Ion channel ligands in clinical development – Quarterly review (Q3 2024)

The main focus of this series is to highlight the progress being made in ion channel clinical drug development, which is a key validation parameter for target selection along with other considerations such as human genetic data, cryo-EM structures for drug design, availability of relevant animal and iPSC models, and medical and commercial drivers in each therapeutic indication. I’d like these discussions to help overcome perceptions that ion channels are ‘difficult’ drug discovery targets, and the tendency for historical failures to get blamed on the target class rather than the discovery process itself. We all know that drug discovery is a tortuous and expensive journey regardless of target or modality, so it is important to recognise the successes (and learn from the pitfalls) of ion channel modulators reaching clinical trials.

It was a relatively quiet quarter of ion channel clinical drug discovery news in Q3 2024, with 18 items in my database including a mixture of positive and negative news for several ongoing early and mid-stage clinical programs.

In the peripheral disease indication section there was good progress for Milestone Pharma’s cardiac Cav1.x blocker Etripamil which aced a 2nd Ph III trial in paroxysmal supraventricular tachycardia (PSVT) and received FDA acceptance of an NDA for the nasal spray CARDAMYST, and IView Therapeutics gained IND approval to start a Ph I/II trial of their TRPM8 ligand IVW-1001 for dry eye. Several respiratory ion channel programs also progressed in Q3, with Vertex gaining FDA acceptance to file an NDA for their 5th CFTR drug combination ‘Vanza triple’ which includes a mix of Vanzacaftor, Tezacaftor and Deutivacaftor CFTR Cl- channel correctors and potentiators, Enterprise Therapeutics finally starting a Ph IIa trial of their ENaC blocker ETD001 in CF patients, and Nocion Therapeutics also starting a Ph IIb trial in chronic cough of their Nav1.x blocker Taplucainium (NTX-1175/ NOC-100). Finally, Sionna Therapeutics announced the acquisition of several CFTR ligands from Abbvie, consisting of? Ph II candidates ABBV-2222 and ABBV-3067 (aka galicaftor and navocaftor) and the Ph I corrector ABBV-2851. There was also positive news in the pain arena, with Vertex receiving FDA approval for an NDA filing for their Nav1.8 blocker Suzetrigine (VX-548) to treat moderate-to-severe acute pain after it had aced several Ph III trials, and Latigo Biotherapeutics successfully completing the 1st Ph I safety trial of their Nav1.8 candidate LTG-001.

In contrast there was mixed news in Q3 for CNS ion channel programs, with positive progress for several epilepsy clinical studies and early stage trials in Fragile X syndrome, ALS and Charcot Marie Tooth disease, but a project-ending failure in Essential Tremor for the Sage/Biogen GABA-A PAM SAGE-324. ?Most activity in epilepsy was around Nav1.x targets, with Stoke Therapeutics resolving issues to get the clinical hold lifted on the mid-stage trials of the Nav1.1 Dravet gene therapy ASO candidate STK-001(Zorevunersen), and Praxis sharing a slew of positive updates including the start of a global confirmatory Ph II trial of their Nav1.2 ASO PRAX-222 (Elsunersen) in DEE patients and the beginning of several mid-stage trials of their Nav1.6 blocker PRAX-628 (Vormatrigine) in focal onset and generalized epilepsy, as well as promising efficacy of their Nav1.2/Nav1.6 blocker PRAX-562 (Relutrigine) in a Ph II trial in DEE patients. Xenon also shared positive Ph IIb data on their Kv7.2/7.3 anti-convulsant XEN1101 (Azetukalner) which enabled the start of Ph III trials in focal and tonic-clonic seizure patients, and Quralis announced they were expanding the indication of their Kv7.x PAM QRL-101 from ALS to include epilepsy patients. GRIN Therapeutics also announced positive Ph Ib data for their NMDA GluR NR2B subunit NAM Radiprodil in patients with rare NMDA receptor mutations, but Takeda‘s anti-convulsant candidate drug Soticlesat (TAK-935), that indirectly modulates NMDA receptors and excitatory amino acid transporters, seems to have stalled after failing it’s 2nd Ph III epilepsy trial. I finish with positive news from a trio of CNS companies; Quralis successfully completed dosing the 1st cohort of ALS patients with their Kv7.2/7.3 PAM QRL-101 which has allowed further Ph I testing to continue, while Kaerus Biosciences started a Ph I trial of their BK channel modulator KER-0193 in Fragile X syndrome, and Actio Biosciences received FDA Orphan & Rare Disease designation for their TRPV4 inhibitor ABS-0871 in Charcot Marie Tooth disease type 2C.

