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.
Starting with the positive news from Q1 2023, there are two examples of first-in-class small molecule Kv7.x and SK channel modulators showing efficacy in ALS (QurAlis) and atrial fibrillation (Acesion Pharma), as well as continued clinical progress for a Nav1.1 ASO in Dravet epilepsy (Stoke Therapeutics), a Nav1.x inhibitor in schizophrenia (Newron Pharmaceuticals SpA), a Nav1.7 ASO in chronic pain (OliPass Corporation), and a K2P antagonist in sleep apnea (Bayer). In contrast the news was decidedly mixed for depression, with several NMDA programs encountering scientific and financial setbacks, and a pause on Eliem Therapeutics GABA-A PAM whilst Zuranolone continued to make good progress towards FDA approval in several depression indications (Sage Therapeutics/Biogen). Below I summarise the Q1 2023 clinical updates and M&A news on a total of 18 small molecule, natural product and genetic therapies targeting a wide range of central and peripheral ion channels.
1. CNS
There is a mixed bag of positive and negative news in Q1 of 2023 on various GABA-A, NMDA, Kv7.x and Cav3.x channel modulators being developed for depression, ALS, epilepsy, pain and other CNS disease indications.
While Kv7.2/7.3 programs from Xenon and Biohaven have been making clinical progress in epilepsy, Quralis have continued their work on KCNQ channel openers in ALS and announced the first-in-man dosing of QRL-101 in a Ph I five dose SAD trial in human volunteers in January 2023, which is expected to conclude in Q3. Touted as a precision therapy based on preclinical work in patient-derived iPSC neurons, the selective Kv7.2/7.3 M-channel opener has been shown to inhibit the neuronal hyperexcitability that leads to excitotoxicity and motor neuron degeneration, and the drug’s effects will be monitored using electrophysiology and neurofilament protein biomarkers to establish effective doses for subsequent efficacy trials. Also, Quralis announced an $88 million Series B fundraising in March 2023 which will support further studies of QRL-101, as well as their ASO splicing modulator QRL-201 which is designed to modulate expression of STMN2 protein in motor neurons of ALS patients.
There was more good news for Sage & Biogen’s GABA-A PAM drug Zuranolone in the advanced stages of clinical development for depression, which I have covered in previous 2022 quarterly reports. The NDA was filed last year, and in Q1 the FDA approval of this was announced with a priority review to enable a proposed PDUFA approval by August 2023. Zuranolone is one of the new, rapid-acting oral medications designed to more effectively treat drug-resistant and serious depression (and as such are in competition with ketamine-like NMDA antagonists), and it looks like the FDA will approve it for both post-partum depression (PPD) and major depressive disorder (MDD) based on previous clinical trials and ongoing open label studies. Fierce Pharma listed Zuranolone as one of their ‘Top 10 most anticipated drug launches of 2023’ in February 2023, and hopefully its approval will be less contentious than Alzheimer’s drugs like Lecanemab (Eisai/Biogen) or Donanemab (Eli Lilly) and the Duchenne muscular dystrophy gene therapy SRP-9001 (Sarepta/Roche).
In contrast, the news was decidedly mixed in terms of NMDA antagonists being developed as anti-depressants. Let’s start with the positive news, from NRx Pharma who are a new player on my ion channel company radar and apparently well advanced in clinical development of a novel NMDA ligand cocktail for bipolar depression patients at risk of suicide. Patients are currently enrolling in a Ph IIb/III trial of NRX-101 which is expected to report topline results in Q4 2023, and positive discussions with the FDA in Q1 2023 has expanded the indication to non-hospitalised patients, and a meeting is scheduled for Q2 2023 to discuss granting a Break Through Therapy designation. NRX-101 is a fixed dose oral formulation of D-cycloserine and lurasidone, the former a co-agonist of NMDA receptors and the latter an atypical anti-psychotic medicine (Latuda) primarily known to inhibit dopamine, adrenergic and 5-HT GPCRs.
I previously reported on Relmada Therapeutics, who had faced down several Ph III trial failures for their NMDA antagonist REL-1017 in major depressive disorder (MDD) and been awarded a Fierce ‘rotten tomato’ award in 2022 for an unusual approach to high placebo response rates. Well, they are persisting with this strategy and the company announced in Q1 that they have completed further analysis and detected hints of efficacy and clinical trial design and patient recruitment improvements that warrant spending their remaining cash by making changes to an ongoing study and initiating a new trial to reduce placebo responses.
