Expert opinions

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Ion channel ligands in clinical development – Quarterly review (Q1 2024)

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

The news in Q1 2024 was generally quite positive, with another CNS player going public (Neumora Therapeutics) and positive clinical results for a range of peripheral and CNS ion channel programs. ARMGO published the results of a Ph Ib trial for their RyR modulator in myopathy, and NMD Pharma received IND approval for a Ph IIb study of their ClC-1 inhibitor in myasthenia gravis. Sensory systems also got a look in with positive results of Alcon’s TRPM8 agonist in dry eye and new player Sensorion revealing promising interim results from a Ph II trial of their 5HT-3 antagonist in hearing loss. There was also a glut of positive news from various CFTR and ENaC programs for cystic fibrosis, including promising Ph III results for Vertex’s ‘Vanza triple’ CFTR combo drug, and fundraising and collaborations for Sionna Therapeutic’s small molecule CFTR modulators, Prime Medicine’s new prime editing CFTR gene therapy program, and a Series B raise for Enterprise Therapeutics to help support their ENaC program. Nav1.8 was in the news again in Q1 2024 as Vertex continued their good run with some positive but mixed outcomes from two large Ph III trials of VX-548 in acute pain patients, and Latigo Biotherapeutics breaking stealth with a Series A raise, publication of preclinical data on their Nav1.8 blocker LTGO-33 and confirmation of a Ph I clinical trial (LTG-001). In the CNS epilepsy space Praxis Precision Medicines revealed positive Ph II data for their selective Nav1.6 antagonist, and Encoded Therapeutics and Stoke Therapeutics also achieved good seizure reduction with their ETX001 AAV and STK-001 ASO gene therapies to normalise Nav1.1 expression in Dravet epilepsy patients. In company financial news, Series B rounds successfully closed for Nocion to support their Nav1.x blocker NTX-1175 for cough and pain and Engrail Therapeutics GABA-A PAM ENX-102 for anxiety, while Praxis completed a stock offering to finance their portfolio of epilepsy and essential tremor ion channel modulators. Finally, there was closure news for a number of ion channel companies I have been following for several years, with wind-up orders for Bellus Health (P2X3 cough antagonist) and Kineta (nAChR ligand for pain), and Eliem Therapeutics closing down their remaining ion channel programs and pivoting to auto-immune indications.

1.      Peripheral disease indications

a. Cardiac and Musculo-skeletal ion channel targets

I previously included information on the novel RyR ryanodine receptor allosteric ligands from ARMGO Pharma in my Q3 2023 blog, and this quarter the results of the positive Ph Ib clinical trial of ARM210 in rare muscle myopathies linked to RyR dysfunction were published in Lancet. The open label dose escalation trial demonstrated safety, tolerability and desired PK of daily 120 and 200 mg doses, with the higher dose also exhibiting some clinical efficacy to improve muscle fatigue and strength. This promising data paved the way for the follow-up Ph II trial of ARM210 in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), which started dosing in Q3 of 2023 (NCT05122975).

On the back of their Series B financing round in Q4 2023, NMD Pharma announced this quarter that the IND for a Ph IIb test of ClC-1 inhibitor NMD670 in the primary indication of myasthenia gravis was approved by the FDA. This follows on from positive Ph I/IIa data in myasthenia patients in 2021-2022 which first revealed the human clinical efficacy of NMD670, which is also being tested in other neuromuscular diseases such as Charcot-Marie Tooth and  Spinal Muscle Atrophy as I outlined in previous blogs. The idea behind NMD670 is that inhibition of CIC-1 ion channels, which are the dominant conductance in skeletal muscle membranes and set the resting potential and dampen muscle excitability, can restore neuromuscular transmission and allow for enhanced muscle strength and mobility. The company published a comprehensive peer-reviewed paper in Science Translational Medicine in March 2024 summarising the preclinical and early human clinical data for NMD670.

