QurAlis' QRA-244 — An Alternative for Retigabine (Trobalt)?

Discussion in 'Research News' started by Tezcatlipoca, Mar 26, 2021.

    1. Tezcatlipoca
      Question it

      Tezcatlipoca Member

      Hello! I have been looking into Retigabine. We all know how great it was for tinnitus (with a lot of users' tinnitus lowering to 1/10), however the side effects were many and life threatening, so it was finally discontinued in June 2017.

      Now, after looking around, I found this Pharmaceutical Company:

      QurAlis

      They are an ALS focused biotech developing a Kv 7.2/7.3 ion channel opener optimized for both safety and efficacy as a potential treatment for motor neuron hyperexcitability-induced neurodegeneration in ALS patients.

      "QRA-244 a Potent, Selective KCNQ2/3 Opener and a Potential Therapy for Motor System Hyperexcitability induced Disease Progression in ALS Patients,” showed that QRA-244 has comparable effects to retigabine (ezogabine) at up to 20-fold lower concentration in motor neurons differentiated from patient-derived iPSCs as measured by an all-optical electrophysiology experiment. Importantly, QRA-244 showed dramatic reductions in side effects associated with retigabine including fatigue/somnolence, dizziness and bladder retention in head-to-head pre-clinical studies."
      The full article can be found here:

      QurAlis' Selective Kv7 Opener, a Drug Candidate for ALS, Demonstrates up to 20-Fold Increase in Potency and Dramatic Reduction in Side Effects Compared to Retigabine in Preclinical Models
       
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    2. serendipity1996
      No Mood

      serendipity1996 Member Podcast Patron Hall of Fame

      Tinnitus Since:
      2011 - T, 2016- H, relapsed 2019
      Cause of Tinnitus:
      noise-induced
      Great find. Hopefully they will start clinical development soon. I think Xenon is furthest along with their Retigabine reformulations - XEN-496 is now entering Phase 3.
       
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    3. AUTHOR
      AUTHOR
      Tezcatlipoca
      Question it

      Tezcatlipoca Member

      Interesting. I remember reading about them but I am not really knowledgeable about their reformulation. Were they able to get rid of the side effects too?
       
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    4. serendipity1996
      No Mood

      serendipity1996 Member Podcast Patron Hall of Fame

      Tinnitus Since:
      2011 - T, 2016- H, relapsed 2019
      Cause of Tinnitus:
      noise-induced
      Yes, their intention with reformulation was to get a safer product without the side effects of the original Retigabine. Although being realistic I am guessing it's not free of side effects but hopefully none that would land them with a black-box warning...
       
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    5. Croaker
      Haunting

      Croaker Member Benefactor

      Tinnitus Since:
      01/2019 T, 04/2020 H
      Cause of Tinnitus:
      Headphones/Car Alarm/Immune Response?
      XEN-496 is the same active molecule as Retigabine. XEN-1101 is their newer molecule with reduced side effects.
       
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    6. AUTHOR
      AUTHOR
      Tezcatlipoca
      Question it

      Tezcatlipoca Member

      So we can expect the same side effects for XEN-496, but fewer side effects for XEN-1101?
       
    7. Croaker
      Haunting

      Croaker Member Benefactor

      Tinnitus Since:
      01/2019 T, 04/2020 H
      Cause of Tinnitus:
      Headphones/Car Alarm/Immune Response?
      Probably. XEN-1101 is in Phase 2. Xenon Pharma claimed that no adverse events occurred in Phase 1. I’m not sure if they’re looking for the visual snow problems that Retigabine had, it seems like fixing the urinary retention and skin pigmentation were their biggest concerns.

      Edit: no serious adverse events, except for somebody who passed out from having their blood drawn :D
       
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    8. AUTHOR
      AUTHOR
      Tezcatlipoca
      Question it

      Tezcatlipoca Member

      Oh so it's safe now? That's fantastic!
       
    9. weab00
      Gloomy

      weab00 Member Benefactor

      Location:
      Joe Dart's basement
      Tinnitus Since:
      05/2019
      Cause of Tinnitus:
      some good mf music
      What is the mechanism of action for channel blockers possibly ameliorating hyperacusis?
       
    10. Croaker
      Haunting

      Croaker Member Benefactor

      Tinnitus Since:
      01/2019 T, 04/2020 H
      Cause of Tinnitus:
      Headphones/Car Alarm/Immune Response?
      Along with the anecdotes we’ve got on here, there’s this from Dr. Fuchs.

