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 as they enter clinical trials.
It was another relatively quiet quarter of news in Q4 2025 for ion channel clinical drug discovery, with a mixture of clinical trial failures and positive updates from a diverse set of peripheral and CNS programs, and moderate sized deals and funding news. The big news in terms of new drug approvals was Milestone Pharma gaining FDA marketing approval for their Cav1.x blocker Etripamil (Cardamyst) for cardiac arrythmia, and additional approval of Sage/Biogen’s GABA-A PAM zuranalone (ZURZUVAE) for post-partum depression in Canada, after EU approval last quarter and US approval in 2023. There was also very promising mid- and late-stage results for several Nav1.x programs from Praxis, Encoded, Stoke and Biogen in rare and common forms of epilepsy, and Praxis are getting close to FDA approval of their Cav3.x modulator for Essential Tremor, so the CNS space is definitely showing signs of delivering new drugs in 2026 after several drug approvals in 2025 for peripheral indications. In contrast, news was mixed for respiratory and pain programs, with Eli Lilly facing yet another failure in their pain portfolio (P2X7 ligand), but progress for a TRPM8 ligand for migraine and Xenon returning to some familiar old analgesia targets (Nav1.7 and Kv7.x). There was also a significant and positive flow of financial news for UK, US, Israeli and Asian biotechs working on therapeutic programs for pain, depression and epilepsy. Pacira Bio (US) and iN Therapeutics (Korea) signed licensing deals for Nav1.x and Nav1.7 analgesia ligands, and Chinese company Hyperway Pharma raised a decent Series B to help progress a range of clinical programs including a Nav1.8 inhibitor for acute pain. Israeli company Syremis Therapeutics was created with a $165 million Series A round to develop mAChR and NMDA-R modulators for depression, and UK academic spin-out EpilepsyGTX came out of stealth with a decent $33 million series A for their anti-convulsant Kv gene therapy, while Axsome in-licensed an old AZ GABA-A modulator for epilepsy. Finally, there is a significant M&A item I previously missed where Novartis acquired Regulus Therapeutics for $800 million upfront to access their ASO kidney disease TRPP1/2 gene therapy Farabursen.
In the peripheral disease indication section there are mixed (and delayed) updates for a diverse range of cardiac, respiratory, renal and pain ion channel programs. Mixed news for mid-stage respiratory programs as Arcturus Therapeutics revealed underwhelming interim data from the lowest dose of their CFTR mRNA gene therapy in the 1st small cohort of an ongoing Ph IIb MAD trial, and Enterprise Therapeutics and Nocion Therapeutics teasing about Ph II data on their small molecule ENaC and Nav1.x inhibitors in cystic fibrosis and chronic cough, respectively, with both companies expecting critical efficacy results to be released in 1H 2026. Maze Therapeutics feature again in the renal space after I caught up on previous news that they had already started Ph II trials for the small molecule APOL1 inhibitor MZE829, with topline data scheduled for release shortly after this blog comes out. There is also generally positive news in the pain space, with TRPM8 antagonists (Kallyope) and agonists (Dongwha Pharma) showing good results in mid-stage trials of migraine and pruritis, respectively, and Xenon returning to some traditional analgesia ion channel targets by starting Ph I trials of both Nav1.7 inhibitors and Kv7.x openers. In contrast, Eli Lilly announced yet another failure of a program in their ‘master protocol’ pain portfolio as the last of the original ion channel programs, a P2X7 ligand licensed from Asahi Kasei back in 2021, was dropped after failing to show analgesia efficacy in Ph II trials across multiple chronic pain indications. To round up there was a major piece of positive clinical development news this quarter when Milestone Pharma received FDA approval of their Cav1.x blocker Etripamil (Cardamyst) for treating Paroxysmal Supraventricular Tachycardia (PSVT), a form of cardiac arrythmia. This marks the 3rd novel ion channel ligand approved by the FDA in 2025, making it a record year!
