Expert opinions


Ion channel ligands in clinical development – Quarterly review (Q2 2023)

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 models, and therapeutic indications. I’d like this discussion 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 big news item in Q2 2023 was the positive Ph I results for Bellus Health’s P2X3 antagonist Camlipixant for persistent cough, which triggered their buyout by GSK as the leading contender in the active field of P2X2/3 antagonists I had reviewed in past updates. Key players in the field of Nav1.x modulators for epilepsy continued to announce positive clinical data and program developments (e.g. Stoke Therapeutics Nav1.1 ASO for Dravet, Praxis Precision Medicines PRAX-562 and PRAX-628 small molecules), as well as news on several Cav CNS programs (PRAX-944, Lario Therapeutics). There were also announcements on new clinical Kv3.x (Autifony) and Kv7.x programs (Lundbeck), as well as clinical updates on CLC-1 programs for neuromuscular disease (NMD Pharma) and a TRPV1 pain asset (Grünenthal).  Below I summarise the Q2 2023 clinical updates and M&A news on a total of 10 small molecule and genetic therapies targeting a wide range of central and peripheral ion channels.


1. Nav1.x channel clinical programs progressing well

Just two companies to highlight this quarter, both of whom have featured in previous blogs but continue to supply updates as they progress their Nav1.x modulator programs in epilepsy.

First up is Stoke Therapeutics, who revealed promising Ph I/IIa data for their Nav1.1 ASO STK-001 in Dravet epilepsy patients, which is being tested in both the UK and the US to establish the most effective dosing regime. The interim Q2 update included data from 55 enrolees, showing that the ASO was well-tolerated and exhibited some dose-dependence with higher and/or multiple doses reducing the number of seizures. I previously outlined that Stoke had received approval from the FDA to administer higher doses of their ASO drug which is designed to increase the expression of Nav1.1 channels in the brains of children and adolescents suffering from Dravet syndrome epilepsy (in comparison to Nav1.x programs in pain which aim to reduce sensory neuron excitability driven by Nav1.7 and Nav1.8 channels). Dravet patients suffer from genetic mutations and haplo-insufficiencies which reduce the expression, trafficking and function of Nav1.1 channels, especially in inhibitory neurons, so genetic and small molecule (e.g. Lundbeck) ligands have been designed to promote Nav1.1 channel activity and reset the excitatory-inhibitory balance in the CNS by increasing the excitability of inhibitory neurons and thereby dampen down epileptic discharges. As such Dravet patients need to avoid traditional anti-convulsant drugs which non-selectively inhibit Nav1.x channels (or open inhibitory Kv3.x and Kv7.x channels, see section 2 below).

Second is Praxis Precision Medicines who continued their regular updates on several Nav1.x inhibitor programs for various epilepsy patient cohorts. In May the company announced positive results in a Ph I trial showing that PRAX-628 was safe and tolerable, with PK exposure values confirming its preclinical profile and demonstrating a 15 fold safety margin over the in vivo seizure threshold, compared to a 3 fold margin for a leading anti-epileptic drug. The hope is that once-daily dosing will not need titration and can achieve seizure reductions at significantly lower dosages than current anti-epileptics (i.e. 10-30 mg compared to 150-300 mg for the likes of Lamotrigine, Lacosamide and Carbamazepine).  A Ph II trial has thus been planned for Q4 and is expected to readout by EOY, with another Ph II slated to start in Q1 2024 in patients suffering from focal epilepsy. The initial Ph II study will use a photo-paroxysmal response (i.e. photosensitive epilepsy) as the primary endpoint, similar to the approach previously taken by Eliem Therapeutics with their GABA-A PAM ETX-155 and other players in this field, which generally translates well to clinical efficacy in focal epilepsy. Interestingly, company presentations compare the in vivo efficacy and safety margin of PRAX-628 to the Kv7.x opener XEN-1101 from Xenon. PRAX-628 is a mixed Nav1.x blocker which demonstrates ‘functional selectivity’ for over-active Nav channels, typically achieved by a voltage- and state-dependent mechanism that targets the open and/or inactivated conformation of the protein. I’ve not seen any published in vitro or biophysical data on PRAX-628, but company presentation show that it inhibits both inactivated (use- and frequency-dependence) and persistent current components with 50-105 fold selectivity over resting state tonic block.

Similar progress is being made with PRAX-562, as enrolment of pediatric DEE epilepsy patients began in Q2 and the 16 week trial is expected to readout topline results in Q4 2023. Up to 20 patients will be chosen based on genetic profiling for gain-of-function mutations mainly in Nav1.2 and Nav1.6 channels. PRAX-562 is a non-selective Nav1.x blocker with a novel mechanism to selectively inhibit persistent currents, typically seen in Nav1.6 currents where gain-of-function mutations are found in DEE patients (Developmental Epilepsy and Encephalopathy), but which also occur in Nav1.2 and Nav1.3 channels that also contribute to various pediatric epilepsies. A similar mechanism was exploited by various ‘late Nav1.5’ blockers developed a decade ago for cardiac arrythmia, angina and atrial fibrillation by the likes of Gilead (Ranolazine, Eleclazine) and Pierre Fabre (F-15845). As with PRAX-628, PRAX-562 is more potent than other marketed anti-epileptics (by 3-10 fold for peak current) but is even more potent (nM vs microM) and selective for the disease-producing persistent currents (60 vs 20 fold), both features which should allow for lower dose ranging and fewer side-effects.

