The main focus of this series is to highlight the progress being made in ion channel drug discovery, which is a key validation parameter for target selection along with other considerations such as human genetic data, availability of relevant animal models, and therapeutic indications, etc. I’d like this discussion to help overcome perceptions that ion channels are ‘difficult’ 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.
In Q3 of 2022 industry players strived to move on from pandemic delays and financial and regulatory challenges seen in Q2, with some positive clinical trial results and FDA market approvals for a number of ion channel modulators across various CNS and peripheral disease indications. However, there were also some notable clinical failures and challenges for the small companies developing their portfolios of ion channel ligands, leading to a couple of major M&As as well as lay-offs and cutbacks. Below is a brief summary of the relevant clinical announcements and drug discovery news in Q3, ranging across both traditional and less well-known ion channel targets. The good news is that despite the long timelines of drug discovery and recent market situation, ion channel modulators for many classic targets (e.g. Cav3.x, Kv7.x and Nav1.x voltage-gated channels, and ligand-gated GABA-A, NMDA, AMPA, ASIC1, TRPx and CFTR receptors) are making excellent progress through the clinic and into the market.
1. A tale of two T-type Cav3.x blockers for Essential Tremor
In a typical tale of clinical development for a validated target, two companies had compounds in clinical trials at the same time for the same therapeutic indication, but one fell by the wayside whilst another continued to progress.
Sadly, Neurocrine’s T-type calcium channel blocker NBI-827104 failed to demonstrate efficacy in a small Ph II trial of 30 adult patients with Essential Tremor. Also, the company indicated that the drug was still undergoing a Ph II trial in pediatric epilepsy patients, but a subsequent news update in Q4 2022 suggested it had failed for this CNS indication as well, suggesting that the company may not continue any further clinical development for this drug candidate. More on this in my Q4 update.
In contrast, Praxis Precision Medicines announced in May 2022 that their T-type blocker PRAX-944 had achieved statistically significant positive results in a small Ph II trial for Essential Tremor (part B open label extension). The drug is also being tested in a larger Ph II dose-ranging trial that was due to conclude in Sept 2022 and report topline data in Q4 2022 (now delayed to Q1 2023 according to a Q4 corporate update), but the Q3 result had given them confidence to amend the primary efficacy endpoint to Modified Activities of Daily Living, the FDA-suggested efficacy endpoint for Essential Tremor. Patients in the Ph IIb study showed a 42% improvement in their daily living score, and the drug dose was well tolerated with no new safety findings.
PRAX-944 is also undergoing testing in a Ph IIb trail in Parkinson’s patients in 2H 2022 with readout expected in 2023; these patients typically also suffer from motor co-ordination problems. I’ve included the slide below, as like me some of you may think that Essential Tremor refers to the uncontrolled movements seen in Huntingdon’s and Parkinson’s Disease patients, but I have learnt this is not the case and the two are quite different. Also, Essential Tremor includes a strong genetic (inheritable) component as well as being triggered by other internal and external factors.
There could be many reasons why two compounds designed to modulate the same ion channel target may have disparate success. As many ion channel modulators rely on a state-dependent mechanism-of-action, the Neurocrine and Praxis compounds may have differed in their relative degree of preference for binding to the inactivated state of Cav3.x channels, and exhibited variable use- and frequency-dependence, important modalities to inhibit over-active and burst firing excitatory channels. Similarly, the degree of selectivity amongst the Cav3.x gene family and other Cav1.x and Cav2.x channels in CNS neurons and other tissues may have limited the maximum dose and lead to unwanted side-effects; NBI-827104 is a 75 fold state-dependent, ~10 nM pan-Cav3.x blocker with 2-5 mM potency against Cav1.2 and hERG channels, but it’s not clear how selective or state-dependent PRAX-944 is. Also, the level of target engagement may differ due to PK and pharmacodynamic parameters. Finally, there may have been subtle differences in the patient populations enrolled into each of the small Ph II studies. Interestingly, corporate presentations on the Praxis website suggest that they employed a novel formulation of PRAX-944 to achieve ‘modified release’ of a high drug dose (120 mg) which reduced the peak CMax exposure (which might induce side effects) but prolonged the overall exposure over CMin to achieve sustained efficacy, leading to success in their Ph II clinical trial population.
