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 another busy quarter of ion channel clinical drug discovery news to conclude 1H 2025, confirming the accelerating pace of industry progress and notable clinical successes and drug approvals seen in Q4 2024 and Q1 2025. Highlights include approval of a first-in-class TRPM8 agonist for dry eye (the 3rd ion channel drug approved by the FDA in 2025), EU approval of the GABA-A PAM Zuranolone for post-partum depression, and some significant financial news on company collaborations and M&A activities (including Eli Lilly acquiring Nav1.7/1.8 pain biotech SiteOne Therapeutics). However, in Q2 2025 the global drug discovery ecosystem was adversely affected by a chaotic stream of pronouncements and directives from the US government affecting NIH funding, FDA regulatory management and vaccine and drug approvals, which combined with financial pressure from ongoing economic headwinds, high interest rates and tariff uncertainty, lead to significant reductions in VC funding and IPOs, company closures and a record number of biotech layoffs compared to 1H 2024. It seemed that 30-50% of the articles in some of my news sources were trying to explain, understand and keep track of the endless to-and-fro of US government agency changes which made it a little harder to extract the relevant information, but that is nothing compared to the disruption that many colleagues and industry players are trying to deal with so my thoughts and best wishes are with y’all.
In the peripheral disease indication section there was a mixture of mostly positive news but also some setbacks in the pain and respiratory space. There are new early stage clinical entries with Bayer’s gIRK3.4 blocker for atrial fibrillation and Breye’s Cx43 opener in diabetic retinopathy, as well as FDA approval (the 3rd for an ion channel drug in 1H 2025) for Alcon’s TRPM8 agonist for dry eye. In the cystic fibrosis space Vertex gained EU label expansion for their CFTR triplet Kaftrio to treat young patients but temporarily paused the Ph I gene therapy drug VX-522, while Sionna selected the combination of small molecule CFTR correctors and stabilisers for mid-stage clinical trials. There was also mixed news in the pain space, with positives being the high profile acquisition of US biotech SiteOne Therapeutics by Eli Lilly for their Nav1.8 and Nav1.7 programs, alongside updates on Encoded and Xenon’s Nav1.7 pain ligands and a new Xenon Kv7.x opener being lined up for early stage pain trials, and continued progress for AlzeCure’s TRPV1 antagonist in mid-stage testing. A bit more confusing are updates on two companies developing traditional Nav1.x blockers as topical pain treatments, with new entry Allay gaining funding to continue Ph IIb studies of Bupivacaine (as ATX101) in post-surgical pain, but Algo failing a mid-stage chemotherapy pain trial of their topical Amitriptyline formulation (called ATX01). Finally, I share some doubts about the NMDA channel selectivity of ketamine and the ketamir-2 analogue being developed by MIRA for neuropathic pain.
In contrast to the large pulse of financial news on CNS ion channel programs this quarter, there is less to share in terms of clinical trial updates and drug approvals, and some of it is decidedly mixed. Just one entry in the epilepsy space as the ostensible Nav1.6 blocker Relutrigine (PRAX-562) from Praxis continues to show promising seizure reductions in an open label extension of a previously successful Ph II rare disease trial, with possibilities of extending its use to other genetic epilepsy patients. ‘One good / one bad’ in depression, with approval of Biogen’s GABA-A PAM Zuranolone in the EU for post-partum patients, but variable efficacy for Xenon’s Kv7.x opener Azetukalner in a Ph II trial in MDD. Also mixed news for schizophrenia programs, with failure of a mixed ionotropic/GPCR receptor modulator from Atai Life Science but positive Ph I results and Ph II funding for Monument’s nAChR agonist combo and IAMA’s NKCC1 blocker, and Newron gaining the greenlight for their global Ph III campaign with the Nav1.x blocker Evenamide.
