It was a very busy quarter of ion channel clinical drug discovery news as the year ended with 40 items in my database for Q4 2024, including a mixture of positive and negative news for several ongoing early and mid-stage clinical programs, as well as some new ion channel collaborations and company M&A activity, and a CFTR drug approval.
In the peripheral disease indication section there is a mixture of hits and misses for previously discussed clinical programs and several new entries. There was significant but mixed news for respiratory ion channel programs, with Vertex gaining market approval for their 5th CFTR drug combination Alyftrek, a ‘Vanza triple’ drug combination CFTR Cl- channel correctors and potentiators, but the Roche/Genentech TRPA1 blocker failing in a Ph II trial for chronic cough. Also a mixture of news in the pain space, with Latigo Biotherapeutics successfully completing a Ph I safety trial for their 2nd Nav1.8 candidate and Vertex posting positive efficacy and safety data in the registration-enabling Ph III trial of their lead Nav1.8 blocker Suzetrigine (VX-548) in moderate-to-severe acute pain, and the clinical hold being lifted on Rapport Therapeutics AMPA Tarp modulator program in neuropathic pain. However, Vertex had to reveal a clear miss for the same compound in an important Ph II efficacy trial for chronic pain, and Eli Lilly published on the clean sweep of misses in their three chronic pain studies of a TRPA1 blocker. In contrast two cardiac and skeletal muscle ion channel programs advance for Infensa Biosciences and NMD Pharma. We can finish with a trifecta of positive progress for three clinical programs targeting APOL1 channels in chronic kidney disease with clinical trial and funding news from Vertex, AstraZeneca and Maze Therapeutics.
There is mostly positive news this quarter for a range of CNS programs developing Nav1.x, Kv7.x and K2P channel modulators in epilepsy and neurodegeneration, but less promising developments in a number of NMDA, GABA-A and P2X7 ligand-gated projects in neurodegeneration and depression. Most activity this quarter in epilepsy was around Nav1.1, with Stoke Therapeutics revealing long-term efficacy and safety data on their Dravet gene therapy ASO candidate STK-001 (Zorevunersen), and Xenon revealing their preclinical work on small molecule Nav1.1 activators for Dravet epilepsy. Xenon also presented more open label Ph IIb extension data on their Kv7.2/3 anti-convulsant modulator XEN1101 (Azetukalner) in focal onset epilepsy, and enrolment in a 2nd Ph III trial of the drug that will look at patients with tonic-clonic seizures. GRIN Therapeutics also announced the start of a Ph II trial of their NMDA NR2B-selective NAM Radiprodil in patients with tuberous sclerosis complex and focal dysplasia who suffer from seizures as well as other neurological and developmental symptoms. NMD Pharma are also targeting rare CNS diseases by starting a Ph IIa trial of their CLC-1 channel activator NMD670 in Charcot-Marie-Tooth disease, following on from mid-stage success in neuromuscular indications. Finally, aussie biotech Bionomics are pushing on with their a7 nAChR PAM BNC210 in social anxiety and PTSD. In contrast, the picture was very mixed for ion channel programs in other complex CNS indications. Cerevance revealed positive Ph I safety data on their anti-neuroinflammatory K2P inhibitor CVN293 slated for various neurodegenerative indications, but Sage Therapeutics had to admit defeat on all fronts for their NMDA PAM drug SAGE-718 (dalzanemdor) which failed in mid-stage trials in Alzheimer’s and Huntington’s disease in Q4, after an earlier fail in Parkinson’s disease. Sage also decided to phase-out their i.v. antidepressant drug Zulresso and several development candidates, leaving just one approved drug (Zuranalone/Zurzuvae) from their extensive GABA-A PAM portfolio. Finally, there was news in Q4 that JnJ had dropped not one but two Ph II P2X7 antagonists (JNJ-54175446 and JNJ-55308942) that were being developed as anti-depressant and bipolar disorder drugs.
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1. Peripheral disease indications
a. Cardiac and skeletal muscle ion channels
This quarter there are two brief but positive clinical updates from players in this field that I have covered previously.
Aussie biotech Infensa Biosciences announced that they plan to start a clinical trial of their ASIC1a channel blocker in cardiac ischemia in 2025. This work will be supported by a recent grant of A$17.9 million from the Medical Research Future Fund in Australia, following on from the company’s initial raise of A$23 million back in 2022. ASIC1a channels in muscle cells are activated by pH changes when circulation is compromised and tissue damage occurs, and while the native funnel web spider toxin Hi1a is efficacious in animal models, extensive preclinical optimisation was required to create peptide analogues with suitable PK and toxicology profiles suitable for clinical administration as a cardioprotective agent.
Danish biotech NMD Pharma are progressing their ClC-1 channel inhibitor NMD670 for a number of musculo-skeletal indications including myasthenia gravis, spinal muscle atrophy and Charcot-Marie-Tooth disease, and this quarter they published the results from the previous Ph I PK-PD trial of NMD670. The drug was generally safe and well-tolerated, apart from some myotonia at the highest doses (1200 – 1600 mg) related to target engagement and increases in muscle excitability and contractility which are desired effects to treat muscle weakness in affected patients.
b. Respiratory disease
Just two items in the section this quarter, but they are both very significant: Vertex get another CFTR drug combo approved, while the prospects for TRPA1 as a respiratory drug discovery target fade with news from Roche/Genentech.
