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

It was a very busy quarter of ion channel clinical drug discovery news as the new year began, after a busy previous quarter at the end of 2024, proving that the sector is continuing to grow and investments are paying off as more early and mid-stage clinical programs progress. Highlights include approval of a first-in-class Nav1.8 blocker for acute pain alongside a repurposed K-ATP opener approved for Prader-Willi syndrome, and numerous company collaborations and M&A activities that were announced in Q1 2025.

In the peripheral disease indication section there was an overwhelmingly positive flow of news items related to previously discussed clinical programs, alongside several new entries. Two biotech companies working on the challenging musculo-skeletal condition Charcot Marie Tooth (CMT) disease both announced progress for their ion channel programs, with NMD Pharma receiving Orphan Drug status for their ClC-1 blocker and Actio Biosciences started Ph I dosing of their TRPV4 inhibitor. Similarly in the cystic fibrosis space, where Boehringer Ingelheim started a Ph I safety study of their lentivirus CFTR gene therapy and Vertex followed up the US approval of the new CFTR drug triplet Alyftrek with approval in the UK this quarter. The big news this quarter, for both ion channel drug discovery in general and pain programs specifically, was the FDA approval of Suzetrigine (Journavx) for acute pain, the latest Nav1.8 small molecule inhibitor from Vertex. There were also positive updates from Latigo Biotherapeutics and SiteOne Therapeutics on their early stage Nav1.8 blockers, as well as promising Ph II neuropathic pain analgesia data for Algiax Therapeutics on their GABA-A PAM, and news that Dogwood Therapeutics (previously Wex Pharma) had started another Ph II trial of Halneuron (TTX), this time in chemotherapy pain. Finally, ketamine is another CNS receptor ligand that has potential as an analgesic working via NMDA inhibition, and this quarter there was news that MIRA Pharma had started a Ph I trial of ketamir-2 while PharmaTher were close to gaining FDA approval of their injectable KETARX. The lone setback in Q1 2025 was news that Milestone Pharma continue to struggle to obtain FDA approval of their Cav1.2 nasal spray for cardiac arrythmia.

Compared to Q4 2024 there is more good than bad news for a plethora of ion channel programs tackling a diverse array of CNS indications. In epilepsy, Stoke Therapeutics firm up plans for Ph III testing of their Nav1.1 ASO zorevunersen and announce a collaboration with Biogen to help with this work, while Xenon and Neurocrine Biosciences bounce back from the failure of their Nav1.6-selective blocker by triggering a Ph I test and milestone for a back-up compound that inhibits both Nav1.6 and Nav1.2 channels. Also, Rapport Therapeutics reveal promising human PK and target engagement data on their AMPA TARP g8 modulator that supports the ongoing Ph II trial in focal epilepsy. There was also promising PK and PD data for the Kv7.2/7.3 opener being developed by QurAlis for ALS and epilepsy, and positive Ph III efficacy data for Axsome’s NMDA modulator against agitation in Alzheimer’s Disease patients that may pave the way for an NDA application later in the year. And once again Bionomics (now Neuphoria) stun me with another late comeback, as they announced a milestone payment from Merck and Ph II dosing of their a7 nAChR PAM in Alzheimer’s patients after being listed as a collaboration on their website for many years. Positive news on two depression programs this quarter as well, with Neurocrine Biosciences taking over the Takeda AMPA PAM osavampator and starting a Ph III trial in treatment-resistant depression, while Xenon‘s Kv7.2/7.3 modulator XEN1101 (Azetukalner) has begun dosing in two Ph III trials in major depressive disorder (MDD). It gets even busier for other CNS indications, where GRIN Therapeutics received multiple drug designations for neurodevelopmental disorders from US and EU regulators for their NMDA NAM radiprodil, and another player enters the Essential Tremor space as Saniona and their new partner Acadia Pharma start a Ph I safety trial of an a3-selective GABA-A PAM previously touted as an analgesic. Also, the BK modulator from Kaerus Bio returned favourable PK and PD data in a Ph I trial that lines it up well for planned efficacy testing in Fragile X syndrome, and Soleno Therapeutics celebrate the 2nd ion channel drug approval in 2025 for their repurposed K-ATP opener diazoxide for Prader-Willi syndrome. Finally, there are two pieces of negative news in Q1, as Praxis Precision Medicines faces down another failure of their Cav3.x blocker PRAX-944 (Ulixacaltamide) in Essential Tremor, and a rather speculative late stage test of Biohaven’s Kv7.2/7.3 opener BHV-7000 fails to improve bipolar mania.

