Expert opinions

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Ion channel ligands in clinical development – Quarterly review (Q4 2023)

The big news in Q4 2023 was mixed, with failure of a TRPA1 pain program at Eli Lilly, FDA rebuffing Merck’s P2X3 cough drug Gefapixant, Neurocrine Biosciences (via Xenon) Nav1.6 blocker failing to reduce seizures in focal epilepsy patients, and Boehringer Ingelheim dropping their ENaC inhibitor for cystic fibrosis. On the plus side, Xenon’s Kv7.2/3 opener showed efficacy in a Ph II epilepsy trial (but missed in major depression), Vertex continued their good run with a positive outcome from a chronic pain test of their Nav1.8 blocker VX-548, and Praxis Precision Medicines finally being able to show that their Nav1.2 ASO PRAX-22 reduces seizures in youngsters with DEE epilepsy. There were also a couple of large M&A deals announced in Q4 of 2023, including the significant acquisition of Caraway Therapeutics by Merck for their TMEM175 and TRPML1 lysosomal ion channel programs for neurodegeneration. Other major CNS deals also got attention, and I highlight how ion channel programs are included in the assets of Karuna Therapeutics acquired by BMS alongside their high profile advanced schizophrenia treatment KarXT, and a mid-stage GABA-A modulator included in the Cerevel neurology assets acquired by Abbvie.

The main focus of this series is to highlight the progress being made in ion channel clinical drug development, which is a key validation parameter for target selection along with other considerations such as human genetic data, cryo-EM structures for drug design, availability of relevant animal models, and therapeutic indications. I’d like this discussion to help overcome perceptions that ion channels are ‘difficult’ drug discovery targets, and the tendency for historical failures to get blamed on the target class rather than the discovery process itself. We all know that drug discovery is a tortuous and expensive journey regardless of target or modality, so it is important to recognise the successes (and learn from the pitfalls) of ion channel modulators reaching clinical trials.

1.      Peripheral disease indications

a. Cardiac and Musculo-skeletal ion channel targets

First up are Acesion Pharma who I have mentioned in previous blogs. Their initial intravenous SK KCa channel blocker AP30663 completed a successful Ph II trial in atrial fibrillation conversion earlier this year, and the results were published in Nature in December. The company have also been working on an oral follow-up AP31969 to maintain sinus rhythm in  chronic AF, and it entered a Ph I FIM study this quarter as well.

There is also a financing update from NMD Pharma, who are developing muscle CLC-1 ion channel modulators for myasthenia gravis, and in Q3 I highlighted their additional efforts to use NMD670 to treat spinal motor atrophy (SMA, Ph II trial) and musculo-skeletal defects in patients with Charcot-Marie Tooth disease (CMT, Ph 0 exploratory trial). All this clinical work is going to be expensive, and in Q4 they announced an $80 million Series B funding round which will support this work in Denmark and in the US.

b. Sensory system modulators

The Axxam spinout Acousia (highlighted in the Q3 2023 and previous blogs), based in Germany, announced that they had gained German approval for Ph II efficacy testing of their Kv7.4 opener ACOU085 in testicular cancer patents undergoing chemotherapy. The drug is classed as an otoprotectant as it can both reduce, and hopefully prevent, the common side-effect of cisplatin-induced hearing loss by acutely and chronically enhancing the function of outer hair cells (OHC) in the cochlea of the inner ear. ACOU085 is delivered transtympanically as a slow-release gel formulation. The Ph II study was slated to begin this quarter, but the first patent was eventually dosed in February of 2024.

Next up is something a little different from the usual small molecule modulators, highlighting the clinical potential of a largely academic optical technique to treat patients with different types of blindness. Kiora Pharmaceuticals (formerly knows as EyeGate Pharma) are developing KIO-301 for the treatment of retinitis pigmentosa and other under-served retinal diseases such as choroideremia and Stargardt’s Disease. KIO-301 is an example of a photoswitchable small molecule which changes conformation (cis/trans) and receptor binding affinity in response to illumination, in this case targeting inhibitory HCN hyperpolarisation-activated cation channels (and perhaps also Kv channels?) in retinal ganglion cells, which then increases cell excitability and ‘reanimates’ damaged retina. Also of note is that the scaffold is not cell-permeable (and is injected intra-vitreally), so additional retinal and disease specificity is achieved by relying on the opening of large ion channel pores (in this case P2X7 receptors) to enable ligand entry into the target cell cytoplasm (see Fig. 1), similar to the approach taken by Nocion Therapeutics with their sensory neuron  cough and pain ligands. KIO-301 was granted Orphan Drug status by the FDA in March 2022, and recently completed a successful Ph Ib clinical trial in Australia in 2H 2023, with ‘meaningful vision improvements’ in blind patients in the ABACUS-1 study revealed in November. These allowed for an IND approval in Q4 of 2023 to expand the Ph Ib study to patients with late stage retinitis pigmentosa (and introduce a sham group), and also treat patients with other inherited retinal diseases. A full Ph II study in retinitis pigmentosa patients is planned for 1H 2024.