Figure 1: NMD670 ClC-1 inhibitor can restore skeletal muscle function (

Mixed news for Milestone Pharma however, who are trying to tackle pushback from the FDA on their Cav channel cardiac drug Etripamil. The drug is being tested in paroxysmal supraventricular tachycardia (PSVT) as a self-administered nasal spray, but the FDA was not happy with the data format and analysis in their NDA and sent them a refuse-to-file letter in December 2023, which the company is responding to after meeting with the FDA this quarter, with the aim to re-submit their NDA in Q2 2024. The drug appears safe and effective in the Ph III trial but the timing of adverse event reporting was non-standard, although the FDA did not request further clinical data prior to submission of the revised NDA. Assuming this process goes well and the drug is approved (and Milestone receives a $75 million royalty payment to help roll the drug out to market), the company can then pursue a much larger population of patients suffering from atrial fibrillation, for which the FDA has indicated a single additional Ph III clinical trial is required (as it has already completed a Ph II study in AF) to support a supplemental NDA, which Milestone is gearing up to start in 2H 2024.

b. Sensory disorders I wrote about the Aerie Pharma TRPM8 agonist AR-15512 back in Q2 2022 after it had failed a Ph IIb trial for dry eye and their ophthalmic portfolio was bought by Alcon for $770 million. At that time Alcon decided to proceed with two Ph III trials which were expected to complete in 2023, and now we see that their confidence was well founded as positive results were posted this quarter.  The topical eye drop formulation significantly improved tear production at day 14 compared to placebo in a combined study of over 900 patients, with secondary endpoints showing rapid onset of drug effect from day 1 and sustained effects out to 90 days. The company plans to file an NDA with the FDA later this year, and is now in a strong clinical and market position as a competing dry eye treatment from Aldeyra Therapeutics was rejected by the FDA in late 2023. Agonists of TRPM8 act as cooling agents (think menthol), and in the case of dry eye are thought to activate sensory neurons in the dorsal root and trigeminal ganglia which innervate the cornea and eyelids and control tear production.

We also have a new ion channel player in this series this quarter, with news from the French hearing loss company Sensorion that their 5HT-3 ligand-gated ionotropic receptor channel antagonist SENS-401 achieved good exposure levels in an ongoing hearing loss Ph II trial. As with the Aerie/Alcon TRPM8 dry eye story above, the company has come back from a Ph II failure in sudden hearing loss patients in 2022, proceeding with small studies in cochlear implant patients that showed promising drug exposure levels in the inner hear and hints of functional efficacy. Full data is expected later in 2024, but the asset is listed as being up for partnering and this may fall to their existing collaborator Cochlear who make hearing implants and have a global license option on SENS-401. The company website also reveals they have preclinical hearing loss programs for another ion channel connexin 26 (encoded by the GJB2 gene), which forms gap junctions between cells in the cochlear. Gene therapies targeting otoferlin have also been in the news recently with Chinese company Refreshgene Therapeutics (AAV1-hOTOF) and US players Regeneron/Decibel (DB-OTO) and Akousos/Eli Lilly (AK-OTOF) revealing promising early efficacy data, and Sensorion are also active in this space with their AAV SEN-501.

c. Respiratory disease

Vertex are not resting on their CFTR laurels, with news that a new cystic fibrosis combination therapy known as ‘Vanza triple’ returned positive Ph III data this quarter. Designed as an improved (efficacy, dosing convenience) follow-on to Trikafta, it is a mixture of Vanzacaftor, Tezacaftor and Deutivacaftor CFTR correctors and potentiators, and proved to be non-inferior to Trikafta on lung function and superior against several secondary endpoints in the two Ph III trials. The company will use a priority review voucher to allow for an IND submission in mid-2024, and the new data may allow daily dosing in both teenage and younger CF patients.

I first wrote about Nocion’s novel charged Nav1.x antagonists in Q3 of 2021 after they started dosing their lead candidate NTX-1175 (NOC-101) in a small Ph IIa trial for chronic cough, which was to be followed by a 2nd study in acute cough, including patients with covid-19. I can’t find the results of these Ph IIa trials on the internet or the clinicaltrials.gov register, but Nocion appeared to hit the buffers in 2023 according to various news reports so their status was uncertain until recently. This quarter Nocion are in the news after a $62 million Series B fundraising round (see section 3 for more details), and part of these funds will be used to support progression of NTX-1175 (now called Taplucanium Dry Powder) for a Ph IIb trial which is slated to begin later this year and deliver topline data ‘before the end of 2025’. Similar in some ways to Nav1.7 and P2X3 antagonists that have been developed by the likes of GSK, Shionogi, Merck and Bellus Health for cough, some of which have entered the clinic and gained market approval, so-called ‘nocion’ ligands interact with the same targets but through a different binding mechanism, and also operate through a larger variety of large pore channels (TRPx, P2X) to target a wide range of Nav1.x channels present in sensory neurons, so the hope is that a wider efficacy profile can be achieved with lower doses and avoid side-effects. Similarly, Nocion are also talking about testing NTX-1175 or similar antagonists in various pain phenotypes, where it is hoped to overcome the efficacy and safety challenges faced by many high profile Nav1.7 clinical programs in the past (and more on that in my Q2 2024 blog with regards to Merck’s MK-2075).

