Expert opinions

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Ion channel ligands in clinical development – Quarterly review (Q3 2023)

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.

The big news in Q3 2023 was the approval of two GABA-A modulators for CNS disease, namely Marinus’ ganaxolone (Ztalmy) for CDKL5 epilepsy in the EU, and Sage-Biogen’s zuranolone for post-partum depression in the US. I will also highlight the seemingly unreported failure of major TRPA1 pain clinical trials (Eli Lilly). Key players in the field of Nav1.x modulators for epilepsy continued to announce positive clinical data and program developments (e.g. Stoke Therapeutics Nav1.1 ASO for Dravet, Praxis Precision Medicines PRAX-562 and PRAX-628 small molecules), as well as a Kv7.x epilepsy modulator (Biohaven), and news on several Cav programs (PRAX-944, Milestone Pharma). There were also announcements on new clinical RyR, K2P, TRPA1 and TRPV4 programs (ARMGO, Cerevance, Genentech, Actio Bio), as well as clinical updates on CLC-1 programs for neuromuscular disease (NMD Pharma) and a deal on a TRPV1 ophthalmology asset (Novartis). Below I summarise the Q3 2023 status of small molecule and gene therapy clinical candidates for peripheral and CNS diseases, as well as recent M&A news and licensing deals from some ion channel players.

1.      Small molecule ion channel modulators

a.   Peripheral disease indications

Let’s start with a couple of cardiac ion channel modulators in the clinic. First up is new player to this blog ARMGO Pharma, who announced commencement of a Ph II trial to investigate the safety and efficacy of ARM210 (also known as S48168), a ryanodine receptor allosteric modulator (NAM?), for the treatment of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The disease mechanism involves dysregulation of intracellular Ca2+ handling in cardiomyocytes caused by rare mutations in the RyR2 gene, producing ‘leaky’ intracellular Ca2+ release channels that can be ameliorated by their selective ‘gating corrector’. ARM210 was granted orphan drug designation by the FDA in 2020, as well as well as a rare pediatric disease designation. The Ph II trial is supported in part by an Orphan Products Development (OPD) grant from the FDA, and is being carried out at the Amsterdam University Medical Centre in the Netherlands and the Mayo Clinic in Rochester USA.

Second is Acesion Pharma who I have mentioned in previous blogs. They are developing SK KCa channel blockers to treat atrial fibrillation, and their 1st clinical candidate AP-30663 aced a Ph II trial for AF conversion in Q1 2023. They are also working on a back-up compound AP31969 (more on that in the Q4 update). In Q3 this year they announced a €45 million Series B funding round to support the ongoing clinical development of their ion channel modulators, with a focus on the back-up compound which is orally bioavailable and designed for treatment of chronic AF, in contrast to AP30663 which is administered i.v. in hospital settings.

I wrote previously about the Cav1.x L-type channel inhibitor Etripamil in my Q4 2022 blog, where the nasal spray effectively reduced paroxysmal supraventricular tachycardia (rapid heart beats) in a Ph III trial. Results from an open label follow-on study were published by Milestone Pharma in Q3, showing continued efficacy when patients self-administered the spray, showing a return to normal heart rate in 60-75% of patients within 30-60 minutes, without significant cardiovascular side-effects. Etripamil has yet to receive FDA market approval, but it is hoped to reduce medical care costs as in the US there are 50,000 ER visits per year for PSVT, and each patient typically experiences ~10 episodes annually. Etripamil is also being tested as a treatment for atrial fibrillation, and another trial is set to start by the end of 2023 in children and adolescents with PSVT.

Next are two players working to address debilitating musculo-skeletal rare diseases. Actio Biosciences have a focus on rare disease ’channelopathies’ including TRPV4, and announced in Q3 that they had raised $55 million in a Series A round.  Their lead program is targeting TRPV4 in Charcot-Marie Tooth disease, specifically CMT 2C patients who suffer from severe muscle weakness, vocal cord paresis and respiratory complications, as well as serious bone diseases. Part of this newly-funded work will involve the creation of mouse genetic models of CMT disease, in collaboration with the Rare Disease Translational Center at the Jackson Laboratory (JAX) in the US.