Figure 1: Mechanism-of-action of Kiora Pharma’s photoswitchable retinal ligand KIO-301.

c. Respiratory diseases

The two Q4 updates in this category were unfortunately negative, but on the upside they were up against fierce competition from major players in the cough and cystic fibrosis therapeutic areas who have made progress in the clinic and respiratory disease market in 2023, so patient needs are being met.

The bumpy road for Merck’s P2X2/3 cough drug Gefapixant finally came to an end in the US (whilst it remains approved in Japan and the EU), with the FDA eventually rejecting market approval by a resounding 12:1 adverse ruling of the AdComm meeting in Q4 2023. The main issue was ‘moderate’ clinical efficacy to reduce refractive cough frequency in clinical trials, which also exhibited a high placebo response and some of the well-known taste side-effects for this class of drug.  This was actually the 2nd FDA rejection of Gefapixant, the 1st in 2022 triggering a recount of cough data in two previous clinical trials to address the FDA concerns, but ultimately to no avail. This likely leaves the Bellus Health P2X3-selective ligand BLU-5937 (Camlipixant) as the leading contender in this market, with Ph III trials underway and the company recently acquired by GSK in Q2 2023.

Also falling by the roadside was Boehringer Ingelheim’s cystic fibrosis drug candidate BI 1265162. This is an ENaC channel inhibitor that targets a different mechanism to Vertex’s CFTR ‘potentiators’ and ‘correctors’ to re-balance fluid and mucus levels in the lung of CF patients, regardless of their CFTR genetic mutations. DrugHunter included this ligand in their December 2023 ‘molecules of the month’ poster, and referenced a recent publication which summarised the discovery and development of this inhalable compound, but this paper also revealed it had been terminated at Ph II for lack of efficacy (2022 paper here), and was now being made available as a tool compound through BI’s opnME open access portal. On the plus side, this news may open up some more opportunities for Enterprise Therapeutics own ENaC modulator ETD001, which is slated to enter Ph II trials in coming months after they close their next funding round.

d. Pain

We have to start with the high profile and much-covered announcement in Q4 2023 from Vertex Pharmaceuticals that their Nav1.8 blocker VX-548 had aced another pain clinical trial, in this case a Ph II study of chronic neuropathic pain. Previous Ph II studies which I covered in past blogs (and three ongoing Ph III trials) had focused on broad patient populations suffering from acute pain after bunionectomy and abdominoplasty operations, and both had demonstrated significant analgesia for the highest dose of VX-548 against a number of primary and secondary endpoints, and also beaten placebo and a standard-of-practice pill containing an NSAID and opiate combination. The significance of the new trial is that it was the first demonstration that VX-548 could also reduce chronic pain (in this case diabetic painful neuropathy, DPN), which is the holy grail of analgesia drug discovery as chronic pain patients are poorly served by current treatments and there is a major effort to wean them off addictive opioids.

However, while VX-548 met it’s primary endpoint to reduce pain scores and all three dosing levels were statistically significant against the pre-drug baseline, the sample size of the trial did not allow for statistical comparison against the standard-of-care Lyrica (Pregabalin, a Cav channel a2d subunit modulator), and the study rather surprisingly did not include a placebo group. Looking at the data (Fig. 2), it is clear that VX-548 matches the performance of Pregabalin across multiple pain metrics, and is unlikely to be statistically different. They seem to have lost ~10% of participants from several study sites which probably didn’t help for sample sizes, and are characterising this as a POC trial. Nevertheless, VX-548 slightly exceeded the pain score analgesia produced by Pregabalin across all three dosing regimes (‘low’ and ‘middle’ doses were similar to the acute pain trials, and the DPN trial also had a ‘high’ dose of 69 mg bid), and the new drug achieved this with once daily dosing compared to thrice daily for the gabapentinoid. Some mild side-effects were seen with VX-548, but these are expected to be less common and severe than typically seen for Lyrica (which carries a warning for breathing difficulties and CNS effects such as suicidal ideation), and can be so debilitating that patients actually choose to stop this pain medication.