On the plus side we have news that the FDA has approved a 5th CFTR drug from Vertex for the treatment of young cystic fibrosis patients with certain CFTR Cl- channel regulation protein mutations. The new drug will be called Alyftrek and is a combination of one old and one new corrector (tezacaftor and vanzacaftor, respectively) alongside a new potentiator deutivacaftor (which is a deuterated analogue of the previously approved Vertex drug ivacaftor (VX-561, Kalydeco), in-licensed in 2017 after it was originally developed by Concert Pharmaceuticals as CTP-656). This new ‘vanza triple’ was developed and has been approved to replace the original triple drug combo Trikafta (Kaftrio in EU and UK), as it demonstrated some superiority in certain Ph III clinical trial endpoints, can be dosed orally once a day compared to twice daily for the old drug, and shows efficacy against 30 additional CFTR mutations in addition to the most common F508del variant.
On the negative side there is news in Q4 from Roche/Genentech that the TRPA1 antagonist they were developing for chronic cough failed in a Ph II trial, and appears to have been dropped from their pipelines. The companies had originally looked at TRPA1 as a pain target (similar to Eli Lilly – more on that below) but extensive preclinical work had indicated poor potential as an analgesic target but more promise in respiratory indications such as asthma and cough. They published on the discovery and optimisation of GDC-6599 (RG6341) earlier in 2024, which involved de-risking some preclinical toxicity issues (metabolite-induced coagulation) and demonstrating respiratory efficacy in rodent cough models, but first took it into a Ph IIa trial in patients with chronic cough in 2023. However, despite being safe and well tolerated (vindicating their preclinical optimisation work) the drug failed to show any clinically meaningful improvements in chronic cough frequency or severity. Another factor in removing the TRPA1 drug from their clinical pipeline is likely to be competition with more advanced P2X3 antagonists such as Merck’s Gefapixant (approved in Japan) and GSK/Bellus health’s Camlipixant which is undergoing late phase III trials on the back of promising Ph II efficacy trials that I covered in previous blogs.
c. Pain
There is continued progress for two Nav1.8 candidates and a Cav channel clinical pain program in Q4, a hold on an AMPA ligand, and final confirmation of the failure of a TRPA1 pain program that I covered previously.
There is a lot of attention right now on Nav1.8 channels as novel pain targets thanks to ongoing trials for the Vertex blocker VX-548, but also in the mix are Los Angeles outfit Latigo BioTherapeutics who have several early stage clinical candidates in play. The company previously announced that their first Nav1.8 clinical candidate LTG-001 had aced a Ph I safety trial in August 2024, and this was followed this quarter by dosing of the 1st patient in a Ph I trial of their 2nd Nav1.8 candidate LTG-305, which is expected to read-out topline results in mid-2025. LTG-001 exhibits a rapid absorption profile and is being developed as a non-opioid treatment for acute pain (similar to earlier Ph II and III studies for VX-548), while LTG-305 is being pitched as a treatment for musculoskeletal chronic pain – where the greatest unmet medical need exists, and VX-548 has struggled somewhat.
Speaking of Vertex, there was a flurry of press releases, LI posts and other science discussions around their Nav1.8 analgesia program for VX-548 (Suzetrigine) following the release of Ph II and Ph III clinical trial results in Q4. Starting with the large acute pain Ph III trial, the general consensus was that this late phase result was a bit mixed and similar to previous Ph II data, with VX-548 showing a good safety profile, lower side-effects than positive control comparator, and placebo-beating short-term analgesia in both abdominoplasty and bunionectomy patients previously studied in Ph II. However, various primary and secondary measures of analgesia produced by VX-548 (50-100 mg) as a monotherapy were only similar or slightly inferior to that produced by standard treatment with an opioid and NSAID combination (hydrocodone and acetaminophen). Several factors have been discussed that may explain this profile, including potential heterogeneity in the very large 1000+ patient cohorts in each acute pain study, and subsequent analysis and commentary on the fact that fast-acting analgesia was absent (vs placebo) for the first 6 hours in bunionectomy patients as they had received a local anaesthetic during surgery which may have occluded subsequent Nav1.8 inhibition by VX-548. Interestingly, some patients in both surgery groups were treated with a combination of Suzetrigine and ibuprofen, and in both cohorts this paradigm clearly beat placebo, opening up the possibility that Suzetrigine may be marketed as both a monotherapy but also a substitute for addictive opioids like Vicodin in combination with NSAIDs in moderate-to-severe acute pain patients. Finally, the anaesthesiology conference presentation also included single arm Ph III data from acute administration of Suzetrigine to a varied group of ~250 patients who experienced pain due to diverse surgical procedures (orthopedic, plastic, ear-nose-throat, urological) or non-surgical situations, which was pitched as a ‘real world’ scenario for treating moderate-to-severe pain. Over 80% of patients in each group rated Suzetrigine pain relief (50-100 mg every 12 hours for up to 14 days) as ‘good’ or better, and only 15% as fair or poor. Side-effects and adverse events were limited, positioning Suzetrigine as a potential new analgesic which could replace addictive opioids in drug combinations for acute pain care; the PDUFA decision is expected a the end of January 2025.
