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, etc. 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 good news in Q4 is that many industry players have successfully overcome pandemic delays and financial and regulatory challenges from earlier in 2022, and there are only three clinical set-backs from a list of 20 notable ion channel clinical development news items in this quarter, alongside two licensing and M&A deals. Below is a brief summary of the relevant ion channel clinical announcements and drug discovery news in Q4, ranging across both traditional and less well-known ion channel targets, and involving traditional small molecules as well as a number of RNA and gene therapies. The good news is that despite the long timelines of drug discovery and post-pandemic market situation, ion channel modulators for many classic and several novel targets (e.g. Cav3.x, Kv7.x, KNa, K2P, Cl- and Nav1.x voltage-gated channels, and ligand-gated GABA-A, NMDA, AMPA, nAChR and CFTR receptors) are making excellent progress through the clinic and into the market.
There is a lot of news to cover in Q4 as 2022 came to an end, and in this quarter many of the clinical projects involve CNS neurological indications. So, for those new to these reports and the neuroscience field, I thought I’d start with a brief overview of the mechanisms at play. A key concept in treating neurological disease is the over-arching principle of ‘E/I balance’, where the net or local activity of Excitatory and Inhibitory neurons sets the overall tone or excitability level in specific brain regions, and becomes pathologically altered in disease states. It is thought that E/I balance can be selectively modulated with ligands binding to voltage- and ligand-gated ion channels themselves or their accessory signalling complexes. For example, up- or down-regulation of Nav1.x channels selectively expressed on inhibitory or excitatory neurons is being used to reduce over-excitability in epilepsies (e.g. Stoke Therapeutics, Praxis Precision Medicines, Lundbeck, Xenon). Similarly, inhibition of NMDA and AMPA receptors can reduce excitatory glutamatergic neurotransmission, and activation of inhibitory GABA-A receptors and hyperpolarising potassium conductances (e.g. Kv7.x, K2P) can curb neuronal over-excitability. What is especially promising for patients is that E/I imbalances may underlie the early hyperexcitability seen in other neurological diseases such as ALS and Alzheimer’s, where it leads to neurotoxicity, neuronal damage and cell loss which ultimately results on long-term neurodegeneration. By learning more about the clinical profile and efficacy of a wide range of new excitability modulators in the epilepsy (and pain) fields, we may soon be able to leverage this knowledge and new clinical candidates as early interventions for the growing burden of age-related CNS diseases.
a. Potassium channels
A number of clinical and preclinical KCNQ Kv7.2/3 epilepsy programs have been making good progress in 2022. Top marks in Q4 go to Xenon who announced that XEN1101 had achieved positive interim results in an extended open label Ph IIb for focal onset epilepsy. There was long term seizure reduction efficacy (80-90%) and patient retention rates during months 14-20, with 5 – 17.5% of patients achieving freedom from any seizures over 6 -18 months.
Following behind Xenon are Biohaven Pharmaceuticals who licensed a Kv7.2/3 program (BHV-7000) from Knopp Biosciences earlier in 2022 and have now announced that this asset is progressing towards a clinical trial in focal epilepsy in Canada. On the preclinical front, Eliem Therapeutics continue to work on their small molecule program for Kv7.2/3 and appear close to nominating a lead candidate. I also reported in Q3 that the EU-US biotech Saniona had announced the nomination of a preclinical lead candidate for their Kv7 epilepsy program. Like the other players mentioned above, this is a Kv7.2/3 selective compound that addresses many of the drawbacks of GSK’s Retigabine, including reduction of the bladder relaxation side-effects produced by inhibition of other Kv7.x channel subunits.
Also, an old favourite potassium channel of mine made the news in Q4, with Praxis Precision Medicines signing a collaboration with UCB for a KNa KCNT1 ion channel epilepsy program. Back in the day when I was doing my PhD in Australia many ion channel experts either didn’t believe that a potassium channel could be activated by Na+ ions, or that a protein could sense small changes in intracellular Na+ in the face of large standing cytoplasmic Na+ concentrations. The original single channel and macroscopic recordings in chick neurons were eventually linked to the Slack family of ion channels cloned in Drosophila, and now we have identified rare mutations in the KCNT1 gene associated with rare diseases including developmental encephalopathy and epilepsy.
b. GABA-A ionotropic Cl- receptors
A number of GABA-A positive allosteric modulator (PAM) clinical programs are active for various CNS diseases, aiming for increased inhibitory neurotransmission to dampen unwanted brain activity in pain, epilepsy and depression, without causing significant side-effects produced by earlier benzodiazepines that lacked selectivity between multi-subunit GABA-A ionotropic receptor complexes.