1. Peripheral disease indications
a. Cardiac
Just the one item in this category this quarter, and a bit of a blast-from-the-past for me as it involves an atrial fibrillation (AF) ion channel target that was a big part of the drug discovery work carried out at Xention, the 1st biotech I worked at after moving to the UK in the 2000s. The scientific rationale is that the Kir3.4 gIRK4 IKACh channel subunit is upregulated or becomes constitutively active in AF (but is complexed with unaffected Kir3.1 subunits), and Bayer have been working on a selective inhibitor for the past few years which has yielded the lead candidate BAY 3670549 which entered Ph I trials at the end of Q2 2025 to assess safety, PK and PD in healthy volunteers. Preclinical data has shown it to induce rapid cardioversion back to normal sinus rhythm suggesting it could be an effective cardiac arrythmia treatment obviating the need for a defibrillator, electrical cardioversion or sedation. Apparently this asset is linked to a long-running cardiovascular collaboration with the Broad Institute in Boston, which started in 2015 and has been renewed every 5 years since then.
b. Respiratory disease
There was mixed news for Vertex and their CFTR modulator portfolio in Q2 2025. On the plus side the company received a label extension for Kaftrio in the EU to treat younger cystic fibrosis patients down to 2 years of age who have at least 1 non-class 1 mutation in CFTR. Kaftrio is a ‘triplet’ combination of ivacaftor/tezacaftor/elexacaftor, and can also be dosed in combination with Kalydeco (ivacaftor), which would expand on the current estimate of ~4000 eligible patients in the EU with other CFTR mutations. On the downside, Vertex have decided to pause their CFTR mRNA gene therapy study of VX-522, which is the result of a $75 million collaboration with Moderna. The Ph I/II MAD study was paused before higher doses were tested due to emergence of tolerability issues, perhaps linked to the nebulized lipid nanoparticle formulation or expression of the CFTR transgene, but the hiatus is said to be temporary. This might be unwelcome news for competitors pursuing similar CFTR gene therapy approaches such as ReCode Therapeutics and Arcturus Therapeutics (see my blog on ion channel gene therapy here for more details), who are expected to release their own clinical data this year. Vertex also announced that they were to discontinue all AAV gene therapy programs, perhaps also linked to immunogenicity and off-target safety effects seen with other gene vector programs this year.
On the plus side Sionna Therapeutics continues to make progress with their CFTR small molecule drug candidates, selecting the two ligands they will use in upcoming mid-stage clinical trials, based in part on their performance in in vitro heterologous cell and native human CF patient bronchial epithelial assays. The company has been developing a complementary portfolio of CFTR correctors (SION-2222/galicaftor and SION-109) and novel nucleotide binding domain (NDB-1) stabilisers (SION-451 and SION-719) but felt that additional efficacy (and lower dosing and safety issues?) might be achieved by combining them, much like Vertex’s potentiators and correctors. In June they announced that SION-719 will be tested in a Ph IIa trial in CF patients as an add-on treatment, while SION-451 will be evaluated in Ph I safety trials in combination with either SION-2222 or SION-109. The trials are scheduled to start in 2H 2025 and readout in mid-2026.
c. Other peripheral indications
Connexin gap junctions and pannexin hemichannels are a relatively niche and under-exploited class of transmembrane proteins in the ion channel drug discovery pantheon, but I was drawn into this space thanks to a consultancy client project a few years ago which revealed a number of peptide, gene therapy and small molecule agonist and antagonist programs for a diverse array of indications such as cardiovascular disease (Tonabersat/Xiflam with GSK; Danegaptide with Wyeth/Zealand Pharma), migraine, epilepsy, diabetic nephropathy and neurotoxicity. Connexin and Pannexin hemichannels are of particular interest in neurodegeneration as they allow flux of ATP from inside damaged cells to activate P2X receptors and activate the NLRP3 inflammasome, and this mechanism may also be relevant in pain and inflammatory diseases. Breye Therapeutics is a 2019 spin-out from Zealand Pharma and have continued development of the Cx43 gap junction opener Danegaptide for ophthalmology applications, and this quarter announced that it had aced a Ph Ib trial in diabetic retinopathy. Unlike some players, the company is focused on oral rather than vitreal injectables, and the drug can prevent cell-cell uncoupling that leads to retinal capillary breakdown and vascular leakage in response to hyperglycemia, which were confirmed by retinal imaging in the patients with diabetic retinopathy or macular edema. Ph II studies await further fundraising, as this outfit has been operating on a bit of shoestring since founding 6 years ago and coming out of stealth in 2022 with €4 million of seed investment.