In the Q2 2023 review I included a brief mention that the Danish biotech NMD Pharma were also beginning to explore the potential of their CLC-1 ion channel modulator NMD670 to treat CMT disease, including type 1 and type 2 patients in a Ph 0 exploratory trial. NMD670 recently showed positive results in a Ph I/11a trial in myasthenia gravis, and in Q3 the company announced that they had also started a Ph II trial of NMD670 in patients with Type 3 spinal motor atrophy (SMA), a rare genetic disease that affects the neuromuscular junction and causes progressive muscle weakness.

Whilst the global covid-19 pandemic is thankfully now over, it doesn’t mean that infections with SARS CoV2 coronavirus variants will stop, as this pathogen has now joined the existing pantheon of seasonal human, swine and bird ‘flu populations that circulate across the globe. Just as researchers are still trying to develop effective drugs and vaccines for various types of ‘flu, there is ongoing work to find selective and effective inhibitors of SARS Cov2 infection to reduce disease symptoms, hospital admissions, and mortality rates in at-risk populations. In Q3 of 2023 a small Aussie biotech called Biotron completed a Ph II trial of their ion channel inhibitor BIT225, which is an amiloride analogue that blocks viroporin channels important for viral cell entry and replication. I might be a bit biased about this story, as I like to highlight the growing number of successful Aussie biotech stories, and because this company was spun out of my PhD supervisor Peter Gage’s laboratory at JCSMR in the Australian National University. The company’s lead compound BIT225 has been tested in several safety and anti-viral efficacy trials for HIV and HCV, and recently completed a Ph I trial in patients with covid-19.

I will finish up this section with contrasting stories on TRPA1 inhibitors in the clinic for cough and pain, which seem to reflect the current thinking on which disease indication is most suited for this long-running ion channel target.

Genentech have been working on TRPA1 for many years, publishing on a series of sulphonamide antagonists (Chen et al., 2018) and a biased non-covalent agonist GNE-551 (Liu et al., 2020). As with many previous TRPA1 small molecule scaffolds their inhibitors suffered from poor solubility, so a pro-drug of lead compound 20 was created to allow for oral testing in preclinical animal models where it effectively demonstrated in vivo target engagement against AITC-induced pain. A close analogue of the compound 20 sulphonamide was then developed called GDC-0334 with improved oral bioavailability and 2 fold lower TRPA1 potency (IC50 of 1.8 nM (Balestrini et al., 2021) but still significantly more potent than previous antagonists such as the Glenmark clinical candidate GRC-17536 and preclinical competitors from Abbott (A-967079) and Hydra (HC-030031). This publication also revealed that GDC-0334 had entered early clinical development, administered orally in a Ph1b study in healthy subjects subjected to an AITC skin challenge PK-PD experiment that showed dose-proportional reductions in dermal blood flow, itch and pain scores similar to that seen in animal models. Significantly, GDC-0334 was less effective against pain and itch in human volunteers compared to the marker of local inflammation and smooth muscle activity, suggesting that it may be better suited to respiratory conditions such as cough and asthma. In related work, Genentech had also published their TRPA1 CRISPR knockout rat (Reese et al., 2020), which similarly suggested that TRPA1 was less involved in pain or itch behaviours and showed more promise as a drug discovery target for respiratory indications such as asthma.

A common sight these days for ion channel drug discovery: TRPA1 cryo-EM structure with GDC-0344 bound

It would appear that GDC-0334 was dropped in 2021 after the Ph I trial due to toxicity issues in preclinical species. The follow-up GDC-6599 has now emerged as the clinical candidate, with an ACS presentation in Q3 2023 demonstrating it was well tolerated in a Ph I trial and on-track for efficacy testing in a Ph IIa trial for chronic cough later in 2023 and into 2024.

