The main point of this document is to highlight the progress being made in ion channel drug discovery, which is a key validation parameter for target selection along with other considerations such as human genetic data, availability of relevant animal models, and therapeutic indications, etc. I’d like this quarterly series to help overcome perceptions that ion channels are ‘difficult’ discovery targets, and the tendency for historical failures to get blamed on the target class rather than the discovery process itself. We all know that drug discovery is a tortuous and expensive journey for any ligand, so it is important to recognise the successes (and learn from the pitfalls) of compounds eventually reaching clinical trials. It is also important to note that owing to the long timelines of drug discovery that several of the ion channel targets highlighted below may be regarded as ‘traditional’ or obvious candidates familiar to many within and outside of the field. What is clear is that many new and novel ion channel targets are now being investigated in early discovery and preclinical programs, and although these are beyond the scope of this clinical development update, it is evidence of the improvements in ion channel drug discovery and target validation that have occurred in recent years, and which promise greater success in the future.
Owing to the complex interplay of excitatory and inhibitory neurons in controlling neuronal excitability and CNS patho-physiologies such as epilepsy, there are numerous voltage-gated ion channels and synaptic ligand-gated receptor channels that are attractive and proven targets for anti-convulsant drug discovery, chief of which are Kv7.x ‘M’ channels, GABA-A receptors, and Nav1.1, Nav1.2 and Nav1.6 channels. Drug discovery projects for these targets are aiming to modulate ion channels present on specific populations of excitatory or inhibitory neurons through development of sub-type specific inhibitors and activators or potentiators. These ligands are hoped to deliver more efficacious anti-convulsant therapy with fewer side-effects and better patient compliance than seen with traditional ion channel modulators, thereby meeting the large unmet medical need in common, rare and development epilepsies.
a. KCNQ ‘M-current’ potentiators
Building on the clinical success of Retigabine (Ezogabine), several companies are developing fast-follower and novel ligands with a similar mechanism-of-action to potentiate the activity of KCNQ ‘M-currents’ and thus dampen neuronal excitability from resting membrane potential and during repetitive firing. The chief aim is to achieve better KCNQ gene family subtype selectivity with a preference for neuronal Kv7.2/7.3 channel heteromers that underlie the M-current, and avoid activity against the cardiac KvLQT1 isoform and other neuronal Kv7.x homo and heteromers. This profile also makes KCNQ modulators attractive targets for analgesia.
The big news in Q1 2022 was that the Kv7 preclinical research program at Knopp Biosciences in Pittsburgh USA had been spun-out into a vehicle called Channel Biosciences which was acquired by Biohaven Pharmaceuticals. BHV-7000 (formerly known as KB-3061) is claimed to be a next-generation activator of Kv7.2/7.3 channels with potential to be a best-in-class drug for epilepsy, pain and affective disorders of the CNS. The lead compound has improved potency and reduced GABA-A activity over competitors with potential for low dose efficacy and fewer side-effects. Biohaven anticipates entering the clinic in 2022, initially targeting patients with focal epilepsy (more here).
The main clinical competition at this stage is Xenon’s XEN1101, a more potent and selective Kv7.2/7.3 potentiator with improved pharmacokinetics and therapeutic index than ezogabine, and reduced tissue pigmentation side-effects. Xenon reported positive primary and secondary endpoints in a dose-dependent Ph II trial in focal epilepsy in Q4 of 2021. Xenon are also undertaking a Ph III trial of a pediatric formulation of ezogabine in neonatal KCNQ2 developmental and epileptic encephalopathy (DEE).