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1.      Peripheral disease indications

a. Cardiac and skeletal muscle ion channels

Let’s start with two brief but positive clinical updates from small biotech companies working on the challenging medical condition of Charcot Marie Tooth (CMT) disease, which progressively affects musculo-skeletal function. I’ve covered NMD Pharma‘s work on CMT2 with their muscle ClC-1 channel blocker NMD670 in the past, and this quarter the Danish company received Orphan Drug Status for this indication from the FDA. This designation comes on the back of ongoing Ph IIa trails of the drug in CMT1 and CMT2 patients started in 2024, and NMD670 also receiving orphan drug status for the treatment of myasthenia gravis. There is also good news for these under-served patients as San Diego genetic medicine company Actio Biosciences has started dosing in their Ph I trial of TRPV4 inhibitor ABS-0871 in CMT2C patients, a phenotypically distinct subtype of CMT neuropathy that affects the vocal cords, bladder, respiration and the blood-nerve barrier and has been linked to gain-of-function mutations in the TRPV4 channel expressed in nerves, muscle and bone. ABS-0871 ABS-0871was granted orphan drug designation and rare pediatric disease designation in Q3 2024. I also want to give a shout-out to my colleague John Ridley for sharing the Actio news item, as we worked together pitching a deck on TRPV4 as a rare disease channelopathy for CMT over 10 years ago at a virtual biotech we co-founded, which was unsuccessful as investors were reluctant to provide funds for mid-stage clinical trials that may last 2 or more years to reveal any effect of a TRPV4 inhibitor on a slow, complex and progressive musculo-skeletal disease. This sort of calculation between money and science and patients is a hard pill to swallow sometimes, but very much part of the drug discovery business, so chapeau to both companies (and their investors) and the rare disease communities helping to move these pivotal studies forward!

Setbacks come in many guises, and this quarter Milestone Pharma had another for their Cav1.2 blocker drug etripamil (Cardamyst), which is a fast-acting nasal spray to treat atrial fibrillation and paroxysmal supraventricular tachycardia (PSVT) that was covered in my previous blog. This quarter the revised NDA they sent to the FDA was rejected in a CRL, although it is important to note that it was down to CMC issues (nitrosamine impurities) that will likely require a manufacturing site inspection, rather than another critique of the drug’s safety or efficacy which is now firmly established.

b. Respiratory disease

Just two items in the section this quarter, but both are significant for the field. Boehringer Ingelheim are beginning a Ph I cystic fibrosis gene therapy safety trial of their inhalable CFTR lentivirus drug BI 3720931, with the results informing dosing regimes for a follow-up Ph II efficacy trial. This is a gene replacement therapy resulting from work by researchers at Imperial College London and the Universities of Oxford and Edinburgh and the UK Respiratory Gene Therapy Consortium (formerly Oxford Biomedica).  Traditional AAV gene therapies have struggled to gain traction in the lung due to innate immune responses to viral ‘infections’, but several companies are pursuing alternative viral delivery of CFTR gene copies (ReCode Therapeutics, Carbon Biosciences, Nosis Bio, 4D Molecular Therapeutics, Arcturus Therapeutics, Spirovant) as well as gene editing (Prime Medicines) and ASO/RNAi approaches (Splisense) to try and produce one-and-done treatments or alternatives to currently approved small molecule potentiator and corrector combinations.

Speaking of which, after Vertex gained the approval of the only ion channel drug in 2024, the same triple combination of deutivacaftor/tezacaftor/vanzacaftor called ALYFTREK was approved in the UK this quarter. This is an improvement on previous ‘triplet’ combinations as it only requires once daily dosing, can treat a wider range of rare CFTR gene mutations, and contains the new drug potentiator deutivacaftor (VX-561) which is a deuterated version of ivacaftor (Kalydeco) that Concert Pharmaceuticals originally developed (CTP-656) before it was sold to Vertex in 2017.

c. Pain

The big news this quarter, for both ion channel drug discovery in general and pain programs specifically, was the FDA approval of Suzetrigine, the Nav1.8 small molecule inhibitor from Vertex. This quarter there are also updates from two other companies testing Nav1.8 blockers in the clinic, as well as promising analgesia data from a GABA-A PAM and updates on two ketamine programs and long-running stories around a TTX-based ligand and TRPV1 pain patch.

Although it seems like ago as I write this blog in May, the eventual approval of Vertex’s VX-548 (Suzetrigine, Journavx) for moderate-to-severe acute pain by the FDA in January 2025 was a big deal for many of us in the field, and received a lot of column inches (including an article in Nature that I was interviewed for, alongside proper luminaries like Seve Waxman). I have provided detailed updates on the VX-548 journey over the last 2 years, and this approval is driven by rapid, placebo-beating analgesia produced by moderate doses of Suzetrigine given to abdominoplasty and bunionectomy patients in several large Ph III trials (published here). It is notable that 50-100 mg Suzetrigine failed to achieve superiority over a standard-of-care analgesic (opioid and NSAID combination) and it’s guide price of $31 per day for twice daily dosing is more expensive than common opioid drugs, but the rationale for approval and widespread use is to replace opioids and reduce the risks of abuse and tolerance and societal impact, especially in the US although other countries are now also reporting issues with an opioid ‘epidemic’. However, major questions still remain over the utility of VX-548 and other Nav1.8 blockers (and Nav1.7 inhibitors for that matter) to reduce chronic pain (Fig. 1), especially after a Ph II trial of VX-548 in patients with lumbo-sacral radiculopathy (lower back pain/sciatica) failed to demonstrate any analgesia over placebo. All eyes are now on a larger Ph III trial of Suzetrigine underway in diabetic peripheral neuropathy patients, with stated aims to optimise for variable placebo responses and improve multi-site compliance after issues with an earlier Ph II study. While results from that study released at the end of 2023 showed statistical significance and clinically meaningful analgesia, the study groups were small and there was no difference compared to the clinical comparator Pregabalin. Surprisingly, the ongoing Ph III trial does not list a positive control even though the study will be powered sufficiently to show a significant difference.