Let’s finish this section on a big positive, with the FDA approval of a 2nd novel ion channel drug in 2025 (and the 3rd overall) for Alcon’s TRPM8 agonist acoltremon (AR-15512) for dry eye. I first covered this program in my Q2 2021 blog after it entered Ph II trials with the original company Aerie Pharmaceuticals, but it hit some turbulence when this trial failed to shift the primary endpoint later that year, but a revised protocol was used for the Ph III trial that reflected the dose-dependence and time-course of drug effect revealed in the Ph IIb trial, and was ultimately successful in mid-2023. However, in 2022 Alcon acquired Aerie for $770 million (most of this for 2 approved glaucoma and ocular hypertension medicines it should be noted) as they looked to build up their ophthalmology portfolio after being spun-out from Novartis, and now the long wait for AR-15512 has paid off with it’s approval as Tryptyr, a twice daily eye drop which can rapidly stimulate tear production. It should be noted that AR-15512 stimulates corneal nerves but is not an analgesic per se, although there may be pain applications for such a ligand as it can induce cooling sensations; this was explored in some detail by Mark Field in a LI post (Figure from Yang et al. (2017)).
d. Pain
We have to kick-off this section with the announcement that Eli Lilly acquired SiteOne Therapeutics in a deal worth up to $1 billion (more on the deal in Section 3). Ostensibly this M&A is driven by the early stage Nav1.8 blocker STC-004 which completed a successful Ph I trial earlier this year which I covered in the Q1 2025 blog. Accordingly, Eli Lilly have now added this candidate as a Ph I asset in their corporate pipeline, but it remains to be seen if SiteOne’s original plans for a Ph II study in 2H 2025 stay on track ,or if Eli Lilly enter it into their rolling Ph II chronic pain master protocol (CPMP) where drug candidates have been tested in multiple pre-determined patient populations (osteoarthritis nociceptive pain, diabetic peripheral neuropathic pain and chronic low back pain), which has delivered mixed results and notable failures for TRPA1 and SSTR4 ligands. SiteOne have also been working on Nav1.7 antagonists, which may also be of interest to Eli Lilly who haven’t been very active on this target in recent years.
Another old/new pain target is Kv7.2/7.3, which seems to have fallen out of favour as a potential modulator of nociceptor excitability but is making good progress in the CNS to treat epilepsy. Xenon have (finally) decided to expand the potential therapeutic application of their Kv7.x opener CNS portfolio (XEN1101/Azetukalner) by starting a Ph I safety study of a new follow-on candidate XEN1120 which is being positioned as an analgesic, alongside a new Nav1.7 blocker XEN1701 which is being prepared for an IND application to support a Ph I trial in Q3 2025.
Now we turn to news from some very well-established pain targets and ligands. A new player to me is Allay Therapeutics, who were featured in an Endpoints article for their ongoing Ph II work with the Nav1.x blocker ATX101 and recent $57 million Series D funding round. It turns out that the candidate is a ‘reconfigured’ version of the local anaesthetic Bupivacaine, formulated in a biopolymer for long-lasting analgesia (up to 30 days) after topical application and designed to treat post-surgical pain in applications such as orthopedic, plastic reconstruction and gynaecological surgeries. ATX101 concluded a successful Ph IIb trial outside the US in 2024 and is mid-way through a Ph IIb trial in the US for knee replacement surgery which the company plans to use alongside data from a future Ph III trial slated for 2026 to submit for FDA approval. Allay was originally founded in Singapore, and is also undertaking a Ph I/IIb trial of ATX101 in Japan with partner Maruishi Pharmaceuticals.
Along similar lines (and with a confusingly similar drug name), Algo Therapeutix have also been developing a topical slow-release formulation of a traditional Nav1.x blocker for pain, but unfortunately saw it fail in a Ph II trial in chemotherapy-induced peripheral neuropathy (CIPN). In this case ATX01 is a twice daily topical application of the tricyclic antidepressant and non-selective state-dependent Nav1.x blocker Amitriptyline, prepared in a proprietary long-lasting hydrogel. The issue, as with many pain studies, was a high placebo response which eroded any significant treatment arm efficacy, and perhaps not unsurprisingly there is talk of ‘encouraging signals’ at the highest dose of 15%, clinical site variation and post-hoc analysis, and an intent by the French biotech to try again in another mid- or late-stage trial with a revised drug and placebo run-in period, etc. ATX01 is also being tested in a Ph II trial in patients with Erythromelalgia, a rare genetic pain condition linked to gain-of-function mutations in Nav1.7 channels and other nociceptor proteins, as well as diabetic peripheral neuropathy (DPN) and phantom limb pain, according to the company website.