News on several other companies working in the CFTR respiratory disease space is included in Section 3 below as it mainly concerns financial rather than clinical developments.

d. Pain

Vertex continued to dominate the pain drug discovery news in Q1 of 2024, with somewhat mixed data from two highly anticipated Ph III trials of the selective Nav1.8 antagonist VX-548 that followed-on from their previous Ph II efforts which I reported on in my Q4 2023 blog. As before there was a significant reduction in acute pain in patients after abdominoplasty and bunionectomy surgeries, which was the topline news as each study had over 1,000 participants each. Beating placebo is obviously the 1st challenge for any analgesic and that was clearly achieved for many, but the devil is in the details and the randomised clinical trial design: VX-548 failed to beat the standard-of-care analgesia mixture of an opioid and anti-inflammatory (hydrocodone and acetaminophen; Vicodin) in either pain study, but did match it for the tummy tuck patients. These results are certainly promising and come as a welcome change for those of us who have worked in pain drug discovery and seen many programs crash and burn for the past decade or so, but challenges remain and chief among them is seeing more convincing efficacy of VX-548 in ongoing Ph III trials in chronic pain than those reported previously in smaller Ph II studies. There has also been much discussion around the relevance and market potential of a new and potentially expensive non-opioid pain drug for acute pain when existing options are cheap and effective (and theoretically carry little risk of opioid addiction, tolerance or abuse), although the obvious benefits of such a drug for chronic pain in the shadow of the global opioid crisis is irrefutable.

Getting almost as much attention as Vertex in Q1 2024 were Latigo Biotherapeutics, who came out of several years of stealth in Los Angeles (ex-Amgen Thousand Oaks staff) with news about their $135 million Series A raise, followed by a peer-reviewed paper on their potent and selective preclinical Nav1.8 blocker LTGO-33 which I quickly reviewed in a LinkedIn post at the time. There was some speculation that a Ph I clinical trial registered for LTG-001 was for this Nav1.8 ligand, which was later confirmed in staff interviews with various news outlets (e.g. see this Biopharmadrive article and a LinkedIn post). Like Vertex, they will first target Ph II trials in acute pain such as bunionectomy and abdominoplasty later this year, and then later move into testing in patients with chronic pain conditions. Latigo have other ion channel programs, which may be the source of another ligand LTG-4090 which is also slated for a Ph I trial later in 2024.

It looks like Eli Lilly still has some irons in the pain fire, after the comprehensive failure of their TRPA1 antagonist LY-3526318 in several Ph II chronic pain trials which I covered in my Q3 and Q4 2023 blog articles. This quarter I can report that their P2X7 ligand LY3857210 was in several Ph II trials as part of their ongoing chronic pain master protocol (CPMP) which continuously enrols patients with chronic low back pain, diabetic peripheral neuropathy and osteoarthritis pain. It looks like these trials were completed in mid-2023 (NCT05630196, NCT05620576 and NCT05620563) and while no results have yet been published the asset remains listed in the company pipeline. The selective, brain penetrant small molecule was licensed from Asahi Kasei Pharma in 2021 (previously called AK1780) for an upfront payment of $20 million and downstream development and regulatory milestones up to $210 million and $180 million in sales milestones and additional royalties if it reaches market, after Asahi Kasei got it safely through SAD and MAD Ph I trials. P2X7 channels have fallen out of favour as clinical analgesic targets despite promising preclinical data, so it will be interesting to see if positive Ph II results turn this trend around. Meanwhile, other P2X7 ligands have been re-purposed for depression and other psychiatric indications (e.g. JNJ-54175446), and there has been a resurgence of interest in P2X7 large pore channels as an upstream trigger for NLRP3 inflammasome activation in neuroinflammatory, retinal and neurodegenerative disease.