Fast on their heels are Eliem Therapeutics, who came out of stealth mode in 2021 with announcements of several funding rounds and a new website listing a preclinical Kv7.2/3 program that was initially expected to yield a lead candidate by the end of 2021, in preparation for clinical trials in pain and epilepsy in 2022. Despite delays with a GABA-A epilepsy clinical program in Q1 2022 (see below), IND-enabling preclinical work on their KCNQ modulator project is continuing into 2022 according to a recent investor call.
b. GABA-A positive allosteric modulators (PAMs)
Another popular method to reduce neuronal excitability in epilepsy is to increase the level of inhibitory ‘tone’ in the CNS by enhancing the activity and efficacy of the neurotransmitter GABA, largely through PAM of inhibitory GABA-A receptor channels. The major issue is the diversity of GABA-A receptor subunits and heteromers and their effects on cognition and sedation, resulting in a prolonged search for subtype-selective modulators with an improved therapeutic index that work through different binding sites and mechanisms to classical benzodiazepines.
In March 2022 Marinus Pharmaceuticals gained FDA approval to market its oral neurosteroid GABA-A modulator Ganaxolone (as Ztalmy), initially for CDKL5-deficiency childhood epilepsy after a successful Ph III trial and following a Ph II failure in 2019 that almost derailed the biotech company. This followed a partnership with Orion Pharma announced in Q3 2021 to support their EU NDA and marketing of oral and i.v. Ganaxolone for CDKL5 childhood epilepsy as well as refractory epilepsy and the related CNS excitability disorder tuberous sclerosis. There was some excellent background on newer GABA-A PAMs for epilepsy and depression in a recent Drug Hunter post in March 2022, noting their selectivity for extra-synaptic GABA-A receptors and issues with short half-lives and GABA-A inhibiting metabolites seen with the previous i.v. administered neurosteroid Brexanalone (Zulresso) from Sage Therapeutics, which are improved upon with the oral Ganaxolone.
Different issues have delayed Eliem Therapeutics progression of their GABA-A PAM ETX-155 for epilepsy and depression. The discovery of an unexpected metabolite in Q4 2021 delayed the IND for Ph II trials in depression, and the Ph Ib trial in photosensitive epilepsy has now been interrupted after interim analysis of PK data from 3 patients showed insufficient drug exposure. These ADME and PK challenges highlight the problem of species translation in drug discovery, as a second non-human species alongside rodent data (typically dog) is required for FDA approval, but even use of nonhuman primates might not identify such issues. I would be interested to know if humanised translational assays such as microphysiological organ-on-a-chips that use immortalised cell lines and iPSCs would be able to detect such metabolites and enable more accurate prediction of in vivo drug dosing and exposure?
c. Nav1.6 inhibitors
It would be remiss not to mention the ongoing efforts of Xenon and Praxis to progress their Nav1.6 inhibitors in epilepsy. Xenon’s NBI-921352 (XEN901) was licensed to Neurocrine Biosciences in 2021 and will enter clinical trials in genetically-validated childhood and treatment-resistant adult focal epilepsy in 2022, whilst PRAX-562 is also targeting gain-of-function Nav1.6 mutations in a Ph II trial of pediatric patients with DEE.
In contrast to the clear genetic validation of specific ion channels in CNS diseases such as epilepsy, deconvolving the causes and developing new treatments for depression is more complicated. The current challenge is to find novel mechanisms and ligands to overcome treatment-resistant disease, and increase efficacy and meet unmet medical need in major depressive disorders (MDD). Several neurotransmitter ion channel targets are being actively pursued, including GABA-A receptors and the old favourite, NMDA receptors.
a. GABA-A positive allosteric modulators (PAMs)
Sage Therapeutics have been working on neurosteroid PAMs to increase GABAergic inhibition in the brain and improve mood and reduce anhedonia in depression, and announced positive results from a Ph III trial for MDD in Feb 2022 for their lead candidate SAGE-217 (Zuranolone), which is being co-developed with Biogen (BIIB125). Although primary and some secondary endpoints were met as an additive treatment to a standard SSRI anti-depressant, and the compound helped to more rapidly reverse depressive symptoms, there are some doubts as to whether this rapid efficacy can be sustained and if side-effects will reduce patient compliance. The companies are seeking FDA approval for an NDA for MDD in 2H 2022, and for postpartum depression in 2023.
