The main focus of this series is to highlight the progress being made in ion channel drug discovery, which is a key validation parameter for target selection along with other considerations such as human genetic data, availability of relevant animal models, and therapeutic indications, etc. I’d like this discussion to help overcome perceptions that ion channels are ‘difficult’ discovery targets, and the tendency for historical failures to get blamed on the target class rather than the discovery process itself. We all know that drug discovery is a tortuous and expensive journey regardless of target or modality, so it is important to recognise the successes (and learn from the pitfalls) of ion channel modulators reaching clinical trials.
The challenges of drug discovery became even more obvious in Q1 2022 as the industry faced a number of external (pandemic recovery, war in Ukraine) and internal challenges (delayed FDA reviews, clinical trial failures), and the financial markets and publicly-traded companies responded accordingly in Q2 with some major corrections and curtailed R&D. Below is a brief summary of clinical announcements made in Q2, heavily weighted in this quarter towards traditional rather than novel ion channel targets. The good news is that despite the long timelines of drug discovery, many ion channel projects for these ‘classic’ targets (e.g. GABA-A, NMDA-R, CFTR, KCNQ, Kv1.3 and Nav1.x channels) are making excellent progress towards the clinic.
1. GABA-A receptor modulators
A number of GABA-A positive allosteric modulator (PAM) programs are active for various CNS diseases, aiming for a rapid and sustained increase in inhibitory neurotransmission to dampen unwanted brain activity, without significant side-effects produced by earlier generations of ligands that lacked selectivity between multi-subunit ionotropic receptor complexes.
The current challenge in depression is to find novel mechanisms and ligands to overcome treatment-resistant disease, with faster onset and greater efficacy to meet unmet medical need in major depressive disorders (MDD) compared to monoamine uptake inhibitors. Several neurotransmitter ion channel targets are being actively pursued, including GABA-A receptors and an old favourite, NMDA receptors (see section 6).
Staring with the positive news, Sage Therapeutics GABA-A PAM Zuranolone (SAGE-217) backed up previous efficacy in MDD with positive results in Ph III trial for post-partum depression, meeting all primary and secondary endpoints. A 50 mg dose of Zuranolone demonstrated statistically significant (p = 0.0007) and clinically meaningful improvement in depressive symptoms after two weeks, while some secondary endpoints saw improvement as early as day 3 and were sustained up to day 45. These results again demonstrate the fast onset of this ligand in comparison to traditional anti-depressants, and greater durability than seen in a previous study of major depression announced in Q1 of 2022. Sage and its partner Biogen have started a rolling NDA submission for MDD which should complete in 2H 2022, while an NDA filing for postpartum depression is anticipated in early 2023.
However, the news has not all been good in Q2 for GABA-A anti-depression drug programs. Firstly, Eliem Therapeutics plans for Ph II clinical trials in depression for their GABA-A PAM ETX-155 have been delayed for a second time. I reported in Q1 that they had put a temporary hold on all work with ETX-155 due to PK issues and an unexpected metabolite affecting predicted drug exposure in a small Ph Ib photo-epilepsy trial, and this has been extended into Q2 with a company announcement in April. Like Sage, Eliem had planned Ph IIa trials in major depression and perimenopausal depression, with dosing to start in 1H 2022 and topline data expected in 2H of 2023, but these timelines are slipping until a full understanding of the drug exposure and PK profile can be obtained and the IND that was filed with the DSA in Q1 is amended accordingly.
More surprising was the failure of Praxis Precision Medicines GABA-A modulator in a Ph II/III depression clinical trial, especially as it shares a similar mechanism-of-action to the Sage and Eliem drugs. PRAX-114 missed the primary endpoint as well as all of its secondary endpoints in patients with major depressive disorder. The drug had faced challenges before with a temporary clinical hold in late 2020 for undisclosed reasons before studies were allowed to continue. The whole portfolio for the GABA-A PAM has now been cancelled, as a concurrent SEC filing noted that Praxis will shut down ongoing Phase II trial on moderate depression (MDD) but still read out data in Q3 of 2022, and will stop enrolling patients in Phase II studies of PRAX-114 in post-traumatic stress disorder and essential tremor. The disappointing news came just after a bullish investor conference, and has led to staff layoffs and a big drop in share price, which will put pressure on their other ion channel programs for other CNS indications (PRAX-944 for essential tremor and PRAX-562 for childhood epilepsy).