Figure 2: VX-548 Nav1.8 blocker matches analgesia of Pregabalin in chronic DPN pain trial

As well as two Ph III acute pain trials underway in larger groups of bunionectomy and abdominoplasty patients that are expected to readout in Q1 of 2024, Vertex are also running a Ph II trial in another chronic neuropathic pain indication, lumbo-sacral radiculopathy. The company also said they will seek FDA approval to follow-up on the recent result by starting a Ph III trial in a larger group of DPN patients, which hopefully will be designed and powered sufficiently to allow statistical comparison to placebo and standard-of-care reference drug groups.

Another ‘old’ analgesia story and target mechanism that is still working its way through the clinic is TTX injections. Wex Pharma has conducted several Ph II and III efficacy trials of Halneuron in North America and Asia in patients suffering from chemotherapy and cancer and pain in the last few years which reached statistical significance, but the drug is yet to be approved by the FDA. In Q4 of 2023 they announced their first clinical test in Europe, starting a Quantitative Sensory Testing (QST) study in healthy Dutch volunteers to determine dose-dependent effects of TTX on different pain sensations.

And we also have a new spin on some traditional pain targets in Q4, with the Israeli start-up Bsense Bio Therapeutics revealing that they have nominated a clinical candidate from their novel, dual TRPV1-Kv7.2/3 modulator program. BSEN661 was the earlier preclinical lead, and now BSEN760 has been developed, which is a small molecule that synergistically combines inhibition of TRPV1 receptors and activation of M-current Kv7.2/7.2 channels, thereby interfering with the detection and transmittal of painful stimuli. It is an intriguing mechanism directed at validated analgesia proteins (which may co-localise in DRG sensory neurons), and I am keen to find out more about this scaffold and it’s selectivity for each class of nociceptor signalling target, and also it’s safety profile. Poking about a bit in the literature published by the company’s co-founders from Tel-Aviv University reveals a collection of papers describing a series of so-called ‘NH’ small molecules (e.g. diphenylamine carboxylates) discovered and later optimised as Kv7.2/3 activators that act in a similar fashion to scorpion and sea anemone gating modifier toxins to trap the voltage-sensor and promote M-channel opening (Fig. 3), but which were also serendipitously found to inhibit TRPV1 receptor VSDs in an analogous fashion to tarantula spider toxins. Intriguingly, these authors also described analogues that had opposite (and potentially very painful) effects, activating TRPV1 receptors whilst also stabilising the closed state and inhibiting Kv7.2/7.3 channels. Small molecule VSD binders are better known as Nav1.x inhibitors (think Nav1.7 sulphonamides, and recent Nav1.8 blockers such as Latigo’s LTGO-33), but there may be a lot more opportunities for similar modulatory mechanisms and binding sites on other voltage-sensitive ion channels.

Figure 3: Dual TRPV1 inhibiting and Kv7.2/7.3 activating VSD gating modifier small molecule.

The key to the Bsense ligands seems to be that the small molecule retains pM-nM potency for both targets, and thus very low exposures can achieve dual target engagement and drive efficacy without the need for higher exposures at which off-target effects on other ion channels and GPCRs, etc can dial-in safety concerns. The company claim that BSEN760 is nM potent in vitro and in vivo after oral dosing in chronic neuropathic and osteoarthritis pain models, but without locomotor or body temperature and thermal sensation deficits typical of past TRPV1 and Kv7.x modulators. The company is also targeting tinnitus and itch, and aims for an IND filing in 2025.

I will finish this section with more information on the notable failure of Eli Lilly‘s TRPA1 pain antagonist LY-3526318. In the Q3 blog I went into quite some detail on this topic after Eli Lilly posted full results, including statistical analysis, from a Ph II trial in osteo-arthritis knee pain that showed a complete lack of efficacy against almost all primary and secondary endpoints. The bad news continued, as the company also posted topline results for the diabetic peripheral neuropathy and lumbo-sacral lower back pain Ph II clinical trials. Neither dataset included a full statistical analysis and I have not tried to analyse it myself, although it appears that there was some moderate efficacy on some pain score readouts in the lower back pain sample, but less effect in most secondary endpoints (e.g. rescue medication). Significantly, Eli Lilly have since omitted LY-3526318 from the clinical development pipeline listed on their website. While this is obviously disappointing news, especially given the major effort that Eli Lilly put into developing this TRPA1 antagonist as a novel non-opioid analgesic for chronic pain, it doesn’t necessarily signal the death knell for the target. I’ve worked on several TRPA1 drug discovery projects over the years, for both pain and respiratory indications, and it now seems clear that the former therapeutic area is no longer validated (and Genentech would seem to agree, as I outlined in my Q3 2023 blog). However, Genentech (GDC-6599) and a couple of other pharma and biotech companies are still working on TRPA1, and the focus now seems firmly to be on cough and other respiratory diseases, so I look forward to seeing how those progress in the future.