While Eliem Therapeutics are under the spotlight after a recent clinical failure for a non-opioid analgesic, their development of the GABA-A PAM ETX-155 for MDD and perimenopausal depression was also put on temporary hold in Q1 2022 due to PK issues with an unexpected metabolite and low drug exposure in a small Ph Ib epilepsy trial. Assuming these issues can be resolved, they are likely to amend and complete the IND application already submitted to the FDA and resume enrolment in its Ph IIa trials for depression as planned in 2022 with topline data expected in 2H 2023.
Praxis Precision Medicines are also developing a GABA-A PAM for MDD, with PRAX-114 currently in a Ph II clinical trials as a monotherapy and adjunct treatment, with readouts expected in April and June 2022.
b. Other ligand-gated ionotropic synaptic receptors
NMDA glutamate-gated ionotropic channels are fundamental to learning and memory and synaptic plasticity in the CNS, and have been the target of numerous drug discovery programs over recent decades (e.g. Memantine), but fell out of favour due to a narrow therapeutic index. Nevertheless, some companies have returned to this target as a potential treatment for pain and complex CNS ailments, and Gilgamesh Pharma recently announced plans for a Ph I trial of their NMDA antagonist GM1020 in depression. The compound is an oral, non-competitive NMDA receptor antagonist with claimed potential for rapid and sustained anti-depressant activity with fewer aversive dissociative side-effects compared to previous NMDA modulators. GM1020 is slated to complete IND-enabling toxicology studies in 1H 2022, with clinical enrolment to begin in 2H 2022.
It is worthwhile to note that Gilgamesh Pharma, along with a growing list of new biotech and pharma companies, are also working on psychedelic-based medicines to treat major depression and other complex neuropsychiatric diseases such as PTSD and anxiety. Another NMDA modulator, ketamine, is a key ingredient in many of their plans, alongside serotonergic ligands such as psilocybin, ecstasy (MDMA) and DMT.
Something I picked up in Q1 on Facebook of all platforms, is an effort by the University of Cambridge (UK) to re-purpose a P2X7 ligand from JnJ (JNJ-54175446) for treatment-resistant depression. It would appear that the P2X7 angle is to reduce inflammation, presumably occurring in the CNS and involving activity of microglia. They are actively recruiting on social media for clinical trial participants, as part of a university-led consortium funded by the Wellcome Trust that also includes Lundbeck, GSK and Janssen.
c. Other ion channel targets
Finally, Xenon announced in Q1 2021 that their selective Kv7.2/7.3 opener XEN1101 that is being developed for focal epilepsy (see above) was also going to be tested in a Ph II trial as a treatment for major depressive disorder, in a collaboration with the Icahn Medical School at Mt Sinai. I wasn’t aware that ezogabine or other KCNQ openers had shown positive results in depression models or clinical trials, and this would represent a novel ion channel target in this clinical population. Enrolment began in Oct 2021 and the 60 patient study is expected to complete in Jan 2024.
Some may be surprised by the level of activity for ion channel modulators in this therapeutic area, but there is a rich anti-tussive drug discovery history over the last decade for several ligand- and voltage-gated ion channel gene families, especially for alleviating chronic cough. For example, GSK and others have worked on several Nav1.3 and Nav1.7 antagonists, and TRPA1 antagonists remain in the mix. Interest in anti-tussives has also been reinvigorated owing to the SARS CoV2 coronavirus pandemic and the need to treat and control acute and chronic cough in infected patients and those suffering from ‘long covid’.
Targacept‘s a7 nAChR agonist Bradanicline/TC5619/ATA-101 is being repurposed for cough by Johns Hopkins in a Ph II trial. It is an effective anti-tussive in guinea pigs (the most common preclinical model for cough), and clinical trials are based upon observations that nicotine and smoking can (paradoxically) reduce cough and protect against covid-19 symptoms.