There are several other US companies following close behind Vertex with their own early stage Nav1.8 clinical trials, which I covered in the Q4 2024 blog. This quarter Latigo BioTherapeutics received FDA fast-track status for their 1st Nav1.8 clinical candidate LTG-001, which is a rapidly absorbed i.v. formulation for acute pain and passed a Ph I trial in 2024. Similarly, SiteOne Therapeutics revealed positive Ph I data for their oral Nav1.8 blocker STC-004, which exhibited rapid absorption and a t1/2 suitable for once-daily dosing and promising target engagement in a cold pain PD readout, facilitating plans for a Ph II study in 2H 2025.

While voltage-gated Nav1.7 and Nav1.8 channels still capture most of the attention in the pain space these days, other targets are still in play (e.g. Kv7.x, TRPM3). Classical CNS ligand-gated ionotropic receptors are also undergoing clinical trials but their mechanism-of-action could involve modulation of both peripheral and CNS processes contributing to chronic pain. An example of this is are inhibitory GABA-A Cl- receptors which can control nociceptive signalling in peripheral sensory ganglia and the spinal cord, and this quarter German company Algiax Therapeutics revealed promising efficacy data from a long-running Ph IIa study of their GABA-A PAM AP-325 in patients suffering from post-surgical neuropathic pain. The original trial first started enrolling in Q2 2020 and completed in Q4 2024 across 27 sites in the EU, and results were eventually disclosed after the JPM conference in January 2025. Highlights include a rapid onset and long-lasting reduction of pain score over 10-36 days which was statistically significant and ‘clinically meaningful’, with >25% of patients reporting a >50% pain reduction compared to 11% in the placebo group, and a reduction in use of rescue medication for breakthrough pain. AP-235 did not exhibit any CNS side-effects such as sedation, drowsiness or dizziness seen with many other GABA-A PAMs such as benzodiazepines, although preclinical data suggests that the spinal cord is a major focus of drug action.

Ketamine is another CNS ion channel modulator that has some application to peripheral indications such as pain, and this quarter there are two news items on this topic. First up are Mira Pharma who announced the start of a Ph I safety trial of ketamir-2 which is being developed to treat neuropathic pain. This analogue of ketamine is optimised for oral delivery and its formulation and PK and ADME properties rely on the active metabolite nor-Ketamir-2 which avoids the rapid-acting high of ketamine and usual hyper-locomotor and dissociative side-effects, and does not fall under the normal controlled drug restrictions for a CNS active drug. The Ph I trial is being run in Israel, but an IND was submitted for ketamir-2 to the FDA in Q4 2024. The company also revealed that they are developing a topical version of ketamir-2 for neuropathic and inflammatory pain, highlighting the complex pharmacology of this archetypal NMDA receptor antagonist that may act on ion channel and other targets in the periphery as well as the CNS, and the fact that chronic pain involves patho-physiological processes in the PNS and CNS. PharmaTher also got an FDA approval date for their injectable ketamine formulation KETARX (initially given as June but later pushed back to August 2025), which is being positioned for use as a surgical anaesthetic as well as the management of pain, depression (Ph II ready), ALS (IND accepted) and Parkinson’s disease (Ph II/III). The explosion of clinical and patient interest in ketamine as a neurology treatment in the US has led to significant supply and regulatory issues, so the company is hoping to address this after FDA approval of their product.

I’ll finish up this section on analgesia with news of two well-known players and their old-school pain ligands. Wex Pharma have been working on applications for the Nav1.x channel blocker TTX seemingly forever, but have now changed their name to Dogwood Therapeutics and announced that a Ph IIb trail of Halneuron (subcutaneous injection) in chemotherapy-induced peripheral neuropathy (CIPN) has started, after a Ph II trial in cancer pain demonstrated significant efficacy. The new company also raised $5 million to support work on Halneuron this quarter. Grunenthal are another well-established player in the analgesia space with marketed opioid drugs and ultimate ownership of Qutenza which is a patch containing desensitising doses of the TRPV1 agonist capsaicin. Qutenza has been approved to treat postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN), and this quarter the company announced a licensing deal with Apotex to sell the drug in Canada.

d. Cancer

I’ve received some stick for being a reluctant proponent for the role of ion channels as therapeutic targets to treat cancer, as to my eyes the profusion of academic work on immortalised rodent and human cancer cell lines (grown in labs for ~50 years) and mouse models lacks compelling human translatability. Also, data showing changes in ion channel expression in cancer cells may merely be another marker of genetic dysregulation, rather than a causative link to disease progression. I also responded to a question in my recent DDW webinar with Axxam’s Jean-Francois Rolland that there is a lack of clinical validation for this hypothesis, perhaps indicating a gap between the story being told in published work and the Go/No-go level of proof required for drug discovery projects. That being said, I am aware of a drug repurposing Ph II open label clinical trial of the K-ATP opener Minoxidil in ovarian cancer that was underway in 2023-2024, but no results have been officially posted as yet. Also, this quarter there is news that French academic spin-out Mabqi Therapeutics has received €5 million to progress their TRPV6 monoclonal antibody MQI-201 through preclinical toxicity and efficacy testing and bioproduction scale-up as a treatment for metastatic pancreatic cancer, but this work is still at the early phase and human dosing is not expected until 2027.