All of this may inform the last item, concerning Eli Lilly‘s TRPA1 antagonist LY-3526318. This was touted as late as last year as a very promising analgesic, and was being tested in Ph II trials in osteo-arthritis knee pain, lower back pain and diabetic peripheral neuropathy as part of their much-publicised Chronic Pain Master Protocol (CPMP) that recruited patients with different types of pain ready for inclusion in trials of one of their 4 different analgesic drug candidates (including a P2X7 ligand they licensed from Asahi Kasei in 2020); Eli Lilly acquired the ion channel assets of Hydra Biosciences in 2018, but I am not sure if/how LY-3526318 is related to their historical TRPA1 scaffolds. The TRPA1 OA trial completed in Q3 2022, and when I went to check on the clinical trial website for this report I was surprised to see that full results had been quietly posted in July, but they didn’t make for pretty reading which may explain the lack of publicity. Disappointingly, the TRPA1 antagonist failed to meet the primary pain reduction endpoint, and missed all of the other secondary pain endpoints as well as alternate markers such as physical function, sleep, and rescue medication use. Similarly, results from the lower back pain Ph II trial were submitted in June 2023, and also showed a mixed picture of moderate efficacy on some pain score readouts but less effect in most secondary endpoints (e.g. increased rescue medication on drug vs placebo, no improvement in daily function) and more adverse effects, but I have not carried out my own statistical analysis as yet.

We don’t know if this lack of analgesic efficacy for the TRPA1 modulator was target-related or due to poor PK and low target coverage, so I look forward to further analysis and data. However, taking it together with the extensive target validation efforts of Genentech suggests that TRPA1 may not be a good pain target in humans, and is more promising for respiratory indications.  Nevertheless, kudos to Eli Lilly for publishing their negative clinical trial results, even if they didn’t put out a press release or news item about it. Pharma and biotech companies are frequently criticised for not publishing clinical results, or revealing them in press releases before peer-reviewed publication or posting to the clinicaltrials.gov website, but the truth is that academic clinicians are just as liable to miss such reporting guidelines. Clearly, such a negative result is much more risky to publicly reveal for a small biotech company relying on one or a couple of clinical programs compared to a global pharma giant such as Eli Lilly.

b.   CNS disease indications

Starting with the many ion channel modulator epilepsy treatments currently in development, I’ll begin with Q3 updates from Praxis Precision Medicines on two of their Nav1.x antagonists that I have covered in some detail in previous blogs. First up is PRAX-562, a non-selective Nav1.x subtype blocker that has an additional and unique profile to preferentially inhibit persistent currents through neuronal Nav currents, a biophysical feature seen in Nav1.6 gain-of-function mutations in patients with Developmental Epilepsy and Encephalopathy (DEE) and which also occur in Nav1.2 and Nav1.3 channels that contribute to various pediatric epilepsies. The company shared full results from two Ph I safety trials in Q2, and pediatric DEE epilepsy patients began enrolment in a 16 week Ph II study in Q2 which is expected to readout topline results in Q4 2023. There was also a clinical update on PRAX-628, another non-selective neuronal Nav1.x blocker which demonstrates ‘functional selectivity’ (i.e. state-dependence) to inhibit over-active channels in excitable CNS neurons. The company previously announced positive results from a Ph I trial in Q2, with PK exposure values confirming its preclinical profile and demonstrating a 15 fold safety margin over the in vivo seizure threshold compared to a 3 fold margin for a leading anti-epileptic drug, suggesting that low doses would be effective in epilepsy patients. In Q3 they revealed EEG biomarker data from this Ph I study which showed that indeed they could detect promising PD effects after a single dose of the lowest 5 mg drug administration, which was sustained during the 10 day treatment regime, seen at all doses, and was significantly different from placebo. Accordingly the company has now begun a Ph II efficacy trial in patients with photo-sensitive epilepsy (photo-paroxysmal response) which is expected to conclude by the end of 2023, followed by a Ph II trial in focal epilepsy patients in 1H 2024.

There are also several Kv7.x channel programs targeting epilepsy – Eliem’s ETX-123 appears to be paused for financial reasons, Xenon’s XEN1101 is currently in Ph III trials, and Biohaven announced promising interim results for BHV-7000 from a Ph I PD target engagement biomarker study. Using EEG spectra to monitor changes in brain activity they found that low doses of the drug produced expected changes in excitability, but without side-effects on drowsiness known to occur with other anti-epileptics, enabling higher doses to be tested. Also, additional PK studies had found a favourable formulation to allow once daily extended release drug dosing in planned Ph II/III studies. The company had earlier revealed results from their Ph I SAD/MAD study in March on a neurotherapeutics conference poster, showing it was well tolerated and did not cause CNS side-effects such as somnolence or dizziness which are seen with current anti-convulsants, paving the way for Ph II efficacy trials later in 2023.