More disappointing was the result from Vertex’s long-awaited Ph II efficacy trial in chronic pain, where the unmet medical need and push to avoid opioids is greatest. Suzetrigine produced weak but statistically-significant analgesia to meet the primary endpoint after 12 weeks, but failed to beat placebo in a study of 100 patients with lumbo-sacral radiculopathy (lower back pain/sciatica). Not surprisingly there was extensive industry discussion of this poor result, and some LI posts that delved a little deeper into the study, one of which was quite interesting as it noted the high BMI scores for all participants which might have exacerbated their ongoing pain and reduced the efficacy of Suzetrigine. Others have also speculated about the mechanism-of-action of VX-548, which appears to be a resting/closed sate blocker with little preference for inactivated Nav1.8 channels and exhibits weak reverse use- and frequency-dependence, all of which may reduce functional selectivity for inhibition of overactive Nav1.8 channels in sensory neurons. On the upside, chronic dosing over 3 months revealed a good safety profile with low side-effects, as seen in the recent acute pain Ph III study, and patients were allowed to continue taking NSAIDS (up to 500 mg every 4-6 hours) during the study which may have obscured a specific effect of Suzetrigine. The company stated that they will try and progress to a larger Ph III trial, and more carefully optimise for variable placebo responses and site compliance, and hopefully this test will also include a positive control comparator such as pregabalin or amitriptyline which are routinely prescribed for chronic pain patients.
This quarter we have a new entry (for me) in the pain portfolio, as Chinese company Xgene Pharmaceuticals announced that their pain drug combo XG005 achieved significant analgesia and beat placebo in a Ph IIb trial in chronic osteoarthritis pain patients in China. They later revealed in December that another Ph IIb trial of XG005 in bunionectomy patients in the US had also shown dose-dependent and statistically significant acute pain reduction after 48 hours with oral dosing of 750-1250 mg tablets. The company specialises in creating novel drug combinations, and XG005 is a prodrug conjugate mixture of a Cav channel a2d1 gabapentinoid and a COX-2 inflammatory enzyme NSAID inhibitor that is being tested as an oral medication in both acute and chronic pain. The company also lists a topical version (XG004) which recently completed a Ph Ib/IIa trial in osteoarthritis patients in Australia, where knee pain was reduced and statistically significant improvement in sleep quality was also seen. This approach might be as ‘sexy or cool’ as a novel first-in-class Nav1.8 blocker, but there remains an urgent and worldwide need for more effective non-opioid analgesics, and if this combination of a Pregabalin-like drug can achieve a lower NNT and fewer side effects than the parent gabapentinoid drug, then patients and clinicians will be happy.
I revealed Rapport Therapeutics work on the AMPA TARP g8 modulator RAP-219 in a previous blog in Q2 2024 after their IPO funding round, and public disclosures on RAP-219 as a novel anti-epileptic at the EILAT conference. The drug candidate completed preclinical and initial Ph I clinical development when it was at JnJ/Janssen, and Rapport had announced they were planning on taking it to Ph II in focal epilepsy later in 2024, alongside future plans for testing in neuropathic pain and bipolar disorder. However, we hear this quarter that the FDA had placed a clinical hold on the Ph IIa IND application for diabetic peripheral neuropathic pain (DPN), requesting additional information and protocol amendments. These issues appear to be specific to this program, as the Ph IIa trial in focal epilepsy is ongoing, along with plans for a proof-of-concept test in bipolar disorder.
The final nail appears to have been driven into the coffin of Eli Lilly‘s failed TRPA1 pain program, with formal publication of results from all 3 of the clinical trials of LY3526318. I covered this extensively in my Q3 and Q4 2023 blogs after discovering public disclosure of the trial results (including some statistical data) on the clinicaltrials.org website. The TRPA1 antagonist had originated in a deal with Hydra back in the day, and this ligand was previously known as HX-270. The clinical trial results for LY3526318 were overwhelming disappointing, with a complete miss to beat placebo on primary endpoint and most if not all secondary outcomes in osteo-arthritis (nociceptive) and diabetic neuropathy (neuropathic) pain patients, and a small but statistically-insignificant improvement in pain scores in patients with lower back pain. The drug had been tested as part of Lilly’s self-touted Chronic Pain Master Protocol where patients were continuously enrolled into a large pool and then assigned to specific trials for a set of potential analgesic drug candidates (this TRPA1 ligand as well as a P2X7 channel blocker being developed in collaboration with Asahi Kasei, a TGFalpha monoclonal antibody, and a SSTR4 GPCR agonist which also failed in 2024), an approach ostensibly designed to increase drug trial consistency and accelerate timelines. Whilst this concept may still work, it would appear that the usual approach of choosing common and much-sampled pain patient populations had undermined the effort, in contrast to more frequent and recent calls for more informed and aggressive pain patient stratification to find the most appropriate disease indication for each analgesic drug mechanism-of-action. One could also make the counter-argument that these ligands were never meant to be personalised precision medicines, and Lilly were looking for agnostically effective analgesics that could reduce pain across broad and common pain phenotypes, so the search goes on for such a utilitarian ligand.
