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 relatively quiet in terms of ion channel clinical drug discovery news in Q3 2025, with largely positive updates from a diverse set of peripheral and CNS programs and some big deals in the commercial sector. One new ion channel drug reached the market in the EU this quarter with the European Commission accepting Biogen’s (via Sage) GABA-A PAM zuranalone to treat post-partum depression (as ZURZUVAE), following similar approval from the FDA in 2023. There was also a significant and positive flow of financial news for UK, EU and US biotechs, including Servier acquiring Kaerus Bio for $450 million to access a BK channel blocker in Fragile X and Saniona licensing a preclinical Kv7.2/3 opener to Jazz Pharma for over $200 million in upfront payments and development milestones to bolster their epilepsy pipeline. US biotech Kriya raised $320 million in a series D round to progress their gene therapy programs which include a couple of ion channel chemogenetic projects, and Maze Therapeutics continued their roll with a $150 million private financing round to support their renal ion channel and transporter clinical programs.  

In the peripheral disease indication section there was again a mixture of mostly positive news but also some setbacks for cardiac, auto-immune, pain and respiratory programs. There was significant progress for early stage clinical gene therapies targeting the cardiac SERCA2a Ca2+ ATPase transporter in Duchenne cardiac myopathy (Medera Inc) and CFTR in respiratory disease (Splisense), as well as the small molecule ENaC inhibitor for CF from Enterprise Therapeutics. Maze Therapeutics also completed a successful Ph I study of their SLC inhibitor for kidney disease, but Eli Lilly dropped the Kv1.3 inhibitor they acquired from DE Shaw Research a few years ago after a messy and truncated Ph II trial in auto-immune psoriasis. There was also mixed news in the pain space, with Vertex dropping acute pain indications for the Suzetrigine back-up Nav1.8 blocker VX-993 after a Ph II fail, and a restricted focus on diabetic neuropathy for mid-stage trials of suzetrigine and VX-993 in chronic pain after pushback from the FDA on other peripheral neuropathic pain indications. On the plus side, another Chinese biotech (Hengrui Pharma) breaks cover with a Ph I stage Nav1.8 blocker, and Stanford spin-out Afasci Inc reveals Ph I data on their non-opioid analgesic scaffold with dual action against Cav3.x channels and an epoxide hydrolase enzyme. 

In the CNS section there is far more news and all positive progress compared to the mixed picture last quarter. Entries in the epilepsy space include Actio Bio starting Ph I dosing of their KCNT1 blocker and Xenon enrolling patients in a Ph III study of their Kv7.x opener azetukalmer for focal seizures. Rapport reported positive results from a Ph IIa study of their AMPA modulator while SK Biopharma reported promising efficacy of Cenobamate in a Ph II study that may allow label extension to treat tonic-clonic seizures. Stoke and Biogen started Ph III dosing of their Nav1.1 ASO for Dravet epilepsy while Praxis reported positive Ph II data on their Nav1.6 blocker vormatrigine and the start of Ph III dosing of their mixed Nav1.2/Nav1.6 blocker relutrigine and Nav1.2 ASO elsunersen for pediatric DEE. There was also welcome positive news for Neurocrine’s AMPA modulator in a Ph II trial for major depression, as well as news that Seaport had started dosing in a Ph IIb depression study of their GABA-A PAM and that Xenon had started Ph III dosing of their Kv7.x opener in trials for major and bipolar depression after mixed results in Q2 in a Ph II trial in MDD. Newron Pharma had finally started dosing in their massive global Ph III campaign for mixed channel blocker Evenamide in schizophrenia, and Monument Tx continue to progress their nAChR ligand by. starting a Ph II trial in schizophrenia. Positive news also for Neurizon’s ostensible nAChR ligand that extended survival in a Ph Ib trial in ALS that has triggered a Ph II study, and Newleos following up on their inaugural funding entry last quarter with the start of Ph Ib trials of their GABA-A PAM in anxiety.    