2. CFTR cystic fibrosis Cl- channel modulators
I highlighted two CF-related drug discovery stories in Q2, one being the cessation of a clinical candidate from an Abbvie–Galapagos collaboration, and the other the public launch of the new player Sionna Therapeutics. There was a similar mix of news in Q3. On the downside, a company I was not previously aware of, Eloxx Pharmaceuticals, announced that their CF genetic therapy ELX-02 failed in a Ph II trial. The drug is an aminoglycoside analogue designed to promote ribosomal read-through of nonsense STOP signals in mutant CFTR genes, increasing mRNA stability and CFTR Cl- channel regulator protein expression. Despite increasing CFTR channel activity in the small sample of CF patients when dosed together with Vertex’s Kalydeco/Ivacaftor (a CFTR ‘potentiator’), the drug failed to improve lung function or sweat Cl- concentration, either alone or in combination with Kalydeco. Drug exposures were also lower than expected from preclinical studies, suggesting that the subcutaneous delivery method (or formulation) was sub-optimal. This was disappointing news, as the RNA drug was targeted at CF patients with mutations that are not well treated with current CFTR therapies. However, the company is also planning to request FDA approval for a similar trial using an inhaled formulation of ELX-02, and they also continue discussions with the CF Foundation, who agreed to fund the development of ELX-02 with up to $15.9 million earlier this year. On the positive side, Enterprise Therapeutics released promising initial Ph Ib data in September at the European Respiratory Society conference on the safety, tolerability, and pharmacokinetic profile of ETD001, a novel muco-regulatory drug which is an inhalable ENac epithelial sodium channel inhibitor. The drug was relatively well tolerated and achieved expected exposures after SAD and MAD nebuliser dosing.
It is fascinating to see the continued activity in the CFTR ion channel modulator field, despite (or perhaps thanks to) the ongoing success of Vertex’s CFTR corrector and potentiator drug franchise which has set a high bar for competitors but one that many are willing to challenge.
3. TRPx modulators
Perhaps like many others I was under the impression that TRPx channel clinical development had largely ceased after the initial efforts over the last 20 years to progress TRPV1 and TRPA1 ligands for pain and respiratory disease had come up short, leaving some preclinical programs working on TRPM3 and various TRPCx and TRPVx targets. Having worked on TRPV1 and TRPA1 programs in the past, I was pleased to hear recently in a pain drug discovery roundtable webinar that Eli Lilly were still working on some TRPA1 assets they acquired from Hydra Biosciences a few years ago, and were quite bullish on their prospects. This has now become public as the TRPA1 inhibitor LY-3526318 has completed a Ph II trial in osteoarthritis knee pain patients. The drug is also being tested in patients with lower back pain and diabetic peripheral neuropathy as part of the company’s ‘chronic pain master protocol’ (CPMP) which is a protocol to run randomized, placebo-controlled Ph II clinical trials of multiple interventions to accelerate the development of new treatments for chronic pain. No results have been posted for the OA knee study despite completion, and the other trials are still ongoing, but having this many shots on goal should provide at least one success for a TRPA1 pain ligand after over a decade of trying and many attempts to match and beat the trailblazing Ph II results of Glenmark’s TRPA1 antagonist GRC17536 in diabetic neuropathy completed in 2014 but only published this year.