In the CNS section there was a lot of positive progress for epilepsy programs, but mixed updates for ion channel ligands in depression and other CNS indications. Interim results from early Ph I/II safety and efficacy trials of Nav1.1 gene therapies in young Dravet epilepsy patients from Stoke and Biogen (Zorevunersen) and Encoded Therapeutics (ETX101) were very promising, with testing continuing in Ph III and Ph II studies, respectively. Praxis Precision Medicines are also making great progress with two Nav1.x small molecule inhibitor programs that aced Ph II trials for common focal onset (Vormatrigine) and rare developmental Nav1.2 and Nav1.6 epilepsies (Relutrigine), with the latter result setting up a potential NDA for 2026. Xenon also started Ph I testing of a mixed Nav1.6/Nav1.2 small molecule blocker in collaboration with Neurocrine Biosciences, a follow-up to a Nav1.6-selective ligand that failed to deliver in a previous Ph II trial. The Canadian company also provided updates on their Kv7.2/7.3 opener Azetukalmer which completed enrolment in a Ph III study in patients with focal onset seizures (and delivered very promising results at time of writing in March 2026 as I was finishing up this blog). In contrast there was mixed news for depression programs after Neurocrine Biosciences and Biohaven both revealed failures in Ph II trials of their NMDA NAM and Kv7.x PAM ligands, respectively. On the plus side, new Welsh biotech Draig Therapeutics announced the start of a Ph II study of their AMPA PAM in patients with major depression. Sadly here was also more bad news for Neuphoria Therapeutics after their nAChR ligand failed again in social anxiety at the Ph III stage, and despite it living on in mid-stage testing for PTSD and the company receiving a milestone from Merck for another nAChR program, the company (previously Bionomics) seems to once again be facing down investors and looking for another financial survival strategy. In contrast, QurAlis published promising data from a Ph IIb biomarker trial showing that their Kv7.2/7.3 opener could reduce motoneuron hyperexcitability in a small cohort of ALS patients. Finally, Praxis finally brought their Cav3.x blocker Ulixacaltamide through some unremarkable Ph II and interim Ph III readouts in patients with Essential Tremor to reveal very positive results from the completed Ph III trial, which enabled favourable discussions with the FDA that may shortly lead to drug approval, marking the end of a long journey from when PRAX-944 was developed in the 2010s by UBC academic spin-out NeuroMed and then Zalicus as an analgesia candidate.
1. Peripheral disease indications
a. Cardiac and skeletal muscle
We can start this final quarter of 2025 with more positive news for ion channel drug discovery and clinical development with the 3rd NCE ion channel drug for the year, with FDA approval of Milestone Pharma‘s Cav1.x blocker Etripamil (Cardamyst) for cardiac arrythmia in December. I previously covered the slow and sometimes tortured progress of this nasal spray formulation through late-stage trials in Paroxysmal Supraventricular Tachycardia (PSVT) over the last few years (e.g. Q4 2022 and Q1 2024 blogs) as it faced an initial Ph III failure and FDA pushbacks on the original NDA due to CMC issues, and the Fierce Biotech article linked above notes it is the first drug the company has had approved in it’s 22 year history. The treatment allows for acute self-administered dosing by patients when they experience abnormal heart rhythm, falling between chronic dosing with beta blockers or other Cav1.x channel blockers of mixed efficacy and side-effects or expensive and traumatic hospital-administered IV conversion therapy. Another Ph III trial is planned to allow label expansion to patients with a specific form of atrial fibrillation, which could increase the patient population 5-6 fold in the US alone.
b. Respiratory disease
Like many others I have been waiting on an update on Nocion‘s ongoing Ph IIb study of their novel Nav1.x blocker NTX-1175 (NOC-110, now called Taplucainium) in chronic cough since it eventually started dosing back in November 2024. Some have taken the lack of news as a negative (we all know those glass half-empty types, especially in the world of biotech and VC where things are either black or white), but a cursory look at the recruitment and treatment protocol on the NCT clinical trials website (NCT06504446) or ASPIRE Study site would explain why things are taking so long as they try to recruit, screen, treat and carry out follow-up studies on over 400 prospective patients. So, I was gladdened to see the company tease on their plans for Ph III studies in a LI post this quarter, and follow-up with a press release in January 2026 noting that topline results were expected to be published in mid-2026. More on this and their Series B extension to help fund these clinical studies in the Q1 2026 update…
I and others may also be waiting on mid-stage clinical results from UK outfit Enterprise Therapeutics on their ongoing Ph IIb study of ENaC inhibitor ETD001 in cystic fibrosis, which started dosing in Q3 2024 and completed recruitment in Q3 2025, as noted in my past blogs. As with Nocion, a press release teased that headline data should be expected in early-2026, so this work seems to be progressing as well. The press release primarily covered the fact that positive Ph I data on ETD001 had been formally published in Q4 2025, including safety and tolerability at high doses and therapeutically beneficial slow uptake after inhalation into the lungs and systemic circulation of healthy volunteers. Biomarker data on renal and plasma potassium levels demonstrated good target engagement, and aligned well with preclinical data that had been published in January 2025.