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1.????? Peripheral disease indications

a. Cardiac ion channels

There was good news for Milestone Pharma and their cardiac Ca2+ channel antagonist Etripamil on both clinical and regulatory fronts. Their original Ph III trial of the nasal spray in North American and European patients with paroxysmal supraventricular tachycardia (PSVT) had been successful in 2022 (discussed in my Q4 2022 blog), and was published in Lancet in June 2023. This quarter they announced that a similar Ph III trial in China had also been successful, following licensing of Etripamil to Ji Xing Pharmaceuticals back in 2021.? My previous blog in late 2022 had discussed regulatory issues with this drug, as the FDA had rejected the company’s initial NDA in Q3 2023 and they planned to re-submit it in Q1 2024. Well, the FDA has now accepted their revised application, and issued a final decision date of March 2025 for the drug-device combo, which will be called CARDAMYST. Etripamil is also being tested a treatment for a much larger population of patients suffering from atrial fibrillation with rapid ventricular rate (AFib-RVR). The drug completed a Ph II trial for this in 2023, and the FDA had indicated that after the spray was approved for PSVT that a single additional Ph III AF study would likely allow an expansion of cardiac indications through a supplemental NDA. These discussions are progressing positively with the FDA agreeing on various study design parameters and study endpoints, but inevitably lead to some delays so previous plans to wrap this up in Q1 have now slipped to an anticipated registrational study application in Q2 2024.

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b. Respiratory disease

More positive news this quarter on the cystic fibrosis front with several CFTR and an ENaC channel program making progress across early and late stage trials, as well as Nocion’s Nav1.x blocker finally entering Ph IIb for cough. ?

Vertex continues to lead the field, with their massive CFTR franchise delivering a 5th drug candidate for market approval. The FDA accepted an NDA filed in May 2024 for ‘Vanza triple’, a combination of Vanzacaftor, Tezacaftor and Deutivacaftor CFTR Cl- channel correctors and potentiators, for cystic fibrosis patients aged 6 years and older with at least one F508del mutation or other responsive mutation in the CFTR gene. Vertex also began public presentations of medical data from Ph III trials of ‘Vanza triple’ in Q3 of 2024. This new drug combo follows on from the previous triple Kaftrio (Trikafta in the US) which included Ivacaftor, Tezacaftor and Elexacaftor and was approved in 2019. The company cashed in a Priority Review voucher that will reduce review time to 6 months and result in a PDUFA decision date of January 25th 2025.

I previously highlighted Sionna Therapeutics as a new CFTR player back in Q2 2022 and the start of a Ph I trial of their lead candidate SION-638 in Q4 2022, followed by their Series C funding round in Q1 2023. It looks like some of these monies were put to use in this quarter when the company announced their acquisition of Abbvie’s CF clinical assets. The deal includes the Ph II candidates ABBV-2222 and ABBV-3067 (aka galicaftor and navocaftor) which demonstrated promising efficacy as measured by changes in patient sweat Cl- production and lung function (but failed as a combination with C1 or C2 inhibitors), for which Sionna will assume further development responsibilities. The package also includes the Ph I corrector ABBV-2851. It appears that Sionna is looking to create combinations of the Abbvie CFTR transmembrane domain 1 corrector and potentiator assets with some of their existing pipeline of CFTR nucleotide binding domain modulators to create novel CFTR drugs to compete and differentiate with the various Vertex CFTR corrector and potentiator combos. Sionna also has an ICL4-targeted Ph I candidate SION-109 in phase 1, so the stated plan is to combine their NBD1 stabiliser SION-638 with one or more of the three Abbvie TMD1 modulators and/or the ICL4 ligand SION-109. Abbvie developed some of their CF modulators in a collaboration with Galapagos which started in 2018 and ended in 2022, but in this recent deal they made an equity investment in Sionna and maintain a right to receive late-stage development and commercial milestones and royalties, so all is not lost from their initial investment.