Finally there is a promising update on a pain program I may have been involved with in my past life at a preclinical CRO company: Biohaven in-licensed a TRPM3 program from KUL university in Europe a few years ago and have been steadily progressing the lead candidate BHV-2100 to the point of it entering Ph I safety trials in Q1, according to the company website pipeline and comments on LinkedIn. Assuming these have gone well, the company is planning Ph II trials in 2H 2024 in migraine and neuropathic pain. The company is very good at posting posters and publications on their website, which include 2023 IASP and 2024 AAN posters on BHV-2100 where you can see it’s excellent nM potency and TRPx gene family selectivity as well as preclinical toxicology and efficacy data, all of which look very promising. Of course we’ve heard this many times before for preclinical pain targets and programs, so I am keen to hear how it works in actual human pain patients!

2.  CNS disease indications

a. Epilepsy

This quarter there were several positive announcements and clinical updates on various ion channel modulator programs for epilepsy.

I’ll begin with an update from Praxis Precision Medicines on their Nav1.6 state-dependent inhibitor PRAX-628 which returned positive results from a small Ph IIa trial in photo-sensitive (photoparoxysmal) epilepsy patients. Some topline results were revealed in 2023 but now we have the full dataset which showed a remarkable 100% response rate for the higher dose of 45 mg and an 80% rate for the lower dose 15 mg, measured as reductions in EEG brain signals induced by light stimulation. These results will enable it’s progression into Ph IIb trials in focal epilepsy in 2H 2024, driven in part by clinical knowledge that efficacy in photosensitive epilepsy is a good predictor of efficacy in more generalised types of seizures. Preclinical data showed PRAX-628 to be a selective sub-mM inhibitor of persistent currents seen in SCN8A channel mutations found in young epilepsy encephalopathy patients, as well as demonstrating desirable use-dependent inhibition of over-active Nav1.6 channels whilst preserving the baseline activity of peak inward currents important for normal neuronal function. The company posted positive data in 2023 on PRAX-562, which has a broadly similar mechanistic profile to PRAX-628 but inhibits both Nav1.6 and Nav1.2 channels affected in a broader population of epilepsy patients.

Exciting news also for Encoded Therapeutics who were granted IND approval in the US and CTA approval in Australia, allowing for small Ph I/II clinical trials of their Nav1.1 gene therapy ETX101 to begin in young patients with Dravet epilepsy in 1H 2024. The company also received approval for a similar Ph I/IIa clinical trial in mid-2024 in young patients with Dravet epilepsy in the UK, as part of their global clinical program. These trials are part of a bigger program, starting with dose-escalation safety and efficacy studies on seizure burden and symptom alleviation, and then looking at longer-term effects of a therapeutic dose on neurodevelopment and complex behaviour as young patients mature.

Stoke Therapeutics had their own good news in Q1, announcing positive data from a pair of Ph I/IIa open label trials of their Nav1.1 ASO STK-001 in Dravet epilepsy patients. The high dose of 70 mg produced significant and sustained reductions in seizure frequency when applied to patients already receiving best available anti-convulsant medicines, with reductions of 85% after 3 months and 74% 6 months after the last dose of STK-001. The open label extension (OLE) studies also showed durable reductions in seizures and clinically meaningful improvements in multiple measures of cognition and behaviour over 12 months with continued dosing of lower doses of 30 mg and 45 mg. These must have been an amazing result for the treatment-refractory children and adolescent patients and their families, as many patients were taking 3 or 4 small molecule anti-convulsants to try and control their seizures. Whilst adverse events were noted in 20-30% of patients (elevated CSF protein marker levels rather than clinical symptoms), only 1/81 patient withdrew from these studies. This latest data is being discussed with the FDA to obtain approval for a full Ph IIb registrational study which will use a combination of an initial treatment with the high 70 mg dose followed by 45 mg maintenance dosing.