Not such good news for another CF player Arcturus Therapeutics, whose inhaled CF mRNA gene therapy ARCT-032 appeared to miss a key secondary efficacy endpoint in a small Ph IIb MAD study, albeit at the lowest dose and after analysis of a small cohort of 6 class I CF patients after 4 weeks of treatment. The company was naturally upbeat in revealing the interim analysis, but investors and industry experts were not so impressed according to this Fierce Biotech article. All is not lost, as another small cohort is being recruited to receive a higher dose, and the company also intends to initiate a larger and longer 12 week Ph IIb in 1H 2026.
c. Other peripheral indications
I previously covered the work that US biotech Maze Therapeutics are doing with renal APOL1 channel and SLC transporter programs to treat chronic kidney disease in my Q4 2024 blog, along with funding news in Q1 2025, and they also featured in the recent blog I wrote on ‘renal channelopathies’ that is available here on the Nanion website. The company gave an update on both programs in Q4 to highlight presentations they were making at the American Society of Nephrology’s (ASN) Kidney Week in November in Houston, Texas, with the SLC6A19 small molecule inhibitor MZE782 having completed a Ph I safety and PK study. However, I had missed the fact that Ph II dosing of the small molecule APOL1 inhibitor MZE829 had started back in February 2025, with topline data expected to be released at the end of Q1 2026. Intriguingly, a company presentation from November 2025 seems to suggest that MZE829 acts to both inhibit pre-existing APOL1 channel activity by blocking the pore, and also inhibit APOL1 channel protein assembly and formation (see Figure), but I have not seen data that backs up the latter claim.
TRPM8 seems to be having a ‘mini-moment’ as an ion channel drug discovery target in 2025, peaking with the FDA approval of Alcon’s TRPM8 agonist Acoltremon (Trptyr) for dry eye ocular pain in May. I now have two more entries for this small chapter from news in Q4 2025. First up is a lead from a LI post from Wolfgang Liedtke at Anavex Life Sciences who critiqued a small Ph II study of another TRPM8 agonist, Cryosim-1, in patients with chronic prurigo (painful itch). Topical application of 0.1% and 0.5% cream significantly alleviated many measures of itch, discomfort and dryness compared to placebo, but the higher dose also elicited some side-effects (stinging, erythema). However, Wolfgang rightly noted the near-impossibility of conducting a placebo-controlled trial with a ligand that rapidly evokes skin colling (and perhaps also carries a refreshing minty odour), so how such ‘blinded’ data will be treated by regulators remains to be seen. Cryosim-1 has also produced significant positive efficacy in similar small Ph II trials of pruritis (2024 paper) and scalp itch (2022 paper). You have to dive quite deep into the recent clinical trial paper to find out that the study was supported by Korean company Dongwha Pharm Co., Ltd, but I can’t find any mention of this ligand on their website…
d. Pain
The TRPM8 story continues into pain and migraine, where several genetic studies had shown an association with this neuronal gene (e.g. 2016 paper). New York biotech Kallyope had two migraine programs validated by their platform of transcriptomics, circuit mapping and optogenetics, and a large Ph IIb trial of their TRPM8 blocker Elismetrep (K-304) read out this quarter with positive results including significant pain relief and freedom from migraine-associated symptoms such as nausea and light sensitivity. Four doses were tested but no data on dose-dependent efficacy has been revealed as yet, although side-effects were described as ‘mostly mild’. The company plans to initiate two registrational Ph III studies in mid-2026. One might question the commercial prospects of a new migraine drug given the success of CGRP modulating monoclonal antibody ligands already on the market, but this is an oral pill for acute dosing with a different mechanism-of-action that may gain traction compared to slower acting weekly or monthly injections designed to reduce migraine episodes, that acts on a different population of trigeminal sensory neurons according to company interviews. The sulphonamide drug was originally developed by Mitsubishi Tanabe Pharma (MT-8554, 2012 patent) who previously tested Elismetrep in Ph II in patients with painful diabetic peripheral neuropathy, before Kallyope acquired the candidate in early 2024. Another migraine drug (K-645) with an undisclosed mechanism that the company was also testing in a Ph IIa trial was dropped at the same time due to interim analysis showing lack of efficacy, allowing the company to now focus fully on Elismetrep.