Finally, the Nav1.2 down-regulating ASO PRAX-222 now has approval for an initial cohort to start dosing, with topline results expected in 2H 2023. This treatment is delivered intrathecally and designed to treat early-onset SCN2A DEE, so the FDA has been very cautious and the 21 week trial design reflects an attempt to minimise risk and assess safety in the young patients after every 4 week dose.


2. Cav channel programs

I previously reported in the Q1 2023 update that Praxis Precision Medicine had revealed mixed results for their T-type Cav3.x inhibitor PRAX-944 (Ulixacaltamide, previously known as Z-944 before Praxis took over the NeuroMed/Zalicus patent), which failed to meet it’s primary endpoint and statistically exceed placebo response in a Ph II trial for Essential Tremor, but did significantly improve secondary endpoints such as daily functioning, and was well tolerated. It looked like the company had decided to persevere with this program, and this was confirmed in plans outlined in company presentations in Q2 where meetings were scheduled with the FDA in June to design a larger Ph III trial to support a marketing application, which appeared to go well and result in two different 12 week, single dose (60 mg) Ph III trial designs which will use the modified Activities of Daily Living II score as the primary endpoint (as it showed ‘nominal’ statistical significance of p=0.042 in the Ph II trial). Enrolment is planned to start in Q4, with eventual marketing approval in 2025. It seems reasonable to assume that a combination of moderate efficacy and safety of PRAX-944 in their Essential 1 Ph II trial, and the recent failure of Neurocrine Bioscience’s competing T-type blocker for the same indication (which I outlined in the Q4 2022 blog), has created an opportunity for further clinical progression and eventual marketing to meet the unmet medical need of Essential Tremor patients.

The New Drug Application (NDA) will also require additional safety and toxicology data, including 300 patients with 6 month exposure and 100 patients with 12 months of treatment. This may reflect the fact that a significant  number of adverse events and patient withdrawals were seen amongst the 78 patients dosed with PRAX-944 in the Ph IIb trail.

Praxis Precision Medicines Q2 clinical update and Ph II results for PRAX-944 in Essential Tremor

Given the company’s ongoing clinical trials for several Nav1.x antagonists and the dual Ph III trials requested by the FDA for PRAX-944, it is perhaps not surprising that Praxis also announced a fundraising effort in Q2, which was over-subscribed and raised $63.3 million at the end of June 2023.

There was also some interesting calcium channel drug discovery news in Q2 from Lario Therapeutics, who revealed some IP on the relatively neglected Cav2.3 R-type Cav channel, so-called as it was ‘resistant’ to most reference Cav antagonists. Cav2.3 is primarily expressed in peripheral and CNS neurons, controlling presynaptic neurotransmitter release. A more recent story implicates Cav2.3 as a target of Cdkl5 kinase phosphorylation, and thus it would seem this IP may be applicable to development of novel anti-convulsants as pediatric patients with Cdkl5 mutations can suffer from rare developmental epilepsies (who are also be targeted by Marinus Pharmaceutical’s GABA-A PAM Ganoxolone, as discussed in my Q3 2022 update). The press release also mentioned potential CNS applications for Parkinson’s and other neurodegenerative diseases, as well as pain and endocrine disorders where R-type Cav2.3 channels regulate sensory neuron neurotransmission and neuropeptide secretion.

Lario are one of a number of ion channel spin-outs from the CRO company Axxam in Italy, who developed a number of internal R&D drug discovery programs which have now been divested into a number of subsidiary companies – more on this in my Q3 update.


3. Kv channel programs

The UK/Italian company Autifony (originally spun-out from GSK in 2011) has been working on various modulators of Kv3.x channels (KCNC family, IDR delayed rectifier and IA transient outward potassium currents) which control CNS neuron excitability, especially in fast-spiking interneurons, as potential treatments for a range of neurological diseases. There was an unsuccessful clinical trial for tinnitus hearing disorder (AUT00063, Kv3.1 opener; Hall et al., 2019) and a successful schizophrenia clinical program in collaboration with Boehringer Ingelheim (AUT00206, Kv3.x opener), but this was handed back in late 2020. Autifony have now announced that human dosing has started for their Kv3.x activator AUT00201 in a Ph Ib trial for progressive myoclonic epilepsy (NCT05873062). The company is also working on Fragile X syndrome (re-formulated AUT00206) and Alzheimer’s Disease (Kv3.4 inhibitors). Lundbeck have also published on Kv3.x modulators for CNS disease indications including Alzheimer’s Disease, with a recent cryo-EM paper showing their Kv3.1 opener ligand Lu AG00563 bound to a novel pocket.