There are also at least two companies working on TRPM8 agonists for several therapeutic indications, with dry eye being a shared ailment. TRPM8 ionotropic receptors are one of the cold receptors, and are notably activated by colling agents such as menthol and icilin which make them attractive for taste research as well as potential analgesia targets. Although Aerie Pharmaceuticals ophthalmic compound AR-15512 failed to show primary endpoint efficacy in a Ph IIb dry eye trial last year, the company has proceeded to open up two Ph III trials in this quarter to chase positive signals seen in some secondary measures. Others saw the potential as well, and Alcon acquired Aerie for $770 million in Q3 to boost their own eye drug pipeline, with completion of the current dye eye trials expected in Q1-Q2 2023. In contrast, Axalbion announced positive results from a Ph II trial of their TRPM8 agonist AX-8 in chronic cough, which is also being tested against dry eye. AX-8 is in some way a topical rather than an oral anti-tussive, as it is delivered as an orally disintegrating tablet placed on the back of the tongue, and as such represents a novel mechanism-of-action. Whilst there was some efficacy against cough frequency and quality of life outcomes in 51 patients with refractory or unexplained chronic cough, the company may have been surprised to see that the primary endpoint of cough reduction after 8 hours was not met, but that more immediate and significant benefits were seen at earlier timepoints (15 min – 4 hrs). As this more rapid effect was not expected or built into the POC trial design, a follow-up study is no doubt planned. Axalbion’s TRPM8 agonist is going up against a slew of more advanced P2X2/3 ionotropic antagonists from the likes of Merck, Shionogi, and Bellus Health (as outlined in my Q2 review). Importantly, there is some evidence that several of these clinical P2X2/3 antagonists only reduce coughing in patients with very high tussive rates, whereas AX-8 showed effects regardless of baseline cough frequency and thus may help a broader base of patients.
4. Kv7 KCNQ channel modulators
My Q1 and Q2 reviews highlighted a number of companies working on Kv7.2/3 channel activators for epilepsy, aiming to build upon the efficacy of GSK’s now-withdrawn anti-convulsant Retigabine (Ezogabine) and improve key features such as gene family selectivity, chemical stability, and scaffold-related side-effects. Those companies include Xenon who have a Ph III trial planned in 2H 2022 for XEN-1101, Knopp Biosciences who licensed a preclinical Kv7.x portfolio to Biohaven Pharmaceuticals (with the lead compound BHV-7000 slated to enter the clinic in 2H 2022 in patients with focal epilepsy), and Eliem Therapeutics who publicly revealed a small molecule preclinical program for Kv7.2/7.3 in 2021 which is now expected to yield a lead candidate by the end of 2022. I was thus surprised to learn in Q3 that the EU-US biotech Saniona had announced the nomination of a preclinical lead candidate for their Kv7 epilepsy program, as I had reported in Q2 that the company was facing serious financial difficulties and that two of their programs have been left in limbo when they were forced to cut budgets, reduce their US workforce and executive team, conserve cash, and reorganise their pipeline. This is promising news as they also claim to have a Kv7.2/3 selective compound that addresses many of the drawbacks of Retigabine, including reduction of the bladder relaxation side-effects mediated by other combinations of Kv7.x channel subunits, although they remain behind the other competitors in this space.
The idea of gene family selectivity and subunit tissue expression patterns are important for validating ion channel drug discovery targets and designing screening cascades to identify and develop safe and effective drugs, and the Kv7 family is a perfect example of this. Whilst Kv7.2/3 channels control peripheral and central neuron excitability (making them targets for analgesia and epilepsy drug development), Kv7.1 channels are predominantly expressed in the heart (CV risk), Kv7.5 in skeletal muscle and Kv7.4 channels in (bladder) smooth muscle and the inner ear with attendant potential side-effects of non-selective Kv7 channel modulators. However, as Kv7.4 channel mutations are associated with some forms of inherited or genetic deafness, this makes them a target for drug discovery and Acousia Therapeutics announced the first dosing of patients with a Kv7.4 channel opener ACOU085 in a Ph Ib aging-related hearing loss clinical trial in Q3, which will assess safety and tolerability as well as measure early signs of hearing improvement and target engagement. They also published a paper in Nature detailing the preclinical efficacy of the Kv7.4 channel agonist to protect hearing function and promote outer hair cell survival in a mouse model of age-related hearing loss, confirming prediction of previous in vitro and ex vivo studies with Kv7.x openers.