Finally, Atai Life Sciences NMDA antagonist failed to show efficacy in a Ph IIa trial for depression, leading to company layoffs in March 2023. PCN-101 is a single R-isomer of ketamine which was hoped to deliver rapid responses after i.v. administration, and although it missed the primary endpoint the drug did improve secondary endpoints up to 2 weeks after dosing; a separate i.v.-to-subcutaneous bridging study continues and is expected to conclude by mid-2023. The company had previously ‘de-prioritised’ three programs in Q3 2022, and is now conserving cash to focus on lead asset RL-007, a modulator of cholinergic, glutamatergic and GABA-B receptors that is in a Ph II 2 trial for cognitive impairment associated with schizophrenia, and GRX-917, a deuterated version of anxiety drug Etifoxine which is set to enter a phase 2 trial in 2023.
Mixed news also for Eliem’s GABA-A PAM ETX-155 for depression, which I have extensively covered in my 2022 quarterly reports. After a string of minor setbacks, delays and issues during and after the covid-19 pandemic, the company eventually announced that it was halting work on this clinical project which lead to staff and company cutbacks in Q1 2023. My understanding is that development of ETX-155 has been ‘paused’ rather than abandoned, and I imagine that it may get re-activated depending on clinical progress with other GABA-A PAM anti-depressants (e.g. Sage’s Zuranolone), and additional fundraising as the company revealed that these cuts were made to extend their current 2 year cash runway. On the plus side, Eliem are doubling down on their preclinical Kv7.2/7.3 epilepsy program, and I was excited to watch what might have been the first public disclosure on ETX-123 since it was first listed on their website in early 2022 at the recent RSC-SCI ‘Ion channels as therapeutic targets’ symposium in Cambridge UK. ETX-123 is claimed to be more potent and selective than Retigabine for KCNQ2 over cardiac KCNQ1 and auditory KCNQ4 channels and is more metabolically stable, so is expected to generate fewer side effects in vivo that lead to Ezogabine’s removal from the market a few years ago.
There was also mixed news for Praxis Precision Medicine’s T-type Cav3.x inhibitor PRAX-944 (Ulixacaltamide, previously known as Z-944 before Praxis took over the Neuromed/Zalicus patent), which I reported in Q4 2022 was undergoing a Ph II trial in Essential Tremor. Unfortunately it failed to meet it’s primary endpoint and statistically exceed placebo response, but the company has decided to progress to a larger Ph III trial later this year as the drug did significantly improve secondary endpoints such as daily functioning, and is well tolerated. I’m not sure how this affects other clinical trials of PRAX-944 in Parkinson’s disease but I imagine they will continue. I previously reported on the failure of Neurocrine Bioscience’s T-type blocker for Essential Tremor in Q4, but further due diligence has shown me that Sage and Biogen are still progressing their GABA-A steroid PAM Sage-324 for this indication. It is currently in a Ph II trial, although a previous small mid-stage study in 2021 showed that efficacy overlapped with side-effects such as sleepiness and dizziness, which may limit dosing options, efficacy and patient compliance.
It looks like the rather tortured path of Aptinyx’s NMDA PAM NYX-458 for Parkinson’s dementia and cognitive impairment has finally come to an end, with the company announcing they will scrap the program after it failed to do much better than placebo over a 12 week study period. Moreover, the company has been forced to reduce costs and halt the Ph IIb clinical trial for their remaining PTSD drug NYX-783 which was expected to report results later this year. Coming on the back of a previous failed clinical trial for their NMDA receptor PAM NYX-2925 in fibromyalgia pain in 2022, these setbacks seem to indicate the inevitable demise of the company which was strongly backed after it spun out of Naurex following a $560 million buyout by Allergan in 2015.
Switching to genetic treatments for CNS disease and updates from Q4 2022, it was very promising to hear that Stoke Therapeutics had received approval from the FDA to administer higher doses of their ASO drug STK-001 designed to increase the expression of Nav1.1 channels in the brains of children and adolescents suffering from Dravet syndrome epilepsy. Various open label Ph I/IIa studies are being carried out in the UK and US, starting with single doses and then progressing to repeat doses and/or higher doses. Dravet patients are not recommended typical anti-convulsant drugs as these non-selectively inhibit voltage-gated Nav1.x channels, whereas in Dravet syndrome there are genetic mutations and haploinsufficiencies which reduce the expression, trafficking and function of Nav1.1 channels, particularly in inhibitory neurons, so genetic and small molecule (e.g. Lundbeck) drug discovery programs aim to promote Nav1.1 channel activity and reset the excitatory-inhibitory balance in the CNS by increasing excitability in inhibitory neurons.