Enhancing the activity of inhibitory GABA-A ionotropic receptors is a validated mechanism to treat epilepsy, with clinical anticonvulsants such as Vigabatrin and Tiagabine targeting GABA metabolism and some older anxiolytic benzodiazepine PAMs being used off-label. The search for more selective GABA-A PAMs without addictive and other side-effects is an active area, and in Q2 there was positive news from another player when Engrail Therapeutics announced positive Ph Ib safety and target engagement data for their GABA-A PAM anti-epileptic. ENX-101 selectively increases inhibitory neurotransmission by GABA-A receptors containing a2, a3, and a5 subunits whilst blocking a1-containing complexes, a profile designed to promote anti-seizure efficacy while minimizing sedative effects normally seen with non-selective benzodiazepines. The compound has a long half-life allowing once daily administration and favourable safety profile in healthy volunteers without significant side-effects. Human biomarker data indicated the desired target engagement in the CNS, with few effects on alertness, psychomotor function, or attention after repeated administration. There was some transient sleepiness, but no sedative-like increase in EEG delta power signals. On the back of this, an international Ph II trial in focal epilepsy patients has been agreed with the FDA.
In my Q1 summary I included updates from a number of other players in the GABA-A PAM epilepsy field. Marinus Pharmaceuticals recently gained FDA approval to market its oral neurosteroid GABA-A modulator Ganaxolone (as Ztalmy) in the US, initially for CDKL5-deficiency childhood epilepsy, whilst a tie-up with Orion Pharma in Q3 2021 enabled 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. Sage Therapeutics are working to address shortcomings of their i.v. administered neurosteroid Brexanalone (Zulresso) by working on other GABA-A PAMs. Finally, Eliem Therapeutics are fighting to overcome some PK and CMC issues with their GABA-A PAM ETX-155 in an effort to re-start a Ph Ib trial in photo-epilepsy in 2H 2022.
GABA-A receptor channels underlie and regulate a wide variety of CNS functions owing to the heterogeneity of their subunit combinations and distribution across different neuronal cell types and brain regions. Alongside subunit- and area-specific sedative and anxiolytic effects, GABA-A proteins are postulated to have effects on cognition and Gedeon Richter recently described a negative allosteric modulator (NAM) lead compound targeting a5 subunits that demonstrated oral efficacy in schizophrenia-related cognition animal models. The series was derived from a literature starting point and developed by scaffold hopping and MedChem optimisation to yield a lead compound with improved potency, selectivity, metabolic stability, ADME properties and cardiac safety suitable for oral administration.
2. CFTR cystic fibrosis Cl- channel potentiators
The ongoing success of Vertex’s CFTR corrector and potentiator drug franchise has set a high bar for competitors, and in Q2 we saw one of them pull out while another came out of stealth. On the downside, Abbvie canned the CFTR triplet therapy they had licensed as part of a $245 million deal a few years ago for a portfolio of drugs from Galapagos after it failed interim analysis in a Phase II proof-of-concept study. However, the company remains committed to CF as their dual therapy was efficacious, and they are lining up a new C2 corrector ABBV-567 to replace ABBV-119, which it plans to test as a triplet therapy together with their existing C1 corrector ABBV-2222 and potentiator ABBV-3067 in a Phase II study launching in early 2023. The new compound is structurally distinct from ABBV-119 and has a better PK profile which enables higher drug exposure, with potential for better efficacy and/or tolerability compared to Vertex’s Trikafta combination.
Similarly undeterred is the new CFTR player Sionna Therapeutics, a spin-out from Sanofi-Genzyme that was formed in 2019 and officially emerged from stealth in Q2 2022 with a $111 fundraising round. The company has a portfolio of small molecules targeting the major F508del mutation which have demonstrated ex vivo efficacy in patient-derived epithelial cells, in contrast to Vertex who failed to reverse CFTR Cl- channel trafficking and function for this mutant but found success targeting less common protein mutations.
