABA in XEN1101 and non-GABA in BHV-7000? Does GABA have something to do with tinnitus reduction? Or is it more the Potassium channels? Between XEN1101 and BHV-7000, which would be your best bet?

 

What happened here, have Biohaven acquired the rights and bought the product from Knopp Biosciences?

 

I think so. Yesterday I stumbled upon another Kv7.2 trial in Phase 1. I forgot to bookmark it but there are more companies working on this.

 

@InNeedOfHelp, do you think the Kv7.2 modulators would help treat hyperacusis?

 

I'd say so. I wouldn't be surprised if it influenced neuropathic pain too as antiepileptics are known to calm down nerves. Antidepressants and antiepileptics are the drugs of choice for neuropatic pain.

I'm no expert in how the pharmaceuticals target the brain but it seems that hyperacusis is a byproduct of tinnitus (hyperexcitable/central gain), so I assume that solving tinnitus might solve hyperacusis. This is also what Dr. Susan Shore states. Hyperacusis tends to be solvable easier then tinnitus. Numerous people had their hyperacusis resolve from taking Retigabine (Trobalt). What I assume it will not solve are things like ear fullness, clicking, popping etc which seem more related to physical damage compared to something happening in the brain.

XEN1101 will likely be also ototoxic, just like any other mediciation that targets the brain.

 

Interesting thoughts, @InNeedOfHelp! My understanding is ear fullness and clicking (TTTS) is a middle ear disease in that the muscles that connect to the stapes do not work properly. Sometimes Cyclobenzaprine is used to treat it.

I had a dreadful day and decided to reach for 300 mg Gabapentin + 0.5 mg Clonazepam. Only so long I can take bilateral loud tinnitus, especially with the hearing sensitivities.

It seems antiepileptics have a small beneficial effect in many.

 

GABA has nothing to do with Kv channels.

Kv channels are intrinsic to tuning hyperpolarization and firing rates.

GABA is like hitting the brakes hard, allows Cl- to flood in to hyperpolarize.

 

They stated the BHV-7000 Phase 2/3 trial will begin in 2H 2023. How long will that trial take?

I think it’s good that Pfizer bought Biohaven as it will make the market launch much easier as most countries ended up using Pfizer COVID-19 vaccine.

Does BHV-7000 only target Kv7.2 & Kv7.3? Do we know if it also targets Kv7.4?

 

Pfizer was already a pharmaceutical giant before COVID-19.