Similarly, there is more positive news for Newron Pharmaceutical’s Nav1.x blocker Evenamide, which I previously reported in Q4 had shown promise as an anti-psychotic in a Ph Ib efficacy trial in patients with treatment-resistant schizophrenia. That was based on 6 month data, but now we have more positive 12 month data showing that the drug’s effect increased from 30% at six months to 50% after a year, continuing the trend seen between six weeks and six months. A full placebo-controlled Ph II/III trial is planned for later in 2023 to confirm these promising results. Evenamide (NW-3509) is a novel anti-psychotic scaffold which state-dependently inhibits neuronal firing, reducing excessive synaptic release of the excitatory neurotransmitter glutamate by selectively inhibiting presynaptic Nav1.x channels (although I still need to discover if it exhibits any sodium channel subtype selectivity).
I’m not sure if this next item is positive or negative news, but it could be viewed as a mixture of both. Goldfinch Bio was founded in 2016 and raised over $200 million over three rounds lead by Third Rock, Gilead Sciences and Eventide, making it onto my radar when they were revealed as working on TRPCx ionotropic receptors for chronic kidney disease (specifically FSGS, Focal Segmental Glomerulo Sclerosis). Their lead compound GFB-887 had demonstrated mid-stage clinical efficacy and tolerability, and Goldfinch had signed a significant collaboration with Gilead in 2019 for diabetic kidney disease and raised $100 million of Series B funds in mid-2020, but this renal drug discovery journey is now at an end. The Q1 news is that Goldfinch has closed down (lack of funding), but their clinical and preclinical assets have been purchased by Karuna Therapeutics ($15 million upfront payment and up to $520 million in potential milestone payments plus royalties for each candidate), who will re-purpose the TRPC4/C5 modulators for CNS diseases such as mood and anxiety, alongside their own mAChR ligands. So, this may be a loss for kidney disease drug development (which is where I know TRPC4/5/6 receptors best), and a new opportunity in neurological disease (where I know a lot less about the role of this TRPC family).
Finally in this section, I wrote in Q4 2022 about the acquisition of Redpin Therapeutics by Kriya Therapeutics to bring together their respective chemogenetic and gene therapy platforms to treat CNS disease. On the flipside, I found out in Q1 2023 that the similar chemogenetic company CODA Biotherapeutics had folded. Originally backed by Versant Ventures and MPM Capital and supported by Series A financing in 2018 ($19 million) and 2019 ($15 million) and another major funding round of $28 million in late 2021 lead by Pacira Pharmaceuticals, CODA had been developing genetically tunable ligand-gated ion channel receptor (5-HT3, GlyR) vectors to treat epilepsy and neuropathic pain, which had demonstrated promising preclinical efficacy. It is not clear why their journey has come to end (although they did have some venture debt with SVB, which folded itself in Q1 this year as many in the biotech and financing fields are well aware), although the rot seemed to have started earlier in Q4 2022.
2. Peripheral disease indications
For me the most exciting news in Q1 2023 was that Acesion Pharma had finally delivered positive clinical data after working for many years to validate SK channels (Small conductance Ca2+-activated potassium channel, KCNNx genes) as a therapeutic target for atrial fibrillation (AF). Previous dogma was that more atrially-restricted potassium channels like Kv1.5 and IKACh (gIRK3/4) would be safer and more effective AF targets, whilst the wider distribution and unclear need for selectivity for SK2 or SK3 channels made them a lower priority. History now tells us that Kv1.5 modulators are safe but do not modify AF in human patients (Merck’s MK-448 and Xention’s D0103), and IKACh programs have to my knowledge stalled at the preclinical stage. After years of cautious preclinical work (including in pigs and horses), Acesion have proven the doubters wrong and shown in a Ph II trial that both low and high i.v. doses of AP30663 can convert AF to sinus rhythm and significantly exceed placebo responses. However, there were transient effects after infusion on cardiac ECG QTc which was attributed to hERG channel block, so the company is already developing a follow-up with greater SK specificity and oral dosing, as well as planning a Ph I trial of a chronic AF treatment to compliment their cardioversion treatment.