The next item is unequivocally specific, as Encoded Therapeutics presented preclinical data on their Nav1.7 gene therapy program at ASGCT conference in May (abstract 1925). The AAV miRNA construct doesn’t have a public name or number as yet, but the data looks promising as it produces potent, selective and dose-dependent knockdown of SCN9A gene expression by up to 70% in native DRG sensory neurons and ‘durable’ analgesia in a rat preclinical pain model. Encoded are already in the clinic with their Nav1.1 Dravet epilepsy gene therapy ETX101 which I have covered in past blogs, but many of us who’ve worked in the pain field and seen the failure of numerous Nav1.7 small molecule programs are waiting anxiously to see how this next generation of Nav1.7 gene therapies perform, both preclinically and eventually in human patients…
Also on the topic of erythromelalgia (and traditional pain targets), AlzeCure gained FDA approval of their pre-IND package and orphan drug status for their topical TRPV1 antagonist ACD440, which previously completed a successful Ph Ib PK-PD trial and a Ph IIa trial in patients with chronic peripheral neuropathic pain in 2023. The drug was applied in a gel for an hour before being removed each day (presumably to avoid numbness or loss of heat sensitivity); the Ph Ib trial measured pain in UV-B sensitised skin (pinprick), and in normal skin after exposure to thermo-nociceptive CO2 laser light, as well as laser-evoked potentials and EEG signals. This data package will now allow Ph IIb/III trials to begin in rare disease erythromelalgia patients. This quarter the company also announced a funding round of SEK58.5 million ($6.1 million), primarily to progress their Alzheimer’s drug candidate ACD856 into Ph II trials; intriguingly, the press release also revealed their desire to try and out-license ACD440. There is some mystery around it’s origins, as AlzeCure states it was in-licensed from an undisclosed ‘Big Pharma’ several years ago and AdisInsight indicates this was AZ (no surprises there as they had a large presence in Sweden), but PatSnap indicates it was Acturum Life AB, who own and run the bio-innovation park on the AZ site in Södertälje.
I covered two items last quarter on progress being made using ketamine or its analogues for pain indications, assuming that this was mediated through GluR NMDA ionotropic channel inhibition. Well, since then I have come across several papers and articles suggesting that ketamine may also act on opioid receptors, which obviously would contribute to peripheral analgesia, so I am now in two minds about posting further updates on this topic, especially in the pain category. Anyway, lets conclude this hand wringing with another update from MIRA Pharmaceuticals who havereceived approval of their IND application to the FDA which will enable the start of a follow-on Ph IIa trial for an undisclosed neuropathic indication in the US in Q4 2025, after their Q1 Ph I trial in Israel concludes. The company has developed an analogue called Ketamir-2 that is optimised for oral delivery and relies on the active metabolite nor-Ketamir-2, and at this stage I don’t have any knowledge if this is purely an exceedingly low affinity (470 microM) but long acting NMDA antagonist as claimed, or also has opioid receptor activity (only tested at 10 microM), but as it lacks the hyper-locomotor and dissociative side-effects typical of ketamine the latter may be the case, especially as it shows consistent analgesia in a wide range of preclinical pain models (at 30-300 mpk).
To learn more about B’SYS Nav1.x channel cell lines and assays visit https://bsys.ch/cell-lines/?category_id=4#content_start
2. CNS disease indications
In contrast to the large pulse of financial news on CNS ion channel programs (outlined in Section 3), there is a smaller number of clinical and drug approval news items in Q2. The developments are mixed, including ongoing anti-seizure efficacy of a Nav1.6 blocker in epilepsy, a GABA-A drug approval but variable efficacy for a Kv7.x opener in depression, and clinical progress for Nav1.x and nAChR ligands but failure of a mixed ionotropic receptor modulator in schizophrenia.
a. Epilepsy
Praxis Precision Medicines revealed ongoing long-term efficacy of Relutrigine (PRAX-562) against seizures in a small cohort of Developmental and Epileptic Encephalopathy (DEE) epilepsy patients in the open label extension of their previous 4 month Ph II study. After 11 months of continuous dosing there was a promising continuation of mean seizure reduction (90%) and periods without seizures (67 days), both of which can make a huge difference in patient and family quality of life, daily functioning and later development milestones. Not surprisingly, enrolment in the registrational EMBOLD cohort 2 study is ongoing but slow due to the rarity of affected patients and the need for robust genetic screening, with topline results expected in 1H 2026. These young epilepsy patients have mutations in either Nav1.2 (SCN2A) or Nav1.6 (SCN8A) channels and Relutrigine is being used as, despite it being labelled as a Nav1.6 blocker, Praxis’s own published data shows it to have a functional selectivity to inhibit persistent current across multiple CNS Nav1.x isoforms. Indeed, the company also released preclinical data showing the Relutrigine could be useful in reversing symptoms in multiple models of DEE, opening the possibility of it’s clinical use for a wider population of both rare and more common epilepsy patients once it is approved. The company also revealed that PRAX-562 may be granted Breakthrough Therapy designation by the FDA in Q3 2025, and the company is planning to start a large registrational 4 month study shortly that will dose Relutrigine in a wider group of up to 160 DEE patients, perhaps also including Dravet epilepsy patients.