Given this latest in a series of setbacks for TRPA1 as a clinical analgesia target, I was still holding out some hope that applications in respiratory ailments like asthma and chronic cough might keep it alive as a drug discovery target. Well, that optimism has been dashed by this quarter’s news on the Roche/Genentech cough program failure outlined in section 1.b above, leaving serious question marks over any remaining TRPA1 programs.
d. Other
I’m excited to write this section as it lifts the lid for readers on another active area of ion channel drug discovery they might not be aware of, which involves the APOL1 channel implicated in chronic kidney disease. I first mentioned Vertex‘s APOL1 clinical candidate inaxaplin (VTX-147) in my very first blog in Q1 2022 when it aced a Ph II trial in patients with Focal segmental glomerulosclerosis (FSGS). This quarter the company provided an update on several of their kidney disease drugs, including the fact that enrolment and dosing was progressing for the Ph III arm of the global follow-up Ph II/III testing program for inaxaplin. This is a channelopathy disease, as several ethnic and geographic groups (e.g. Africans and African-Americans) exhibit a high frequency of gain-of-function mutations in the APOL1 gene which are linked to FSGS and other chronic kidney diseases.
Following close behind Vertex are several other pharma and biotech companies also progressing earlier stage APOL1 clinical programs. Of note is AstraZeneca who announced a successful 2nd Ph I safety trial of their APOL1 ASO gene therapy AZD2373, which is targeted to so-called G1 and G2 mutant mRNA and reduces the expression of faulty, over-active APOL1 channel proteins. Significantly, this Ph I trial was carried out in patients with West African heritage and APOL1 disease genotypes, and exhibited similar safety, tolerability and PK-PD profiles with rapid distribution after sub-cutaneous injection and suitable long-term availability over days-weeks as seen in a previous Ph I trial on non-African healthy volunteers. Most importantly, both Ph1 PK-PD studies showed dose-dependent reductions in plasma APOL1 protein expression, strengthening the case for Ph II efficacy studies in patients with chronic kidney disease in 2025. The drug originated as ION532 (Ionis-APOL1Rx) and is being developed as part of a collaboration between Ionis Pharmaceuticals and AZ that started in 2018.
Also working in this space are Maze Therapeutics who reported a successful Ph I study of their oral APOL1 small molecule inhibitor MZE829 in Q4 2024. This study started a year ago based on promising preclinical data showing reduced albuminuria in chronic and acute humanized models of APOL1 kidney disease and improved kidney pathology (APOL1 is mostly expressed in specialised podocyte cells that line the blood-tissue barrier around the glomerulus, controlling the integrity and function of this key filtration interface). PK data showed dose-dependent increases in plasma levels for doses of 350-480 mg, with a t1/2 of 15 hours that predicts effective exposure from once-daily dosing. The Ph II trial is scheduled to start in Q1 2025.
Switching focus completely, I have a small but important update on Kiora Pharmaceuticals , who I highlighted a year ago in Q4 2023 based on their novel HCN channel photoswitch ligand KIO-301 for retinal disease. They announced plans for a Ph II study in retinitis pigmentosa sometime in 2024, and in October that was confirmed with the approval of their IND application. The prior Ph Ib trial in 2H 2023 showed meaningful vision improvement, but discussions with the FDA focused on adding additional functional vision tests such as navigation course and object identification and studies in patients with severe vision loss irrespective of underlying genetic mutations. This is an international effort, as the Ph Ib was carried out in Australia, and since then KIO-301 has received EU orphan status.
2. CNS disease indications
There is mostly positive news this quarter for a range of Nav1.x, Kv7.x and K2P channel modulators in epilepsy and neurodegeneration, but less promising developments in a number of NMDA, GABA-A and P2X7 ligand-gated projects in neurodegeneration and depression.