I highlighted the ￡33 million Series B fundraising round by Enterprise Therapeutics in my Q1 2024 blog, and noted previously the delay in progressing their ENaC inhibitor ETD001after a successful Ph I trial in 2023, so I am pleased to report that the Ph IIa trial has now commenced (no doubt helped by an injection of new money and recovery from bottlenecks in clinical trial testing during and after the pandemic). The efficacy trial is being run in CF patients in the UK and Europe who are either ineligible for or are not receiving CFTR modulators (i.e. as they have novel gene mutations) and will measure recovery in lung function to demonstrate clinical proof-of-concept for this first-in-class drug treatment; it is expected to read-out in mid-2025. As ETD001 works independently of CFTR modulation it offers the potential to treat the >10% of patients with high unmet medical need but no currently effective treatment for their life-long ailment.? At the end of Q3 Enterprise also received FDA ‘rare pediatric disease designation’ for ETD001 in the US, as it may offer a useful alternative to the many CFTR modulators from Vertex which are only now being allowed to be tested in young CF patients.

The wait is also finally over for Nocion Therapeutics, who faced some pandemic delays in progressing their novel Nav1.x blockers for cough and pain into the clinic, as the much-anticipated Ph IIb efficacy trial began to enrol chronic cough patients in Q3. Nocion have updated an old story where the likes of GSK developed Nav1.3 and Nav1.7 blockers for cough, by leveraging the fact that charged Nav1.x inhibitors (like QX-314) cannot cross the cell membrane to block nerve excitability, but inflammatory and other pathophysiological signals can induce persistent large pore conformations in channels like P2X7, TRPV1 and TRPA1 that are also expressed on nociceptors, allowing the entry of these ‘nocions’ (such as NTX-1175/ NOC-100/ Taplucainium) to selectively block Nav1.7 and other Nav1.x channels in over-active sensory neurons. ?The current focus on cough is interesting and topical for two reasons: the previous Ph II a trial occurred in 2021 and the choice to target cough was no doubt influenced by ongoing covid-19 infections, and boosted by the clinical success and deals around several P2X3 blockers that had shown great potential in cough and other respiratory indications (e.g. Merck’s Gefapixant, Bellus Health/GSK BLU-5937/Camplixant).

c. Pain

There is promising progress on 2 different but well known pain targets this quarter, with further positive updates on the Vertex and Latigo Biotherapeutics Nav1.8 programs, and an update on a TRPV1 capsaicin program.

Last quarter I spent some time discussing the acute and chronic pain clinical trials of the Nav1.8 blocker Suzetrigine from Vertex (VX-548), which had largely aced two Ph III trials in acute pain in bunionectomy and abdominoplasty patients. Based on this promising data the drug had been submitted to the FDA and approved for a rolling NDA schedule in Q1 2024, and this quarter the FDA approved the NDA for Suzetrigine to treat moderate-to-severe acute pain. The drug already achieved Fast Track and Breakthrough Therapy status from the FDA in 2022, and now it looks like it may get the final nod from the FDA by January 2025. However, this story is not finished yet and I will discuss more details on the Ph III acute pain trials in the Q4 2024 blog after Vertex disclosed more complete data in various conference and investor presentations, which notably addressed the head-to-head performance of VX-548 against standard-of-care analgesics, and hinted at a regulatory & marketing pitch to use Suzetrigine not as a stand-alone competitor to the likes of Vicodin, but rather as a substitute for the opioid constituents in combination with traditional NSAIDs. There is also the not insignificant matter of awaiting results from the recently initiated Ph II and Ph III trials in chronic pain patients with diabetic peripheral neuropathy (DPN) and painful lumbosacral radiculopathy, respectively, for which Suzetrigine could make a marked impact as the first non-opioid analgesic approved in over a decade.