2.     CNS disease indications

There is mostly positive news this quarter for several Nav1.x programs and an AMPA modulator for epilepsy, success for Kv7.x, nAChR and NMDA programs in neurodegeneration, and progress for AMPA and Kv7.x programs in depression. In other CNS indications an NMDA NAM gets multiple drug designations for neurodevelopmental disorders from US and EU regulators, more players enter the Essential Tremor space with a selective GABA-A PAM while another Cav3.x blocker fails, a Kv7.x opener fails in bipolar mania, and a BK modulator progresses in Fragile X syndrome and the 2nd ion channel drug is approved in Q1 with a K-ATP opener for Prader-Willi syndrome.

a.     Epilepsy

Stoke Therapeutics continue making good progress in their advanced ASO program for Nav1.1 Dravet epilepsy. This quarter they announced approval of plans for global Ph III clinical trials of zorevunersen (STK-001), which are due to start in Q2 2025. On the back of this news the company also announced a collaboration with Biogen to support further development and commercialisation of zorevunersen in all territories outside the US, Canada and Mexico. The deal included a $165 million upfront payment and up to $385 million in clinical and market milestones and net royalties from ROW sales, with the companies agreeing to share development costs.

More positive news was also shared for Rapport Therapeutics AMPA receptor modulator program, which I covered briefly in my Q4 2024 update. Their lead program RAP-219 has an interesting mechanism to modulate the interaction between AMPA GluRs and specific TARP  accessory proteins expressed in different CNS tissues, and is currently undergoing testing in a Ph IIa trial for focal epilepsy that is expected to read-out in mid-2025. This quarter they announced results from detailed MAD-2 and PET imaging Ph I studies that showed rapid target engagement and therapeutic exposures in the brain for dosing regimes chosen for the Ph IIa epilepsy study, and confirmed the localised expression of the cognate γ8 TARP accessory protein in the hippocampus and cerebral cortex of human volunteers that matched that seen in preclinical animal studies (originally conducted by Janssen on JNJ-55511118 which was in-licensed to seed Rapport; Fig. 2), and minimal expression in the cerebellum and brain stem which should limit side-effects and improve tolerability. Also, as mentioned above in section 1, CNS ion channels may be useful modulators of pain processing in the spinal cord, and RAP-219 is also being studied for pain according to company documents, and inhibition of AMPA TARP g8-containing receptors was previously shown to be analgesic by Eli Lilly researchers.

I’ll wrap up this section with another story about the ups and downs of ion channel drug discovery, and the value of persistence as well as comprehensive science (in contrast to the sometimes desperate hopes of companies trying to save or rebrand less-than-stellar single assets). I previously covered the journey of XEN-901, a selective Nav1.6 blocker originally developed as an anti-convulsant by Xenon and subsequently licensed to Neurocrine Biosciences (as NBI-921352) but which failed to show efficacy in a Ph II focal epilepsy trial back in Q4 2023. Xenon researchers have published extensively on the preclinical development of this program, with experiments designed to determine the degree of Nav1.x fractional block to inhibit CNS excitability, and significantly for this news item, a comparison of the anti-convulsant efficacy of small molecules from this program which have different degrees of selectivity for Nav1.6 vs Nav1.2. These profiles resulted from optimisation of Nav1.7 aryl sulphonamides they previously worked on for pain, as this scaffold typically has weakest selectivity against Nav1.6 and Nav1.2 channels, and their preclinical work suggested that small molecules with a preference for Nav1.6 were more efficacious against seizures, in both wild type and a Nav1.6 epilepsy mutant knock-in mouse (Fig. 3). Well, human translation of that specific hypothesis seems to have failed, but they are not giving up and this quarter the two companies announced that a back-up compound NBI-921355 with a mixed Nav1.2 and Nav1.6 inhibition profile has been selected for a Ph I safety study, triggering a $7.5 million milestone payment from Neurocrine Biosciences to Xenon.

b.     Neurodegeneration

There are a trio of positive news items for neurodegeneration projects this quarter from companies I’ve covered in previous blogs. First up are QurAlis who released positive topline data from a Ph I study of their selective Kv7.2/7.3 modulator QRL-101 which is being developed to treat ALS (and epilepsy). The proof-of-mechanism study showed dose-dependent and statistically significant effects on primary and secondary measures of motor nerve excitability that are used as biomarkers of ALS disease progression and mortality. Significantly, the decreases were ~50% greater than those seen with the non-selective Kv7.x opener Ezogabine (Retigabine) in a single-dose ALS study, which paved the way for QurAlis to develop their portfolio of next-generation Kv7.x openers. Similarly, the Ph Ib study revealed brain penetration and changes in EEG and cortical inhibition measures that will facilitate the co-development of QRL-101 as an anti-convulsant, with a similar mechanism to Xenon’s XEN-1101 (Encukalner) which is currently in Ph III trials for focal and tonic-clonic epilepsy and Biohaven’s BHV-7000 which is starting a Ph II/III trial in focal onset epilepsy.