a. Epilepsy
I previously covered Xenon Pharmaceutical’s Kv7.x modulator epilepsy program status in Q3, after they presented data out to 30 months from an ongoing Ph IIb open-label extension study of XEN1101 (Azetukalner). This quarter they presented additional 6 months of OLE data at the American Epilepsy Society general meeting (AES), showing continued seizure freedom and improved quality of life, as well as a favourable tolerability profile in patients after 5 years of dosing. The follow-up pair of Ph III studies (X-TOLE2 and X-TOLE3) in more focal onset epilepsy patients are now mid-trial, with topline data expected to be revealed in 2H 2025. In addition, a parallel Ph III trial of Azetukalner (X-ACKT) has started enrolling patients with primary generalised tonic-clonic seizures (PGTCS), the 2nd major epilepsy population that Xenon is targeting with this ion channel drug. Finally, Xenon revealed a slew of earlier stage preclinical ion channel programs targeting Kv7.x, Nav1.7 and Nav1.1 for ‘various indications’, which are being progressed towards IND filings in 2025. Xenon are already testing the Kv7.x modulator Azetukalner in mid-stage clinical stage trials for moderate depression (as covered in my Q3 2024 blog), but now also reveal work on ‘multiple development candidates’ (and presumably back-ups) in epilepsy, MDD as well as pain. Ditto, the primary therapeutic indication for a Nav1.7 modulator is likely pain, but it remains to be seen how advanced this program is and whether Xenon have had a chance to learn from the mis-steps of previous clinical programs in terms of novel binding sites, selectivity, drug-like properties, poor PK, and on-target cardiac and hemodynamic side-effects. Finally, the company reveals an interest in Nav1.1 with plans to nominate a lead candidate in 2025; Nav1.1 is a genetically-validated seizure target in Dravet epilepsy patients that other companies such as Stoke and Encoded are already targeting with mid-stage genetic therapy clinical candidates. It looks like Xenon are playing catch-up, but exploiting a different mechanism-of-action of small molecule activators to promote activity of Nav1.1 channels suffering from poor expression and/or loss-of-function (an approach also taken by the likes of Lundbeck and Takeda).
Speaking of Nav1.1, a longtime player in the field Stoke Therapeutics, who I have covered extensively in previous blogs, also provided some updates on their Dravet epilepsy gene therapy at the AES meeting after the temporary FDA hold was lifted in Q3. The RNA-binding ASO STK-001 (now called Zorevunersen), has already been shown to reduce seizure severity and frequency in young patients in several Ph I/IIa open label studies in the UK and the US, as an adjunctive treatment. The new data is from open label extensions of these prior studies, and showed that low dose maintenance treatment in 73 patients continued to show disease-modifying reductions in seizures and slow wave EEG activity, and improvement in other symptoms such as cognition and behaviour for up to 24 months, and was well tolerated with no serious clinical safety signals. Whilst all this looks very promising and has lead to meaningful improvements in the young epilepsy patients and their caregivers, the real test will be the double-blind Ph III Emperor trial, which will be carried out in the US, UK, EU and Japan and is scheduled to start in mid-2025.
b. Neurodegeneration (Alzheimer’s Parkinson’s, etc)
Let’s start with some positive news, as Cerevance announced positive Ph I safety data for their K2P THIK (KCNK13) channel inhibitor CVN293. The drug was well tolerated for up to 14 days of chronic dosing and demonstrated dose-dependent exposure and robust brain penetration, supporting its potential advancement to Phase 2 studies in neurodegenerative diseases characterized by neuroinflammation such as Frontotemporal Dementia, Amyotrophic Lateral Sclerosis and Alzheimer’s Disease. I’ve written before about it’s novel mechanism-of-action, where K2P channel inhibition could prevent NLRP3 inflammasome activation and reduce neuroinflammation associated with diverse neurodegenerative diseases.
In contrast, Sage Therapeutics experienced two major setbacks for their NMDA PAM neurodegeneration drug SAGE-718 this quarter, following on from an earlier failure in Parkinson’s disease in Q2 2024. The pressure was on to extract some positive efficacy data from two ongoing Ph II trials of dalzanemdor, but prospects dimmed when a Ph II trial in Alzheimer’s Disease failed to meet it’s primary endpoint of improving executive function as well as secondary measures of cognition as reported in October. All hope rested on the remaining Ph II trial in Huntingdon’s Disease which was expected to complete in 1H 2025, but an early peek at topline data in November dashed them as no improvement in cognition was seen after 12 weeks, along with no statistically significant or clinically meaningful differences seen for secondary endpoints such as visual attention, task switching and daily life measures. The company quickly announced they were abandoning all further development SAGE-718, as well as news of staff layoffs affecting half of the R&D team and some C-level executives. All of this has brought the company the undesirable reward of a 2024 ‘rotten tomato’ award from Fierce Biotech after “pretty much everything that could have gone wrong for the brain-focused biotech seems to have occurred”. Tackling complex CNS neurodegenerative diseases is slow and difficult, especially as we still know very little of how they develop and progress, and given the underlying variability amongst otherwise similar patient populations and the lack of reliable biomarkers. However, I would add that some doubts developed after I saw preclinical data on SAGE-718 presented at the Biophysics Society “ion channel drug discovery” satellite meeting in February 2024 (some of which were published in 2023) where the effects on various rodent behavioural model readouts were very subtle, so I am not surprised by this final outcome.
c. Depression
Just like ‘Blue Monday’ (I’m writing this blog in a grey January here in the UK) – there was bad news in Q4 with three setbacks for anti-depressant ion channel projects.