1.      Peripheral disease indications

 a.     Cardiac and skeletal muscle

Just one entry in this category this quarter, and it represents a broadening of the ion channel church to include transporters (which are also transmembrane ion translocators, after all). New entrant Medera Inc (and its clinical division Sardocor) announced dosing of the first patient with their gene therapy designed to deliver the gene for the sarcoplasmic Ca2+ ATPase transporter into the heart. The AAV1.SERCA2a construct is a one-time treatment aimed at reversing cardiomyopathy associated with Duchenne Muscular Dystrophy (DMD) and the Ph Ib study is enrolling a dozen male patients with DMD to assess if the gene therapy, delivered directly into the heart via coronary blood vessels, can correct Ca2+ dysregulation and reduce cardiac complications such as fibrosis and heart failure which are the leading cause of mortality in DMD patients.  Gene therapy for DMD has been in the spotlight this year with the serious side-effects of Sarepta’s dystrophin gene replacement therapy, so here’s hoping that a different AAV vector and functional gene can achieve efficacy with safety.

b.     Respiratory disease

Two brief updates this quarter from players in the cystic fibrosis (CF) space. Enterprise Therapeutics announced that they had completed enrolment for a Ph II CF study of the ENaC blocker ETD001, with topline data expected in early 2026. The UK biotech has been steadily working on their 2nd CF program for several years, and the Ph II enrolment started in  mid-2024 but has taken some time to close as it is targeting patients who are ineligible for or are not receiving CFTR modulator therapy (i.e. Vertex drug combinations). Head of Biology Henry Danahay gave a marvellous talk on the ETD001 program at the RSC-SCI ion channel drug discovery meeting in Cambridge (UK) back in March 2025, and chemists can dig deeper into the MedChem aspects of this small molecule work in this paper.

More good news arrived from SpliSense who revealed positive data from an ongoing Ph II study of their ASO therapy SPL84 which delivers a copy of the CFTR gene directly into the lungs of CF patients with the 3849 C-to-T splicing mutation. The safety profile was clean and efficacy demonstrated by improvement of lung function in 70% of patients compared to placebo, which is claimed to be the first clinical evidence of potential benefit for an inhaled ASO therapy in a pulmonary disease. Caveats include the fact this is a small study of patients with a specific mutation, and cohorts 1 and 2 received lower doses (25 & 50 mg administered weekly over 9 weeks), with data from the last cohort receiving 100 mg still to be released. The company was understandably pretty upbeat about these results validating their CFTR pipeline and gene therapy approach, highlighting the advancement of two more inhaled CFTR ASO treatments designed to reduce expression of mucin proteins for CF, asthma, COPD and IPF.

c.  Other peripheral indications

Not so great news (again) from Eli Lilly, who have apparently dropped the Kv1.3 small molecule antagonist DES-7114 they acquired from D.E. Shaw Research in 2022 for $60 million.  The latest in a long series of small molecule and peptide Kv1.3 antagonists designed to reduce T-cell activity in auto-immune disease, the ligand was a claimed to be a potent and selective blocker in patents, and Eli Lilly renamed it LY397206 and put it into a Ph II psoriasis study in Dec 2023. However, it looks like this study was wound up early in mid-2025 with only a few patients completing dosing in the drug and placebo groups, and now there is news that the candidate was removed from Eli Lily’s pipeline. This is obviously not a good sign, and while there is some indication in the clinical trial listing for efficacy vs placebo in primary and secondary outcomes these were not significant, there is also concerning information about adverse events, protocol deviation and incorrect dosing amongst both patient groups in the posted results which will cloud any meaningful conclusions.

Better news for Maze Therapeutics who completed a successful Ph I safety study of their SLC6A19 neutral amino acid transporter inhibitor MZE782 for chronic kidney disease and phenylketonuria. The SAD and MAD results show the drug to be safe and well tolerated, and bonus efficacy measures of kidney function (glomerular filtration rate, phenylalanine secretion) confirmed target engagement and better-than-expected pharmacodynamics. These positive findings open up plans to conduct Ph II studies in CKD and PKU patients in 2026, with once and twice daily dosing. I previously wrote about Maze in Q3 and Q4 2024 when they started this Ph I study and again in Q1 2025 on the back of their IPO, and they appear again in Section 3 after a $150 million private funding round, so they are definitely on a roll.