b. Depression
Despite the ongoing issues from their fractured collaboration with Sage, Biogen gained a positive recommendation for European approval of the GABA-A PAM neurosteroid Zuranolone (Zurzuvae) for post-partum depression, just as Sage achieved in the US in 2023. The daily 50 mg oral drug is notably effective with rapid and sustained reductions in depressive symptoms and is the first to be specifically approved for this type of depression in the EU.
I’m no sage (excuse the pun) but in my Q1 blog I did note that the therapeutic expansion of Xenon‘s Kv7.x opener Azetukalner from epilepsy into depression may carry some risk given the number of other ion channel modulators that had failed for this indication, and indeed this quarter the company revealed decidedly mixed news from their X-NOVA Ph II study. While the LinkedIn post didn’t share any details, following the link to the JAMA paper showed that 10-20 mg of XEN-1101 produced dose-dependent and clinically meaningful, but statistically insignificant, reductions in the primary endpoint of depression rating scores at week 6 vs placebo. The onset of moderate efficacy was rapid and improved anhedonia was significant, and the drug was well tolerated with adverse events and discontinuation similar to placebo. It would seem that these results are promising enough for the company to continue clinical development of Azetukalner in depression, and they have hired a CCO to help guide it to eventual approval.
c. Schizophrenia
Newron continue to progress their Nav1.x inhibitor Evenamide with approval of a global Ph III program that will dose the drug as an add-on treatment for patients with treatment-resistant schizophrenia who are already taking antipsychotics. One international trial will start immediately and run over 52 weeks with an initial readout after 12 weeks, with the 2nd to run in the US over 12 weeks that is scheduled to start in Q3 2025.
I wrote about fundraising news for UK biotech Monument Therapeutics in Q4 2024 and Q1 2025 that were linked to a Ph I study of their nAChR ligand MT1988 that started in November 2024. Well, that has now read out with positive safety signals showing it was well tolerated with only mild to moderate adverse events reported. MT1988 is a fixed-dose combination of two existing nAChR agonists and is designed to improve cognition in schizophrenia patients, which like Evenamide will be dosed as an add-on therapy to traditional antipsychotics. The company plan to use a combination of cognitive and behavioural biomarkers to select appropriate patients and monitor clinical target engagement and efficacy in the planned Ph II studies.
There is a new entry this quarter for a biotech working on transporters, which are gaining ground as drug discovery targets and closely related to ion channels. As well as passively or actively translocating ions across plasma and organelle membranes, the activity of transporter proteins can alter the distribution of ions in cells and organelles and thereby alter the driving force and physiological function of ion channels. While solute transporters are the focus of drug discovery in metabolic diseases, neuronal transporters are of interest as drug discovery targets for pain, epilepsy, psychiatric, neurodevelopmental and neurodegenerative diseases as their modulation can alter the excitatory-inhibitory balance of synaptic and neuronal signalling. IAMA Therapeutics are a small Italian biotech focused on developing small molecule inhibitors of NKCC1, a sodium-potassium chloride co-transporter, as it can affect Cl- homeostasis and thus GABA-A channel inhibition of neuronal network firing. This quarter they announced promising Ph I data on their NKCC1 ligand IAMA-6 which proved to be safe and well tolerated, with a favourable PK profile. The candidate is effective in preclinical models of epilepsy and neurodevelopmental conditions such as autism and Fragile X syndrome, but it is not clear which indication they will target for mid-stage trials, but the website also mentions interest in schizophrenia and neuropathic pain. These plans will be supported by a €15 million investment round that closed in early Q2 2025.