I’ve extensively covered the ion channel work being carried out by Xenon on their Kv7.x programs for epilepsy and depression and Nav1.x collaborations with Neurocrine Biosciences on epilepsy over the last few years, but this quarter they broke cover big time to reveal a return to their roots in pain. An investor presentation and webinar in October 2025 gave details on not one but two early phase pain programs, including Nav1.7 inhibitor XEN1701 and Kv7.x opener XEN1120 that had both started Ph I safety and dosing SAD/MAD studies. The label expansion of a Kv7.x opener is perhaps not unexpected given their ongoing success in late stage trials for CNS indications with Azetukalner, and is certainly welcome as this ion channel target had rather fallen off the radar as an analgesia drug discovery mechanism despite extensive preclinical data and more recent human DRG sensory neuron studies. Xenon’s return to Nav1.7 is perhaps not unexpected but still a little surprising, given they had pioneered Nav1.7 human genetics and small molecule programs over 15 years ago, but like many other clinical candidates these had failed to achieve meaningful analgesia in human pain patients. The company likely feels, like many others, that there is untapped potential in Nav1.7 and learnings from the past can be applied to develop better analgesics against this target, although the recent demonstration of on-target cardiac and hemodynamic side-effects in NHPs and human patients will remain a key challenge. Their preclinical data suggests an approach to improve PK-PD by optimising free fraction and tissue distribution and better manage the xC50 target coverage required for analgesia vs side-effects, as well as explore the requirement for CNS exposure of Nav1.7 antagonists to modulate spinal cord neurotransmitter release and brain pain circuits.
In contrast, the bad news continues for Eli Lilly and their multi-pronged approach to testing a diverse panel of analgesia ligands in 3 groups of pain patients. Their Chronic Pain Master Protocol (CPMP) enrolled patients with nociceptive (osteoarthritis), neuropathic (diabetic peripheral neuropathy) and mixed pain (chronic lower back pain) across a series of Ph II trials, but the TRPA1 and SSTR4 ligands were both discontinued over the last 2 years for lack of efficacy. Now there is news that another ion channel ligand from the original panel, targeting P2X7 ionotropic receptors (LY3857210), has also been dropped from their pain pipeline, again for lack of efficacy. The P2X7 asset was licensed from Asahi Kasei in 2021 for $20 million upfront, and while the Japanese pharma notes that the licensing pact remains active it’s not clear what future work or therapeutic indication may be pursued. However, it looks like Eli Lilly are keeping faith with their FDA-approved clinical trial testing regime, as the Ph I Nav1.8 inhibitor (STC-004, now LY3526318) they recently gained access to by acquiring SiteOne Therapeutics in May 2025 is being lined up for Ph II testing under the CPMP program. Many have questioned the rationale behind such ‘streamlined’ clinical trial enrolment across multiple pain populations, as the benefit of rapid enrolment and dosing may not pay off in terms of efficacy, especially given the growing call for more specific patient stratification efforts to enable testing of potential new non-opioid analgesia drugs in appropriate therapeutic indications with proven preclinical translation and human validation.
2. CNS disease indications
a. Epilepsy
The prospects for a number of mid- and late-stage Nav1.x and Kv7.x channel modulators in epilepsy are looking very positive on the other hand, and I am quietly optimistic that one or more may get FDA approval by the end of 2026.
Let’s start with data from the Q3 and Q4 updates from Praxis Precision Medicines, who are progressing 3 different clinical Nav1.x programs for both common and rare types of epilepsy, and getting close to nominating a development candidate for a rare population of patients with mutations in the Nav1.2 channel. Most promising was the news that an ongoing Ph II study of the small molecule Relutrigine (PRAX-562), a non-specific Nav1.x inhibitor with potent selectivity to block persistent currents, in patients with Developmental and Epileptic Encephalopathies (DEEs) carrying Nav1.2 or Nav1.6 variants had been stopped early due to overwhelming signs of efficacy. On the back of this and an earlier positive result from the 1st cohort of the same EMBOLD study, discussions took place with the FDA which have resulted in an NDA application and the possibility of drug approval later in 2026 for ~5000 genetically-stratified DEE patients in the US alone. Another Ph II study of Relutrigine in a broader population of DEE patients (EMERALD) started enrolling in Q3 2025 and is expected to report topline date by the end of 2026, and if positive could pave the way for an additional NDA submission to the FDA in 2027.
Also making progress is Praxis’s 2nd non-selective Nav1.x inhibitor Vormatrigine (PRAX-628), which exhibits potent and state-dependent block of neuronal Nav1.x channels with superior functional selectivity and therapeutic index compared to other Nav1.x anti-convulsants. Unveiling of results from a Ph II study in focal onset seizure epilepsy showed it to be a fast-acting, effective and durable, with a 56.3% reduction in seizures over 8 weeks and around a fifth of patients achieving total seizure reduction in the last 4 weeks of the RADIANT study, alongside favourable DDI, tolerability and safety profiles after once-daily dosing. Late stage Ph II/III studies are already underway with results expected in 1H and 2H 2026 which may enable approval of Vormatrigine as an add-on or follow-on epilepsy therapy within a year, along with another Ph III study being planned for 1H 2026 to test it as a monotherapy for focal seizures.