I previously reported in Q3 on Saniona’s a3-selective GABA-A PAM SAN711 for neuropathic pain that exhibited positive Ph I data. More good news was forthcoming in Q4, with the company announcing that SAN2219, an a2/a3-selective GABA-A PAM, has been selected as their preclinical lead candidate for epilepsy after demonstrated promising efficacy in several in vivo seizure models. The compound resulted from several years of preclinical optimization of novel GABA activators with selectivity for a2/a3/a5 receptor subtypes. Saniona had previously announced funding restrictions and layoffs in 2022, but have received additional loan funding in Q3 and now look to be lining up several of their more advanced preclinical and clinical assets for out-licensing (see section 5).
c. AMPA GluR antagonist
AMPA GluRs are the most widespread excitatory neurotransmitter receptor in the mammalian brain, making them an obvious target for anti-convulsant drug discovery. Fycompa (Perampanel) is a selective, non-competitive AMPA receptor antagonist originally developed and successfully marketed for pediatric and adult epilepsy patients by Eisai after FDA approval in 2017 for partial onset, generalised and tonic-clonic seizures. In Q4 it was announced that Eisai has sold the US commercial rights of Fycompa (alongside an option on a rare epilepsy asset) to Catalyst Pharmaceuticals for an upfront payment of $160 million in addition to future milestone payments and royalties. Catalyst are familiar with ion channels, as the company already markets the Kv potassium channel blocker Amifampridine (a 4-AP analogue) for Lambert-Eaton Myasthenic Syndrome, an auto-immune disease that targets Cav channels at the neuromuscular junction.
In a related piece of news in Q4, a chemogenetic platform using engineered ligand-gated ionotropic receptors to control neuronal excitability in epilepsy and pain got a big validation tick, when Kriya Therapeutics acquired Redpin Therapeutics. Kriya is a gene therapy company, and can now apply this expertise to expressing the exogenous ionotropic receptor proteins developed by Redpin for CNS indications. Similar to the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technique pioneered for GPCRs, Redpin has engineered inhibitory and excitatory Cys-loop ligand-gated ion channel receptors (e.g. GlyR, 5HT-3) to only respond to the FDA-approved smoking cessation medicine varenicline (Chantix), and in this way selectively silence or activate disease-causing neurons in specific locations within the brain. Varenicline was chosen as the ligand as it is effective at small doses and has good brain penetration (and the nAChRs it was originally designed to activate have a limited distribution and role in the CNS). News about Redpin has been limited since a $15.5 million series A closed in 2020, backed in part by Takeda. Kriya seems to be relying on M&A to build applications for its gene therapy platform, having acquired a rare disease AAV company Warden Bio earlier in 2022, and then licensing antibody technology for oncology applications from Twist Biosciences.
d. Nav1.x modulators
I promised in my Q3 report to bring together some recent news on the Nav1.2 and Nav1.6 inhibitor PRAX-562 from Praxis Precision Medicines. The good news is that the company announced the beginning of a Ph II trial of PRAX-562 in pediatric patients with developmental and epileptic encephalopathies (DEEs). Praxis were also planning to start testing the Nav1.2 modulators PRAX-222 (an ASO being developed as part of a collaboration with Ionis Pharmaceuticals and RogCon Inc) and PRAX-628 in DEE and focal epilepsy patients, with Ph II and Ph I trials beginning in Q4 before follow-up Ph II studies in 2023. PRAX-562 had received a clinical hold from the FDA on its IND application (in part as it was dosing pediatric patients selected by patho-physiology and genetic profiling), but this was resolved in October 2002 without further studies being required before clinical testing could begin.