More good news for another company I have covered in the past as Axsome announce successful completion of the final two Ph III studies of their NMDA modulator AX-05 in Alzheimer’s Disease, paving the way for an NDA application to the FDA later in 2025. However, it was not all good news for AX-05 (a mixture of dextromethorphan and bupropion NMDA and monoamine transporter inhibitors) and certainly does not represent a ‘cure’ for this growing ailment, as the positive findings were against measures of agitation prevention and relapse whereas another Ph III study of failed to meet the primary endpoint of reducing overall agitation score over 5 weeks, although there were numerical improvements in the AX-05 arms for both primary and secondary agitation measures. So this new drug, if approved, could improve patient symptoms and quality of life for patients and their carers, but is not a much sought after disease modifier.

A final positive note on an Aussie company I have repeatedly written off in the past due to their mixed clinical news and slow progress on several ion channel programs, only to be proven wrong over the last few years as they repeatedly resurface! I’m talking about Bionomics, who renamed themselves (a common play by troubled companies) as Neuphoria Therapeutics in Q4 2024 and have just made a surprise announcement that an a7 nAChR collaboration with Merck that has sat in their pipeline for many years has finally borne fruit, leading to payment of a $15 million milestone. The asset is now called MK-1167 and the PAM has been entered into a Ph II trial for mild-moderate Alzheimer’s Disease. As with AX-05 this a study to see if MK-1167, dosed alongside standard acetylcholinesterase inhibitors, can improve dementia symptoms such as memory and mental activity, rather than slow disease progression. This is another story of drug discovery perseverance, as well as another example of the slow and opaque progress of biotech assets once they are taken over by big pharma. Neuphoria remain in control of their leading ion channel asset BNC210 which I have written about previously, an a7 nAChR NAM in mid-stage clinical trials for acute treatment of social anxiety disorder and chronic treatment of post-traumatic stress disorder.

c.     Depression

Better news this quarter on three anti-depressant programs compared to three setbacks in Q4 2024, improving my mood as I find myself writing this blog on yet another grey ‘blue Monday’ here in the UK spring. Let’s start with more positive news from Neurocrine Biosciences, who started a Ph III trial of the AMPA PAM NBI-1065845 (osavampator) in patients with treatment-resistant depression in January. The company also announced that they had taken over exclusive worldwide rights to the drug from it’s originator Takeda, from who they in-licensed the asset in 2020 as part of a larger neuropsychiatry collaboration, and taken through a successful Ph II major depression study in 1H 2024 as part of the initial collaboration. Takeda in turn have taken back Japan rights to what was originally called TAK-653, and each company will cover development costs and share in royalty payments from each territory.

I mentioned Xenon‘s Kv7.x modulator XEN1101 above in the epilepsy section, but Azetukalner is also being developed as an anti-depressant and the company announced that enrolment had started this quarter in two of the three planned Ph III studies in major depressive disorder (MDD), and the first in a pair of studies in bipolar depression was also on track to begin by mid-year.  This is a major therapeutic expansion for the Kv7.x channel opener into more complex CNS indications, where it is competing with several successful GABA-A PAM clinical programs from Sage and Marinus but following on from several unsuccessful NMDA and nAChR receptor mid-stage programs in MDD and bipolar depression.

I’ll wrap up this section with news that JnJ have gained FDA approval of the NMDA inhibitor  Spravato (esketamine) as the first stand-alone monotherapy for both major depressive disorder (MDD) and treatment-resistant depression, following its 2019 approval as an adjunctive treatment alongside traditional oral (e.g. monoaminergic) anti-depressants. Administered as a nasal spray, the drug benefits from the well-characterised rapid action of ketamine on CNS GluRs, and being a controlled substance it’s use comes with enhanced prescription rules and guidelines in the US.

d.     Other CNS indications

On the back of a promising Ph Ib open label trial and initiation of a Ph II trial of the NMDA NAM radiprodil that I covered in the Q4 2024 update, GRIN Therapeutics have received FDA Breakthrough Therapy designation and Orphan Drug status and EMA Priority Medicine designation for radiprodil to treat seizures and other symptoms in patients with gain-of-function mutations in GluR N2B linked to GRIN neurodevelopmental disorder. Significantly for these young rare disease patients, a Ph III trial is now scheduled to start in mid-2025. Radiprodil is another drug with a complicated past as I alluded to in the Q4 blog, having originated at Gedeon Richter (RGH-896) in Hungary over 15 years ago as an analgesic; you can hear a more detailed history in this recent piece from Global Genes.