3. Nav1.x channels
The second blow for the efforts of Praxis to develop CNS-targeting ion channel modulators in Q2 2022 involved their Nav1.2 antisense program for epilepsy, PRAX-222, which received a temporary clinical hold from the FDA in late April. Although a letter detailing the reasons for the hold was expected from the FDA within 30 days of April 28 2022, no further public disclosure has been forthcoming to my knowledge but it would seem that the whole program has now been cancelled and company layoffs ensued. Praxis had earned orphan drug designation in rare childhood epilepsy for PRAX-222 from both the FDA and European Medicines Agency in January 2021 and January 2022, respectively. PRAX-222 is an antisense oligonucleotide targeting gain-of-function mutations in SCN2A Nav1.2 channels associated with early-onset developmental epilepsy, and was being developed as part of a collaboration with Ionis Pharmaceuticals and RogCon Inc. Praxis have other drugs in their pipeline targeting seizures; the small molecule PRAX-562 is set to move into Ph II trials in 2H 2022 for children with SCN2A Nav1.2 and SCN8A Nav1.6 mutations, whilst another Nav1.x small molecule inhibitor PRAX-628 is in IND-enabling toxicology studies and scheduled to start a Ph I trial by Q4 2022 and then a Ph II study in focal epilepsy sometime in 2023.
Another company chasing the success of Vertex in developing sodium channel modulators is Orion Pharma, who recently licensed a Nav1.8 pain drug candidate from Jemincare in China. JMKX000623 is claimed to be a potent and selective Nav1.8 channel antagonist with good membrane permeability, metabolic stability and in vitro safety that translated into significant analgesia in several animal acute and chronic pain models, and received IND approval in China in March 2022. Orion paid €15 million upfront for exclusive global development and commercialisation rights excluding Chinese territories, with additional milestones and royalties if it makes it to market. Orion have previously worked on TRPA1(for pain and perhaps respiratory indications), but perhaps as part of this new deal (and Q1 market headwinds) they announced a major re-structuring and some R&D layoffs as they dropped a COPD drug and moved away from respiratory and neurodegenerative disease to focus on oncology and pain.
This announcement was pretty low key, perhaps as it is preclinical program in contrast to recent high profile press around several Vertex Nav1.8 clinical trials for their initial candidate VX-150, and a more successful follow-up VX-548 which achieved significant analgesia in two different acute pain patient studies. I summarised the Vertex Nav1.8 program in a previous post on LinkedIn and in my Q1 summary (here). The future challenge for Nav1.8 programs is to translate analgesia in animal models and acute clinical pain into effective treatments for chronic pain patients where the unmet need and market potential for non-addictive and non-opioid pain relief is enormous, and many other Nav channel antagonists have failed.
4. Kv1.3 inhibitor for auto-immune disease
After working on Kv1.3 drug discovery projects since 2010 I was well aware of Eli Lilly’s interest in the target for auto-immune disease, and although I was not surprised by news this quarter of them in-licensing a portfolio of compounds for inflammatory and immunology indications I was not previously aware of the source; DES-7114 came from DesRes (DE Shaw Research), the brainchild of billionaire “pharma ‘bro” Dr. David E. Shaw, a computational biology expert and hedge fund founder. The small molecules were designed and optimised using atom-scale molecular modelling simulation of ligand interactions with the Kv1.3 protein structure and structure-based drug design, perhaps aided by a recent cryo-EM structure of the human Kv1.3 channel. There has been long standing interest in Kv1.3 channels as an auto-immune and inflammatory disease target as they are functionally upregulated on activated T-effector and microglia cells, and their inhibition by various small molecules and peptide toxins abrogates disease readouts in a number of animal models for psoriasis, rheumatoid arthritis and MS. Clinical validation of Kv1.3 was achieved by Kineta Inc Inc in 2017 with a successful Ph Ib trail in psoriasis patients with the sea anemone toxin peptide analogue ShK-186 (Dalazatide).
Whilst a number of biotech companies have developed small molecules and toxin peptides against Kv1.3 up to the preclinical stage over the years (4SC, Bionomics, Circassia, Conogenetix, Evotec, Xention), DES-7114 is a potent, selective and orally available compound that recently completed a Ph I trial, explaining the $60 million upfront deal and potential development and commercial milestone payments of up to $475 million and royalties on worldwide sales. In addition, the first-in-class compound has demonstrated efficacy in several preclinical animal models of chronic inflammatory and autoimmune diseases including ulcerative colitis, Crohn’s disease and atopic dermatitis, indicating a potential to move the therapeutic needle in more specific and less well served patient groups compared to the crowded drug development space for larger but more diverse populations of MS, rheumatoid arthritis and psoriasis patients.