Whereas many epileptic syndromes involve gain-of-function mutations in Nav1.2 and Nav1.6 channels present on excitatory neurons in the brain, Dravet Syndrome is caused by de novo loss-of-function mutations in Nav1.1 channels that control the excitability of inhibitory neurons, so Nav channel blockers are not recommended. Some companies are pursuing Nav1.1 activators (e.g. Lundbeck), and others are developing gene therapy, mRNA and oligonucleotide treatments to promote expression of functional Nav1.1 channels and restore the E/I balance in the brains of pediatric epilepsy patients. In Q4 Stoke Therapeutics announced positive interim results from their Ph I/IIa trials of the ASO STK-001, revealing that single and multiple doses were well tolerated and that seizure frequency had been reduced by 55%, an promising result for this debilitating affliction affecting the quality and life and development of kids and adolescents.
e. Cav3.2 blocker
Finally, I can wrap up the story on Neurocrine’s T-type blocker NBI-827104, which failed a clinical trial for Essential Tremor in Q3, and was then reported in Q4 to have missed its primary endpoint by failing to beat placebo in a small Ph II pediatric epilepsy encephalopathy trial. This small molecule T-type Cav3.x blocker has had a complicated life, being first developed at Actelion as a pain drug (as T-type Cav channels can influence sensory neuron excitability), before the company was acquired by Idorsia who then progressed the asset into the clinic for epilepsy based on its good brain penetration and channel blocking activity. Neurocrine initially got involved in 2019 with a $5 million collaborative licensing deal, and then paying $45 million to take over the program and quickly start their own, ultimately unsuccessful, Ph II DEE trial.
The current challenge in depression therapies is to find novel mechanisms and ligands to overcome treatment-resistant disease, and deliver faster onset and greater efficacy compared to traditional tricyclic anti-depressants and monoamine uptake inhibitors. Several neurotransmitter ion channel targets are being actively pursued in depression, including GABA-A and NMDA receptors.
a. GABA-A inhibitory ionotropic receptor activators
In my Q3 report I summarised the ongoing efforts and clinical data releases from Sage and its partner Biogen to answer criticisms that it’s fast-acting anti-depressant Zuranolone could also demonstrate prolonged action in patients. SAGE-217 is a GABA-A PAM that demonstrated primary efficacy in a Ph III trial for post-partum depression, and answered some questions about duration of effect in part by Q2 results in post-partum depression that exhibited greater durability than a previous study of major depression (MDD) announced in Q1 of 2022. Secondary endpoint data from the Ph III post-partum depression trail were released in Q4, showing that Zuranolone significantly reduced depression and anxiety symptoms from days 3 to 45 compared to placebo. This new data will be used in filings to the FDA to complete a rolling NDA for both post-partum and major depressive disorder, expected by the end of 2022 to enable clinical filings in Q1 of 2023.
I have also been tracking the ups and downs of Eliem Therapeutics efforts to get their GABA-A PAM ETX-155 through Ph I and into Ph II efficacy trials for depression. The compound was also in a Ph Ib trial for epilepsy and this is where a potential PK-PD disconnect was revealed, with lower than expected and variable drug exposures. It now looks like this was a CMC manufacturing issue rather than a problem with the drug per se, and the clinical hold has been removed after a PK study and the company is now able to finally proceed to a Ph I MAD dosing trial and a Ph IIa trial in major depressive disease in Q1 of 2023, with topline data expected in mid-2024. This puts Eliem at least two years behind Sage’s GABA-A PAM Zuranolone for MDD (and it looks like they may be pausing development of this program, but more on that in my Q1 2023 report).
Below is a nice graphic Eliem released on LinkedIn in January 2023 that summarises the mechanism of ETX-155.
b. NMDA excitatory ionotropic receptor inhibitors
Given the widespread distribution of excitatory NMDA GluR ionotropic receptors across the CNS and their involvement in synaptic plasticity, a number of drug discovery programs are developing inhibitors for a range of therapeutic indications, including depression.