I’ve written before (Q4 2022, Q3 2023) about Relmada Therapeutics struggles with their NMDA antagonist NRL-1017, which initially failed in Ph III as a monotherapy for major depressive disorder (MDD) but was eventually progressed to Ph III trials as an adjunctive therapy. Well, there was a steady stream of negative findings in 2H 2024, as publication of results in June from the first Ph III trial showed that the NMDA receptor inhibitor Esthmethadone missed the primary endpoint (but the company was still spinning some marginal efficacy vs placebo with statistical p values of 0.044 and 0.076), and then further interim analysis of another Ph III trial convinced the company to halt both of their ongoing Ph III trials in December and explore `strategic options’ which included mergers, asset sell-offs or outright company sale, although there is still an active psilocybin program for metabolic disease. This is a cautionary tale many of us have seen before where a company refuses to give up in the face of mediocre Ph II and Ph III data confounded by variable patient enrolment and placebo and competitor response rates, and changes in primary therapeutic population – some drugs have come through to eventual success, but most ultimately fail on such a trajectory.
Similar but different news from Sage Therapeutics who were far more sanguine in their assessment of several antidepressant programs based around their GABA-A PAM platform. Firstly, they decided to phase out their drug Zulresso which was approved in 2019 to treat MDD, but sales and uptake suffered from the need for i.v. administration (e.g. sales < $1 million in Q3 of 2024). Also playing a role in this decision was the fact that their oral follow-up Zuranalone had failed to gain FDA approval in MDD last year, but was being continued (as Zurzuvae) as an approved treatment for post-partum depression. The company also apparently decided to drop 2 other development candidates in their depression portfolio. Other setbacks in their neurodegeneration projects outlined above have added to the pressure on the company, triggering some aggressive commercial moves with their partner Biogen which I will cover in the Q1 2025 blog.
Another long-running ion channel anti-depressant story also appears to have come to an end in 2024, with JnJ closing down two separate but related P2X7 assets. First up is JNJ-54175446 which I covered previously in 2022 and 2023 (and started in 2016). The company has been developing these oral, CNS-penetrating P2X7 antagonists to treat neuroinflammation (NRLP3 inhibition) and reduce cytokine production, and chose to test both in MDD and bipolar disorder. They ran a small Ph II study here in Cambridge (UK) in 2022 with unpublished outcomes, but the outcome of another clinical study using sleep deprivation to engage P2X7 receptors in MDD patients was published in 2023 to reveal no change in mood but mild-moderate adverse events. Perhaps not surprisingly, this asset no longer appears on the company pipeline as of Q4 2024. The study did show target engagement in human patients as measured by inhibition of ATP-induced IL-1β cytokine release in peripheral white blood cells, but clearly there is a disconnect when looking for therapeutic effect in the CNS of bipolar and MDD patients, perhaps due to poor translation from preclinical rodent behavioural models and drug-induced mood effects in healthy volunteers, and/or lack of sufficient P2X7 receptor activation in these neurology patients and diseases? This quarter there was news that a 2nd JnJ P2X7 CNS program had also been cancelled, with the company revealing that the Ph II asset JNJ-55308942 had been removed from their pipeline after a clinical study in over 100 bipolar patients with major depressive episodes had completed in May. This ligand has also disappeared from their corporate development pipeline.
d. Other CNS indications
GRIN Therapeutics continue to progress Radiprodil, a selective NR2B NMDA NAM, in several rare and complex neurodevelopmental disorders. This quarter they initiated a Ph II trial in young patients with tuberous sclerosis complex and focal dysplasia type II who suffer from treatment-resistant seizures that affect CNS development and function, sleep, motor function and overall quality-of-life. This comes on the back of positive topline data released in September from an open label Ph Ib trial of Radiprodil in young patients with gain-of-function mutants in NMDA receptors in GRIN-related neurodevelopmental disorders, where the drug produced a remarkable 86% reduction in seizure frequency. Radiprodil was originally discovered by Gedeon Richter (RGH-896) in Hungary over 15 years ago, but failed to show efficacy in its incarnation as an analgesic, so this drug is another example of the long and tortuous path that ion channel modulators can take towards a successful clinical outcome.
NMD Pharma are also targeting a rare and complex neurological syndrome by starting a Ph IIa trial of their CLC1 Cl- channel small molecule activator NMD670 in patients with Charcot-Marie-Tooth disease (CMT), after gaining IND approval from the FDA in June. The randomized, double-blind and placebo-controlled study is being conducted in the US and Europe to ensure enrolment of sufficient patients with rare and genetically-confirmed CMT1 or CMT2 subtype disease. CMT is a progressive inherited ailment that affects peripheral nerves and weakens the neuromuscular junction and muscle strength important for walking, breathing, and overall mobility and quality-of-life. NMD670 is also currently undergoing Ph II trials in the muscle-related diseases myasthenia gravis and spinal muscular atrophy (SMA), as I have reported in previous 2024 blogs. The small Danish biotech company obviously has a lot on, and this work is being supported by a recent €75 million Series B funding round that closed at the end of 2023.