Speaking of Lundbeck, the company announced in Q2 that a package of their Kv7.2 openers had been out-licensed to Neuro3 Therapeutics for CNS disease indications. The deal includes two clinical and one preclinical candidate, but no financial terms were disclosed; Neuro3 get worldwide rights, and Lundbeck retains the option to license them back to develop and commercialise in certain territories after clinical proof-of-concept is achieved. I’d not heard of Neuro3 before, who were founded in 2021 in Hong Kong with a focus on CNS diseases, and who plan to use these assets to explore efficacy in rare epilepsy as well as other undefined neurological and psychiatric indications. Neuro3 CEO Zheng Li used to work at GSK, so is likely aware of their past efforts developing the Kv7.x opener Retigabine as a clinical treatment for epilepsy (now withdrawn due to lack of selectivity and side-effects). Li also worked previously at Lundbeck, who published on the pan-Kv7.x opener Lu AA41178 in 2020 which appears to bind to the same pore site as Retigabine and showed good brain penetration and preclinical efficacy in models of epilepsy and depression.

Something for the chemists – structures of Kv channel modulators AUT00201, Lu AG00563, Retigabine and Lu AA41178

The field of clinical Kv7.x openers for epilepsy is already quite congested (e.g. Xenon XEN1101 and Biohaven BHV-7000), but this is no bad thing given the paucity of safe and effective treatments for both young and adult patients and the high incidence of treatment-resistance. I also highlighted Eliem’s preclinical Kv7.2/7.3 epilepsy program for ETX-123 in my Q1 2023 review. Quralis have also been making clinical progress with Kv7.x openers for ALS, starting with a successful clinical trial for Retigabine (Ezogabine) in 2021 and now their own QRL-101 which started FIM dosing in Q1 2023.


4. Other ion channel programs in clinical development

NMD Pharma are a Danish biotech focusing on neuromuscular diseases, who already have a CLC-1 Cl- ion channel inhibitor (NMD670) that showed efficacy in a recent Ph I/IIa Myasthenia Gravis trial as I reported in my Q4 2022 blog. They announced in May 2023 that they had started a Ph I combined SAD/MAD safety, tolerability and PK study of a 2nd CLC-1 inhibitor for neuromuscular disease. NMD1343 is a ‘back-up’ oral drug with a different profile to their lead clinical candidate. The company also announced promising results from a Ph 0 exploratory trial of neuromuscular deficits in patients with Charcot-Marie Tooth neurological disease, demonstrating the potential for a CLC-1 inhibitor to improve their motor function, and identifying useful clinical biomarkers and endpoints for a potential Ph II clinical trial.

While many of us in the field had thought that the historical ion channel target TRPV1 was no longer in active clinical development, there is news in Q2 (and Q3) of 2023 that there is still life in this Nobel prize-winning ion channel. Grünenthal received Breakthrough Therapy designation from the FDA for the TRPV1 ligand Resiniferatoxin and is conducting a Ph III trial for osteoarthritis knee pain, where the drug will be delivered by intra-articular injection. Resiniferatoxin is a well known peptide ligand of TRPV1 ionotropic receptors (a functional analogue of capsaicin, which has been used in a similar fashion as a desensitising agonist), which acts as a chronic analgesic through activation and then long-term loss of pain-sensing receptors and sensory neuron nerve endings. As such Resiniferatoxin and capsaicin have been tested in clinical trials for various pain ailments and patient cohorts over the last decade, using local injections or dermal patches (e.g. Qutenza, which Grünenthal developed and is marketing with Averitas Pharma Inc in the US).

Finally, we have the big news in Q2 of major developments in the P2X2/3 receptor cough field. Firstly, the generally regarded lead candidate in the this race, Bellus Health’s Camlipixant (BLU-5937) successfully completed a Ph I safety and bioavailability trial. The study compared BID oral extended release formulation with twice daily formulation of BLU-5937, showing expected exposure and PK characteristics for patient dosing. This was closely followed by news in April 2023 that GSK had acquired Bellus, perhaps specifically for their P2X3 antagonist.

I have reviewed the P2X cough field in previous updates (see my Q1 2022 blog), where it was clear that earlier programs (e.g. Merck’s Gefapixant, Bayer’s Eliapixant, Shionogi’s Sivopixant) suffered from poor selectivity between less desirable P2X2 homomers and P2X2/3 heteromers compared to preferred P2X3 homomers, and exhibited less-than-ideal PhysChem and PK properties for low dose dosing to avoid side-effects, notably changes in taste sensation (dysgeusia). The general consensus was that BLU-5937 was a more selective and potent non-competitive inhibitor of P2X3 receptors (see Drug Hunter overview here, including its path from AZ to adMare and then Bellus in Canada) and, as we now know, with better bioavailability and dose control properties and good Ph IIb and Ph III efficacy against chronic cough, making it the #1 P2X cough ligand which has now been quickly snapped up by a big pharma player.


 Dr. Marc Rogers, Cambridge (UK)

aka The Channelogist