Gate Neurosciences came out of stealth in Q3 of 2022 with a $25 million raise from the likes of AbbVie, Eli Lilly, Innoviva, Luson Bioventures, Biocrossroads, ThornApple Capital and others, and made it into this report in Q4 when the company announced clinical dosing of one of their NMDA antagonists for depression. Apimostinel had previously demonstrated rapid and significant anti-depressant effects in a Ph IIa study of MDD, with the current Ph I translational MAD study also including EEG biomarker measurements of NMDA receptor target engagement that will be used to inform an upcoming Ph IIb clinical trial after topline readout in 1H 2023. The other NMDA blocker Zelquistinel is in a mid-stage clinical study for MDD that should read-out in mid-2024. Company staff are originally from Naurex, which was bought by Allergan in 2015 which was in turn acquired Abbvie in 2019, and when they left to form Gate Neuro they licensed a number of familiar ex-Naurex assets for CNS indications such as depression and schizophrenia. The MDD assets included Zelquistinel and Apimostinel, which had been shelved by Abbvie but company founders believe these candidates have potential as they work downstream of existing NMDA modulators (e.g. JnJ’s Spravato and Axsome’s recently approved Auvelity). The company also licensed some preclinical mGlu2/3 GPCR antagonists from Eli Lilly which have antidepressant effects similar to ketamine, and are also being studied for sleep disorders.
Gilgamesh Pharma is another relatively new player in the CNS space, formed in 2019 and announcing a $39 million Series B round in Q4 of 2022. The company touts a now-familiar approach to leverage AI and machine learning algorithms to deconvolve the complex behaviour, pharmacology and genetic signatures of brain circuits to identify new targets and drugs for neurological diseases such as depression, addiction and anxiety (with a splash of psychedelic research). It may thus not be surprising that they have identified (repurposed) Ketamine, a well-known NMDA antagonist, as a possible anti-depressant. GM-1020 is a reformulation designed to produce rapid relief from depression with reduced dissociative side-effects compared to previous versions of the classical NMDA-R blocker. The new funding will support rapid progression of this existing drug into Ph I studies.
Another company in this space had a much wilder ride in 2022, and even got a ‘rotten tomato’ award from Fierce Biotech in the process. Relmada Therapeutics have been developing Esmethadone as a (opioid-inactive) NMDA receptor antagonist for depression, but announced that it failed as a monotherapy in a Ph III trial. REL-1017 was designed to target over-active NMDA receptors while maintaining normal glutamatergic neurotransmission, but it was unable to meet the primary clinical endpoint after once-daily dosing (and so claims of safety and tolerability need to be assessed carefully). The company highlighted an unfeasibly high placebo rate at some clinical sites, and rather unconventionally suggested that post-hoc removal of the offending placebo patient data revealed some efficacy, but analysts and stockholders were not convinced. It remains to be seen if ongoing Ph II and Ph III trials of REL-1017 as an adjunctive therapy in depression carry on or deliver significant efficacy, and whether the FDA will be convinced by any future data.
3. Cystic fibrosis CFTR Cl- channel modulators
I highlighted several CF-related drug discovery stories in Q2 and Q3, and now there is an update after the public launch of new player Sionna Therapeutics, which was formed in 2019 as a stealth spin-out from Sanofi-Genzyme and raised $111 million in Q2 2022. Similar but different to Vertex’s CFTR portfolio, SION-638 is a small molecule that treat patients expressing the major F508del genetic mutation, but it does this by targeting the conserved nucleotide binding NBD1 domain that Vertex were unable to selectively modulate during its industry-defining collaboration with the CF Foundation. Their scaffold exhibits promise to improve function ex vivo in patient-derived lung epithelia. SION-638 has now cleared an IND application and is about to start a Ph I safety trial.
As well as small molecule CFTR Cl- channel ‘correctors’ and ‘potentiators’ such as lumacaftor, tezacaftor, elexacaftor, and ivacaftor which target patients with specific mutations (channelopathies), Vertex has been developing an inhalable mRNA therapy in collaboration with Moderna since 2016, using the lipid nanoparticles we now all know so much about thanks to covid-19 vaccines. VX-522 gained IND approval in Q4, and is set to deliver full length CFTR protein to patients (~5,000) who cannot benefit from currently marketed small molecules as they don’t produce any functional wildtype or mutant CFTR channel proteins. Vertex plan to initiate a Ph I SAD clinical trial for VX-522 early in Q1 of 2023.