d.      Pain

Nav1.8 drug discovery is still very much in the spotlight after the approval of Vertex’s VX-548 (suzetrigine, Journavx) gained FDA approval in Q1 2025 for acute pain, but this quarter there was mixed news for other Nav1.8 programs. Let’s start with Vertex, who announced that a follow-up Nav1.8 small molecule inhibitor VX-993 had failed in a Ph II bunionectomy acute/surgical pain trial that VX-548 had previously aced. None of the 3 oral doses tested in 367 patients managed to produce analgesia that was significantly different to that seen with either placebo or the clinical comparator (NSAID-opioid combo), questioning its utility as a monotherapy for acute pain although prospects of using it in chronic pain indications and/or in combination with opioids to reduce their tolerance and side-effects remains a possibility, and the Q3 2025 corporate update states that a Ph II study of VX-993 (oral) in patients with painful diabetic neuropathy is still enrolling (mirroring the current Ph III trial of VX-548 in DPN patients). Vertex had publicly revealed a previous Ph I study of VX-993 in Dec 2022, and a 2023 corporate slide deck also showed it was readying an i.v. formulation for clinical studies as well, alongside a 6th candidate VX-973 that was already in a Ph I safety trial. I don’t know how VX-993 differs from VX-548 so it is hard to say what may have caused this difference in clinical efficacy, but it does reinforce the difficulty in developing novel non-opioid pain drugs! Another setback was also announced by the company around the same time, with the FDA seemingly disinclined to approve Journavx with a broad label for chronic peripheral neuropathic pain, forcing the company to halt their plans to test the drug in a Ph III trial in patients with lower back pain (lumbosacral radiculopathy) and double down on their efforts against DPN with a 2nd Ph III trial, expected to  start in 2H 2025 and which will complete enrolment by the end of 2026. There has always been a question over the ability of VX-548, and perhaps other Nav1.8 blockers, to effectively reduce chronic pain after mixed mid-stage trial results, and similar discussions over which patient population is best suited to modulation of this pain pathway, and it looks like the FDA had an opinion on this as well so we will all have to wait another year to definitively find out.

I can also reveal a new Nav1.8 player, and another Chinese biotech working on this pain target: Jiangsu Hengrui Pharmaceuticals (Hengrui Pharma) was highlighted in a post on LinkedIn by a MedChem group based on their analysis of a recent patent (W2025176206), revealing a fairly standard patent-busting method that appears to have resulted in HRS-2129, which is now in Ph I safety trials.

Also, this quarter Xenon confirmed that their new Nav1.7 blocker (XEN1701) for pain had progressed from preclinical and IND stage to start a Ph I trial, alongside an ongoing Ph I study of their new Kv7.x opener XEN1120 which is also being developed for pain. Back-up work on additional candidates for both programs are also underway. The company presented an investor webinar in October 2025 that delved into great detail on both of these pain programs, with interesting claims that the Nav1.7 blocker was a ‘goldilocks’ ligand that exhibited good analgesia (e.g. in a humanised mouse model of inherited erythromelalgia, similar to Merck’s approach) but not too rapid onset of action or excessive receptor occupancy as to induce cardiovascular side-effects seen with current generation of Nav1.7 small molecule inhibitors (looked clean in telemetered NHPs). They also claimed that superior CNS exposure and improved plasma free fraction and peripheral tissue distribution would all contribute to a safe and effective clinical Nav1.7 analgesic, something we have been waiting to see for over a decade!  

To conclude I can also reveal a new biotech called AFASCI, Inc who are a spin-out from Stanford working on Cav3.x blockers for pain with a lead candidate AFA-281 that has already completed SAD and MAD Ph I safety trials in 2023 and 2025, respectively. Their scaffold has a novel non-opioid analgesia mechanism involving dual modulation of Cav3.x T-type channels and soluble epoxide hydrolase, which showed efficacy in preclinical models of neuropathic and inflammatory pain and also looks to be lined up for clinical trials in epilepsy. The company also lists other ion channel discovery programs for pain and sleep (AFA-2000) and epilepsy (AFA-279), and their website suggests they are looking for investment and/or partners to take these programs forward as it sounds like they have a lot on their plate.

To learn more about the portfolio of ligand- and voltage-gated ion channel cell lines and assays from B’SYS please visit https://bsys.ch/cell-lines/?category_id=4#content_start

2.      CNS disease indications

 a.     Epilepsy

A busy quarter of largely positive news, and for a change let’s start with Kv channel programs. Actio Biosciences are back as they announce dosing of the 1st patient in a Ph I safety trail of their KCNT1 (KNa, Slack) channel blocker ABS-1230, shortly after the IND was approved by the FDA in July 2025. The first part of this clinical work is being carried out in Australia, with a proof-of-concept Ph Ib/IIa study in KCNT1-related epilepsy patients scheduled to start in the U.S. in early 2026. Gain-of-function mutations in the KCNT1 gene result in dysregulated CNS excitability and neurodevelopment, and is an exceedingly rare disease seen in ~2500 patients in the US with severe and often fatal pediatric encephalopathy. As you might imagine it has been a massive battle to get a program for such a rare disease to the clinic, so huge kudos to the company, investors and patient families and the KCNT1 disease charity for their combined success! As I’ve written previously, Actio are also working on a TRPV4 inhibitor ABS-0871 for rare Charcot-Marie-Tooth Disease, and were recently supported by a $66 million investment round in Q2 2025.  