In contrast to the development of Nav1.2 and Nav1.6 inhibitors for other forms of epilepsy, Dravet is characterised by loss-of-function mutations in Nav1.1 channels which are predominantly expressed in inhibitory neurons of the brain, leading to CNS over-excitability and seizures from a young age. Thus, some companies have (unsuccessfully so far) developed small molecule Nav1.1 activators (e.g. Lundbeck), and there are also players like Encoded and Stoke Therapeutics who are developing genetic treatments to try and correct (mutant or wildtype) Nav1.1 channel expression, and they seem to be making great progress. Encoded are using AAV vectors to express transcription factor transgenes to selectively upregulate expression of the endogenous SCN1A gene in GABAergic inhibitory interneurons with a one-and-done protocol, while Stoke are using an ASO approach to up-regulate Nav1.1 protein production from the normal copy of the SCN1A gene which requires multiple dosing regimes.

To conclude this section we have an update from Saniona who are continuing to progress several preclinical and clinical epilepsy ion channel programs, and announced a SEK 140 million ($13 million) rights offer to support this work. Their lead clinical candidate is the GABA-A a3 subunit-selective PAM SAN711 which has completed Ph I safety studies and is now being lined up for a proof-of-concept efficacy trial in childhood absence epilepsy. The company has another preclinical GABA-A PAM SAN2219 with different subunit specificity, and has also brought their Kv7.x modulator SAN2355 through preclinical efficacy and toxicology studies and is lining it up (perhaps with a partner?) for clinical studies in focal and generalized seizures and paediatric patients with seizures caused by genetic mutations in Kv7.x channels.

Saniona also nominated an a5-selective GABA-A NAM SAN2465 as their clinical candidate for major depression this quarter based on promising preclinical data, but again it looks like they are preferring to partner this rather than develop it in-house themselves. The asset was originally developed for schizophrenia in a collaboration with Boehringer Ingelheim, but was handed back in 2020. It will go up against several other active GABA-A PAM programs and drugs (Sage’s Brexanolone and Zuranolone/Ztelmy, Marinus Pharma’s Ganaxolone) and NMDA ionotropic receptor antagonists (Axsome’s AXS-05/Auvelity, Gilgamesh’s GM-1020, Neurocrine Bioscience’s NBI-1070770, Alto Neurosciences ALTO-202) in this therapeutic space, but I am intrigued that several GABA-A PAMs have failed in depression (Eliem’s ETX-155 and Praxis Medicine’s PRAX-114) so I am interested to find out if a GABA NAM can overcome limitations of this approach?

There was also business news in Q1 2024 from companies in the CNS therapeutic space who are working on indications such as anxiety, depression, schizophrenia, epilepsy, essential tremor and smoking addiction, so I will cover them in the final section below.

3.  Ion channel company news (licensing deals, collaborations, closed programs)

There was a mixed bag of financial and corporate news in Q1 2024 affecting ion channel companies I have covered in previous blogs, ranging from new funding rounds and licensing deals to company closures and pivots away from ion channels after successful and closed clinical programs. I don’t like to focus on the money side of the ion channel drug discovery business, but the density and significance of such news in this quarter warrants a full summary, starting with the positive news and finishing on several end-of-cycle announcements.

First up is Engrail Therapeutics who raised $157 million in an over-subscribed Series B round. The exciting part of this financing news is that the company specifically highlighted it’s use to support ongoing Ph II studies with ENX-102, a GABA-A subtype-specific PAM being tested in generalised anxiety disorder, with several patients already randomized and topline data expected in 1H 2025. The drug comes from a previous acquisition of NeuroCycle Therapeutics in 2021. Interestingly, I reported previously (Q2 2022) that Engrail had achieved positive results in a Ph Ib trial of an earlier GABA-A PAM ENX-101 in focal epilepsy and were planning for a Ph II trial, but this ligand no longer appears in their pipeline and the clinical trial entry (NCT05481905) shows it was withdrawn for ‘business reasons’. The funds will also be used to progress preclinical neuropsychiatry programs into the clinic, including D2/D3 dopamine receptor antagonists ENX-104 and ENX105 in major depressive disorder and mood disorders.