      Relevant part of the abstract:

      “Here, we show that type II afferents are activated when outer hair cells are damaged. This response depends on both ionotropic (P2X) and metabotropic (P2Y) purinergic receptors, binding ATP released from nearby supporting cells in response to hair cell damage. Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term “noxacusis” to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber’s response to hair cell damage.”​
       
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    11. Lucifer

      Lucifer Member Podcast Patron Benefactor Hall of Fame

      Location:
      Prison
      Tinnitus Since:
      -
      Cause of Tinnitus:
      -
      So theoretically, if we can restore OHCs using FX-322, would this stop noxacusis?

      If FX-322 doesn’t help, how long would we need to take Retigabine for?

      Which Retigabine drug is closest to come out in the market?
       
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    12. Matchbox
      Wishful

      Matchbox Member

      Location:
      BC Canada
      Tinnitus Since:
      August 2020
      Cause of Tinnitus:
      Noise Induced, Prednisone (drones), Barotrauma (distortions)
      It opens the channels, it doesn't close them. Big difference. It isn't a fast acting inhibitor, more like a threshold setter channel making it more hyperpolarized via K ion slippage.
       
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    13. xyz
      Alienated

      xyz Member

      Location:
      Germany
      Tinnitus Since:
      2006 mild T 2019 T worsening H onset
      Cause of Tinnitus:
      unknown / probably noise induced
      To open the Potassium channels, does it make sense to supplement with Potassium? I think there are some studies which show correlation between high Potassium intake and better ear health, but has it also some effect on the Potassium channels?
       
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    14. Aaron91
      Gloomy

      Aaron91 Member Podcast Patron Benefactor Ambassador Advocate

      Tinnitus Since:
      2007
      Cause of Tinnitus:
      Loud music/headphones/concerts - Hyperacusis from motorbike
      My theory and research into this has always suggested yes. Before the Phase 2 readout I was planning on making a post going into further detail as to why but having had the rug pulled from under our feet I can't be bothered now. I know that @100Hz has also been doing some similar research but I'm not at liberty to say much more. OHCs to me are the culprit. I think @FGG has some reservations in that sensitisation may remain even after you've fixed/replaced the OHCs. I'm a little more hopeful about this just from looking at other examples of peripheral-centralised pain as well as from looking at a lot of anecdotal experiences of hyperacusis - many people get better, suggesting then that sensitisation is reversible, at least in some people and to some extent.
       
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    15. Lucifer

      Lucifer Member Podcast Patron Benefactor Hall of Fame

      Location:
      Prison
      Tinnitus Since:
      -
      Cause of Tinnitus:
      -
      Which Retigabine drug is closest to coming out in the market?

      I had a look at XEN-496 and it’s going to take them awhile for them to complete Phase 3. It has a study completion date of December 2022.
       
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    16. Matchbox
      Wishful

      Matchbox Member

      Location:
      BC Canada
      Tinnitus Since:
      August 2020
      Cause of Tinnitus:
      Noise Induced, Prednisone (drones), Barotrauma (distortions)
      No. K ions leak from the inside to the outside of the membrane to maintain constant charge delta.

      More on the outside will do nothing unless you were deficient.

      K channel drugs help to increase the charge differential (hyperpolarization) by opening pores to let K ions slip out of the cell.
      XEN-496 will work. The mechanism is sound as f. Hugs Kv7.1 subunits like white on rice.

      XEN-1101 is pretty novel in its shape and mechanism, but same target.
       
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    17. 100Hz
      No Mood

      100Hz Member Benefactor

      Tinnitus Since:
      2015
      Cause of Tinnitus:
      Noise exposure
      I'm a bit hazy on this, haven't done much on it for a while but the conclusion I came to is that FX-322 could work as long as it either, a) fixed wherever rogue ATP / cytokines etc. were being released from (so if the broken ATP release site was replaced by PCA process then it would fix it but if it was from a gap junction hemi-channel for instance then maybe not as it might not be covered by the scope of PCA), or b) if noxacusis is down to enlarged ribbons then FX-322 could replace the OHCs that have enlarged ribbons but only if they were damaged enough to be flagged for PCA.