Next up are two items related to K+ channel modulators for complex genetic CNS disorders.  First are Kaerus Bio who revealed significant topline safety, PK and PD data on their BK KCa modulator KER-0193 being developed for Fragile X Syndrome. The drug was safe and well tolerated in both SAD and MAD arms involving 56 patients, and also exhibited a favourable profile in an EEG biomarker study group with significant brain excitability PD effects and a ‘unique topography’ of action in cortical regions linked to Fragile X dysfunction and previously seen in preclinical studies. Not so novel but still significant is the fact that Soleno Therapeutics have gained FDA approval to market VYKAT XR to treat hyperphagia in young patients with Prader-Willi Syndrome, which is an extended release formulation of the K-ATP channel opener diazoxide. Based on the average weight of the young patients the company expects to charge $466,000 per year (with ~10,000 patients in the US), with sales scheduled to start in April 2025. Acadia and Saniona have tried and failed with other treatments for the chronic hunger and eating disorder, but Soleno succeeded thanks to a multitude of Ph III trials and extended open label and withdrawal studies over several years that clearly demonstrated significant efficacy with good tolerability and a low side-effect profile, although it did miss the primary endpoint in a 2023 Ph III trial that required further work to convince the regulators. This is now the 2nd ion channel drug to be approved in Q1 2025 (after Nav1.8 blocker Suzetrigine), an exciting milestone for the field and hopefully a harbinger of more success in 2025!

Switching gears to a very old, and sometimes under-appreciated, story of ion channel auto-antibody diseases (think Myasthenia Gravis/nAChR or Lambert-Eaton/Cav channels), there was news this quarter that Arialys Therapeutics are progressing their anti-NMDA monoclonal antibody ART5803 to Ph I safety studies. The aim here is to bind and remove/inactivate auto-antibodies created against NMDA-Rs ectopically expressed on peripheral neuroendocrine cancers, which then infiltrate the CNS to cause anti-NMDA encephalitis, also known as person-on-fire syndrome. The drug is being administered intravenously but the company seems to believe that some level of CNS exposure would also be helpful to curtail the auto-immune reaction and severe neuropsychiatric symptoms seen in patients. Assuming the MAD study goes according to plan, Ph II studies are being planned for 2H 2025.

The Essential Tremor space continues to be busy, despite challenges and failures for companies working on Cav3.x blockers (Neurocrine Biosciences, Praxis Precision Medicines, Jazz Pharma) and GABA-A PAMs (Sage & Biogen) that I have covered in previous blogs. This quarter Acadia Pharmaceuticals released topline data from a successful Ph I safety study of a GABA-A PAM that they are lining up as treatment for Essential Tremor. The ligand ACP-711 was in-licensed from Saniona last year (see my Q4 2024 blog and news item here), who showed that SAN711 was a selective allosteric modulator of GABA-A receptors containing the a3-subunit with potential as an anti-epileptic and analgesic based on preclinical disease models and a 2022 Ph I safety trial, with a reduced risk of side-effects such as sedation, cognitive impairment and addiction seen with nonselective benzodiazepines. I’m not sure why the companies elected to run a 2nd Ph I study, except perhaps to increase the dose and test it in older patients compared to the initial volunteer cohort in 2022.

In contrast, Praxis Precision Medicine may have to finally give up the ghost on their Cav3.x blocker PRAX-944 (Ulixacaltamide) in Essential Tremor, after it failed in the Ph III trial they pushed through after it produced lacklustre results in a previous Ph II trial that I covered in 2023 updates. Analysis of results by the independent data monitoring committee lead to a conclusion to stop the trial due to ‘futility’ as the primary endpoint was unlikely to be met, but the company said they will allow the full study to complete to ensure all data is collected rather than rely on statistical projections. Moreover, Praxis also said they would continue another Ph III drug withdrawal study of Ulixacaltamide, in an apparent effort to try and find any hint of efficacy; topline results from both Ph III studies are expected in Q3 2025. The journey for this ligand has been truly tortuous, starting life in Canada in the 2010s as an analogue of NeuroMed’s N-type pain blocker NP118809 (Z-160) that was developed at Zalicus to favour Cav3.x T-type channel blockade for epilepsy (Z-944), before Zalicus were acquired by Epirus Biopharmaceuticals and the patent for Z-944 eventually being taken over by Praxis in the 2020s. Notably, Neurocrine Biosciences also saw their in-licensed Cav3.x blocker NBI-827104 fail a Ph II trial in Essential Tremor in 2022, after which they dropped the whole program, so Praxis definitely seem to be pushing against a closed door at this stage.

A perhaps a warning for Xenon’s efforts to expand the therapeutic indications for their Kv7.x opener XEN1101 (Azetukalner) to more complex neuropsychiatric disease like bipolar depression, Biohaven‘s Kv7.2/7.3 channel activator BHV-7000 failed to show efficacy in a late stage Ph II/III trial in bipolar mania. The sample size was pretty decent but the study only used a single dose which was compared to placebo response over a relatively short duration of 3 weeks, so perhaps this failure should not come as a surprise, especially as bipolar disorder is a complex disease (and XEN1101 is being tested against depressive symptoms rather than mania episodes). I was surprised that Biohaven were going after this indication alongside the primary indication of epilepsy, as bipolar disorder is a complex neuropsychiatric disease  which doesn’t have any validated biomarkers or a compelling indication for a role of specific ion channels. I worked briefly on a discovery phase Nav1.2 inhibitor bipolar program 20 years ago, so the general idea is to normalise CNS excitability by blocking excitation driven by Nav1.x channels or increasing inhibitory signalling (e.g. by augmenting GABA-A neurotransmission or enhancing inhibitory Kv channel activity). The upside is that the drug continues to be well tolerated in mid-stage trials with no serious treatment-emergent adverse events reported, raising hope for clean results in ongoing epilepsy and MDD studies.