Praxis Precision Medicines also completed a fundraising effort in Q1, initially targeting a $150-$200 million stock offering which ultimately brought in over $160 million. The company has been busy in recent years with multiple mid-stage clinical trials in CNS indications such as epilepsy and essential tremor which I have been covering in past blogs, so it was inevitable that a cash top-up was required. The offering was predicated on their 2024 milestone expectations which included readouts on 4 active ion channel ligand clinical trials and 2 further planned trials later in 2024, and was helped by release of positive topline data from a Ph IIa study of the Nav1.x blocker PRAX-628 in photo-sensitive focal epilepsy (summarised above in Section 2). They are also expecting data from a Ph II clinical trial of the mixed Nav1.2/Nav1.6 blocker PRAX-562 in developmental epilepsy and encephalopathy and the Cav3.x blocker PRAX-944 (Ulixacaltamide) in two Ph III studies in essential tremor (see below), and to advance their Nav1.2 ASO PRAX-222 (Elsunersen) to a larger trial in developmental epilepsy after promising early data in an exploratory phase conducted in 2023.

Praxis were also in the news in Q1 as they announced a licensing deal for Ulixacaltamide, their T-type Cav3.x blocker for Essential Tremor. The deal with Tenacia Biotechnology (Shanghai) Company includes rights to develop and commercialise the drug in Greater China for $15 million upfront and another $264 million in downstream development, regulatory and commercialization milestones, plus the usual tiered royalties on sales. Ulixacaltamide is currently in a large Ph III trial in the US (NCT06087276); Essential Tremor affects 7 million patients in the US and an estimated 10 million patients in China but there is no effective pharmacological treatment and many resist surgical options (Praxis peer-reviewed article here), so the unmet medical need is clear and significant.

With all the big M&A news in the CNS space in Q4 2023 (Merck acquiring Caraway, BMS buying up Karuna, and Abbvie acquiring Cerevel) I neglected to mention that another CNS player Neumora Therapeutics went public in Sept 2023. The company was originally backed by SoftBank and Amgen since it’s formation in 2021, and after their IPO on the NASDAQ exchange raised $250 million the company is now valued around $2.5 billion. Neumora discloses 7 development programs in neuropsychiatric disorders and neurodegenerative diseases, lead by the kappa opioid antagonist Navacaprant (NMRA-140) which is in Ph III trials for Moderate Depression and in Ph II testing in Bipolar Disorder. They are on my ion channel radar due to a GRIN2 NMDA receptor modulator preclinical program for schizophrenia. Hopefully these IPO funds and their $520 million balance sheet will be used in part to support this early ion channel program, which is going up against other clinical schizophrenia ion channel programs such as Gate Neuroscience’s Zelquistinel NMDA PAM and Newron’s Nav1.x blocker Evenamide.

I have written previously about Nocion’s Nav1.x blockers which they are developing for cough and pain, with the lead candidate NFTX-1175 entering the clinic back in Q3 of 2021 in a Ph IIa trail in chronic cough patients. This quarter the company announced a Series B raise of $62 million which will be used to progress this drug into Ph IIb trials, also in chronic cough, with topline data expected before the end of 2025. Originally designed as analgesics that could enter over-active and inflamed sensory neurons to block Nav1.x channels and alleviate nociceptive signalling, the company also realised that a similar mechanism could target sensitised vagal and airway nerves to reduce cough, much like P2X3 antagonists from Merck, Shionogi and Bellus (now part of GSK – see below); they also tried to leverage this indication by looking at using their ligands to treat covid-19 respiratory symptoms. Further background on issues facing the company prior to this raise are detailed in a March 4th Endpoints News article.

Fundraising news in Q1 2024 has also brought a new ion channel player onto my radar, after Achieve Life Sciences closed a $124 million round ($60 million upfront and up to an additional $64.2 million upon the exercise of milestone-driven warrants). The funds will be used to further progress their lead candidate Cytisinicline which is a nAChR ligand-gated receptor partial antagonist utilised therapeutically for smoking cessation and nicotine dependence (see news article here on the latest clinical readout published in JAMA). The drug has already completed two Ph III trials and is being lined up for an NDA with the FDA which will require additional long-term exposure data to assess safety beyond 12 weeks in an open label study that will run during 2024.