Also tracking well in terms of Nav1.8 analgesia clinical trials are Latigo Biotherapeutics, who published on their lead preclinical Nav1.8 channel blocker LTGO-33 in Q1 of this year, and just announced the successful conclusion of their 1st Ph I trial, for LTG-001. The oral drug proved safe and well tolerated, with rapid absorption (e.g. a Tmax of ~1.5 hours) and predictable PK with dose-proportional exposure in SAD and MAD study groups that bodes well for a rapid and titratable analgesic. It is not clear if the preclinical compound LTGO-33 is the same as the clinical candidate LTG-001, but I do note that the company revealed the initiation of a 2nd Ph I trial for a new compound, LTG-305, in Q4 2024…

Let’s conclude this section with a new twist on an old pain target, TRPV1.? I mentioned previously how I was surprised that pharma and biotech companies were still working on TRPV1 antagonists and desensitising agonist a decade after confounding results of poor efficacy and notable thermosensation side-effects in the initial rounds of small molecule clinical trials. The current focus appears to be on local administration of desensitising agonists such as capsaicin (think Qutenza patch and arthritic knee injections), and this quarter I learnt of another player in this field: Concentric Analgesics published on a successful Ph II trial of their capsaicin pro-drug Vocacapsaicin to deliver post-surgical analgesia in bunionectomy patients (similar to the acute pain studies being used for Vertex’s Nav1.8 blocker Suzetrigine). However, only the highest dose of 0.30 mg/ml delivered statistically-significant pain reduction and reduced opioid use over 96 hours compared to placebo, although the effect did last for up to 2 weeks; lower dose wound site injections of 0.15 and 0.05 mg/ml failed to demonstrate significant effects on primary or secondary endpoints (see Figure). Broadly similar results were revealed for patients undergoing total knee arthroplasty at the recent IASP conference. Side-effects included greater pain on day 0 (presumably by TRPV1 channel activation and before desensitisation and nerve loss), but GI symptoms subsided in the knee surgery patients.

d. Other

I’ll finish this section on peripheral targets with a new chapter from another TRPM8 dye eye player, backing up previous mentions for Aerie Pharmaceuticals/Alcon (AR-15512) which aced a Ph III trial in Q1 of 2024. US company IView Therapeutics gained FDA IND approval to start its Ph I/II trial of IVW-1001 in March this year and announced that they had completed patient enrolment in September. The randomized and blinded placebo-controlled study will dose dry eye patients with high (0.2%) and low (0.1%) formulation of the TRPM8 agonist, which will be administered by an eyelid wipe rather than eye drop as for AR-15512. ?The drug was licensed from Protheragen, who sponsored an earlier Investigator Sponsored Clinical Trial which showed that IVW-1001 had a rapid and short duration of action to provide symptom relief and increase tear production, and cumulative benefit with longer-lasting effects after 2 weeks of administration.

And with a nod to the medicinal chemists who may be reading this blog, I have included some structures of the clinical compounds mentioned above. Below are the cardiac Cav1.x, ENaC and CFTR modulators, and below that the Nav1.x blockers and TRPM8 agonist.

2. CNS disease indications

a. Epilepsy

This was a busy quarter for anti-convulsant programs, with regular updates from active players with Nav1.x and Kv7.x modulators, as well as a new player and a notable late stage failure for companies working on anti-convulsant NMDA ligands.