5. GABA-A receptor modulators
A number of GABA-A positive allosteric modulator (PAM) clinical programs are active for various CNS diseases, aiming for a rapid and sustained increase in inhibitory neurotransmission to dampen unwanted brain activity in pain, epilepsy and depression, without causing significant side-effects produced by earlier generations of ligands that lacked selectivity between multi-subunit GABA-A ionotropic receptor complexes.
a. Pain
Despite cutbacks announced in Q2 2022 to preserve funds, Saniona had some good ion channel project news to report in Q3, as well as a loan to extend their funding runway. The company reported positive Ph I data for SAN711, a GABA-A a3 subunit-selective PAM for neuropathic pain. The clinical candidate was safe and well tolerated across all dosing cohorts, with a favourable absorption and distribution profile and high receptor occupancy measured by PET; there were no serious adverse events, and all 66 subjects completed the study without evidence for side effects such as sedation seen with non-selective GABA-A modulators such as benzodiazepines.
b. Epilepsy
The long and winding journey for Marinus Pharmaceuticals GABA-A PAM seizure drug Ganoxolone outlined in my Q1 and Q2 reviews has finally ended with the commercial launch to market in July 2022. The drug will be called Ztalmy in the US and used in pediatric patients suffering from CDKL5-deficiency epilepsy, whilst a tie-up with Orion Pharma announced in Q3 2021 will enable EU NDA and marketing of oral and i.v. Ganaxolone for CDKL5 childhood epilepsy as well as refractory epilepsy and the related CNS excitability disorder tuberous sclerosis.
Eliem Therapeutics are still fighting to overcome PK deficiencies with their GABA-A PAM ETX-155 that have been attributed to CMC issues, which continue to delay the re-start of a Ph Ib trial in photo-epilepsy to 2H 2022 and also affected two planned Ph IIa trials in major depression and perimenopausal depression.
c. Depression
Sage Therapeutics continue to report positive findings for their GABA-A PAM Zuranolone (SAGE-217) after previous efficacy data reported in a Ph III trial for post-partum depression. A major critique of this fast-acting anti-depressant was its duration of action, which was answered in some 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. An open label extension study of Zuranolone in those MDD patients was reported in Q3 that also demonstrated a durable effect lasting for 5-8 months before a repeat treatment was required. Sage and its partner Biogen are building the case for rapid and prolonged action to support their NDA submissions for MDD (expected in 2H 2022) and postpartum depression (early 2023).
Another interesting development with Sage’s neurosteroid GABA-A PAM portfolio was revealed in Q3 when Lipocine announced that they were going to develop an oral version of Brexanalone for post-partum depression. Building on their expertise with sex neurosteroids, LPCN 1154 is an oral formulation of the i.v. drug Zulresso marketed by Sage and Biogen which Lipocrine hope to test in a pilot PK bridging study in Q1 2023.
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 MDD, including GABA-A and NMDA receptors.
6. NMDA receptor modulators
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 PAMs and inhibitors for a range of therapeutic indications including neurodegeneration, depression and pain, with mixed results.
Alongside their GABA-A PAM portfolio, Sage Therapeutics are also developing NMDA-R PAMs for a range of CNS diseases. In Q2 they announced positive Ph II results for SAGE-718 in Alzheimer’s patients, a novel first-in-class PAM based on an endogenous sterol modulator that is designed to selectively enhance synaptic NMDA-R function. The drug also received FDA Fast Track designation in Q3 2021 for treating cognitive decline in Huntington’s Disease, and Sage initiated a Ph II trial with SAGE-718 for early-to-moderate HD in Feb 2022 which are expected to complete in Q4 2024. The company published a MedChem paper on SAGE-718 in July 2022, as reported by DrugHunter as one of their ‘Molecules of the Month’.