3.      Ion channel collaborations and M&A activity

It was another busy financial quarter in Q1 2025 after a flurry of business activity in Q4 2024 as well, with a number of large and small funding rounds for ion channel companies, a couple of spin-outs breaking cover, and several licensing deals and collaborations between biotech and pharma companies. As noted by others this year there is continued (and welcome) growth in the neuroscience sector (pain, epilepsy, neurodegeneration), as well as financial backing for peripheral targets (respiratory and auto-immune projects).

The continued interest in Nav1.x channels in the pain sector continues, no doubt buoyed by the approval of the Vertex Nav1.8 blocker Suzetrigine as an acute pain drug at the beginning of 2025. One of their close competitors Latigo BioTherapeutics raised $150 million in a very successful Series B round involving existing and a slew of new investors, focused on their collection of early clinical stage Nav1.8 drug candidates as well as some preclinical projects targeting other analgesic ion channels. A little more modest but just as significant in my book was the fact that fellow California pain biotech Navega Therapeutics, a spin-out from Scripps, received a $4 million grant for their Nav1.7 AAV gene therapy program, as the company is developing epigenetic CRISPR and zinc finger tools to regulate Nav1.7 and Nav1.8 channels that may improve upon the selectivity and safety of traditional small molecule approaches. Finally, the Danish biotech Saniona who I have covered previously for their GABA-A PAM and Kv7.x neuroscience programs, announced a JV with their Paris-based partner Cephagenix and €9 million of seed funding to progress a migraine project based on a K-ATP channel ligand sourced from a Danish academic lab.

There were three major deals in the epilepsy space in Q1 2025. Atalanta Therapeutics raised $97 million in a Series B round for their neurology RNAi treatments, highlighting work to bring a rare disease KCNT1 KNa1.1 Slack channel program (ATL-201), alongside a Huntington’s disease project, towards clinical proof-of-concept. ATL-201 is a di-siRNA oligonucleotide able to enter the brain and knockdown gain-of-function mutations in the KCNT1 gene linked to early onset childhood epilepsy and developmental encephalopathy. Atalanta also have a preclinical Nav1.7 RNAi knockdown ligand in development for chronic pain, another example of ion channel gene therapy that I have cover in an upcoming blog on the Nanion website.  Big news for Stoke Therapeutics as well whose work on the Nav1.1 ASO STK-001 (Zorevunersen) for Dravet epilepsy has been progressing well in mid-stage clinical trials, with news they have signed a major collaboration with Biogen to develop and commercialise this program. The deal covers rights outside of North America, with $165 million paid upfront and up to $385 million in clinical and marketing milestones and drug sale royalties while the two companies share future development costs; a Ph III study of Zorevunersen is scheduled to start in Q2 2025, so this first-in-class Nav1.1 ion channel epilepsy project is certainly gaining momentum. Finally, there are two business items relating to the small US biotech Marinus Pharmaceuticals, who successfully brought the GABA-A PAM Ganaxolone (ZTALMY) to the market to treat childhood CDKL5-deficiency epilepsy and encephalopathy disorder (approved by the FDA in 2022, EMEA in 2023 and in the UK in 2024). Firstly, the EU rights to Ganaxolone were handed back to them by Orion Corp before market launch in this region, after they originally in-licensed it in 2021 for €25 million but have since been moving to re-focus on oncology and pain. Secondly and more significantly Marinus were then acquired by Swedish pharmaceutical company Immedica Pharma AB via their Delaware subsidiary Matador. I presume that the companies will work to expand the use of this drug in other rare and more common forms of epilepsy given the drug has a promising effect to modulate both synaptic and extra-synaptic GABA-A receptor channel subtypes.

Two deals in the schizophrenia space were also announced this quarter. I’ve covered work by Italian company Newron Pharma to progress their mixed Nav-Cav blocker Evenamide in past blogs, and this success has resulted in a licensing deal in Korea with Myung In Pharm Co. Ltd. The latter company will share development costs and also facilitate recruitment of Korean schizophrenia patients for the upcoming global Ph III clinical trial program, while Newron will receive an undisclosed upfront payment and development, clinical and regulatory milestones and a share of sale royalties. I have also briefly covered the work of Monument Therapeutics on their nAChR ligand MT1988 for schizophrenia (e.g. raising $1 million in Q4 2024), and this quarter they announced a further $850k in funding to assist with mid-stage clinical development once the Ph I safety trial started in November 2024 reads out in Q2 2025. MT1988 is a fixed dose mixture of well known nAChR agonists, and the company is notably using a patented combination of cognitive and behavioural biomarkers to select appropriate patients and monitor clinical target engagement and efficacy.