I covered the novel HCN channel blocker photoswitch ligand from Kiora Pharmaceuticals in last quarter’s blog, but in Q1 we have positive deal news as they signed a collaboration for the clinical development of KIO-301 for degenerative and inherited retinal disease (e.g. retinitis pigmentosa, choroideremia, and Stargardt disease), and received additional private financing. The worldwide (ex Asia) strategic development and commercialization agreement is with the French company Théa Open Innovation, a sister company of the global ophthalmic specialty company Laboratoires Théa, and includes $16 million upfront and up to $285 million in biobucks for subsequent clinical development and regulatory and commercial milestones, and commercial royalties. The California company also closed a private financing round in Q1 2024 with new institutional healthcare investors that will initially bring in $15 million upfront and provide future access to another $30 million, ostensibly to support their KIO-104 uveitis program but this will undoubtedly strengthen the company and further support development of their novel ion channel ligand.

Cystic Fibrosis news (I am writing this in May which is Cystic Fibrosis Awareness month):

I have written since Q2 2022 about Sionna Therapeutics who had their initial clinical lead SION-638 in a Ph I trial for CF in early 2023, after founding as a spin-out from Sanofi-Genzyme in 2019. Their clinical and preclinical work has seemingly been going well and in Q1 they announced a $182 million Series C fundraising round to further progress their various cystic fibrosis assets and double the number of clinical programs by 2025. The company is taking a focused but diverse approach to finding new treatments for CF, with the original clinical asset SION-638 targeting the nucleotide-binding domain (NBD1) of the CFTR channel that proved unfruitful for Vertex, alongside a new Ph I clinical ligand that targets intracellular loop 4 (SION-109) and SION-676 which is a preclinical ligand that binds to the transmembrane domain (TMD1) and is planned to enter Ph I in 2025. Apparently there are also two other NBD1 ligands set to enter Ph I trials later in 2024, as back-ups for SION-638. Once all the Ph I safety data is in hand the company plans to choose the best NBD1 ligand for a Ph II test, and also determine which combination of NBD1 and ICL4 or TMD1 ligand could be progressed into a Ph II POC study (with SION-109 looking like the best candidate at this stage).

Prime Medicine is a new ion channel player in my database after broadening their prime editing platform to include a CFTR gene therapy program, which received $15 million of preclinical funding from the CF Foundation. They plan to use lipid nanoparticles (LNP) and/or adenovirus vectors to deliver DNA editing constructs.  This deal may sound familiar to old timers in the field like me, as it was a $20 million investment from the CF Foundation which kick-started Vertex’s work in CFTR back in the 2000s, leading to approval of at least 4 new corrector and potentiator drugs in the last decade and creation of a blockbuster CFTR portfolio for Vertex and access to novel treatments for many CF patients. The CF Foundation eventually cashed in over $3 billion of royalty payments in 2014 and another $575 million in 2020, which they are now using to seed further investment in drug discovery and development efforts for CFTR treatments using a variety of modalities and approaches. For example, as well as this recent tie-up on prime editing, the CF Foundation also invested another $20 million in 2021 with the Flagship Pioneering incubator (which includes Moderna in it’s VC stable) to find RNA treatments to regulate CF gene activity. The rationale for these alternative and additional CF treatment options is two-fold: existing small molecule modulators can’t treat all CFTR channel mutations, and patients are now taking daily combinations of multiple drugs with potential issues of compliance, variable drug exposure, and drug-drug interaction and dose-limiting side-effects. Hence the interest of the CF Foundation and industry players in developing DNA and RNA gene therapies which could offer a ‘one-and-done’ treatment applicable to both common and rare CFTR gene mutations, reaching the 10-20% of CF patients currently without effective pharmacotherapy.  Serendipitously, I saw this young chap at KUL proudly post on LinkedIn about his 1st scientific paper which was on CFTR prime editing, so figured he deserved a shout-out as a new researcher in the field.

I covered ReCode Therapeutics’ LNP CFTR gene editing program in Q3 2023, and in Q1 2024 they announced a partnership with Intellia Therapeutics on this preclinical program to access additional gene editing technology. Clearly, a single gene therapy approach and delivery system may not suffice for some or all CF patients, and the field is evolving so rapidly that many players are licensing and developing new tweaks and approaches to improve their flagship programs.