Xenon pop up again with news of their Kv7.x opener Azetukalner completing enrolment in the first of a set of Ph III trials in focal onset epilepsy (X-TOLE2), after reporting variable efficacy in a Ph II trial in MDD last quarter. Topline data from the 1st epilepsy study is expected in early 2026, with other Ph III studies underway to support ex-US regulatory submissions in focal onset seizures and the X-ACKT study in tonic-clonic seizures. The Q2 company update also confirmed that they were continuing with Ph III studies of the drug in both major depression and bipolar disorder (see below).

I outline the licensing deal that Saniona signed with Jazz Pharma on their Kv7.2/3-selective opener SAN2355 for epilepsy in Section 3, but here we can switch to a couple of news items on GABA-A programs and start with Saniona. The company announced they had selected SAN2668 as the clinical candidate for a pediatric DEE developmental encephalopathy program, triggering preclinical development work to enable Ph I clinical studies at the end of 2026. SAN2668 is a GABA-A PAM selective for a2/a3 subunits, and is designed to avoid common side-effects of non-selective GABA-A modulators such as sedation, cognitive impairment and tolerance. Their other GABA-A PAM SAN2219 is at a similar stage of preclinical development and has a broader specificity that is designed to target a broad range of acute epilepsies.

More advanced are SK Biopharma in South Korea, who revealed promising efficacy data for their epilepsy drug Xcopri (Cenobamate) after completing a Ph III study of patients with generalized tonic-clonic seizures, which should enable discussions with the FDA to enable label expansion beyond the current approval for focal seizures (granted in 2019). Cenobamate is a mixed GABA-A modulator and Nav1.x channel inhibitor, and in this Ph III study produced a significant reduction in seizure frequency compared to placebo. While tonic-clonic seizures are less common than focal seizures they are considered more severe due to risk of serious injury and sudden unexpected death (SUDEP), and remain poorly treated with current medications; as noted above Xenon are also pursuing both of these epilepsy indications with Ph III studies of the Kv7.x opener Azetukalner.

There are also positive updates from a number of Nav1.x epilepsy programs this quarter. First up are Stoke Therapeutics and their partner Biogen who revealed that the first patients had been dosed in a Ph III study of Zorevunersen (STK-001) in Dravet epilepsy, an antisense oligonucleotide designed to upregulate expression of Nav1.1 channels. The young patients, genotyped to avoid those with gain-of-function mutations, will receive 4 doses of the gene therapy over 40 weeks and tested for seizure reduction at weeks 28 and 52. The companies also released analysis of an ongoing Ph II open label extension study, now in it’s 3rd year, that supported inclusion of additional secondary endpoints in the Ph III study looking at changes in cognition and behaviour (communication, personal skills) as these had showed signs of improvement beyond the 6 month and 1 year post-treatment mark, alongside durable reductions in seizure frequency and increased number of seizure-free days.     

Encoded Therapeutics also shared an update on their Nav1.1 Dravet epilepsy gene therapy program. ETK101 is a one-time AAV vector containing a transcription factor to upregulate Nav1.1 gene expression in inhibitory GABAergic interneurons, and was granted Regenerative Medicine Advanced Therapy (RMAT) designation based on preliminary analysis of seizure data from patients treated in a ongoing Ph I/II studies (POLARIS). I’ve not heard of this designation before (being focused on ion channel drug discovery)and assumed it was limited to cell and tissue therapy and repair mechanism involving growth factors (e.g. neuroplastogens), but apparently it also includes gene therapies. ETK101 already has Fast Track, Rare Pediatric and Orphan Drug Designations from the FDA, and Orphan Designation from the EMA. ETK101 is currently being tested in young Dravet patients in Australia, the UK and US as part of the POLARIS global initiative, with enrolment in the dose-escalation studies expected to complete in Q4 2025 and release of interim clinical efficacy data expected by the end of 2025. Finally, the company has brought an internal GMP facility online in anticipation of needing more gene therapy materials for mid-stage trials in 1H 2026.