A late entry in December 2022 was the news that Splisense had initiated a FIM Phase I/II clinical trial of SPL84, an anti-sense oligonucleotide (ASO) designed to treat CF patients with the C->T splicing mutation in the CFTR gene. SPL84 is administered weekly by inhalation, and the clinical work will start with a SAD study in healthy volunteers and then followed by a MAD study in genotyped CF patients. The ASO enables correction of the 10 Kb insert at the mRNA level and restores expression of functional protein, which should hopefully improve lung function.
4. Chloride channel modulators
CFTR and related Cl- channels also regulate epithelial function and water transport in the gut, making them and their modulators potential treatments for acute and chronic GI disease and infections. Along these lines, Napo Pharmaceuticals received IND approval for their chloride channel inhibitor NP-300 as a potential treatment for diarrhoea and cholera, where fluid loss is life-threatening. NP-300 inhibits Cl- permeability of epithelial CFTR and Ca2+-activated Cl- channels (e.g. TMEM16A) which are also being targeted in the lung of CF patients by the likes of Vertex and Enterprise Therapeutics; Napo Pharma is a subsidiary of Jaguar Health, a company focused on human and animal GI ailments. As NP-300 is a natural product derivative from the endangered ‘dragon’s blood’ tree (only found in Yemen’s Socotra archipelago), it is regulated under the FDA’s botanical guidance’ and must be sustainably sourced and produced, so NP-300 will fall under a Tropical Disease Priority review Voucher to support progress towards an NDA.
Also targeting Cl- channels, this time in muscle cells, NMD Pharma released positive data from their Ph I/IIa study in Myasthenia Gravis patients in Q4. NMD670 selectively inhibits the postsynaptic CLC-1 channel to reduce contractile myotonia and weakness, and restore neuromuscular junction (NMJ) function in myasthenic patients. The drug was safe and well tolerated, and exhibited clinically-significant improvements in patient scores and electrophysiology endpoints of NMJ activity. This makes NMD670 a novel, first-in-class medication directly targeting Cl- channels, which are renowned for their poor polypharmacology and lack of selective modulators. This novel MoA is also important for myasthenia patients and the competitor space, as it is primarily an auto-immune disease and other treatments from the likes of Argenx, AstraZeneca, JnJ and UCB that are in more advanced clinical studies or have reached the market all target the immune system. Significantly, NMD670 was given orphan drug status for myasthenia gravis by the FDA in Q3 2022, and has also received IND approval for spinal muscular atrophy (SMA) in Q4 2022.
5. Fibrosis disease
Algernon Pharma got FDA orphan drug approval for their ionotropic NMDA receptor modulator NP-120 to treat idiopathic pulmonary fibrosis (IPF). Ifenprodil is an activity-dependent antagonist of GluN1 and GluN2B subunit-containing NMDA receptors, and while it is already approved as a cerebral vasodilator in Japan and France, it is still undergoing clinical studies in the US (e.g. for tinnitus, and a repurposed drug for covid-19). NP-120 recently completed a Ph IIa study in IPF patients, meeting its primary endpoint (lung function) as well as reducing cough frequency and severity and improving quality of life, explain the additional pivot to try and reduce covid-19 infection and symptoms. Unlike other re-purposed covid-19 drugs, the Ph IIa study showed that NP-120 was safe and well tolerated.
The apparent news of Saniona’s demise (or significant contraction) may be over wrought, as the company also announced that a preclinical candidate KCa3.1 inhibitor had been selected from their fibrotic and inflammatory disease program. It may be that internal work on this asset has ceased, as they claim that it is now ready for out-licensing and/or ready to start the regulatory process to enter Ph I clinical trials. SAN903 is a novel small molecule inhibitor of KCa3.1(SK4, intermediate/small conductance Ca2+-activated potassium channel) implicated in immune cell inflammation myofibroblast fibrosis. It acts to prevent cell division and migration, and impede cytokine release and collagen secretion, with potential to treat inflammatory bowel disease and fibrotic indications such as chronic kidney disease.