Not such good news for Atai Life Sciences whose mixed ionotropic and metabotropic receptor modulator RL-007 failed in a Ph IIb schizophrenia trial. The drug has a mixed action against ionotropic NMDA and nAChRs as well as metabotropic GABA-B GPCRs. Also looking to improve cognition in these patients, the drug (now called Inidascamine) missed the primary endpoint compared to placebo, although there were some ‘encouraging’ improvements in the cognition score and other secondary markers such as real-world cognitive capacity, and replication of past subsets of cognitive measures such as symbol coding and verbal memory. The drug is actually being developed in a collaboration with Recognify Life Sciences after Atai took a majority stake in the company in 2021 and the subsequent failure of their ketamine-like psychedelic in 2023, but it seems that Atai have now also given up on RL-007 as well and will concentrate on their pipeline of psychedelics to treat other CNS indications.
Coming soon: An interactive online App to view target gene RNA transcriptome data across all Anatomic iPSC cell lines. https://www.anatomic.com
3. Ion channel M&A and collaborations announcements
It was another busy financial quarter in Q2 2025 with a big M&A announcement in the pain sector and a number of significant funding rounds for ion channel companies, a couple of spin-outs breaking cover, and several licensing deals between biotech and pharma companies in the CNS and peripheral ion channel space. As noted by others this year (shout-out to Grant Smillie’s ‘Neuroscience News‘ LI newsletter) there is continued and welcome growth in the neuroscience sector for both established and new players, but also several setbacks as AstraZeneca shut down their programs and Sage is shuttered.
The biggest deal in this space in Q2 was the acquisition of SiteOne Therapeutics by Eli Lilly for a combined price of up to $1 billion based on an undisclosed upfront payment and downstream milestones tied to the usual regulatory and commercial endpoints. The key asset is the Nav1.8 analgesic small molecule STC-004 which completed a successful Ph I trial in Q1 and has now been added to Lilly’s drug pipeline as it chases down Vertex’s more advanced Nav1.8 portfolio and early stage assets from Merck and Latigo Biotherapeutics, another California biotech. Lilly is looking to bolster it’s weakened pain portfolio after dropping a TRPA1 ligand in 2024, and recent news that they have dropped an SSTR4 agonist program after it failed across all bar one mid-stage trials for different pain indications.
Next up are GRIN Therapeutics who were part of two big announcements in Q2 as they look to progress a number of neurodevelopment and epilepsy programs centred around Radiprodil, a GluR2B NMDA NAM. I have covered this program in my Q4 2024 and Q1 2025 blogs, outlining the rationale for treating patients with gain-of-function mutations in GluR2B that are linked to seizures and other symptoms in patients with GRIN neurodevelopmental syndrome, and the complicated origin of the drug from it’s discovery by Gedeon Richter in Hungary and subsequent work after being licensed to UCB. GRIN Tx have completed a Ph Ib open label trial and started a Ph II trial in Q4 2024, and received FDA Breakthrough Therapy designation and Orphan Drug status and EMA Priority Medicine designation for radiprodil, with a Ph III trial scheduled for mid-2025 alongside Ph Ib/IIa trials testing the drug in tuberous sclerosis complex and focal cortical dysplasia which are neurodevelopmental disorders that can also cause seizures. This successful rare disease work has now been rewarded with a $140 million Series D funding round lead by Blackstone (which helped set-up GRIN Tx in 2021 via its portfolio company Neurvati Neurosciences and a license to radiprodil) and including a significant sum from Angelini Pharma. The Italian drug developer has also signed a licensing agreement to develop and sell Radiprodil outside of North America in a deal worth $50 million for exclusive rights and a further $520 million in potential downstream milestones.
This quarter there were also big reveals on two new CNS spin-outs also working on GluRs. In the US, Seyndeio Bio launched with $90 million and two Ph II NMDA receptor modulators to treat synaptic dysfunction in indications including depression, Alzheimer’s disease and schizophrenia. The lead candidate is Zelquistinel, a NR2B-preferring PAM that also binds to a novel site on NR2A and NR2C subunits independent of the canonical glycine co-agonist site to augment synaptic transmission, learning and memory in preclinical models and is currently being tested in a Ph II trial for major depressive disorder (MDD) alongside a planned biomarker study in Alzheimer’s patients (review paper on ‘stinels in depression). The 2nd asset is the similar NMDA-R PAM Apimostinel which is being evaluated as an acute treatment for MDD (to compete with fast-acting psychedelics like ketamine) in an investigator-led Phase IIa study at the University of Pittsburgh. Syndeio is led by CEO Derek Small who also managed Naurex when they originally developed Zelquistinel, and this asset went to Allergan in 2015 and then onto Abbvie during a series of acquisitions before it re-appeared after AbbVie licensed it to Syndeio after their creation in 2024 by the merger of Gate and Boost Neuroscience (which I covered in the Q1 2025 blog; also see here). The team has strong links to Stanford University through Nobel laureate co-founder Thomas Sudhof as well as alumni from Karuna Therapeutics, and the spin-out round includes aussie VC Tenmile as well as Abbvie and Eli Lily.