On a positive note, the tortuous ride of Axsome‘s NMDA antagonist for major depression has finally finished with FDA approval in Q3. AXS-05, now known as Auvelity, faced numerous delays and setbacks during the pandemic that included delayed FDA manufacturing inspections, deficiency notifications, and prolonged discussions over labelling and post-marketing requirements, all of which have now been surmounted with the NDA approval. AXS-05 is a formulation of the traditional NMDA antagonist Dextromethorphan and monoamine reuptake inhibitor Bupropion. This novel formulation delivers rapid reversal of depressive symptoms as well as rapid washout, both features lacking in current treatments.
Aptinyx are another company with a focus on NMDA-R PAMs for CNS therapies, and I reviewed the mixed success of their various programs in my Q2 review. The new news is not good, as NYX-2925 failed to meet efficacy endpoints in a large Ph IIb clinical trial in fibromyalgia (pain) patients. There was a trend for some early pain relief but this was overtaken by an unexpectedly high placebo response at later times – a frequent issue for analgesia studies. This is unfortunate news, both for patients suffering from fibromyalgia who have few treatment options, but also for Aptinyx as it comes on the heels of Ph IIa and Ph IIb failures in diabetic neuropathy in 2019 and 2022. The company still has ongoing trials for other non-ion channel ligands in cognitive enhancement and PTSD expected to read out in 2023, and enough cash on hand to remain operational until 2024, and received some NIH HEAL funding in Q4 which I will expand on in my next quarterly report.
7. Nav1.x channels
The good news continues for Vertex and their selective Nav1.8 channel antagonist VX-548, which gained FDA approval in Q3 to start Ph III clinical trials in ‘moderate to severe’ pain which are slated to begin in Q4. Interestingly compared to previous ion channel pain players, Vertex continue to focus on acute pain based on strong efficacy in their past Ph II trials that I reported on in Q1 and Q2, with two placebo-controlled studies evaluating VX-548 efficacy and safety for patients experiencing moderate to severe acute pain after bunionectomy and abdominoplasty; a third single-arm study will assess the drug against other types of moderate to severe acute pain. However, Vertex also received FDA approval for a Ph II trial in chronic pain, namely diabetic peripheral neuropathy, which is a more common indication for non-opioid analgesics but also one that may prove more difficult to achieve significant efficacy based on the performance of previous pain ion channel modulators. As an added bonus, Vertex also received an FDA ‘breakthrough’ tag for patients with moderate to severe pain which will expedite planned clinical development efforts and trial data reviews. You can read more about VX-548 and the next generation of non-opioid analgesics in this open access Science article.
Next is a blink-and-you’ll-miss-it update on Exicure, a sodium channel pain company I wasn’t aware of until this quarter when the news broke that their Nav1.7 oligonucleotide knockdown treatment was being wound down. The idea was to silence the pain-sensing Nav1.7 channel (and presumably mimic the human CIP gene deletions and loss-of-function mutations) using an example of their spherical nucleic acid RNA-containing liposomes to treat neuropathic pain. While this seemed to work in rodent models of chronic pain, they failed to achieve the necessary target engagement in non-human primates, taking the costs of further preclinical development and clinical translation beyond their financial means. The company already carried out a round of cutbacks in Q1, and this latest data has forced further lay-offs and efforts to out-license the Nav1.7 program. Exicure also listed a program for Batten disease focused on the lysosomal CLN3 channel, and it is also unclear where this rare disease ion channel asset is headed.
Praxis Precision Medicines have continued with their quarterly clinical updates this year, and I have already outlined the positive news from their T-type Cav3.x channel Essential Tremor trial for PRAX-944 above, so in this section I will focus on two of their Nav1.x programs.