Turning to Praxis Precision Medicines, the company shared three major updates on their Nav1.x modulator programs for epilepsy and developmental encephalopathies this quarter. There was more success for the potent and selective state-dependent Nav1.6 inhibitor vormatrigine (PRAX-628) in a focal onset epilepsy Ph II trial, after it aced a high dose study in photosensitive epilepsy in Q3 2024. Topline data from the RADIANT trial over 8 weeks in 37 patients showed a 56.3% reduction in seizure frequency, with 1/5 patients achieving completely seizure-free for up to 28 days. However, a Fierce Biotech analysis noted there was a rather high 23% drop-out rate, although as with many new epilepsy drug candidates it was tested in patients already taking a number of other anti-seizure drugs (including SK Biopharma’s Xcopri) many of which bring their own side-effects, and the company noted vormatrigine continued to be safe and ‘well tolerated’. Indeed, vormatrigine is already being dosed in additional Ph II/III registrational studies in focal epilepsy, with the POWER1 trial expected to complete in Q4 2025 and the POWER2 expected to initiate this quarter and complete enrolment in 2H 2026, alongside a challenging stand-alone Ph II/III test of the drug that is expected to start in 1H 2026.

Praxis is also continuing to progress it’s non-selective state-dependent Nav1.x blocker PRAX-562 (Relutrigine) for rare epilepsies. The drug produced positive disease-altering effects in a Ph II study last year of patients with Nav1.2 and Nav1.6 mutations (with a 2nd cohort expected to readout in early Q1 2026), which has been used to gain Breakthrough Status from the FDA which allows its use to treat a wider range of Developmental and Epileptic Encephalopathies (DEEs). Also, a global Ph III registrational 16 week study of Relutrigine in a diverse population of DEE patients commenced in Q3 2025.

Finally, Praxis announced this quarter that they have commenced a registrational Ph III study of the Nav1.2 ASO elsunersen in patients with DEE linked to gain-of-function mutations in the Nav1.2 channel gene SCN2A. This channel is primarily expressed in excitatory neurons and can lead to CNS over-excitability, and so the opposite approach is taken compared to Nav1.1 Dravet epilepsy with the ASO is designed to reduce expression and activity of mutant Nav1.2 channel proteins. The 1st cohort includes patients aged 2-18 who receive 1 mg monthly for 6 months, with expansion to younger patients in subsequent cohorts. A Ph I/II dose escalation study of elsunersen in up to 16 DEE patients is currently mid-trial, with topline results expected in 1H 2026.

Let’s wrap-up this section with a quick update from Rapport Therapeutics on their TARP γ8-specific AMPA subunit NAM RAP-219 which I covered in previous blogs. The Ph IIa trial in focal epilepsy used a small group of 27 treatment-resistant patients implanted with a device able to measure brain activity, using a novel primary endpoint of reduction in frequency of ‘long event’ epileptiform waveforms, but there was no control group. The drug significantly reduced the seizure waveform biomarker (by 71%), but the reduction in clinical seizure frequency (by 78%, with 24% seizure-free) was marginally non-significant. So while these results are encouraging and exceeded company and analyst expectations, the small sample size and lack of placebo or blinding and the utility of the novel in vivo biomarker  raises some questions, as noted by others. There will be an OLE for the Ph II epilepsy study by the end of 2025, followed by two Ph III trials scheduled for Q3 2026 both of which will use traditional clinical seizure endpoints. The company revealed plans to develop a long-acting injectable form of RAP-219 to improve epilepsy patient and dosing adherence. RAP-219 is also being tested in an ongoing Ph II trial in bipolar mania with topline results expected in 1H  2027, with additional plans to assess it in a Ph II trial of diabetic peripheral neuropathy to be confirmed later in 2025.

b.     Depression

In contrast to past quarters there is only positive news for ion channel programs targeting major depression. Most significant was the eventual EU approval of Zurzuvae for post-partum depression, following its approval by the FDA in 2023. This drug is a GABA-A PAM originally developed by Sage Therapeutics in collaboration with Biogen, and as I outlined previously Sage has now been wound-up and Biogen has taken over commercial development.