The big news in the UK VC market this quarter, and an even bigger splash in the ion channel player segment, was the emergence from stealth of Welsh biotech Draig Therapeutics with $140 million of Series A funding for the spinout from Cardiff University’s Medicine Discovery Institute (John Atack and Simon Ward). Their focus is on neuropsychiatry and is lead by small molecule DT-101 which is a GluA AMPA receptor PAM that is being lined up for Ph II studies in MDD later this year. Ph I safety and PK-PD testing in 60 volunteers showed good target engagement in the CNS and this data is due to be publicly revealed at a conference as well. The company also plans to use the funding to help progress two other ion channel projects involving GABA-A modulators that are scheduled for clinical trials in 2026; DT-201 is an alpha5-preferring NAM while DT-301 is an alpha2/alpha3-selective PAM.
The final story this quarter on GluRs is news that Seyltx have in-licensed a portfolio of 8 NMDA GluN2B NAMs from NeurOp. Originally designed and tested as stroke treatments alongside analgesia and depression (according to the NeurOp website) and including one asset with Ph I safety data, the deal looks to re-purpose the ligands for chronic cough which is the focus of Seyltex. They have already taken their own GluR2B NAM Ifendopril into a successful Ph II trial in 2022 for chronic cough, to improve upon the non-selective NMDA blocker Dextromethorphan which is available in many cold medicines and cough suppressants.
Changing tack a little, Actio Biosciences raised a $66 million Series B round to support ongoing work on two ion channel assets for CNS and peripheral indications. The latter is a TRPV4 inhibitor ABS-0871 I covered previously for treatment of Charcot-Marie-Tooth disease type 2C, which is enrolling a Ph I trial that may also enable studies in patients with over-active bladder. The company is also working on a rare disease epilepsy program with ABS-1230, a KNa1.1 Slack channel inhibitor designed to treat gain-of-function mutations in the KCNT1 gene in pediatric patients that is slated to begin a Ph I trial in 1H 2025. This ligand has been awarded Rare Pediatric and Orphan Drug designations by the FDA and recently received IND approval and Fast Track designation, and the patent on this chemical matter was also published this quarter according to a DrugHunter update. Also on the topic of KCNT1, Quiver Biosciences received a grant from the KCNT1 Epilepsy Foundation and CURE Epilepsy! for their KNa1.1 rare epilepsy and neurodevelopmental epileptic encephalopathy KNa1.1 and Nav1.6 SCN8A preclinical programs which utilise a combination of ASO gene therapy and patient-derived iPSC neuronal disease models. Quiver also received a $2.15 million SIBR grant this quarter for their CNS drug discovery platform to further develop and utilise sophisticated all-optical electrophysiology and AI/ML analysis techniques to deconvolve complex disease phenotypes and drug effects and safety which are being applied to several ion channel projects (e.g. Nav1.x in pain) as well as other neurodegeneration gene targets.
Biohaven also received a major investment in their CNS drug discovery platform worth up to $600 million, with an initial non-dilutive payment of $250 million and another $150 million due upon achieving regulatory milestones. While it appears that the bulk of this funding is earmarked to progress their lead candidate Troriluzole (a glutamate modulator) towards FDA approval in spinocerebellar ataxia and future M&A deals, I include this item as I have written before about Biohaven’s early clinical work on TRPM3 and Kv7.2/3 modulators for pain and epilepsy, although it is not clear if they may benefit directly from this new funding.