There are also several long-running pharma programs in the clinic developing P2X3 antagonists for cough, with mixed success. One of the main challenges for this approach have been observations that P2X3 ligands have taste-altering effects (dysgeusia) which led to patient withdrawals and a reduced therapeutic index, something that is being addressed with next-generation modulators and altered dosing regimes. Merck’s Gefapixant was a leading contender until the FDA rejected it in late January 2022 due to poor efficacy in a Ph III trial, although the pharma was at pains to note it was not due to safety issues despite significant taste side-effects. The program might not be dead as Merck are keen to develop this ‘pipeline in a product’ and the FDA’s CRL asked for more efficacy data before any resubmission. Similarly, Bayer’s Eliapixant (BAY1817080) was progressing well in 2021 with positive Ph IIb results on primary endpoint efficacy, safety and tolerability, but it was handed back to Evotec in Q1 2022 citing dwindling returns in a competitive market, and perhaps influenced by Bayer’s knockback earlier in the same quarter. There were big plans not just for chronic cough but also in overactive bladder, endometriosis and neuropathic pain, so it now remains with Evotec if and how they choose to take this multivalent P2X3 antagonist forward into further clinical studies.
These recent developments leave two active P2X3 programs. Shionogi reported positive Ph IIa and IIb results in Q4 2020 and Q3 2021 for their antagonist Sivopixant (S-600918), which improved upon the bioavailability of their preclinical candidate and enabled lower human dosing which may have alleviated taste and other side-effects. They are also pursuing efficacy in sleep apnea patients (in Japan). By all accounts the leading P2X3 clinical program is from Bellus Health, who reported positive Ph IIb data in Q3 2021 (with less dysgeusia side-effects) and announced plans for a Ph III trial in 2H 2022, which trumped previously mixed results in earlier Ph II studies in cough and atopic dermatitis. If positive Ph III results are forthcoming in 2022, these may pave the way for the first P2X3 ion channel ligand to enter the market in the near future.
As I highlighted in my previous monthly post, Vertex just announced positive Ph II results for their Nav1.8 program. VTX-458 is the clinical successor to their trial blazing ligand VTX-150 ligand, a potent and selective antagonist of the sensory neuron Nav1.8 channel implicated in several types of chronic pain. Following the path of others such as Pfizer, initial clinical POC studies of sodium channel analgesics have utilised acute pain patients, such as those undergoing molar extraction or removal of bunions, although Vertex did extend this to include a Ph II trial in patients after ‘tummy tuck’ abdominoplasty. Significantly, pain relief was obvious and mostly exceeded the sometime high levels of placebo response seen in such pain trials, but dose-dependency was not seen in the bunionectomy study group.
The challenge ahead of course is to extend these studies to chronic pain indications where non-addictive, non-opioid analgesia is most needed. Careful decisions will be required to avoid the pitfalls of previous studies in common pain populations such as lower back pain, diabetic neuropathy (DPN) and post-herpetic neuralgia (PHN) where previous potent and selective sodium channel antagonists have spectacularly and disappointingly failed.
5. Novel ion channel targets in other therapeutic areas
I was pleased to see that several novel ion channel targets are heading to the clinic in 2022, evidence of more recent target and genetic validation data that is supporting this target class in an expanding list of therapeutic indications.
Firstly, Vertex announced upcoming Ph II/III trials in kidney disease for VX-147, a modulator of the APOL1 protein which functions in part as a non-selective cation channel on intracellular and plasma membrane. This is a genetically-validated ion channel target, as patients (including a preponderance of people of African descent) with a specific set of gain-of-function mutations suffer from proteinuria and decreasing kidney function which can lead to chronic kidney failure. The drug candidate successfully reduced proteinurea by ~50% and improved glomerular filtration rates in a FSGS subset of patients, raising the hope for an expanded indication in other types of chronic kidney disease.
Finally, news from South Korea in March 2022 revealed that a KCa calcium-activated potassium channel program for fibrotic disease from Cellion Biomed was licensed to Bridge Biotherapeutics (lead candidate now called BBT-301). They hope to enter the clinic in the U.S. by the end of 2022 targeting idiopathic pulmonary fibrosis (IPF), as well as jointly conducting studies into new indications for other fibrotic diseases.
Dr Marc Rogers, Cambridge (UK)