There are also a number of preclinical and clinical programs addressing epilepsy with GABA-A modulators (e.g. Saniona’s SAN711 and SAN2219, Engrail’s ENX-101, Eliem’s now-halted ETX-155), but the only one to release news in Q3 was Marinus Pharmaceuticals and it was pretty significant as they has gained EU approval for their drug ganaxolone (Ztalmy) to treat pediatric patients with Cdkl5 epilepsy, following on from its market launch in the US this time last year. This is a rare genetic disease where mutations in the kinase affect downstream phosphorylation targets, many of which modulate neuronal excitability that can be reduced by GABA-A potentiators. I reported in the Q2 2023 update that the biotech start-up Lario Therapeutics were also targeting Cdkl5 epilepsy through the downstream Cav2.3 channel.

Another major therapeutic area for GABA-A PAMs has been for various types of depression, and we had significant news in Q3 with the FDA’s approval of Zuranolone from Sage Therapeutics & Biogen. However, there was some surprise that this approval was only for post-partum depression, as the drug had also shown some efficacy in advanced trials with patients suffering from major depressive disorder (MDD), as I have outlined in previous blogs. Like other next generation GABA-A PAMs, zuranolone has shown more rapid effect than conventional anti-depressants, but they have also been criticised for shorter duration and longevity of efficacy in longer treatment regimes and clinical trial designs. Zuranolone will be prescribed under the name Zurzuvae for post-partum depression and is expected to launch in Q4 of 2023, but will be classified as a controlled substance. I was surprised to read that this limited approval was linked to cutbacks and layoffs at Sage, as it seems pretty clear that they will push on and try to gain approval of zuranolone to treat a wider population of patients with other types of depression.

Another player in the GABA-A CNS psychiatric space is Vistagen, who revealed positive Ph III data for their GABA-A potentiator Fasedienol nasal spray in patients with social anxiety. Like other drugs for this affliction (e.g. Bionomics failed alpha7 nAChR NAM BNC2010), the ultimate hope is for a rapidly acting and self-administered formulation rather than chronic dosing with the potential for CNS side-effects, and the interesting angle here is that Fasedienol is a pherine closely related to steroidal-like pheromones which would normally be sensed in the nose.

I have previously outlined a few 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), including the rather tortured path that Relmada Therapeutics had been forced to take during several Ph III failures of their GluN2D NMDA receptor antagonist REL1017 in 2022. However, the company has persisted with this asset (as it shows “potential efficacy” in those trials) and announced in Q3 that they had started to enrol patients in another Ph III trial in MDD patients. REL-1017 is esmethadone, a opioid analogue with reduced abuse or respiratory depression liability, and designed to functionally inhibit over-active GluRs containing NMDA GluR2D receptor subunits.

I’ll finish this CNS section with news on other neuropsychiatric indications. I reported in Q1 and Q2 that although Praxis Precision Medicine’s PRAX-944 (Ulixacaltamide) had shown mixed results in their Ph II trial in Essential Tremor, the Cav3.x inhibitor was still going to be progressed to Ph III as it significantly improved secondary measures of daily functioning and the company argued that such patient-focused outcomes should be included in clinical assessments of treatment effect. More promising data was revealed in Q3 after analysis of a randomized Ph II drug withdrawal sub-study and an open label extension, which showed that the drug continued to alleviate symptoms over 6 weeks compared to placebo and that this improvement was greater than that seen during the initial 8 week study period. This new Ph II data analysis, taken together with meetings with the FDA at the end of Q2, appears to have resulted in approval to proceed with a revised NDA to allow Ph III testing in two different trials, including additional safety and toxicology monitoring, which are slated to begin before the end of 2023.

Finally, we can add a new player to this series of companies involved in ion channel drug discovery and clinical development, with the news that Cerevance are progressing their K2P THIK-1 channel antagonist CNV293 to Ph I testing in Q3. The CNS therapeutic indications appear to include amyotrophic lateral sclerosis (ALS) and Alzheimer’s Disease, with the latter specifically mentioned as part of a $25 million collaboration announced with Merck in 2022. CNV293 is a selective and potent antagonist of THIK1 (KCNK13) channels which are expressed on brain macrophages and microglia, so their inhibition can reduce neuroinflammatory signalling mediated by glial K+ efflux, cytokine release and NLRP3 inflammasome activation; a small SAR paper was published on C101248 which may be related to CNV293. Cerevance raised a total of $116 million in a Series B round earlier in 2023 which will be used to progress their portfolio of CNS drugs, including CNV293 as well as a GPR6 inverse agonist for Parkinson’s Disease and an orexin 1 antagonist for sleep-wake cycle and addiction treatment.