Praxis also provided updates on two Nav1.2 gene therapies this quarter. Elsunersen (PRAX-222) is an ASO designed to knockdown Nav1.2 gain-of-function mutations found in patients with some rare early-onset DEEs, and is currently undergoing Ph I/II testing in a small cohort of young patients. As this current study (topline results expected in 1H 2026) includes a sham placebo arm, discussions with the FDA this quarter have allowed for a streamlining of the critical Ph III registrational study to omit a sham group, and patients are now enrolling in this study and topline results are expected in 2027. Finally, another Nav1.2 ASO program designed to upregulate expression and channel function of patients with loss-of-function variants in Nav1.2 (PRAX-100) is nearing the stage of development candidate nomination, and the initial therapeutic indication may be in autism rather than epilepsy.
Also making good progress on their late stage Kv7.x opener epilepsy program are Xenon, who announced that enrolment had completed in the Ph III X-TOLE2 study of Azetukalner in patients with focal onset seizures (FOS); topline data is expected in March 2026 (and looked very promising as it was just released as I was writing this section!). Additional Ph III studies of Azetukalner in FOS (for registration outside of the USA, especially Japan) and primary generalized tonic-clonic seizures are already underway and continue to recruit patients. Like several other companies in this space there were also presentations from a Ph II OLE study of Azetukalner out to 2 years in FOS patients at the December meeting of the American Epilepsy Society.
Xenon also announced that a new Ph I study is underway this quarter for a follow-up Nav1.6/Nav1.2 channel inhibitor for epilepsy as part of their collaboration with Neurocrine Biosciences. NBI-921355 differs from the previous attempt using a more selective Nav1.6 inhibitor (NBI-921352, XEN901), which flunked a Ph II focal epilepsy trial as I reported in my Q4 2023 blog. Xenon have published extensive preclinical data on this program, and it looks like a mixed profile is preferred, especially as Nav1.2 inhibition potency also correlates with reduction in seizures in animal models. At the time Neurocrine was reviewing this data with an eye to determining if they would continue work in a more restricted population of patients with SCNA8A DEE, but NBI-921352 appears to have disappeared from their pipeline a time of writing. Xenon have also revealed their work on a preclinical program looking to develop small molecule openers of Nav1.1 channels, designed to treat genetic haploinsufficiency in Dravet syndrome, which is currently at the IND-enabling stage. A lead candidate XPC-837 was included in a detailed poster at the Dec 2025 American Epilepsy Society conference, and a senior scientist presented similar data at the recent ‘Ion Channel Drug Discovery’ satellite meeting at the Biophysics meeting in San Francisco that I attended.
Much more advanced in this space, and pursuing Nav1.1 gene therapies for Dravet epilepsy, are Encoded Therapeutics and Stoke Therapeutics, who both published mid-stage clinical data this quarter. Encoded made ‘first peek’ presentations at the December American Epilepsy Society meeting highlighting interim safety and early efficacy (N=10 patients) Ph I/II clinical data of their one-time AAV therapy ETX101, including a significant 78% reduction in seizure frequency over 7 months at the highest dose tested, and dramatic progressive improvements in behavioural and cognition neurodevelopmental outcomes out to 52 weeks. Additional patients in the ongoing POLARIS studies will receive one of 4 doses of ETX101, after which a pivotal Ph III trial can begin later in 2026 on the back of the launch of a GMP manufacturing facility and receiving Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA, placing them a little behind Stoke’s Nav1.1 ASO Zorevunersen.
Stoke and Biogen also released incremental updates and new publications on their mid-stage clinical data for Nav1.1 ASO Zorevunersen (STK-001) for Dravet epilepsy. The companies presented posters at the December 2025 meeting of the American Epilepsy Society on Ph I/IIa and longer term OLE study data from 80 patients in the UK, EU and USA, and looking ahead (with the benefit of time travel as I write this in March 2026) their formal peer-reviewed paper with the same data was published in the New England Journal of Medicine, revealing the stunningly positive and transformational effect this drug can have in young epilepsy patients. Significantly, this gene therapy exhibited effects on top of existing anti-convulsant drugs, and improved other measures such as cognition and behaviour and brain EEG activity, especially compared to natural history data, suggesting it could be a genuine disease-modifying treatment. While things look good at this stage, the crucial test will be from the 52 week 150 patient Ph III study that is currently underway, expected to release topline data in mid-2027.