I will admit I gave a bit of a poke to the folks at Enterprise Therapeutics in my last blog about delays to their planned Ph II trial of their ENaC antagonist ETD-001 in respiratory disease, but they have responded in fine form to reveal they were working on a Series B round which has now closed with a respectful £26 million ($32.5 million) in hand to support a Ph IIa trail in cystic fibrosis patients slated to start in early Q2 2024 and read-out in md-2025. In contrast to the CFTR treatments discussed above which may be limited to small CF patient sub-groups with specific mutations in the CFTR chloride ion channel, Enterprise’s ENaC modulator is designed to be mutation-agnostic and produce a general improvement in lung function (and reduction in mucus production) across a wider range of CF and other respiratory disease patients, opening up a much larger market.  Thus, the Ph II trial will assess lung function in people with cystic fibrosis who are either ineligible or not receiving CFTR modulators like Vertex’s Trikafta and Symdeko. Labiotech have a nice explainer piece on this here.

Finally in Q1 2024 there is negative news on three companies I have covered in past blogs – which I believe is also important to include to give a full picture on the successes and challenges in ion channel drug discovery, many of which are shared with projects working on other protein targets and should not be simply or flippantly attributed to ion channels being ‘difficult targets’.

Firstly we have news that GSK is closing down Bellus Health a year or so after it was acquired for their P2X3 cough ligand Camlipixant (BLU-5937) which is still progressing in two Ph III trials with GSK and expected to readout in early 2025. This is an unfortunate and common occurrence when a smaller (biotech) company is bought by a larger (pharma) company, and while those in the field like to talk about the innovation and agility of smaller companies to efficiently deliver novel ligands, there is also this financial and organisational downside that has serious implications for their talented staff.

Next is news that Eliem Therapeutics have seemingly abandoned their work on CNS ion channels and neurological therapies and pivoted to spend their remaining funds on autoimmune projects. I had missed the quiet news in mid-2023 that their sole remaining active ion channel project, a preclinical effort directed at Kv7.x M-channels for epilepsy which I have covered in previous blogs (ETX-123), has gone from ‘paused’ to cancelled. This comes after their clinical GABA-A PAM asset ETX-155 had setbacks with CMC, metabolite side-effects and Ph Ib photo-epilepsy trial issues that I covered previously, and efforts to progress it into Ph II for depression hit the wall due to financial considerations, leading to 50% lay-offs in 1H 2023 and a business review in 2H 2023. I was saddened that such a focused and talented ion channel drug development company had been forced to stop their work, apparently from a combination of scientific, post-pandemic financing and strategic reasons. There was also reasonable speculation in some trade papers that Eliem’s GABA-A and Kv7.x ligands faced more advanced competition from players I have been writing about for the past 2 years, several of whom were already in clinical trials (Xenon Pharmaceuticals, Marinus Pharmaceuticals, Sage Therapeutics, Engrail Therapeutics, Cerevel, Praxis) or getting close to the clinic (Biohaven, Saniona). I was further surprised to read in Q1 2024 that the company’s strategic review had decided to leverage their remaining funds (~$100 million) and shareholder investments to perform a major pivot, starting with a merger with a stealth preclinical company called Tango, and then in Q2 there was news that Eliem had acquired an autoimmune company called Tenet Medicines with a Ph II-ready anti-CD19 antibody and raised another $120 million in private funds, clearly and completely moving away from ion channels.

And finally we return to another historic nAChR pain player, Kineta, who have been through the ringer in recent years with reverse mergers (with Yumanity)and in and out-licensing deals, but have now finally thrown in the towel and closed up shop. I have been following them since 2014 thanks to a novel pain program looking to develop a-conotoxin ligands of a9a10 nAChRs, with their lead candidate KCP-506 getting to Ph I in late 2020 before gradually disappearing from view (AdInsights shows it completed in 2023). Their February 2024 press release included the usual close-down language including layoffs, asset sales and licensing, and strategic options for merger, sale or liquidation, but it is now clear that Kineta have to finally be removed from my ion channel company tracker. Many of us have been in a similar situation to these companies, and so I am wishing the best of luck to the past employees of Bellus, Eliem and Kineta!

Dr. Marc Rogers, Cambridge (UK)

aka The Channelogist