2.      CNS disease indications

a. Epilepsy

We should start here as there were quite a few announcements and updates in Q4 on various ion channel modulator programs for epilepsy. I’ll begin with an update from Praxis Precision Medicines on their Nav1.2 gene therapy PRAX-222 for SCN2A developmental epilepsies (DEE). This is an ASO designed to reduce the activity of gain-of-function mutations in the Nav1.2 channel gene and protein, and after some caution from the FDA in 2023 the project has progressed and there is now ‘encouraging initial clinical data’ from the initial cohort of 4 young patients, as well as a newborn baby with a poor prognosis that was genetically profiled and treated through expanded access. Seizures were reduced by 44% and seizure-free days increased after 3 monthly 1 mg intrathecal injections, and this low dose of ASO was well tolerated with no adverse events. This promising start should allow the FDA to approve further enrolment in a global trial in 2024 to dose a larger number of genetically-profiled young children and adolescents suffering from this debilitating and progressive rare disease. There was further good news in November as the European Medicines Agency awarded Priority Medicines designation to PRAX-222 for the treatment of SCN2A-DEE. PRIME designation provides support for priority medicines that target an unmet need. This press release also revealed that PRAX-22 will now be called Elsunersen.

I have previously reviewed several Kv7.x channel programs targeting epilepsy – Eliem’s ETX-123 was ‘paused’ in 2023, but Biohaven announced promising interim results for BHV-7000 from a Ph I PD target engagement biomarker study in Q3 2023. This quarter Xenon published a JAMA paper outlining the efficacy and safety of their selective Kv7.2/7.3 opener XEN1101 in a Ph IIb focal epilepsy trial (X-TOLE) that concluded in 2022. The novel anti-convulsant decreased monthly seizure frequency in a statistically-significant and dose-dependent manner (by 33-50% compared to a placebo response of 18%), and was well tolerated with side-effects similar to standard-of-care anti-seizure drugs. The company website also lists two posters at the Sept 2023 International Epilepsy Congress detailing positive results from the open label extension studies of the Ph IIb trial. Two identical and parallel Ph III trials in focal onset seizure are now underway according to Xenon’s website, testing two doses of XEN1101 as adjunctive therapy in patients already taking anti-convulsants. The company is also expanding their epilepsy portfolio by testing XEN1101 in an ongoing Ph III trial in primary generalized tonic-clonic seizures (NCT05667142).

Saniona have also been quietly progressing their Kv7.x epilepsy program, and this quarter announced the nomination of SAN2355 as their clinical candidate. This drug is another Kv7.2/7.3-selective activator designed to overcome the issues with the non-selective opener Retigabine, which showed promising anti-convulsant effects in human patients but serious adverse side-effects which lead to it’s removal from the market.

In contrast, there was disappointing news in Q4 from Neurocrine Biosciences, whose Nav1.6 blocker NBI-921352 (XEN901, which they licensed from Xenon a few years ago) failed to show efficacy to reduce seizure frequency in a Ph II trial in focal epilepsy. The drug was dosed as an adjunctive therapy (much like Xenon’s XEN1101, above), and it may be asking a lot for one Nav1.x channel antagonist to exert additional effects when patients are already taking one or more other, but less selective, Nav1.x anti-convulsants. XEN1101 is a Kv7.x channel opener and thus has a different mechanism-of-action to Nav1.x blockers, and may affect a different set of neurons (i.e. inhibitory) to those being targeted by Nav1.x antagonists (e.g. excitatory). Whilst further development of NBI-921352 in focal epilepsy is being halted, Neurocrine Biosciences say they will continue to work on SCN8A-related developmental epileptic encephalopathy (DEE), including efforts to advance the pre-clinical dual Nav1.2/1.6 inhibitor they also licensed from Xenon alongside XEN901.