There was good news on PRAX-222 in Q3, an antisense treatment to target Nav1.2 gain-of-function mutations the SCNA2 gene associated with early-onset developmental and epileptic encephalopathy (DEE), which is being developed as part of a collaboration with Ionis Pharmaceuticals and RogCon Inc. Praxis received a temporary clinical hold from the FDA in Q2, but this has now been clarified publicly as a request by the FDA for re-analysis of preclinical chronic toxicology data in non-human species, which has now been addressed by Praxis, earning a green light for human Ph II dosing to start in Sept 2022. Following collection of the safety and efficacy data from the first cohort of patients in the EMBRAVE study, data will be evaluated and submitted to the FDA for authorization for further dose escalation. PRAX-222 received orphan drug designation for rare childhood epilepsy from both the FDA and European Medicines Agency in January 2021 and January 2022, respectively, so this latest news promises a step-change in treatment options for children with intractable epilepsy that goes on to affect their normal neurological development.
I don’t think I’ve mentioned PRAX-628 before, likely as there hasn’t been any public disclosure of new data during 2022. However, Praxis have repeatedly stated that this non-specific Nav1.x blocker is in the final stages of IND-enabling preclinical toxicology studies, and they plan to start a Ph I study by Q4 of 2022 and then a Ph II study in focal epilepsy sometime in 2023. It is an anti-convulsant with a promising MoA (including ‘novel’ binding kinetics and state-dependence) to target over-active Nav1.2 and Nav1.6 channels.
Finally, I will compile an update on the Nav1.2 and Nav1.6 inhibitor PRAX-562 in my Q4 update, as there were some developments late in Q3 and after that are best brought together in one place (but again the news is good).
8. Other ion channels
As well as working on Nav1.x blockers for pain (BIIB074, aka as CNV1014802, Raxatrigine and Vixotrigine, and BIIB095), Biogen had an AMPA modulator BIIB104 in a Ph II trial for cognitive improvement in schizophrenia patients, but the program was discontinued as it failed to meet primary or secondary efficacy endpoints and also exhibited mild to moderate adverse side-effects after achieving the desired drug exposure. The clinical candidate was acquired from Pfizer in 2018 for $75 million upfront and up to $515 million in development and commercialization milestone payments; PF-04958242 was a first-in-class AMPA receptor potentiator originally touted for cognitive improvement.
Merck also faced some clinical hurdles, as their P2X2/3 antagonist Gefapixant for chronic cough received an FDA hold. As mentioned above in the TRPx section above, there are differences and issues with cough patient selection and the methods to assess cough frequency and severity, which the FDA apparently wanted clarified before further patients could be dosed.
There have also been some major changes at Kineta, who were running Ph I SAD and MAD studies of their nAChR a9a10 peptide toxin inhibitor KCP506 in 2021 for chronic pain with a view to progress to Ph II studies in 2023. Kineta ended up becoming a public reverse merger partner for the winding up of Yumanity Therapeutics, whose neuroscience assets were sold to JnJ for $25 million (including the Parkinson’s Disease clinical asset YTX-7739) while Kineta focused on immune-oncology. It’s not exactly clear what has happened to KCP506, as there are no records listed on clinicaltrials.gov and it has disappeared from the pipeline on the company website (but was shown earlier in Q3 2022). There is hope, as Roche-Genentech signed a $359 million deal for KCP506 in April 2018 which was expanded in October 2020 as the Ph I studies began ($21 million received according to recent SEC filing). Genentech apparently have an option to license the Phase I pain asset, which should complete all Ph I studies by Q4 2022, and Kineta revealed in a Q3 investor presentation that this option is still ‘on the calendar’ for 2H 2023.
To end on a definitely positive note (and to highlight a welcome investment in Australian biotech), an ASIC1a ionotropic receptor antagonist developed in laboratories at the University of Queensland and the Victor Chang Cardiac Research Institute and Monash University was out-licensed by the UQ tech transfer office UniQuest to a new biotech start-up called Infensa Bioscience. The company received A$23 million from private equity and angel investors, to fund further clinical development which will start with a Ph I study in Queensland early in 2023. The ligand is an optimised peptide toxin from the Australian funnel web spider that inhibits ASIC1 ion channels activated during stroke, heart attacks and CNS ischemia and injury.
Dr. Marc Rogers,
Cambridge (UK)