5. Kv7 KCNQ channel activators for epilepsy
I highlighted the efforts of several biotech companies in my Q1 summary who are developing fast followers of the Kv7.2/7.3 channel opener Retigabine (Ezogabine) as novel anticonvulsants. 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 control neuronal excitability and firing, and avoiding activity against the cardiac KvLQT1 isoform, as well as reduce bladder side-effects and move away from the Retigabine scaffold that produces epithelial pigmentation. Knopp Biosciences licensed a preclinical portfolio to Biohaven Pharmaceuticals, with the lead compound BHV-7000 slated to enter the clinic in 2H 2022 in patients with focal epilepsy (here). Following close behind are Eliem Therapeutics who came out of stealth in 2021 with several funding rounds and acknowledgement of a small molecule preclinical program for Kv7.2/7.3, which seems to have been delayed slightly and is now expected to yield a lead candidate by the end of 2022, in preparation for clinical trials in pain, epilepsy and depression.
Xenon is well ahead of the pack with its Kv7 channel modulator XEN-1101 now on the way to Ph III testing in epilepsy patients, after acing a Ph IIb trial in Q4 2021. The company leveraged additional data from an expansion study to trigger a $250 million public offering in Q2 that will fund a large Ph III trial slated for 2H 2022. XEN-1101 is a more potent and selective Kv7.2/7.3 potentiator with improved pharmacokinetics and therapeutic index compared to the clinical comparator Ezogabine. The new data showed rapid reduction in focal onset seizures for all doses tested, and 96% of patients completing the randomized Ph IIb stage elected to move into the open label study phase, with 20% remaining on treatment after 2 years. Follow-on efficacy was high with 70-80% of patients seeing a sustained reduction in median seizure frequency over 3-12 months, and 10-20% of patients becoming seizure free. These results are truly stunning and hold out great hope for more effective treatment of epilepsy compared to current non-specific Nav1.x channel blockers such as GSK’s Lamictal (Lamotrigine) and UCB’s Vimpat (Lacosamide). Xenon are also testing XEN-1101 in mid-stage studies in primary generalized tonic-clonic seizures, with Jefferies analysts projecting sales if approved of up to $1 billion in focal epilepsy and over $400 million in PGTCS.
6. NMDA receptor modulators
Given the widespread distribution of excitatory NMDA GluR ionotropic receptors across the CNS and their involvement in synaptic plasticity, a number of drug discovery programs are developing PAMs and inhibitors for a range of therapeutic indications including Alzheimer’s, depression and pain, with mixed results.
Alongside their GABA-A PAM portfolio, Sage Therapeutics are also developing NMDA-R PAMs for a range of CNS diseases. In Q2 they announced positive Ph II results for SAGE-718 in Alzheimer’s patients. The Ph II study was mostly focused on reviewing safety so was not blinded, but early efficacy data shows improved executive performance, learning and memory in patients with mild cognitive impairment and dementia. There was no improvement in attention and psychomotor speed, which Sage said is consistent with prior studies of SAGE-718, which is a novel first-in-class PAM based on an endogenous sterol modulator that is designed to selectively enhance synaptic NMDA-R function. A randomised Ph II trail in AD patients is slated to begin by the end of 2022. The drug also received FDA Fast Track designation in Q3 2021 for treating cognitive decline in Huntington’s Disease, and Sage has initiated Ph II trails with SAGE-718 for early-to-moderate HD and Parkinson’s Disease. These studies are significant as they seek to demonstrate acute symptom reduction effects rather than modify long-term disease progression, hoping to provide meaningful readouts for improved patient quality-of-life faster than competing (and ill-fated) amyloid or tau therapies. As all three neurological diseases are chronic and slow to develop with disease mechanisms occurring decades before symptoms appear, it may be unrealistic to expect a ‘cure’ for neurodegenerative disease (at least in our life time), and thus approaches to improve patient symptoms is a realistic and achievable goal for such drug discovery efforts.
Aptinyx are another company with a focus on NMDA-R PAMs for CNS therapies, but Q2 saw some significant setbacks for several programs within their expansive clinical portfolio. Firstly, their Ph IIb trial of the small molecule NYX-783 for post-traumatic stress disorder (PTSD) was abbreviated due to cashflow issues in the face of the Q1 market contraction. The low dose arm started in Dec 2021 and will continue, but the higher dose arm has been postponed as they preserve resources to complete other Ph II clinical studies of their NMDA-R PAMs in fibromyalgia and cognition. The company is optimistic for a positive outcome in PTSD as the low doses of the drug improved symptoms in an exploratory Ph IIa trial in 2020.