I’d like to wrap up the CNS section with a surprising and positive twist in the long-running drug discovery story from the pioneering Aussie ion channel biotech Bionomics, who I have covered before (and unfortunately tried to write-off). Well, it seems they refuse to die and this quarter they released positive Ph IIb results for their a7 nAChR PAM BNC210 in social anxiety experienced by PTSD sufferers. The study results were published in a New England Journal of Medicine imprint no less, revealing that the study (initiated in July 2024) had seen improved PTSD symptom severity at Week 12 with efficacy observed as early as Week 4, although the effect was marginal with a p value of 0.048 vs placebo; there were also clinically meaningful and statistically significant improvements in secondary measures such as depressive symptoms and sleep. However, significant adverse events were seen (66.7% in treatment group and surprisingly high 53.8% in the placebo group), and alongside headache, nausea, fatigue were some signs of elevated hepatic enzymes, which will no doubt be monitored carefully in future studies and may limit human dosing. This lifeline has now triggered plans for several Ph III trials, with one starting enrolment in July 2024 for social anxiety disorder that is expected to readout in Q3 2025, and ongoing discussions with the FDA for trial design and dosing approval in PTSD which is slated to start in 2H 2025. And finally there is also some corporate change during this period, with Bionomics re-domiciling to the NASDAQ in the US and renaming themselves as Neuphoria Therapeutics.
3. Ion channel collaborations and M&A activity
It was quite a busy quarter (compared to Q3 for sure), with a number of funding rounds, licensing deals and collaborations for CNS and pain biotech and pharma companies.
I’m reluctant to focus on the money side of this business, but lets start with a couple of items on some large funding rounds for CNS players as there has been some hand wringing over the depressed state of the biotech, M&A and IPO market in recent months. First up are Biohaven who announced a successful $250 million public share offer, which will hopefully be used in part to continue progress of their mid-phase TRPM3 (BHV-2100) pain and advanced Ph III Kv7.x (BHV-7000) epilepsy projects, both of which I have covered in previous blogs.
Next up are Seaport Therapeutics in Boston, the CNS start-up that includes ex-Karuna executives, who raised $225 million in a Series B round to progress various CNS drugs. Included in their portfolio is lead candidate SPT-300, a pro-drug of the GABA-A neurosteroid allopregnanolone with similarities to Sage’s Zulresso which was approved as an i.v. for depression a few years ago (but will soon be withdrawn as noted in section 2.c above), but which has been optimised for oral administration which should widen the available patient population considerably. A Ph IIa trial of SPT-300 has already been conducted, with some of these new funds slated to help it advance to a Ph IIb study of major depressive disorder in 2025.
The neuronal ion transporter KCC2 seems to be ‘having a moment’ these days with several publications on mouse and human genetics and new pharmacological tools demonstrating it’s role to regulate peripheral and CNS neuronal excitability. So, it is perhaps no surprise that Axonis Therapeutics have completely come out of the shadows with an over-subscribed $115 million Series A funding round in Q4, focused on their lead candidate KCC2 activator AXN-027 which is currently in a Ph I trial, with plans to progress it into Ph II trials in refractory epilepsy, chronic pain, and spinal cord injury. The company will also sue the monies to develop some preclinical back-up KCC2 modulators. The idea behind small molecule KCC2 openers/activators/potentiators is two fold: loss-of-function mutations have been found in human patients with neurological disorders, and in normal tissue the K+/Cl- counter-transporter helps to reduce cytoplasmic Cl- ion levels and set the resting membrane potential and excitability of peripheral and central neurons, particularly inhibitory neurons that also express GABA-A receptors whose upregulation could help reduce network firing in pain and epilepsy – as shown in a graphic from their website:
There was also a suitably generous $100 million Series C funding round for SiteOne Therapeutics, who haven’t had a mention in my blogs for quite some time due to setbacks and delays with their primary Nav1.7 pain program (which like Merck and Genentech also recently revealed some CV and hemodynamic side-effects of lead candidate ST-2560). Whilst still stating an intention to continue pursuing Nav1.7 as a pain target (and perhaps still involving Vertex who signed a collaboration with them in 2022), this release highlighted their parallel work on Nav1.8 which as most everyone knows is now a very hot analgesia ion channel target (certainly compared to previous front-runners such as Nav1.7, TRPA1, TRPV1 and P2X). The company was founded on the finding that Nav1.7 channels lack sensitivity to saxitoxin, resulting in some reverse engineering of natural product-derived guanidium analogues that potently and selectively blocked Nav1.7 channels and reduced pain in preclinical animal models. However, I am not certain of any structural overlap in their newer Nav1.8 ligands, at least based on a 2023 patent of some bicyclic amides. The company received $15 million of NIH HEAL non-opioid pain grant funding in 2023 for preclinical work on Nav1.8 (and Nav1.7), and now state that their lead program revolves around Nav1.8, so the pivot now seems to be gaining momentum, and will encompass pain as well as cough and itch. And just to clarify any potential confusion in recent news articles and posts on the SiteOne Therapeutics Nav1.7 and Nav1.8 programs, the Nav1.8 lead clinical candidate is indeed STC-004 and this just completed a Ph I safety and PK-PD study in New Zealand.