Another new entry is Amber Ophthalmics who have taken over clinical development of a Connexin43 hemichannel ASO called Nexagon (previously Lufepirsen or CODA-1 at CoDa Tx, InflammX and OcuNexus Tx) and revealed positive topline Ph I retinal injury data in January 2023. Focusing on ophthalmic disease as Cx hemichannels are prevalent in the cornea, both doses of topically administered Nexagon gel produced 40% greater corneal recovery after chemical or heat injury (e.g. Lasik eye surgery) than placebo, but the small interim sample size (N=35 of 108) marginally missed out on being statistically significant at this early stage of recruitment and analysis. This interim data now allows the company to initiate Ph II/III trials in the same type of patients in 1H 2023. The drug has previously been tested in skin wound and diabetic and leg ulcer healing trials, and is one of several ligands targeting connexin gap junctions and hemichannels for a myriad of therapeutic indications in the periphery and CNS.
In Q4 2022 I reported on positive results for Bayer’s K2P antagonist BAY2586116 in sleep apnea, and it now looks like those published findings from a small (N=12) Ph Ib trial have been followed by larger Ph I and Ph II trials which recently completed (but have yet to report results). The drug is delivered topically, either as a nasal spray, nasal drops or by direct endoscopic application, and selective inhibition of TASK1/3 K2P channels increases pharyngeal dilator muscle activity and improves upper-airway collapsibility to relieve obstructive sleep apnea.
In Q3 2022 I reported on positive Ph II results of Axalbion’s TRPM8 agonist AX-8 in patients with chronic cough, and it looks like this promising data has convinced them to conduct a further Ph II study in 2023. AX-8 failed to deliver prolonged relief but unexpectedly showed rapid efficacy after administration of the lingual tablet, so I presume that this new clinical trial will be modified to assess a wider range of earlier timepoints. The company is up against a rather congested field of P2X2/3 anti-tussives, and my Q2 2023 report will include significant news on the leading player, Bellus Health and their clinical candidate Camlipixant (BLU-5937).
Updating a very old story on the use of topical or injected TTX (tetrodotoxin) as a non-selective Nav1.x channel analgesic, WEX Pharma announced that they were expanding a multinational Ph IIb trial of Halneuron for chemotherapy-induced peripheral neuropathy (CIPN) pain by dosing their first patient in Korea, after previous Ph II trials in cancer pain 10-15 years ago. It’s not clear to me how this agent or administration would be superior to existing lidocaine, NSAID or opioid patches, although TTX is obviously a non-opioid analgesic and local injection may limit side-effects compared to transdermal absorption that may deliver drug into the peripheral bloodstream. That being said, CIPN is a growing affliction with poor therapeutic options, and the patient population is easily identified and in great need so any new, non-addictive analgesic option would be very welcome.
This brings me to the last item, with news that Olipass Corp. in Korea have revealed that preliminary data from a Ph IIa trial of their Nav1.7 ASO demonstrated strong and long-lasting analgesic efficacy in osteoarthritis patients. OLP-1002 is delivered as a single sub-cutaneous injection (1 or 2 mg determined in an earlier dose-ranging study in OA patients), and the higher dose provided double the 25% placebo response in pain score reduction after 6 weeks, but was only marginally significant due to the small interim sample size (N=10 in each group), but the study is expected to be sufficiently powered for meaningful analysis after all 30 patients are analysed in each group. The best dose can then be tested in planned Ph II trials in diabetic neuropathic pain, trigeminal neuralgia, CIPN, fibromyalgia and cancer pain. As many of you know, Nav1.7 is a genetically-validated pain target that has proven resistant to almost all selective small molecule antagonists developed over the last 10 years, pushing the field to look at alternative genetic and biological techniques such as antibodies and nanobodies (Tetragenetics/Abcellera, Otsuka/Visterra, Abilita Bio, Oblique Tx, Yumab), RNAi and CRISPR (Navega Tx, OliX Pharma), ASOs (Q-State, the late Exicure), and conjugated toxins that may offer more profound and long-lasting target engagement that comes closer to the genetic ablation occurring in knockout rodents and human Nav1.7 channelopathy pain patients. The other key question these emerging modalities might be able to answer is whether peripherally-restricted Nav1.7 downregulation is sufficient to achieve analgesia, or if effects on Nav1.7 channels in the CNS (and opioid pathways) are also required (e.g. MacDonald et al., 2021).
Dr. Marc Rogers,
Cambridge (UK)