b. Depression
Not such great news this quarter for several ion channel ligands being tested in depression, however. Neurocrine Biosciences have featured in my past blogs with a dizzying oscillation of news on ion channel drug successes and failures across various neuroscience programs, and sadly this quarter it’s another setback as their NMDA NAM fails in Ph II trial for major depression. NBI-1070770 is a NR2B-selective NAM developed to offer regional and state-dependent inhibition of synaptic activity and CNS excitability, much like earlier but less potent and subunit-selective ligands such as Ifenprodil. Unfortunately none of the 3 doses of the drug met the primary endpoint when depression questionnaire ratings were compared to scores of placebo group patients after 5 days. There may be some silver linings that the company suggested it was analysing, such as the rather short readout period and use of NBI-1070770 as an adjunctive treatment rather than a stand-alone anti-depressant, but checking the pipeline as I write this shows no sign of the candidate. The ligand is another of the CNS assets that Neurocrine acquired in a big $120 million licensing deal from Takeda in 2020 that have performed with mixed success in following years. Just looking at the ion channel ligands is not so bad as Neurocrine can boast a 50% success rate so far, as the AMPA GluR PAM Osavampator (NBI-1065845) delivered positive results in another Ph II major depression trial in Q2 2024, and started Ph III testing in Q1 2025.
Also struggling are Biohaven, whose rapidly progressing Kv7.x modulator BHV-7000 (now called Opakalim) failed in a Ph II major depression trial due to lack of efficacy over 6 weeks (primary endpoint). This is a rather short analysis period for anti-depressants, although traditional monoamine uptake inhibitors can take over a month to affect depression scores. The company did note ‘favourable trends’ on some primary and secondary outcomes for certain patient sub-groups, notably those with more severe depression at the start of the study, but despite this silver lining it seems that financial restrictions (and the fact that the drug candidate failed a Ph II/III trial in bipolar mania in March 2025) will terminate any further studies as the company focuses on other CNS assets and therapeutic indications. Notably, BHV-7000 is still in Ph III studies in focal epilepsy, chasing down the lead that Xenon’s Kv7.x opener Azetukalner has on the field for this indication (see Section a. above). However, Biohaven’s lack of success with BHV-7000 in other CNS indications may be worrying for Xenon, as the updates I outlined above for Xenon’s epilepsy program also included updates on Ph III testing of their Kv7.x opener Azetukalner in both bipolar and major depression…
Better news for Biogen, albeit very late given the implosion of their collaboration with now-defunct Sage, is that the GABA-A PAM Zurzuvae ((zuranolone) was approved in Canada for post-partum depression, following approval for the same therapeutic indication in the US in Q3 2023.
Positive news also for new Welsh biotech Draig Therapeutics, who received FDA approval of their IND to conduct a Ph II trial of AMPA PAM DT-101 in major depression, which is anticipated to commence fairly quickly this quarter too. Draig (Welsh for ‘dragon’) burst onto the UK biotech scene in the middle of 2025 with a pretty decent $140 million Series A round to support the neuropsychiatry work spun-out of the University of Cardiff Medicine Discovery Institute, which I covered in my previous Q3 blog.
c. Other CNS indications
Two good and one bad news item in this final section, so I’m feeling pretty well supported by cold hard evidence that neuroscience and ion channel drug discovery are still on the up, but not without some setbacks that can always teach us how to do things better.
I’ve covered the travails of Neuphoria Therapeutics (previously Aussie biotech Bionomics) in past blogs with their a7 nAChR NAM BNC210 (soclenicant), and it now seems that one of the two therapeutic indications they have been pursuing for their lead candidate over the last few years has now been dropped, after it failed to meet primary or secondary endpoints in a Ph III study in social anxiety, after also failing in a Ph II study back in 2022. Interest remains in testing it in PTSD, based on positive results from a previous Ph IIb chronic dosing study that triggered a Ph IIb low dose study that was expected to start in Q4 2025. Neuphoria did receive a $15 million royalty payment from Merck in Q1 2025 for another alpha7 nAChR PAM ligand, now called MK-1167, which has entered Ph II trials for schizophrenia dementia. However, their cash runway is fast running out and the company signalled that a strategic review would start on the back of the BNC201 Ph III failure, and from this an existing hedge fund investor proposed a buyout deal based on their depressed stock price but the financial and political ramifications of this still seem to be reverberating through the company and other investors so I am not sure what the eventual outcome will be.