Also worth mentioning this quarter is the ongoing legal bunfight between major CNS players Sage Therapeutics and Biogen. I covered the numerous setbacks and layoffs at Sage in Q4 2024 and in earlier blogs which included failures of several mid-stage neurodegeneration clinical trials of the NMDA receptor PAM SAGE-718 (dalzanemdor) and the decision to phase-out their i.v. antidepressant drug Zulresso and several development candidates to leave just one approved drug (Zuranalone/Zurzuvae) from their extensive GABA-A PAM portfolio. Biogen owns 10% of Sage shares and had partnered on several of these programs and must have been disappointed with recent developments, leading them to make a $469 million buy-out offer which Sage reviewed and ultimately rejected, and then further escalated the fight by suing Biogen to stop any further unsolicited offers.

I’ll finish the CNS section with news on three neuroscience spin-outs. First up are Gate Neuroscience who I have covered previously based on their own reveal and licensing of ex-Naurex/Abbvie NMDA modulators for depression (in Q3 and Q4 2022), who this quarter themselves acquire a newish spinout from Prof Thomas Sudhof’s lab at Stanford called Boost Neuroscience. The plans sems to be to use the academic expertise in iPSC neurons, synaptic plasticity regulators and CNS network analysis to augment and compliment their clinical work on NMDA receptors, themselves key players in memory formation and synaptogenesis, and expand therapeutic indications from depression to neurodegeneration.  Second on the list are Neuleos Therapeutics who have been spun-out of Roche with seed funding of $93.5 million and a remit to work on several ex-pharma small molecules. In addition to a V1a antagonist (NTX-1472/Ro6953958) for social anxiety and a TAAR1 agonist for substance abuse (NTX-2001/ralmitarant), there are two GABA-A modulators; the g1 subunit-selective PAM NTX-1955 (Ro7308480) under development for generalised anxiety, and the GABA-A a5 NAM NTX-1511 (basmisanil/RG1662) which had failed or been withdrawn in previous mid-stage studies in Down’s and Dup15q syndrome patients but has been given a third chance for improving cognition in other rare neuro-developmental disorders. Lastly there is the official reveal and new name of the CNS spinout from Denali Therapeutics, that was created this time last year to take forward four preclinical small molecule assets while the parent company focused on the BBB-crossing large biomolecules. It has taken some time to wrangle the $200 million external funding but now Tenvie Therapeutics is out of stealth and working in the open on lysosomal TMEM175 and TRPML1 channel programs for neuroinflammation and neurodegeneration, alongside many other UK, EU and US biotech and pharma companies who are working in this new and exciting realm of organellar ion channel drug discovery.

Next up are several financial news items for companies working on peripheral ion channel targets. First up are Cambridge UK biotech Maxion Therapeutics who spun-out of Iontas a few years ago with a modest £13 million seed round in 2023, and this quarter announced a significant $72 million Series A round. Their co-founder John McCafferty started talking to me about his interest in ion channels over 10 years ago, so I am very pleased to see their continued growth and progress as they develop antibody-toxin ‘knotbodies’ against a range of targets including Kv1.3 for auto-immune disease and Nav1.7 and ASIC channels involved in pain transmission. Next are Sionna Therapeutics who raised $191 million in an IPO to further progress their CFTR channel modulators for cystic fibrosis. I’ve written about them before, and these monies will be used for clinical testing of a NBD1 stabiliser alongside other in-house and competitor CFTR modulators in ongoing Ph I and planned Ph IIa and IIb studies.  Sionna also has an agreement from mid-2024 with Abbvie to test three discarded CFTR modulators in a deal with up to $360 million in milestones and rights of first negotiation, including a comparison/combination with Vertex’s Trikafta. Finally, following on from my mini-highlight in the Q4 2024 blog around companies working on APOL1 channel mutations liked to chronic kidney disease, there is news this quarter that Maze Therapeutics also completed a successful IPO that raised $140 million. The major priority will be in completing a Ph II study of their small molecule APOL1 blocker MZE829 that started dosing in Q1, alongside a SLC6A19 transporter inhibitor which is currently in Ph I testing before clinical efficacy testing in chronic kidney disease and  phenylketonuria.

I’ll finish up with collaboration news from specialist ion channel companies that some may not be aware of. Firstly, Japanese companies Veneno Technologies and ASKA Pharmaceuticals announced a collaboration on disulphide peptide (think toxins) modulators of ion channels. Veneno have disclosed work on TRPV2 channels in recent years, but the targets of this new collaboration were not disclosed. Finally, I’d like to highlight a licensing deal between Swedish company Salipro Biotech AB and Boehringer Ingelheim to enable isolation and expression of transmembrane proteins. Targets were not disclosed, but Salipro have published data on the use of their lipid extracting protein saposin to isolate various voltage- and ligand-gated ion channels (e.g. GABA-A, nAChR, 5HT3, TPC1) and organellar pumps and transporters into membrane particles suitable for antibody screening and cryo-EM studies. Expression and reconstitution of large and complex multi-subunit transmembrane ion channel proteins has been a major roadblock in their use in structure-based drug design and screening for antibody ligands, but this challenge is now being overcome through new techniques and novel platforms, greatly accelerating the pace and resolution of ion channel drug discovery.

Dr. Marc Rogers, Cambridge (UK)

aka The Channelogist