Last quarter I spent some time discussing Xenon’s Kv7.x anti-epileptic XEN1101 (Azetukalner) and it’s recent promising efficacy and safety profile in the Ph IIb X-TOLE clinical trial and open label extension in focal epilepsy patients. This quarter they presented more detailed data on the long-term efficacy and quality-of-life improvements in the open label participants at the 15th European Epilepsy congress. While there were significant benefit and reduced disease burden with the intermediate drug dosage of 20 mg out to 30 months (e.g. 90% seizure reduction), I did note previously that only half of the patients remained in the study at this point, with discontinuations from lack of efficacy (13.8%), adverse events (12.0%) or patient withdrawal (12.0%). Post-hoc analysis showed that patients with a lower seizure frequency and/or taking fewer anti-convulsants were higher responders, so the drug candidate is not perfect for all epilepsy sufferers. Some of this data may inform the design and analysis of current Ph III trials in focal and tonic-clonic seizure patients.

Speaking of Kv7.x modulators, there is the (perhaps expected) news this quarter that Quralis will be expanding the application of their neuronal Kv7/2/7.3 M-current PAM QRL-101 into the epilepsy therapeutic space, now that it has reached the clinic for ALS (see below). The company announced the initiation of an exploratory Ph 1 proof-of-mechanism EEG brain activity biomarker study of QRL-101 in healthy volunteers to determine its potential to exert anti-seizure effects, just as it is thought to normalise excitatory-inhibitory balance in damaged ALS neurons. They will obviously be following behind Xenon’s more advanced Kv7.x modulator XEN1101 (discussed above) which has provided some key clinical proof-of-concept for this target, as well as Biohaven’s early stage candidate BHV-2000, and hoping to improve where others have faltered (e.g. GSK’s original Kv7.x PAM Retigabine, Eliem Pharmaceuticals preclinical program). However, there is still a lot of work to do to find the best profile of Kv7.x opener (isoform selectivity, balance between voltage shift and current potentiation, ADME and PK-PD profile) for each of the many types of childhood and adult epilepsies, many of which are still poorly treated with existing anti-convulsants.

Let’s turn now to updates on several ongoing Nav1.x channel epilepsy programs. Stoke Therapeutics have featured in past blogs with their Nav1.1 ASO STK-001 for Dravet epilepsy, and this quarter there was positive news after some previous clinical setbacks. The FDA had put a hold on one of their Ph I/IIa trials of Zorevunersen, but this has been lifted and they can restart testing multiple doses above 45 mg in children and adolescents, alongside an ongoing open label extension study. There had also been mixed news from analysis of data in the Ph IIa trial, where promising efficacy to reduce seizures (by 43%) was tempered by adverse events in a third of the young patients such as CSF protein elevations, vomiting and irritability. With these issues now resolved, discussions are ongoing with the FDA to gain approval of a global Ph III trial design by the end of 2024.

Praxis Precision Medicines continued providing company and clinical updates in Q2 and Q3 of this year for their various epilepsy programs.

·??????? The mixed Nav1.2/Nav1.6 blocker PRAX-562 (Relutrigine) showed promising efficacy in a small Ph II trial of 16 patients with SCN2A-DEE or SCN8A-DEE mutations in Q3, with a 46% reduction in motor seizures during the double-blind placebo-controlled period and a 75% reduction during the open label extension. Most meaningful for the young patients and their families was the fact that 30% of patients saw their seizures disappear completely, a notable achievement for a new anti-convulsant, and although there were some side-effects (such as infections, vomiting, pyrexia, somnolence and constipation), none of the patients discontinued drug administration due to these adverse events. These are rare forms of genetic epilepsy and so patient populations are small, but well stratified using genome sequencing; a registrational Ph II/III trial has now been initiated with a 2nd cohort of the previous EMBOLD study aiming to enrol 80 patients and readout topline results in 1H 2026.

·??????? The Nav1.2 ASO antisense program for PRAX-222 (Elsunersen) is also progressing, and after cautious dosing of the first few early-seizure-onset SCN2A DEE patients in the initial Ph II trial showed efficacy and tolerability, the first arm of a global confirmatory study has been initiated in Brazil. The company plans to advance the program within the US and expand to Europe later in 2024.