On the plus side, QurAlis have released further positive PK-PD and target engagement data for their Kv7.x opener QRL-101 in ALS, on the back of a previous update in Q1 2025 from healthy volunteers. This quarter they revealed similar promising target engagement data in another Ph I proof-of-mechanism study this time in 12 ALS patients, where the selective Kv7.2/7.3 PAM decreased motoneuron excitability in a dose-dependent manner, and was well tolerated with few if any notable side-effects. The initial identification of Kv7.2/7.3 channels by QurAlis founders and scientists as a potential therapeutic target to help reduce excitability and treat and/or modify ALS progression came from a ground-breaking study in human patient-derived iPSC neurons, and new science has recently backed-up this strategy with publication of data showing that loss of neuronal TDP-43, a key marker and driver of ALS disease, leads to mis-splicing and dysfunction of the KCNQ2 gene encoding Kv7.2 channel subunits and disruption of neuronal excitability, providing a compelling disease mechanism. Given the ongoing mid- and late stage work with other Kv7.x openers in epilepsy (see section 2.a above), QurAlis are also planning a Ph II trial of QRL-101 in DEE patients.
Even more promising, after a long and sometimes challenging clinical trial journey, is the news from Praxis Precision Medicines that their Cav3.x blocker Ulixacaltamide (PRAX-944) has finally delivered compelling positive results from two Ph III trials in Essential Tremor, triggering pre-NDA discussions with the FDA and plans for a possible commercial launch in 2026. The drug had failed a previous Ph II trial in Q1 2023 but the company pushed on with a Ph III program, which itself hit trouble after an interim analysis of one trial in Q1 2025 suggested it would fail to meet the primary endpoint to beat placebo, but the company adapted the analysis method and kept the 2nd Ph III study going as enrolment was strong and it involved a different responder-withdrawal design. This belief has paid off, as both Ph III trials delivered positive topline data this quarter against the primary endpoint, significantly improving standard survey measures of daily activity that were deemed clinically meaningful after 8-12 weeks. There was also a significant rate of disease improvement, meeting a key secondary endpoint. That was in October 2025, and by December the company were in discussions with the FDA that enabled granting of Breakthrough Therapy designation for the drug, and yielded a positive pre-NDA pathway for submission of an IND in Q1 2026. It’s been an awfully long and tortured journey from initial discovery and preclinical characterisation of Z-944 by Terry Snutch and colleagues at UBC in Canada and subsequent drug discovery work at NeuroMed and Zalicus in the 2010s, and it was wonderful to see the messages and posts from fellow Cav channel colleagues and scientists on LinkedIn when this news came out!
3. Ion channel company financial news (funding, M&A, collaborations)
In contrast to my preamble to this section in Q3 2025 noting activity around CNS ion channel programs related to neurodegeneration, deals in Q4 seem to have reverted back to the norm and relate mostly to epilepsy and depression (Kv7.x, GABA-A, NMDA). However, there are also 3 deals around pain-related Nav1.7, Nav1.8 and Nav1.x channel projects, highlighting the continued (or is it resurgent?) focus on analgesia on the back of Vertex’s approval of Suzetrigine as a Nav1.8-selective drug for acute pain. I also take this as another sign of the recovery in neuroscience drug discovery and clinical development, which suffered multiple setbacks over the last decade, notably with closures of numerous big pharma departments. This work was maintained and grown in smaller biotech companies, which are now benefiting from licensing deals and outright M&A activity funded by larger companies moving back into this space. I also want give a shout-out to @GrantSmillie who is providing weekly updates on neuroscience deals and clinical news in his LI newsletter.
Let’s start with the pain sector financial news. Chinese biotech Hyperway Pharma announced a $28 million Series B raise (200 million CNY) to support a number of their clinical programs, which includes the Nav1.8 inhibitor HBW-004285. The ligand has completed Ph I safety and dosing trials, with an IND submitted to the FDA and Ph II trials for acute pain in China and the US that began in 2H 2025. Staying in Asia, Korean biotech iN Therapeutics announced an exclusive global licensing deal for their Nav1.7 clinical candidate to Niroda Therapeutics for up to $500 million (750 billion won) but the upfront payment was not disclosed; the Korean company retains rights to Asia marketing. The Nav1.7 inhibitor was in-licensed from Daewoong Pharma (where it was known as DWP-17061) in 2021 and called IN-1011-N17, and has now been renamed Aneratrigine. iN Therapeutics subsequently raised an additional $15.6 million in new funding but Daewoong Pharma retain a 93.91% stake in the company, which was formed as a spin-out of their ion channel business to create iN Therapeutics in 2020. The company machinations of this story go even deeper, as Niroda Therapeutics is a recent US entity created by major VC firms, and includes ion channel veteran Doug Krafte as CSO (ex-Icagen). Niroda are responsible for carrying out clinical trials of Aneratrigine outside of Asia, presumably in the US. Finally, Pacira Biosciences signed an exclusive global licensing deal worth up to $230 million ($5 million upfront) to get hold of AMT-143 (Ropivacaine) from AmacaThera , a non-selective Nav1.x local anaesthetic that is being developed as a new post-surgical analgesic using a proprietary injectable hydrogel for longer-lasting pain relief (7-14 days). Ph II trials are planned for 2026.