Also nice to report some positive news for Neurocrine Biosciences after a string of setbacks for some of their other ion channel programs over the last year or so (Cav3.2, Nav1.6), as their AMPA PAM Osavampator (NBI-1065845, TAK-653) successfully completed a Ph II trial in major depression. The clinical candidate produced statistically significant and clinically meaningful improvement in depression scores and remission rates at Day 28 and Day 56 after daily 1 mg low dose oral administration (but paradoxically a non-significant reduction with the 3 mg dose), and no seizures that are a side-effect of other AMPA modulators. This was a moderately powered dose-finding study and it looks like the 1 mg dose will be taken forward into a series of 5 Ph III studies, which actually started in Q1 2025 based on topline data from the Ph II study that was analysed in Q2 2024. NBI-1065845 was acquired as part of a package of 7 neuropsychiatry assets that Neurocrine licensed from Takeda in 2020 in a deal worth $120 million upfront and up to $1.9 billion in milestone payments, but some of those assets have since failed to deliver in mid- and late stage trials so there must be some relief with this news, and especially for people like me with a predilection for ion channels as it may result in a first-in-class AMPA modulator drug if it makes it to market.

Seaport Therapeutics are also making progress in the MDD space, announcing the start of a Ph IIb trial of their GABA-A PAM candidate SPT-300. The company was founded in Q2 2024 and is run by senior managers who previously created Karuna Therapeutics (bought by BMS in late 2023 for the KarXT/ Cobenfy schizophrenia drug; Fierce15 2025 profile here), and their novel twist on small molecule drug discovery is the Glyph platform (invented in Australia I’d like to note as a proud antipodean) which adds glyceride sidechains to redirect oral drugs away from liver metabolism to the lymphatic system for improved bioavailability and novel target exposure mechanism. SPT-300 is also called GlypAllo as it is a pro-drug formulation of allopregnanalone, similar to the Sage/Biogen series of neurosteroid GABA-A modulators that have were tested in MDD and approved for post-partum depression (i.v. Zulresso and oral Zurzuvae). 

Finally, Xenon confirmed that they were progressing the Kv7.x opener Azetukalner into multiple Ph III trials for both major depression and bipolar disorder depression, despite the drug candidate showing variable efficacy in a Ph II trial in MDD that I reported on last quarter.

c.     Schizophrenia

Two brief updates from companies I have previously covered for their schizophrenia programs. First up are the Italian company Newron Pharma whose mixed Nav-GluR ion channel modulator drug Evenamide has finally started enrolment in a massive global program of Ph III studies as an add-on therapy for treatment-resistant schizophrenia. At least 600 patients in Europe, Asia, Latin America and Canada will receive either 15 or 30 mg (BID) over 52 weeks, so it’s going to be a long wait to see how effective and safe it turns out to be.

Following on from my Q2 2025 blog, there is news that Monument Therapeutics has partnered with the Foundation for NIH to progress their nAChR agonist MT1988 into a proof-of-concept clinical trial in 150 schizophrenia patients across 15 sites in the US. The aim is to assess efficacy of two doses to reduce early symptoms of schizophrenia over 8 weeks, based on preclinical data and well-stablished historical data that nAChR agonists can improve cognition and auditory filtering. The trial is part of the Accelerating Medicines Partnership Schizophrenia (AMP SCZ) program which is a public-private partnership with funding from the NIH and major pharma companies as well as non-profit patient and disease groups. Let’s hope the current turmoil in the NIH doesn’t derail this noble effort to develop and validate novel treatments for debilitating mental health ailments such as schizophrenia.

d.     Other CNS indications

More good news for aussie biotechs with the extremely positive news from a Ph Ib study by Neurizon Therapeutics of NUZ-001 which significantly increased ALS patient survival and reduced mortality and lung function decline over several years of dosing in a Ph I trial that started in Q4 2022 and an OLE that reported topline data in Q3 2025. I have included this entry as NUZ-001 is a repurposed veterinary de-worming drug (S-Monepantel) that is thought to act on nematode nAChRs, but I am not sure if the clinical results (seen with doses of 10 mpk) are solely down to ion channel modulation as similar results are seen preclinically (e.g. in animal models and iPSC motoneuron excitability and TDP-43 protein aggregation assays) with the major sulfone metabolite. Nevertheless these are very promising results for a poorly treated and progressive neurological disease, and the company overcame an FDA hold (requiring additional preclinical PK studies, now completed) which was lifted in October 2025 to enable enrolment of the drug candidate in a Ph II trial under the HEALEY ALS platform initiative at Boston Mass General Hospital. I also include grant finding news for Neurizon in section 3 below.

