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

[lolkas]

I emailed Dr. Tzounopoulos in 2020 concerning the state of potassium channels after acoustic damage (which can be the outcome of glutamate excitotoxicity).

How common would it be for someone to have damaged potassium channels? I would imagine that is something like stroke or genetic mutations? I mean if someone would have their potassium channels damaged, then Trobalt would not work for epilepsy either. I don't think that an acoustic trauma can damage potassium channels, same goes for ototoxic drugs because then people would get not only tinnitus but a bunch of other things (and not just one or two, but probably virtually everything that depend on potassium channels would go sideways.)

 

[Christiaan]

Biohaven Presents Expanded EEG and Safety Data for BHV-7000 at the American Epilepsy Society Annual Meeting

Summary text:

• Biohaven reported full results from the BHV-7000 Phase 1 study examining doses up to 120 mg daily, demonstrating BHV-7000 was well-tolerated at all doses studied without the typical central nervous system (CNS) adverse effects associated with other anti-seizure medications (ASMs), such as somnolence and cognitive/mood disturbances.

• In a Phase 1 electroencephalogram (EEG) biomarker study, BHV-7000 demonstrated dose-dependent target engagement in the brain as measured by changes in EEG spectral power across all brain regions.

• Additional poster presentations at the American Epilepsy Society Annual Meeting will include: BHV-7000 preclinical data, health-related quality of life in patients with focal epilepsy, and functional impairments in patients with KCNQ2‐associated developmental and epileptic encephalopathy (KCNQ2-DEE).

Presentation Highlights:

Poster 2.510: Novel, Selective Kv7.2/7.3 Potassium Channel Activator, BHV-7000, Demonstrates Dose-Dependent Pharmacodynamic Effects on EEG Parameters in Healthy Adults

• In this Phase 1 study, pharmacodynamic activity of BHV-7000 in the brain of healthy adults was demonstrated by dose-dependent increases in EEG spectral power.
• Unlike prior reports where EEG effects of a Kv7.2/7.3 activator showed the greatest power increase in the delta frequency band (Biondi et al. 2022), the highest spectral power increases with BHV-7000 were seen in alpha, beta, and gamma frequency bands.
• While changes in spectral power were observed across all frequency bands with BHV-7000, the minimal impact on slower frequencies (i.e., delta) is consistent with the low incidence of CNS adverse events, in particular somnolence, seen in the BHV-7000 Phase 1 SAD/MAD studies.
• EEG delta activity is associated with somnolence, an undesirable CNS adverse event often seen with other ASMs.

Poster 3.265: A First in Human Phase 1 Study Evaluating the Safety and Tolerability of BHV-7000, a Novel, Selective Kv7.2/7.3 Potassium Channel Activator, in Healthy Adults

• BHV-7000 was safe and well-tolerated at single doses up to 100 mg and multiple doses up to 120 mg daily for 15 days
• No serious adverse events or severe treatment emergent adverse events were reported
• Adverse events typically associated with other ASMs, such as somnolence and cognitive/mood disturbances, were not reported

Poster 2.249: Characterization of BHV-7000: A Novel Kv7.2/7.3 Activator for the Treatment of Seizures

• BHV-7000 is a potent activator of Kv7.2/7.3 channels, impacting both deactivation kinetics and voltage dependence of activation
• BHV-7000 requires the Kv7.2 W236 residue for channel activity
• No significant activation of the GABAA receptor with BHV-7000
• BHV-7000 is potent in the maximal electroshock seizure (MES) test without impact on neurobehavior or motor (rotorod) behavior

Poster 1.487: Determinants of Health-Related Quality of Life of Patients with Focal Epilepsy: A Systematic Literature Review

• This systematic literature review identified multiple factors associated with lower HRQoL in patients with focal epilepsy
• Depression and anxiety were among the most significant and frequent determinants of HRQoL change
• Other relevant and frequent determinants of HRQoL change included cognition, ASM adverse events, seizure freedom, and employment
• A comprehensive understanding of the modifiable determinants of HRQoL is relevant to patient health and well-being and can inform clinical practice and observational/interventional studies

 

[BB23]

• Unlike prior reports where EEG effects of a Kv7.2/7.3 activator showed the greatest power increase in the delta frequency band (Biondi et al. 2022), the highest spectral power increases with BHV-7000 were seen in alpha, beta, and gamma frequency bands.

From this paper about thalamocortical dysrhythmia:

The original description of TCD proposes that normal resting-state alpha activity (8–12 Hz) slows down to theta frequencies (4–8 Hz) in states of deprived input.

From Wikipedia:

At the base of the theory lies diminished excitatory or increased inhibitory input at the thalamic level. This leads to a switch of the thalamocortical neurons from tonic to burst firing and subsequently entrains thalamic and cortical areas with pathological oscillations at around 5 Hz.