Next up are two financial news items related to epilepsy programs. The 1st is a pretty big deal here in the UK given our smaller VC market, as University College London (UCL) academic spinout EpilepsyGTx secured a Series A raise of $33 million in Q4 2025 to support their Kv channel gene therapy program for focal epilepsy, with the funding to be used to advance EPY201 into Ph I/IIa clinical trials over the next few years. I saw one of their scientists present the in vitro and preclinical data at the Sophion 2025 ICMS meeting here in Cambridge UK, describing an AAV vector engineered to deliver a Kv1.1 channel subunit to neurons by injection close to the epileptogenic site and thereby produce a prolonged reduction in neuronal excitability. The 2nd item involves Axsome Therapeutics who I covered before thanks to their work on an NMDA modulator drug for CNS indications (approval of AX-05 as Auvelity for major depression in 2022, and ongoing late stage trials in neurodegeneration). This quarter they announced acquisition of an old AstraZeneca GABA-A ligand for epilepsy in a deal worth up to $83 million that started with a modest $300k upfront payment and will include staged development and regulatory milestone payments of several million each for successive indications, along with much larger downstream sales and royalty payments up to $79 million. This is another rather typical convoluted licensing deal, as the asset was originally developed by AZ in the 2010s as AZD7325, an a2/a3-selective PAM with efficacy as an anxiolytic and additional anti-convulsant activity without significant sedative or addictive effects (see this 2014 paper), and tested in early stage trials for anxiety, autism and Fragile X. The ligand was out-licensed to a Fortress Biotech subsidiary called Baergic Bio in 2019 as part of the AZ Open Innovation program and renamed BAER-101, but it’s not clear if any more work was done on the asset during this time. Then, in 2022 Baergic Bio was itself acquired by Avenue Therapeutics, another Fortress Bio entity, and it is from here that Axsome gained exclusive global access to the drug (renamed to AXS-17) through purchase of the wholly-owned sole-asset subsidiary company. Axsome plans to switch focus slightly and prepare AXS-17 for Ph II trials in epilepsy starting in 2026, based on previous preclinical seizure assay data, where it will go up against mid- and late-stage anti-convulsant small molecule and gene therapies targeting Nav1.x, Kv7.x and GABA-A channels from the likes of Stoke, Encoded, Praxis, Xenon, Marinus/Immedica and Saniona.
Another out-licensing deal in the CNS space has created Syremis Therapeutics, an Israeli company created with US funding and including ex-Karuna CEO Steve Paul and Teva alumni, which launched with a $165 million Series A. Their lead candidate is a an M1/M4 muscarinic AChR agonist ST-905 which is in Ph I safety trials and being developed for schizophrenia (much like Karuna’s KarXT/Cobenfy), and an NMDA antagonist ST-901 (targeting the PCP binding site) currently in IND-enabling studies that is being lined up for a Ph I trial in 2026 as a treatment for bipolar and major depression. Both assets were originally developed at Israeli biotech Clexio Biosciences, where Syremis CEO and co-founder Elizabeth Kogan previously worked. Clexio also have their own NMDA antagonist CLE-100 (esketamine) in Ph II studies for major depression.
This newsletter/blog has never promised or guaranteed to be comprehensive or error-free, and to be clear I do welcome your comments, suggestions and corrections to improve the record (be it in the LI comments section or via LI messages or email to me directly). So to finish this quarterly blog I include a significant ion channel company M&A news item from May 2025 that I missed, and relates to the renal channelopathy space that I recently reviewed in my quarterly preclinical blog on the Nanion Technologies website (here). Regulus Therapeutics have been developing ASO gene therapies against miR-17 that regulate the expression of TRPP1/2 ion channels, also called PKD1/2 or Polycystin complexes as they are expressed in the kidney and mutations are linked to autosomal dominant polycystic kidney disease (ADPKD). Well, after Novartis previously pursued an exclusive global licensing deal in 2H 2024 it acquired the company outright in Q2 2025, primarily for the TRPP ASO drug farabursen (RGLS8429) that had demonstrated safety and efficacy in Ph Ib clinical trials in ADPKD patients published at the end of Q1 2025. And this was not insignificant sum, with $800 million upfront and another $900 million due after clinical and regulatory milestones are met. A Ph III trial had been planned by Regulus for Q3 2025, and while the Novartis pipeline now shows the drug (CYX082) there is no public timeline for the start of further clinical work as yet.
Dr. Marc Rogers, Cambridge (UK)
aka The Channelogist