Another deal that probably also involves Nav1.8 channels (and perhaps other analgesia ion channels), Orion Pharma announced a collaboration with the monoclonal antibody company Abilita Therapeutics. Abilita have previously worked on Nav1.7 channels while Orion have history with TRPA1 and Nav1.8 (e.g. in-licensing the clinical Nav1.8 pain asset JMKX000623 from Jemincare, which I covered in my Q2 2022 blog), but the deal also listed future work to find mAbs for oncology targets as well.
Keeping on the pain theme, the small Irish outfit Relevium Medical received additional funding of €4.6 million from the Disruptive Technologies Innovation Fund (DTIF) to progress their TRPV1 capsaicin gel for OA knee pain. This follows on from a €2 million award from the European Innovation Council (EIC) in 2022 to develop a triple-action injectable treatment for osteoarthritis. I mentioned previously how I was surprised that drug discovery work on TRPV1 was continuing many years after major pharma dropped the target due to systemic body temperature effects, but this has left space for several biotech and pharma players working on topical and injectable reagents to locally desensitise or block TRPV1 activity in painful tissues.
A new entry into the database and my ongoing narrative on ion channel companies is the small Manchester (UK) outfit Monument Therapeutics, who raised another £1 million in equity investment to support in part the clinical development of their nAChR agonist MT1988. This funding will help initiate a Ph I PoC study to look for improved cognition in schizophrenia patients, as well as preclinical work in autism.
On the back of a successful Ph I study in October for their APOL1 kidney ion channel program (MZE829), Maze Therapeutics closed a $115 million Series D funding round in December 2024. These new funds will be used to progress several of their kidney disease assets, including the APOL1 ligand which is due to enter Ph II efficacy trials in Q1 2025. Together with the clinical updates I outlined for the AZ and Vertex APOL1 clinical programs in section 1.d above, it would appear that work on this novel kidney ion channel is heating up and progressing well, and may well bring in more players depending on how these more advanced assets fare going into 2025.
Now we have ‘1 good, 1 bad’ in terms of ion channel collaborations. Good news for Danish biotech Saniona as well, as Acadia Pharmaceuticals announced a licensing deal for their GABA-A PAM SAN711 for Essential Tremor. The $582 million biobucks deal includes a $28 million upfront payment, to be followed by potential milestones up to $147 million if certain development and commercial events are met for the primary and a second indication, plus downstream sales and marketing royalties up to $435 million (according to Fierce Biotech). Acadia are in charge of future clinical development, regulatory submissions and commercialization activities for SAN711, and will provide funding so that Saniona can continue with their ongoing Phase 1 study and prepare for a Phase 2 trial in Essential Tremor slated to start in 2026. Acadia have a CNS focus with programs for both rare (Prader-Willi syndrome) and common neurological indications (Alzheimer’s disease and other neuropsychiatric disorders). I previously covered the recent mixed news in the Essential Tremor space, where Neurocrine Biosciences Cav3.x T-type blocker NBI-827104 failed to show efficacy in Ph II studies earlier in 2024, but Praxis Precision Medicine had decided to progress another Cav3.x T-type blocker PRAX-944 into Ph III trials after mixed Ph II data. In contrast, Saniona’s SAN711 has a different target and MoA as it is an alpha3-selective GABA-A receptor PAM which is expected to dampen over-active CNS neurons and help improve fine motor control. Saniona appear to be retaining rights to develop SAN711 as an anti-epileptic and analgesic, supported by their preclinical work to-date.
Speaking of Neurocrine Biosciences, there was disappointing news in Q4 that their long-running ion channel collaboration with Idorsia had been terminated after repeated failures of their Cav3.2 T-type blocker NBI-827104 (ACT-709478). I have previously covered the genesis of this program, which started as an analgesic at Actelion and then was re-branded and tested as an anti-epileptic at Idorsia, before Neurocrine licensed it in 2019 and re-purposed it for Essential Tremor and DEE epilepsy. Ph II efficacy trials in those latter indications both failed in 2022 leading to Neurocrine closing down their program, and this quarter Idorsia followed by ending the development agreement after failing to see efficacy in further analysis of an open label extension epilepsy study they had been running. This ion channel modulator has certainly had quite a tangled and convoluted journey, but we are left with more recent ion channel ligands for other targets in the Essential tremor and epilepsy space, so the work goes on!
And to conclude I have a short but positive update on Evenamide (NW-3509), a Nav blocker that also inhibits glutamatergic neurotransmission and reduces neuronal excitability which I have covered previously. Newron Pharmaceuticals have been running a comprehensive Ph II/III program in schizophrenia patients which has produced some promising results (covered in my Q2 2024 blog), and this quarter they announced a licensing deal for clinical development and eventual marketing in Japan with EA Pharma, a subsidiary of Eisai Co Ltd. EA Pharma will develop, manufacture and commercialize Evenamide in Japan and other designated Asian territories, in return for paying Newron €44 million upfront and contributions to running the big Ph III trial in H1 2025, as well as regulatory and commercialization milestones up to a maximum of €117 million, and double digit sales royalties.
Dr. Marc Rogers, Cambridge (UK)
aka The Channelogist