2.      Gene therapies and biologic treatment modalities

I figured it may be useful to breakdown this quarter’s update into small molecules vs biologics and gene therapies, seeing as there has been considerable discussion about the implications of the US IRA legislation to curb future patent protection periods on small molecules, and the recent high profile approval of gene therapies (including CRISPR reagents) in the UK and US. While it is true that biologics make up an increasing fraction of FDA drug approvals in recent years, and even reached parity in 2022 (Senior 2023; BiopharmaTrend article), commentaries suggesting this may be the demise of small molecule drug discovery are clearly an over-reaction (says this biologist). I am sure that both categories of modalities will continue to play equally important roles in drug discovery, and this includes ion channels. I have highlighted a number of biological ligands targeting ion channels in previous updates (e.g. for Nav1.x and CFTR channels), and I will introduce a couple of new ones below.

I’ve written previously about the novel anti-sense oligonucleotide (ASO) that Stoke Therapeutics are developing to increase the expression of Nav1.1 channels in young patients suffering from Dravet epilepsy. Dravet patients suffer from genetic mutations and haplo-insufficiencies which reduce the expression, trafficking and function of Nav1.1 channels, especially in inhibitory neurons, so genetic and small molecule (e.g. Lundbeck) activators have been designed to promote Nav1.1 channel activity and reset the excitatory-inhibitory balance in the CNS by increasing the excitability of inhibitory neurons and thereby dampen down epileptic discharges. Stoke have been providing positive updates during 2023 on their ongoing Ph I/IIa trial of the ASO STK-001, and in Q3 they revealed that interim data on PK, safety and efficacy was going to be presented at the 35th International Epilepsy Congress. I applaud their transparency and wish them good luck in achieving clinical success for this deserving patient population.

I previously discussed the Nav1.2 ASO PRAX-222 being developed for rare pediatric epilepsies, which will be updated by Praxis Precision Medicines in Q4.

Another epilepsy gene therapy entering clinical development is UniQure’s AMT-260, which is an miRNA treatment using AAV9 adenovirus vectors to silence the aberrant expression of the GRIK2 gene that encodes a subunit of the excitatory Kainate ionotropic GluR. The company announced IND approval from the FDA in September, and they expect to start clinical trials either by the end of 2023 or early 2024. This gene therapy is hoped to be a one-time treatment for refractory temporal lobe epilepsy, the most common type of focal epilepsy in which a majority of patients do not respond to current anti-convulsants.

No thanks to covid-19 we now all know a lot more about lipid nanoparticles (LNPs) as a drug delivery system, and ReCode Therapeutics have built their company around this technology to deliver gene therapies for a range of rare diseases. In Q3 of 2023 they announced an extension of their Series B financing, adding $50 million to the initial $210 million raise, which will be used for progression of programs in CNS, lung, liver and musculoskeletal rare disease indications. The lung therapy is directed towards cystic fibrosis (CF) and includes an advanced preclinical gene therapy to correct rare mutations in the CFTR apical chloride channel by i.v. and inhaled drug delivery. This gene therapy will go up against Vertex’s mRNA drug VX-522, and small molecule ‘correctors’ and ‘potentiators’ from the likes of Vertex, Novartis (Icenticaftor) and Sionna Therapeutics (SION-638).

Finally there is news on a new therapy for a ‘classical’ ion channel disease mechanism that many non-clinicians may not be aware of: auto-antibodies. I remember learning about ion channel diseases as an undergraduate in New Zealand through examples such as Myasthenia Gravis and Lambert-Eaton Syndrome, where the body’s immune system turns in on itself and generates antibodies which target nAChR and Cav channels at the neuromuscular junction. We now know of many more ion channel auto-antibody ailments (see here for a quick overview), and Arialys Therapeutics announced in Q3 that they have raised $58 million in seed money to specifically target anti-NMDA antibodies that are associated with ‘person-on-fire’ neuropsychiatric condition. Their lead candidate ART5803 was granted Orphan Drug Status by the FDA to treat antibody-driven encephalitis, and was previously purchased from Astellas Pharma.