6. Other clinical ion channel announcements
I’ve covered the ups and downs (mainly delays) in 2002 affecting Axsome Therapeutics NMDA modulator AXS-05, which was finally approved as Auvelity by the FDA in Q3 for major depressive disorder. They got more good news in Q4 as the drug managed to meet the primary endpoint in a Ph II study in Alzheimer’s patients, significantly reducing agitation which is a major quality of life issue and also a daily challenge to family and carers. AXS-05 is a reformulation of the monoamine reuptake inhibitor Bupropion and the classical NMDA receptor antagonist Dextromethorphan, which as outlined above is also being used with some success in depression patients.
Still on NMDA glutamate receptors, Neumora announced in Q4 that the company had raised another $112 million, in part to fund their preclinical GRIN2 (NR2A in old school nomenclature, e subunit) precision therapy program. Genetic mutations in GRIN2 are associated with rare epilepsies, and may have utility to treat opioid addiction, but the company has not revealed publicly what specific neuropsychiatric disease indication is being targeted by this program. The company previously dropped a GRIN2B discovery stage program, also for unspecified neuropsychiatric disorders.
Moving to the periphery, Bayer published positive results in a Ph1b sleep apnea trial for a K2P antagonist, BAY2586116. Animal experiments had shown that inhibition of certain K2P potassium channels could increase pharyngeal dilator muscle activity and reduce obstructive sleep apnea, which they tested in human volunteers using a potent and selective TASK1/3 channel antagonist. The drug was delivered topically, either as a nasal spray, nasal drops or by direct endoscopic application. The drug improved upper-airway collapsibility regardless of topical application route, highlighting the therapeutic potential to target K2P channels to treat sleep apnea.
In an update on an old ion channel drug development story (as many past ion channel drugs such as Verapamil and Diltiazem were approved as cardiac anti-arrhythmics), a new class IV Cav channel blocker aced a Ph III trial after failing a similar study in 2020. Milestone Pharma announced in Q4 that Etripamil had beaten placebo to rapidly convert supraventricular tachycardia to sinus rhythm within 30 minutes of repeat nasal spray dosing (54 – 64% response compared to ~30% placebo responders, 17 vs 53 minutes, respectively). It had failed previously with single dosing and a delayed measure of arrythmia conversion, but talks with the FDA had allowed a redesign which has now delivered clinical success. The company now plans to file for FDA approval by the middle of 2023.
I’ll finish up with two blasts from my past.
I knew about Newron Pharmaceuticals from their previous work on the monoamine oxidase B blocker Safinamide (Xadago) for Parkinson’s disease, and the state-dependent Nav blocker Ralfinamide for pain. In Q4 the company announced that another state-dependent Nav channel antagonist Evenamide showed promise as an anti-psychotic in a Ph Ib efficacy trial in patients with treatment-resistant schizophrenia. The drug is thought to reduce excessive presynaptic release of the excitatory neurotransmitter glutamate, but the effect to reduce psychosis was small and this was an open-label trial, although the drug did significantly improve psychosis symptoms in a previous Ph IIa study. A full placebo-controlled Ph II/III trial is planned for 2023 to confirm these promising results.
Finally, it looks like the long ion channel drug discovery for the Australian biotech Bionomics may finally be coming to an end. Their a7 nAChR NAM BNC210 failed to show primary endpoint efficacy in a Ph II clinical trial for social anxiety, although as is often the case there was some ‘trend toward improvements’ for both primary and secondary endpoints which the company wished to explore further before tapping out on this therapeutic indication. BNC210 was originally touted as a potential treatment for PTSD, and there is an ongoing Phase IIb study expected to deliver topline data in mid-2023. The company raised another $5 million in Q4 and claims to have a strong cash position into 2024, so although R&D activities have long since ceased the story hasn’t ended just yet and they are planning to complete clinical and out-licensing activities before the shutters come down after 20 years. Bionomics were early players in the ion channel field (e.g. a Kv1.3 inhibitor for auto-immune disease), and were even more significant given their location in the relative life science and VC desert downunder, so I have mixed feelings about this news, but remain optimistic for ion channel drug discovery in Australia with the recent news that AbCellera had acquired the Sydney start-up Channel Bio to further their work on ion channel antibody therapeutics, and the recent spin-out of Infensa Bioscience ftom the University of Queensland.
Dr. Marc Rogers,