A question to people with a better understanding of what's going on in our damaged brains; can the increase of the alpha activity help us in regards to tinnitus and maybe visual snow syndrome? Are the potassium channel activities and these alpha waves connected in any way? Maybe the restoration of those give increase to alpha waves? Can anyone more knowledgeable enlighten me?

 

[Anuar Lukios]

How common would it be for someone to have damaged potassium channels? I would imagine that is something like stroke or genetic mutations? I mean if someone would have their potassium channels damaged, then Trobalt would not work for epilepsy either. I don't think that an acoustic trauma can damage potassium channels, same goes for ototoxic drugs because then people would get not only tinnitus but a bunch of other things (and not just one or two, but probably virtually everything that depend on potassium channels would go sideways.)

Correct me if I'm wrong, but some studies have demonstrated that, when a neural injury occurs (for example, due to acoustic trauma), there is a temporary reduction in the activity of Kv7.2/Kv7.3 channels, which can lead neurons to become pathologically active, right?

 

[Muggumbo]

Correct me if I'm wrong, but some studies have demonstrated that, when a neural injury occurs (for example, due to acoustic trauma), there is a temporary reduction in the activity of Kv7.2/Kv7.3 channels, which can lead neurons to become pathologically active, right?

Would this mean if a person recovered after an acoustic trauma that these neurons settled down over time? Or would it mean that the potassium channels recovered?

 

[Anuar Lukios]

Would this mean if a person recovered after an acoustic trauma that these neurons settled down over time? Or would it mean that the potassium channels recovered?

From what I understand (but I could be mistaken), in some people, there is a spontaneous return of potassium channels to "normal," but for those with chronic tinnitus like us, this doesn't happen.

 

[ErikaS]

After a long awaited response, this was Biohaven's response to MyTomorrows regarding my case for expanded access...

Thank you for your email and contacting Biohaven on behalf of a tinnitus patient interested in access to BHV-7000. I am one of the team members at Biohaven that facilitates expanded access requests. Currently, Biohaven is working diligently on our KV7 platform and it's development. We are committed to our research of novel therapies for people suffering from neurological and neuropsychiatric diseases, and rare disorders. Unfortunately, at this time we are unable to offer expanded access to BHV-7000 secondary to the current stage of development.

We have received outreach from tinnitus sufferers and requests for tinnitus clinical trials and expanded access has been shared with our medical and clinical development leadership. At this time I do not have any additional information to share regarding tinnitus clinical trials/expanded access. Our website will contain any press releases related to any future news related to the BHV-7000 program.

Same info as shared before, but at least they are acknowledging that they are receiving outreach from tinnitus sufferers regarding a clinical trial and expanded access and it's been shared with higher ups. Whether that will do anything remains to be seen, but I hope it's at least the truth.

 

[BB23]

Characterization of BHV-7000: A Novel Kv7.2/7.3 Activator for the Treatment of Seizures

BHV-7000 activates the Kv7.2/7.3 channel with an EC50 value of 0.6 µM. At 1 µM, BHV-7000 slowed deactivation kinetics from 7.9 ± 1.9 ms to 32.3 ± 6.9 ms and shifted the half-maximal activation potential by -15.2 mV. In rat primary cortical neuron cultures, BHV-7000 produced a concentration dependent hyperpolarization of the resting membrane potential. Similar to other Kv7.2/7.3 activators, BHV-7000 does require the W236 amino acid for its activity. Further, BHV-7000 demonstrated little to no effect against the human α1β3ɣ2 GABA receptor at 10 µM and showed no significant activity in off-target pharmacology panel screens. In the MES model, BHV-7000 provides protection against seizures with a brain EC50 of 0.12 µM and a TD50 >20 by NS, a sensitive measure of tolerability.

I'm having massive brain fog at the moment. Below I posted Retigabine's voltage data from the Gabapentin paper @Nick47 found. Can we make a comparison and say anything regarding whether BHV-7000 is stronger than Retigabine or not?

Thus, retigabine (30 µM) shifted the voltage dependence of KCNQ2/3 activation by −30 mV (Fig. 3H) and increased current at −60 mV by 6-fold(Fig. 6I), however, the EC50 value for retigabine was in the micromolar (not nanomolar) range (Fig. 3J), which is ∼1000-fold less potent than gabapentin

 

[BB23]

OK. Enough. I need a break from Tinnitus Talk. Here's another paper. Apparently the main target for Retigabine wasn't Kv7.2/3. It was Kv7.3 and the paper lists all the half maximal activation potentials of Retigabine, which is higher than BHV-7000's data. I don't know how to read this information, if you have a better understanding, let me know, but I am inclined to think BHV-7000 is weaker than Retigabine now. This paper confirms the data I found in the Gabapentin paper. Retigabine shift in the half-activation voltage of KCNQ2/3 by -30mV, and At 1 µM, BHV-7000 slowed deactivation kinetics from 7.9 ± 1.9 ms to 32.3 ± 6.9 ms and shifted the half-maximal activation potential by -15.2 mV. Maybe it's dose dependent, I don't know. I don't like what I see.