3.      Ion channel company licensing deals and collaborations

There were also several interesting announcements made in Q3 2023 concerning various ion channel companies and their drug discovery programs. First up is the acquisition and renaming of Boston-based Q-State Biosciences as Quiver Bioscience, following their buyout by the VC company Exponential Capital Management. This transaction fully completes and accelerates their metamorphosis from a bio-engineering outfit to a clinical development company, allowing them to progress ongoing work on Nav1.7 and Nav1.8 small molecules and ASOs for various chronic pain indications (osteoarthritis, lumbo-sacral, cancer), as well as use their bespoke platform of iPSC cells, optogenetics and AI-ML software analysis to develop therapeutics for neurodevelopmental disorders and neurodegeneration.

Next up is a rather intriguing and still slightly mysterious collaboration quietly announced between AstronauTx in the UK and Saniona in Denmark. I’ve written about Saniona before due to their clinical work on GABA-A ionotropic receptors (for neuropathic pain and epilepsy) and preclinical work on KCa3.1(for fibrosis) and Kv7.x channels (for epilepsy), but I have no information on what ion channel they will be working on with AstronauTx, who are a spinout from UCL Alzheimer’s Research UK Drug Discovery Institute (DDI) and initially funded by the UK Dementia Discovery Fund (DDF) to focus on Alzheimer’s Disease. Saniona will receive research funding worth SEK15 million (€1.3 million) during the 1st year of the R&D period, and up to SEK1.9 billion ($177 million) in milestone payments and royalties upon delivery of a clinical product.

I promised in my Q2 2023 update to go into more detail on the various ion channel companies spun out of Axxam in Italy, and in the meantime their new bio-incubator Golgi Neuroscience also announced the out-licensing of a P2X7 program to Breye Therapeutics, who are the latest in a series of spinouts tracing back to work on gap junction peptides by Zealand Pharma in Denmark. Breye Tx originally had a focus on ophthalmological disease where these ‘gaptides’ can increase cell-cell coupling, and interestingly there is a downstream connection to P2X7 channels as gap junction channels can release cytosolic ATP to activate these ionotropic purinergic channels and activate the NLRP3 inflammasome. The P2X7 ligands are being positioned as anti-inflammatory and neuroprotective drugs, which may have widespread therapeutic uses that includes dry AMD and early diabetic retinopathy.

Axxam have invested in several internal R&D projects over the last decade alongside their CRO work, something that I know first-hand from setting up an ion channel CRO is difficult owing to limited resources and staff bandwidth. There is also the much-discussed issue of competition between projects, both internally and the perceived conflict these may have with external client projects. Some CROs maintain both types of drug discovery work in parallel, others create subsidiaries, and in the case of Axxam they have spun-out a number of companies in the EU and US to further develop these preclinical assets to the clinical stage. Most recently they transferred all these assets to a biotech company called Golgi Neuroscience.  Below is a table of the ion channel spin-outs from Axxam that I am aware of:

Ion channel spin-out companies and out-licensing deals from Axxam

Finally, there is news on a TRPV1 antagonist that I was completely unaware of, adding to the surprise I shared in my Q2 2023 update (in reference to Grünenthal’s TRPV1 resiniferatoxin injection for osteo-arthritic knee pain entering Ph III trials) that anyone was still working on this historical analgesia ion channel target! Apparently Novartis had been developing the TRPV1 small molecule antagonist SAF-312 (Libvatrep) for many years, and had stopped development but not binned it after testing it in neurogenic bladder pain, but resurrected it in 2021 as a topical treatment for ocular pain where it successfully alleviated primary pain endpoints in a Ph II trial of laser surgery patients suffering from chronic ocular post-operative pain. Closely following the successful readout of this trial in June 2023, Novartis announced the sale of SAF-312 and the 2nd generation preclinical TRPV1 antagonist OJL332 along with the marketed ophthalmic drug Xiidra as well as rights for use of the AcuStream delivery device in dry eye indications to Bausch & Lomb in a deal worth $1.75 billion.

Dr. Marc Rogers, Cambridge (UK)

aka The Channelogist