      What Trobalt's mechanism suggests to me from what I read about it is that it masks, or disables the tinnitus causing mechanism (and I hope the pain causing mechanism as well), and not just that but it seems to do it very consistently in comparison to other meds. FX-322 has much more of unknown factor about it where noxacusis is concerned in my opinion because a) we don't typically have much apparent hearing loss and b) people with loads of hearing loss typically don't have noxacusis.

      I believe Xen etc. would need to be taken for life, but hope also (complete speculation this bit) maybe as a preventative measure for when you wanted to do something noisy if it wasn't a requirement to keep it sustained at a constant level in the system.
       
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    18. StoneInFocus
      Fine

      StoneInFocus Member

      Tinnitus Since:
      2012
      Cause of Tinnitus:
      Hearing damage, ear infections
      Although I have a very superficial understanding of this matter, I wonder why researchers haven't continued on this particular track of finding a cure to pain hyperacusis. To me, this sounds like the most promising area of a possible hyperacusis treatment, but I could be wrong. Why are there no more studies done on the role of the KNCQ channel in the experience of pain hyperacusis? It has been seven years since the study came out and as far as I know nothing came of it. I seriously do not understand what is taking so long.
      Why do you think this is so?
       
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    19. StoneInFocus
      Fine

      StoneInFocus Member

      Tinnitus Since:
      2012
      Cause of Tinnitus:
      Hearing damage, ear infections
      In addition to my previous post, here is an interesting part of the book 'Hyperacusis and Disorders of Sound Intolerance: Clinical and Research Perspectives', written in 2018:

      "In the future, a better understanding of the physiology of type II ANFs, especially regarding their activation in patients who experience sound-induced pain, might facilitate development of new treatments for hyperacusis. However, a better understanding of the physiology, and the development of new drugs, requires an animal model of pain hyperacusis, which is unfortunately not available yet. Nevertheless, the finding that retigabine can block the damage response of type II AN fibers (Liu et al., 2015) provides a promising start for the development of pharmacological interventions, as this drug is already approved for human use. Moreover, if the induction of auditory pain in hyperacusis is at the periphery, then the side-effects of retigabine (and those of any other potential new drug) could be minimized if delivered locally through systems for drug administration to the inner ear, and we might thus see some progress toward clinical trials in the not too distant future" (Fagelson & Baguley, 2018, p. 72).
       
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    20. Padraigh Griffin

      Padraigh Griffin Member Podcast Patron Benefactor

      Tinnitus Since:
      05/2020
      Cause of Tinnitus:
      Unknown/Stress
      Interesting. Another one going into a Phase 1 at the end of this year. Pre-clinical 20 times more potency than Retigabine and far less side effects. 2022 is a busy year.
       
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    21. Jerad

      Jerad Member

      Location:
      Ohio; United States
      Tinnitus Since:
      2002
      Cause of Tinnitus:
      Medication ototoxicity
      Are you referring to RL-85 or another drug that is entering Phase 1 soon?
       
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    22. StoneInFocus
      Fine

      StoneInFocus Member

      Tinnitus Since:
      2012
      Cause of Tinnitus:
      Hearing damage, ear infections
      I have very little knowledge of the anatomy of the ear, but I wonder if an intratympanic injection of Retigabine would yield similar results on humans as the application of the substance to the nerve fibers of rats did.

      On a side note, would it be possible to get one's hands on some samples of QRA-244 or one of the chemicals developed by Xenon Pharmaceuticals through some sort of early access program?
       
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    23. StoneInFocus
      Fine

      StoneInFocus Member

      Tinnitus Since:
      2012
      Cause of Tinnitus:
      Hearing damage, ear infections
      So I've checked their website, QRA-244 is not listed as being currently in the pipeline.

      However, the company is developing another Kv7.2/7.3 opener named QRL-101.

      The description reads:

      "Our lead therapeutic product candidates are QRL-201 and QRL-101. QRL-201 is a first-in-class molecule for the treatment of ALS that aims to restore STMN2 expression in ALS patients and QRL-101 is a first-in-class Kv7 opener for the treatment of ALS that aims to reduce hyperexcitability-induced neurodegeneration."​

      I have sent the company an email asking when they expect QRL-101 to enter its clinical phase and whether they've already considered a compassionate use program, this was their response:

      "Dear [StoneInFocus],

      Thank you for your interest in the QurAlis QRL-101 program. We expect QRL-101 to reach the clinic end of this year or early next year.


      As you may know, there are many steps in clinical development and unfortunately, we are still a significant amount of time away from a consideration of a compassionate use program."​
       
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