There are also a number of clinical programs addressing epilepsy with GABA-A modulators, although Eliem’s ETX-155 was parked after issues with their Ph Ib photo epilepsy trial. In this quarter Saniona continued their phoenix impression by presenting positive preclinical results in a predictive animal model of absence seizures at the October Society for Neuroscience conference for SAN711, which is an a3-selective GABA-A PAM. I am including it here in this clinical update as the asset has a safe Ph I profile (for an initial indication in neuropathic pain which has since been dropped) and showed good CNS receptor occupancy in a human PET study, and is now being lined up for Ph II testing (perhaps via out-licensing) in childhood absence seizure epilepsy. The company also has a follow-up in SAN2219 which is a preclinical asset with mixed a2/a3/a5 GABA-A ionotropic channel selectivity that they think is suitable for both common and rarer forms of epilepsy. I wasn’t the only one to have doubts about the future of Saniona a few years ago when they hit the buffers, but kudos to their staff and investors for sticking with it and continuing to develop and progress their ion channel portfolio for epilepsy and fibrotic disease (SAN903).

b. Depression

In this quarter we have a decidedly mixed bag of news for ion channel ligands under clinical development to treat depression.

I made a brief mention previously about a neuro-inflammatory P2X7 ligand that the University of Cambridge was trialing for depression (JNJ-54175446, in Q1 of 2022), and updated clinical trial records show that the Ph II study started in 2019 and was expected to complete primary stage by the end of 2023 and end sometime in 2024. In Q4 there is further news from Johnson & Johnson (via a DrugHunter post) that they ran their own clinical program staring in 2016 and have now published data from a Ph Ib study showing the ligand to be safe and reasonably well tolerated, but did not alter mood or depression ratings in a rather brief 10 day study period of a small sample of patients suffering from MDD. Researchers used a novel technique of acute sleep deprivation to elicit transient changes in mood, and the only meaningful outcome seems to be a reduction in acute anhedonia after sleep deprivation; a note of caution that this was a small Ph I PK-PD study and so not powered to pick-up subtle changes in behaviour and mood, which will require a larger Ph II study. Also, whilst the P2X7 blocker was designed to reduce CNS microglial release of inflammatory cytokines, there was no difference in a key cytokine concentration in blood samples from the patients, although the drug was able to reduce IL-1b release from LPS-stimulated PBMCs in ex vivo samples.  Several other companies are pursuing P2X7 inhibitors as neuroinflammatory treatments, with potential to treat neurodegenerative disease, as these large pore ion channels are upstream regulators of the NLRP3 inflammasome.

I have previously outlined the players looking to develop NMDA GluR modulators for depression (e.g. Gilgamesh Pharma’s GM-1020, NRx Pharma’s NRX-101, Atai Life Sciences failed PCN-101, and the tortured path of Relmada Therapeutics’ REL1017).  To finish up this section we have the news that Alto Neurosciences raised a $45 mill Series C fundraising round, with the money largely slated to support 4 ongoing and planned Ph II trials in depression, PTSD and neurodegeneration. These include a BDNF ligand (ALTO-100) and ALTO-300 (the atypical antidepressant agomelatine which targets the melatonin and serotonin signalling systems), as well as a PDE4 ligand for schizophrenia and an H3 ligand for MDD. However, the ALTO-202 NMDA NR2B ion channel program that I have been tracking seems to have dropped off the radar; it is not listed on the website as an active clinical program, nor listed on the NCT clinical trials website, although the company pipeline shows it has completed Ph I testing (and I had information it was expected to complete a Ph IIa trial in mid-2023). It is also not mentioned in the Q4 2023 funding press release, although there is reference to “ALTO-203 going into Ph II POC trials in 2024-2025”, which one might speculate is a back-up to the previous NMDA-R clinical candidate?

Finally, there is some disappointing news that Xenon Pharmaceuticals Kv7.2/7.3 opener XEN1101 failed to show efficacy in a Ph II trial in major depression. The drug failed to achieve statistical significance over placebo, but the biopharma company seemed keen to highlight some positive data in secondary readouts such as a “clear dose response” and a “clinically meaningful” difference between the placebo and high dose treatment arm in a secondary depression rating scale, and was keen to continue assessing it’s potential (see this Endpoints article). XEN1101 was successful in a Ph II epilepsy trial (see above), so further clinical development is likely, perhaps for both CNS indications.

There was also news in Q4 2023 from major players in the CNS space who are working on indications such as schizophrenia and neurodegeneration, but they were the subject of major M&A announcements this quarter so I will cover them in the final section below.