·??????? Finally there was news on PRAX-628, a 100-200 nM potency Nav1.6 blocker with complex state-dependence that has been shown to have improved isoform and functional selectivity for over-active Nav channels. Vormatrigine had completed a Ph I safety and high dose Ph II efficacy trial in photo-paroxysmal epilepsy in 2023, paving the way for a comprehensive Ph II/III campaign in 2024. The company has now revealed more details of this program, which include an observational study in partnership with the Epilepsy Consortium that started this quarter, a Ph II PK, safety and efficacy study in patients with focal onset seizures or generalized epilepsy that is expected to start in 2H 2024 and readout topline results in 1H 2025, and two 12 week Ph II/III studies designed to show efficacy in a larger population of focal epilepsy patients; POWER1 has already been initiated in Q3 with topline results expected in 2H 2025, and the POWER2 trial is slated to enrol patients in 1H 2025.

There was mixed news for NMDA anti-convulsants in Q3 2024. One the plus side, I can make the inaugural mention for GRIN Therapeutics, who revealed promising topline results from their Ph Ib trial of NR2B NAM Radiprodil in epilepsy patients with gain-of-function mutations in GRIN1, GRIN2A, or GRIN2B NMDA receptor genes (GRIN-related neurodevelopmental disorder). As a rare and severe pediatric disease the patient population is small and poorly served, and so a small group of 15 young patients were enrolled firstly into a 28 day screening/8 week maintenance period Ph Ib study, and then into an open label extension cohort to evaluate the safety, tolerability, PK and efficacy of Radiprodil. Results were positive, with a median 86% reduction in seizure frequency which occurred over and above the effect of background anti-seizure medications; 71% of patients experienced a significant and life-changing >50% reduction in seizures, improving to 90% in 43% of patients and one young kid even becoming seizure free within one month of treatment onset. The open label study is ongoing as of Q3 2024, and these results will be collated to support discussions with US and other regulators for a pivotal Ph III trial in 2025. Interestingly, not all GRIN-related neurodevelopmental disorder patients suffer from seizures, so the company has set-up a separate cohort to see if Radiprodil can also improve other symptoms.

On the negative side, the long-running story around Takeda‘s epilepsy drug Soticlesat (TAK-935) seems to have come to an unfortunate end, after it narrowly failed not one but two Ph III trials and the company took a $143 million financial charge in Q3. I have included it in this section as the drug (in-licensed from Ovis Therapeutics for $196 million in 2021) is thought to reduce CNS neuronal excitability by altering levels of 24S-hydroxycholesterol (24HC) through inhibition of Cholesterol 24-hydroxylase (CH24H) enzyme, and indirectly reducing NMDA receptor activity as the enzyme product acts as a NMDA PAM and also modulates EATT excitatory amino acid neurotransmitter transporters. Hopes were high for seeing some efficacy in separate Ph III studies, but TAK-935 failed to significantly shift the primary endpoint of seizure frequency in patients with either refractory Lennox-Gastaut syndrome or Dravet epilepsy (close at p=0.06, but statistics don’t lie), although there was some positive efficacy against secondary objectives in the latter study (e.g. responder rate, caregiver and clinician global impression of improvement, seizure intensity and duration over 16 weeks), and Soticlesat still has Orphan Drug Status for Dravet epilepsy with the FDA. All up this suggests the program may soon be closed, although the company was bullish and kept it in their pipeline (as their neuroscience division currently lacks a launch candidate, according to Fierce Biotech), and they made the usual noises about digging deeper into the data and seeing signs of efficacy in the Dravet Ph III secondary endpoints and the previous Ph II trial. If the company does decide to keep faith with this program, I trust it will be for the right reasons.