There is also positive follow-up news for Newleos Therapeutics who started dosing of their GABA-A PAM NTX-1955 in a 2nd Ph Ib trial in the EU for anxiety, after the 1st Ph Ib was started in July 2025. Newleos is a recent spin-out from Roche and brought over 2 clinical stage GABA-A programs in Q1 2025 (hence their inaugural entry in my blog series), with NTX-1955 (formerly RO7308480) being a y1-selective GABA-A PAM with extensive preclinical anxiety animal model data and Ph I safety and target engagement data. Their other CNS ion channel ligand is NTX-1511 (basmisanil) an a5-selective GABA-A NAM that Roche tested but then abandoned after mid-stage trials to improve cognition and other symptoms in patients with neurodegeneration (AD, PD) and rare neuro-developmental indications (Down’s Syndrome and Dup15q syndrome). Patient family and disease charity groups were understandably dismayed when Roche discontinued development of basmisanil, so it is heartening to see that a moderate VC and pharma investment into Newleos has given this program another chance. 

3.      Ion channel company financial news (funding, M&A, collaborations)

The continuing interest in ion channels for CNS drug discovery and clinical development is not just limited to epilepsy, schizophrenia and depression (e.g. Nav1.x, Kv7.x and GABA-A modulators) but now also includes programs for neurodegenerative indications such as ALS (Kv7.x) and Parkinson’s disease. The latter is driven by human and rodent genetic data and emerging small molecule pharmacology showing that dysfunction in lysosomal ion channels such as TMEM175 and TRPML1 are linked to disease onset, progression and severity, and this strong target validation rationale is driving extensive drug discovery efforts across the globe. I’ve previously covered news from several pharma and biotech companies working on these targets, and this quarter two of the smaller players also announced funding news. Lysoway Therapeutics are based in Cambridge (Boston, US) and have preclinical small molecule agonist programs for both TRPML1 and TMEM175, and this quarter they received a grant of nearly $3 million from the Michael J Fox Foundation to support their TRPML1 Parkinson’s program, which they will use to prepare the lead candidate for clinical trials in 2026. I highly recommend readers spend some time exploring the Lysoway website as it has some very useful science-driven content and explainers on both TRPML1 and TMEM175 and their role in protein autophagy-lysosome recycling and how this may be able to treat neurogenerative disease. I have also started following a small TRPML1 biotech on the other side of the world in South Korea called Threebrooks Therapeutics as they have started posting updates on their preclinical program as well. This quarter they announced a start-up grant worth $1.1 million to progress their TRPML1 agonist for Alzheimer’s disease, in collaboration with an ex-pat Korean professor at the Alzheimer’s Disease Centre of Boston University School of Medicine.

Alongside Kv7.x modulator programs for ALS from the likes of QurAlis and InTherapeutics, other ion channels are also being targeted for this CNS indication (see this recent open access review). Aussie biotech Neurizon Therapeutics announced in Q3 that they had raised A$5 million through a sale of ordinary shares to continue clinical development of their nAChR ligand NUZ-001 for ALS as well as preclinical development for other neurological indications. NUZ-001 was originally a veterinary de-worming drug (S-Monepantel) that is thought to act on nematode nAChRs, and the company took it into Ph I studies in late 2024 and an OLE that read-out positively in Q2 2025, resulting (eventually) in approval for a Ph II trial under the HEALEY ALS platform initiative. While this level of new funding may seem inconsequential by US and EU biotech standards, it is a big deal down-under where commercial investment is very hard to find, and these small biotechs are used to doing more with much less, including getting a novel and very promising ion channel ligand into mid-stage trials for ALS. Moreover, the company inked a global licensing deal in Q3 for rights to NUZ-001 from Elanco Animal Health who hold the IP and GMP know-how for Monepantel, paving the way to further clinical development and commercialisation.  

Now onto some bigger ticket M&A and licensing deals. First up are Gilgamesh Pharma who were the focus of much speculation in Q3 as Abbvie expressed an interest in the company, who have an NMDA ion channel antagonist GM-1020 that I have highlighted in past blogs. Ultimately the deal was limited to acquisition of their psychedelic-like 5HT-2A ligand GM-2505 (bretisilocin) that is under mid-phase clinical development for major depression, in a deal worth up to $1.2 billion with undisclosed upfront and downstream payments. Several biotech news outlets revealed that Gilgamesh would spin-out its other assets into a new entity, so this may include GM-1020 (Blixeprodil) which is an orally active ketamine analogue that started Ph IIa trials in depression back in May 2024 but has yet to post public results.     