3.      Ion channel company licensing deals and collaborations

The big M&A news item in Q4 was the announcement that BMS (Bristol Myers Squibb) had agreed to acquire Karuna Therapeutics for $14 billion to boost their neuroscience portfolio – one of several examples of big pharma returning to CNS drug discovery after many left the field in the 2010’s. Most of the potential value of the deal surrounds Karuna’s advanced schizophrenia drug candidate KarXT, which was accepted for review by the FDA at the end of November and has an approval decision date set for September 26, 2024; it is also being tested in Alzheimer’s Disease psychosis. I include this item in my clinical blog as I have previously discussed how Karuna acquired a package of TRPC modulators in their buy-out of Goldfinch Bio in Q1 2023. These ligands had gone into clinical trials for kidney disease, but Karuna intended to re-purpose them for mood and anxiety, so we will have to keep an eye out for their eventual fate once BMS digests and assesses its new neuroscience assets.

Second on the big ticket MA& list is the news that AbbVie bought out Cerevel for $8.7 billion, another deal designed to boost CNS therapeutic pipelines. Cerevel has a number of mid- and late-stage psychiatric assets and clinical programs, with several targeting dopamine and muscarinic GPCRs to treat schizophrenia, Parkinson’s disease, and dementia-related apathy. The Ph II schizophrenia asset Emraclidine seemed to get a lot of press as it has a similar mechanism of action to Karuna Therapeutics’ late stage schizophrenia drug KarXT (see above). Also in the clinic are the Ph III Parkinson’s disease candidate tavapadon, and a Ph IIa dementia-related apathy asset CVL-871. As above, I include this financial news item as Cerevel also have the anti-epileptic drug Darigabat in clinical  trials for focal epilepsy (Ph II) and panic disorder (Ph I); Darigabat is a GABA-A ligand-gated ion channel PAM with selectivity for a2/3/5 subunits (similar to Saniona’s SAN2219), avoiding the sedative, cognitive and motor side-effects and addictive properties of benzodiazepines which bind avidly to a1 subunits of GABA-A receptors. There is also an interesting drug discovery industry angle to this story, as Cerevel came into existence in 2018 as a spin-out from Pfizer when they closed down much of their CNS R&D programs, as many big pharma did at the time. Pfizer still around 15% of Cerevel (via their investment through Bain Capital), and so some might like to suggest that this is another example of the faster development and more effective innovation that can be achieved at biotech companies (and also the business model where big pharma can seed such efforts and then exercise options or leverage huge financing deals to re-incorporate successful ‘outsourced’ programs).

Another major deal in Q4 in the ion channel space was Merck‘s $610 million acquisition of Caraway Therapeutics. I’ve known Caraway since it was called Rheostat (during my days of BD visits to Boston in 2019), but didn’t quite realise at the time just how hot companies working on lysosomal ion channels such as TMEM175 and TRPML1 were to become as interest in novel and effective treatments for neurodegeneration gained traction, not least as an alternative to the struggling and contentious b-amyloid and tau monoclonal antibodies that were all in large Ph III trials and being thrust in front of the FDA in recent years. Now is certainly the time for lysosomal ion channels, which function to regulate the pH, enzyme function and protein degradation processes critical for removing protein complexes in many rare and more common neurodegenerative diseases, especially Parkinson’s where mutations in the TMEM175 K+/H+ channel are linked to  disease risk, onset and severity. I believe that Caraway may be unique in working on both TMEM175 and TRPML1 channels (and their website had some lovely explanatory graphics on these targets), but the press release suggests that there is most interest in two preclinical programs for the latter target. Also, Abbvie had an earlier option on the TMEM175 program for Parkinson’s and ALS, but I am not sure how that will play out.

Finally, we have an intriguing tie-up between Autifony Therapeutics and Jazz Pharma, who signed a global licensing deal for collaboration on 2 unnamed ion channels for neurological disorders. Details of the deal were not exemplified and the upfront payment was not disclosed, but all up it could be worth $770.5 million, which is pretty mega. This is a preclinical deal, so it may be unlikely that Jazz are interested in some of Autifony’s previous or active programs on Kv3.x modulators for tinnitus and schizophrenia, the latter previously licensed by Boehringer Ingelheim before being handed back in 2020, although BI have come back to work with them more recently on a lysosomal ion channel. Autifony have early discovery and preclinical stage Kv3.x projects on epilepsy (AUT00201), Fragile X (AUT00206), and Alzheimer’s, but it is also possible that Jazz are interested in starting a new project on a novel ion channel target for another CNS indication as well.

Dr. Marc Rogers, Cambridge (UK)

aka The Channelogist