b. Essential Tremor

On the back of multiple failures for Cav3.x ion channel blockers being tested in this CNS indication in recent quarters (Jazz Pharmaceuticals Suvecaltamide (JZP385/MK-8998) Ph IIb trial fail in Q2 2024 and Neurocrine Biosciences NBI-827104 Ph II trial miss in Q4 2022 that eventually lead to cancellation) and a close call when Praxis Precision Medicine decided to progress their Cav3.x blocker PRAX-944 (Ulixacaltamide) into Ph III studies in 2024 despite a Ph II failure in Q1 2023, there is now news that the GABA-A PAM being developed by Sage Therapeutics (SAGE-324) and Biogen (BIIB124) has been abandoned after failing to achieve efficacy in a follow-up Ph II Essential Tremor trial. The drug again failed to meet it’s primary endpoint or exceed placebo in reducing upper limb tremors across 3 dosing groups over 90 days, faring slightly worse than in the previous Ph II trial in 2021 when marginal statistical significance was achieved (p=0.0491); there have also been persistent issues with tolerability and high patient drop-out rates, which are detailed in part in a 2024 publication of results from the 2021 trial. The open label extension study has been terminated and the long-running partners have decided to stop all further testing in this CNS indication, although the drug candidate was handed back to Sage who may find a way to progress it for this or related neurological indications (e.g. pain or epilepsy?). Indeed, the original deal (valued at $1.5 billion according to Fierce Biotech) back in 2020 included mention of epilepsy and Parkinson’s disease (something that Sage has also struggled with in its NMDA programs); cancellation of the ET franchise has deprived Sage of up to $520 million in regulatory and commercial milestones plus up to a $300 million share of net sales, so the financial hit for both biotech companies is going to be significant. Patients must also be dismayed, although Praxis are pushing ahead with PRAX-944 and several EU and US biopharmas have earlier stage Essential Tremor programs in play.

c. Other CNS indications

In contrast, we can finish with 3 positive news items for other CNS indications in Q3 2024.

First up are new entry Kaerus Biosciences who started a Ph I trial of their BK channel modulator KER-0193 in Fragile X syndrome. The culmination of 5 years of internal R&D, academic collaborations and rare disease support from FRAXA, the drug has shown promising preclinical effects to improve behavioural, sensory and cognitive deficits in mouse genetic disease models. I presume it is a BK opener, as Autifony Therapeutics in the UK are developing similar Kv3.x PAMs to treat Fragile X. Kaerus are also developing BK modulators for epilepsies produced by mutations in the KNCNA1 gene, and Kv7.x modulators for multiple CNS indications.

We also welcome a new ion channel company to the blog in Actio Biosciences, who just received Orphan & Rare Disease designation from the FDA for their TRPV4 inhibitor ABS-0871 in Charcot Marie Tooth disease type 2C (CMT 2C). Actio are one of a growing number of companies using human genetics to create precision medicines to target patho-physiology processes that are shared in both rare and common diseases. In this case TRPV4 mutations are found in CMT 2C patients, who live with debilitating peripheral neuropathy and skeletal dysplasia that affect muscle strength, vocal cord activity and respiration which severely degrade their quality of life and survival. This won’t be a quick result: we pitched this target and disease indication to investors at a rare disease channelopathy virtual biotech I co-founded with several colleagues in the late 2010’s but they weren’t keen on the 2 year timeline of a Ph II trial, so ‘chapeau’ to Actio and their investors and the CMT rare disease and patient groups who are deciding to take on this long and hard challenge.

We’ll finish with some good news from a slowly developing story in Amyotrophic Lateral Sclerosis (ALS), another CNS indication with a rocky past and still lacking effective treatments. Quralis spun-out of Boston labs on the back of some pretty cool iPSC neuron phenotypic screening that identified Kv7.2/7.3 M-current channels as useful targets to normalise the ectopic over-excitability and neurodegeneration of ALS motoneurons, and several years later they have completed dosing the 1st cohort of human volunteers in a Ph I MAD trial of their lead clinical candidate QRL-101. There have been no reported safety concerns or serious adverse events so the next dose group are being tested and topline results are expected by 1H 2025. The company previously ran a Ph II trial of the less selective Kv7.x PAM drug Retigabine as part of a licensing deal with GSK, which provided the proof-of-concept data and confidence to pursue this approach with their own and improved Kv7.2/7.3 channel opener ligand.

Dr. Marc Rogers, Cambridge (UK)

aka The Channelogist