Maze Therapeutics are one of a number of biotech companies working on ion channels for chronic kidney disease, and they announced an over-subscribed $150 million private investment in Q3, following on from their $140 million IPO in Q1 2025 and a $115 million Series D raise in Dec 2024. I wrote about their Ph II-ready SLC transporter inhibitor MZE782 in Section 1, and previously highlighted their APOL1 channel inhibitor MZE829 that is in Ph II trials in my Q4 2024 blog. Investors are clearly impressed by their pipeline and therapeutic focus, as chronic kidney disease and end stage renal failure currently lack selective pharmacological or gene therapies and rely on expensive and hard-to-access dialysis and kidney transplants. My next preclinical blog on the Nanion website will review renal channelopathies in detail.

I’ve written about Kaerus Bio’s BK channel modulator KER-0193 for Fragile X in my Q3 2024 and Q1 2025 blogs as they ran it through a successful Ph I study, and this quarter there was news that French pharma Servier liked it so much that they acquired the company outright in a deal worth up to $450 million (undisclosed upfront and downstream milestone payments) to boost their own neurology pipeline. Kaerus is a UK biotech founded in 2016 and backed by Medicxi Ventures, and KER-0193 was originally developed as a BK KCa1.1 (KCAMN1) channel activator at the University of Orleans in France, and is utilised to dampen neuronal hyperexcitability produced by mutations in the FMR1 gene; Servier will sponsor a Ph II trial in Fragile X patients in Europe and the US in 2026.

More good news for Danish biotech Saniona this quarter as well, after they sign a licensing deal with Jazz Pharma for their Kv7.x opener SAN2355 which was under preclinical development for epilepsy (as covered briefly in my Q1 2024 blog). It’s a pretty meaningful deal for Saniona, who seemingly had their backs to the wall a few years ago but have been turning things around as noted in my past blogs; there is an upfront payment of $42.5 million, and additional development and regulatory payments worth up to $192.5 million and up to $800 million in commercial sales and royalty payments if all goes to plan. SAN2355 is a potent and sub-type selective Kv7.2/7.3 heteromer activator designed to improve on previous non-selective Kv7.x opener seizure drugs (think GSK’s retigabine/ezogabine/Potiga), and will fit-in with other epilepsy drugs that Jazz are developing such as the CBD analogue Epidiolex they acquired from UK biotech GW Pharma. Saniona have claimed that their small molecule also distinguishes itself from competitor Kv7.x modulator anti-epileptics such as Xenon’s azetukalner (currently in Ph III trials) and Biohaven’s BHV-7000 (Ph II/III) by avoiding Kv7.4 and Kv7.5 isoform activation that may contribute to urinary retention. Saniona had been funding toxicology studies and GMP scale-up but this will be taken over by Jazz, although timelines for IND submission remain undisclosed.

The final financial entry for Q3 2025 is news that US gene therapy biotech Kriya Therapeutics have raised another $320 million (Series D) for clinical development and R&D work. I briefly covered Kriya back in Q4 2022 after they acquired Redpin Therapeutics to develop neurology applications with their chemogenetic ionotropic receptors, and this new funding round includes mention of several ‘engineered ion channel’ programs which may be a result of that previous M&A. Chemogenetic ion channels are typically excitatory or inhibitory ligand-gated ionotropic channels engineered to respond to FDA-approved drugs (such as anti-smoking nAChR ligand varenicline) which are over-expressed in neurons to control excitability and network dysfunction. KRIYA-748 is listed as a preclinical program for trigeminal neuralgia (perhaps by reducing activity of sensory neurons), and KRIYA-382 is a discovery stage project for focal epilepsy. UK biotech Sania Therapeutics are pursuing similar chemogenetic ion channel applications for neurological indications, and are also at the preclinical stage. I slipped in a section on chemogenetics into my recent preclinical blog on ‘ion channel gene therapies’ as I have been following the field for quite a while and am fond of seeing applications for nAChRs, and ultimately I am keen to see how ion channel gene therapies will perform in human patients…

Dr. Marc Rogers, Cambridge (UK)

aka The Channelogist