KCNQ3 is the principal target of retigabine in CA1 and subicular excitatory neurons

First, expression of KCNQ2-KCNQ4 channels in heterologous cells showed that application of retigabine leads to ∼−40 mV shift in the half-activation voltage (V0.5) of KCNQ3 channels. A much smaller effect was observed for KCNQ2 (ΔV0.5 ∼−17 mV to −24 mV), KCNQ2/3 (ΔV0.5 ∼−30 mV), and KCNQ4 channels (ΔV0.5 ∼−14 mV). Second, similar experiments demonstrated that the retigabine EC50 is 0.6 µM for KCNQ3, fourfold lower than that for KCNQ2 channels (EC50 ∼2.5 µM). KCNQ5 has an EC50 of 2–6 µM, and KCNQ2/3 and KCNQ3/5 heteromers have a comparable EC50 of ∼1.4–1.6 µM

 

[Nick47]

My hope in these Kv7.2/3 openers is dwindling. I cannot fathom that if the science is good, none of these companies would trial it for tinnitus.

Before someone jumps out the woodwork and says 'yes but there is no objective test', I would remind you they carried out a trial for depression using XEN1101. There are no objective tests for schizophrenia or chronic pain either. I'm not buying it. They either know it won't be effective or have very low confidence.

For all the science, we need a trial!

 

[BB23]

→ Preclinical In Vitro and In Vivo Comparison of the KV 7 Activator XEN1101 with Ezogabine

My OCD got the better of me. Check this out:

XEN1101 has better results in shifting the half-activation voltage of KCNQ7.2/3 channels (-42.5mV). Better than Ezogabine and the disappointing (pathetic) results by BHV-7000.

The only thing left to know is how strong RL-81 is compared to XEN1101 when it comes to voltage activation thresholds. If it's even stronger, then it's worth the wait. If not, XEN1101 looks to be the winner from all this data.

My hope in these Kv7.2/3 openers is dwindling. I cannot fathom that if the science is good, none of these companies would trial it for tinnitus.

Before someone jumps out the woodwork and says 'yes but there is no objective test', I would remind you they carried out a trial for depression using XEN1101. There are no objective tests for schizophrenia or chronic pain either. I'm not buying it. They either know it won't be effective or have very low confidence.

For all the science, we need a trial!

You are unfortunately correct. They know this drug won't help everyone and the results would be sporadic. That's why they aren't testing it for tinnitus. They won't be able to match FDA's requirements with the results and would be a waste of time and money. They probably know it will be prescribed off-label for tinnitus for sure though.

Even with Retigabine, the results were not one-size-fits-all, I expect the same thing with XEN1101. If the issue is solely Kv7.2/3, XEN1101 should give better and more long lasting results by looking at all this data. And there will be a few super responders who will heal completely/get permanent improvements from this condition, like what happened with Retigabine, and there will be some who won't respond at all.

Similar to VSS/HPPD, the most successful treatment for those conditions is Lamotrigine. But it has a success rate of 20%. Some heal completely. Same with Keppra. For most these drugs don't do anything.

Also, unless we get more data, BHV-7000 is off my radar for now. We need somebody to test XEN1101 on tinnitus patients NOW!

 

[BB23]

The final piece of the puzzle. I think, based on the attached two papers, RL-81 is either a little stronger or on par with XEN1101.

The table below was taken from this paper which lists the Kv7.2 half-activation voltage data for all compounds. The data matches up with the Kv7.2/3 half-activation voltage data above for the most part.

RL-81 has a Kv7.2 half-activation voltage of -48.1±8.1.

@InNeedOfHelp posted this paper under the XEN1101 thread, which lists similar values for RL-81, BUT it also mentions of an EVEN STRONGER Kv7 opener, by the name of Compound 60. What is Compound 60? Who is developing it?

To sum it up, Compound 60 will the the strongest Kv7 opener (-50 mV), followed by RL-81 (-48.1±8.1 mV or -40mV) and Xen1101 (-42.5 mV). For Retigabine it was -34.3±4.3 mV, and for Gabapentin -9mV. This value for BHV-7000 was listed as -15.2 mV a few posts above, which would make it way inferior to Retigabine.

Kv7.2/ Kv7.3 channels expressed in CHO cells generated voltage-dependent K+-selective currents characterized by a slow time course of activation and deactivation, a threshold for current activation around −40 mV, and a half activation potential (V1/2) of −30.2 ± 0.7 mV. Perfusion with 1 μM retigabine induced a leftward shift in V1/2 (ΔV1/2) of about 10 mV; the same concentration of RL-81 or compound 60 caused a leftward shift of about 40 and 50 mV, respectively. The negative shift in the activation voltage triggered by RL-81 and, more so, compound 60 in Kv7.2/Kv7.3 channels caused a significant fraction of channels to be open at the holding voltage of −80 mV; most of those open channels were closed upon membrane hyperpolarization to −120 mV