I’ll wrap up this CNS news section with the negative developments, as it is important to recognise setbacks to give a full picture of how ion channel drug discovery is progressing, and possible reasons for such failures. The first is from Biohaven again, who apparently withdrew their application to the EMEA for Troriluzole (perhaps to focus on FDA approval?). As we have all seen in recent months these are turbulent times for drug discovery thanks to turmoil in the US around trade tariffs, and specifically exemptions for pharmaceuticals imported from the UK and EU, regulatory delays at the FDA, and renewed discussions around global drug pricing discrepancies. It looks like Evotec continue to face financial issues, and as part of their cut-back measures and layoffs they announced that a GABA-A ion channel ligand they were co-developing with a Chinese pharma has been divested from their portfolio, along with 30% of their other clinical assets. EVT-201 (Dimdazenil /Junoenil) is an a1-selective GABA-A PAM that Evotec took into Ph II trials back in 2007 for insomnia and daytime sleepiness, and it was finally approved for insomnia in China at the end of 2023 thanks to it’s partner Zhejiang Jingxin Pharmaceuticals. Evotec are trying to bounce back from CRO outsourcing and VC market downturns and a disruptive IT hack in 1H 2023, and the Fierce Biotech article quoted above also noted that 400 staff had been laid off in 2024 and the company had shuttered its gene therapy division and halted all remaining clinical development work for its in-house assets, although the company continues to grow its biologics work and benefit from successful collaborations with the likes of BMS, Novo Nordisk and Pfizer.
The most significant piece of disappointing CNS ion channel news in Q2 2025 was the (inevitable?) end of Sage Therapeutics, who I have written about extensively over the years thanks to their work on GABA-A modulators and notable success in getting Zulresso (Brexanolone) and Zurzuvae (Zuranalone) approved as i.v. and oral drugs for post-partum depression. Other results for their extensive GABA-A PAM portfolio were notably less promising including multiple 2024 failures in neurodegeneration (SAGE-718 / Dalzanemdor) and a falling out with their major partner Biogen (who proposed a $469 million buy-out offer which Sage reviewed and ultimately rejected and then escalated to legal action against Biogen). After talking with numerous other interested parties this situation culminated in acquisition by Supernus for $561 million, and the rather rapid shuttering of all new drug discovery work at Sage which has resulted in lay-offs for all ~300 staff.
We can end up on a positive note with a quick review of several financial news items for companies working on peripheral ion channel targets. Following on from my mini-highlight in the Q4 2024 blog around companies working on renal APOL1 channel mutations (Vertex, AZ/Ionis) linked to chronic kidney disease and Q1 2025 news on Maze Therapeutics completing a $140 million IPO to help progress mid-stage clinical studies of their small molecule APOL1 blocker MZE829, there is news that UC spin-out Renasant Bio have come out of stealth with a $54.5 million seed round for their work on TRPP ion channels (PC1/2 proteins, PKD1/2 genes) in autosomal dominant polycystic kidney disease (ADPCD). A rare genetic disease, rare and heterogenous loss-of-function mutations in TRPP ion channels can lead to progressive kidney disease and result in end-stage renal failure, so the company is taking a similar approach to that for CFTR mutations in cystic fibrosis (think Vertex) by looking for TRPP correctors and potentiators.
And to round up this quarter there is news on another new entry into this blog with the $80 million Series A funding round for Mosanna Therapeutics who launched in the EU to repurpose a cardiac Kv channel blocker for sleep apnea. MOS118 is a nasal spray formulation that has been shown to activate pressure-sensing nerves in the nasopharynx and thereby increase upper airway muscle tone to reduce prolapse that leads to apnea. The company was actually founded in Switzerland in 2022 with a €6 million seed round to repurpose the anti-arrhythmic atrial fibrillation drug AVE-0018, which was originally developed by Sanofi-Aventis as a mixed Kv1.5, Kv4.3 and Kir3.x IKACh blocker and taken to Ph Ib/II in France. Mosanna took it on for re-formulation and CDMO optimisation for a Ph Ib trial in the new application in 2023, but apparently ran into issues with nasal irritation and poor drug residency time that required further work to optimise a new microparticle suspension and re-run a Ph I safety trial that started in June this year. Sleep apnea is an interesting niche application for ion channel modulators, as Bayer have exploited a broadly similar approach in taking several K2P TASK potassium channel inhibitors into early stage trials albeit with mixed success, with BAY 2253651 being discontinued in 2021 and BAY 2586116 showing some efficacy in small Ph Ib/II trials published in 2023 and 2024, although it no longer appears in the company pipeline as of Q2 2025. Shionogi were also developing a P2X3 antagonist (Sivopixant, S 600918), initially for chronic cough and pain, but they also ran a Ph II trial in sleep apnea in Japan in 2022 although again this ligand appears to have been discontinued.
Dr. Marc Rogers, Cambridge (UK)
aka The Channelogist