Secondly, another NMDA-R PAM NYX-2925 failed for a second time in a Ph II trial in diabetic neuropathy pain patients. Despite failing in an earlier Ph IIa DBN study in 2019, a post-hoc analysis convinced them to try again but two years later the results are much the same, with no significant daily pain relief after 12 weeks compared to placebo. However, the company remains optimistic for positive readouts with the same drug in a Ph IIb study in fibromyalgia patients owing to its good safety profile, with results expected in Q3 2022.
Finally, we have a topical drug discovery case study from Axsome, who are developing a novel formulation and combination of the NMDA-R antagonist Dextromethorphan and atypical NSRI anti-depressant Bupropion. Despite positive results in May 2022 for AXS-05 in a Ph II trial in patients with major depressive disorder which showed rapid and significant efficacy, the company was hit by FDA manufacturing inspection delays and deficiency notifications which have taken time to resolve. Progress is being made with labelling and post-marketing requirements requested by the FDA, and a new NDA is planned later in Q2.
In Q1 I highlighted the efforts of Gilgamesh Pharma to develop NMDA antagonists for depression after they announced plans for a Ph I trial of GM1020 in 2H 2022 after completing IND-enabling toxicology studies in 1H 2022. The compound is an oral, non-competitive NMDA-R antagonist with claimed potential for rapid and sustained anti-depressant activity with fewer aversive dissociative side-effects compared to previous NMDA modulators. 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 and I reviewed the potential involvement of other ion channels in ketamine’s efficacy in a post last week.
The fraught history for Axsome’s NMDA receptor inhibitor program is emblematic of the challenges (and misplaced assumptions) around some drug discovery strategies. Simplistic views and commentary frequently suggest that drug repurposing and/or reformulation is a quick route to the clinic and market revenue, but although this route may indeed shave some time off the 10+ years for developing a NCE, there are still major scientific and regulatory hurdles to overcome. This process is not helped by the reduced availability of FDA staff for manufacturing inspections and AdComm meetings during and after the covid-19 pandemic, problems that will still take many months to overcome.
7. Other ion channels
In contrast to my Q1 review, this last section is mainly focused on more traditional ion channel targets, and as we saw above the news is mixed. The financial market crash in Q1 ’22 has eroded the value and available resources for many small and large companies, curtailing ongoing clinical development for a number of ion channel targets that may have survived if more cash and shareholder confidence was available. Above we have the example from Aptinyx, and below another example from Sanioma.
Saniona is a EU-US biotech specialising in rare CNS diseases with a focus on ion channels, and two of their current programs have been left in limbo as they were forced to cut budgets, reduce their US workforce and executive team, conserve cash, and reorganise their pipeline following the Q1 market downturn. Being lined up for partnering are SAN-711, a GABA-A a3 subunit-selective PAM at Ph I stage for neuropathic pain, and SAN-903 which is a preclinical KCa3.1 channel blocker for rare inflammatory and fibrotic disease.
Centrexion may be one of the last players working on TRPV1, but their injectable capsaicin drug CNTX-4975 for knee pain flunked in both Ph III trials in Q2 2022. The 1st study completed in 2020 but the results were only uploaded to the federal clinicialtrials.gov site in April 2022, and no press release was issued. Knee pain whilst walking was reduced non-significantly; many patients did not complete the trial and 58% of patients experienced an adverse event, which may not be surprising given the need for intra-articular injection and previous observations of local irritation in patients treated with the Qutenza capsaicin patch, as the mechanism-of-action is thought to require activation followed by desensitisation of TRPV1 receptor channels. In the 2nd trial results filed in March (but still under review) the drug also failed to significantly reduce pain, stiffness and walking function. Centrexion had high hopes for CNTX-4975, which had FDA fast-track designation and was backed by a $40.5 million raise in late 2020. The company has followed a familiar path in the face of a late stage failure by highlighting efficacy and statistical significance in post-hoc analysis across combined study groups, which they plan to use for an NDA filing to the FDA later this year.
Finally, whilst Praxis Precision Medicines have been affected by negative clinical trial results (see section 1 above) and adverse market pressure in Q1, there is one piece of good news that’d I’d like to finish on. Their T-type Cav3.x channel blocker PRAX-944 achieved positive results in a mid-stage Ph IIa study, meeting the primary endpoint of reducing essential tremor in a clinically meaningful and statistically significant manner compared to placebo. The drug was well tolerated and the primary endpoint of the remaining part of the trial will shift from safety to efficacy.
Dr. Marc Rogers, Cambridge (UK)