Addex Therapeutics Ltd

Hello, everyone.

I'd like to thank you all for attending our Q1 2025 financial results conference call. I'm here with Mikael Palinczeff, our head of Translational Finance, who will provide an update on our R&D program. I draw your attention to the press release and the financial statements issued earlier today, which are available on our website. I also draw your attention to our disclaimers. We will be making certain forward-looking statements that are based on the knowledge we have today. I will start this conference call by giving a quick overview of our recent activities and achievements before reviewing our pipeline. I will then hand over to Nisha, who will review in more detail our NGR5 megabattleset modulator program for brain injury recovery, and I'll gather the popular modulations for clinical programs for COT. I will then review our Q1 2025 financial results followed.

With that, we will open the Q&A.

Moving on to the highlights, we have had a great start to the year, with several significant value-creating achievements in our pipeline. We have made excellent progress in our GABA-B positive outset modulator program with our partner, Indivior, who successfully completed IND enabling studies with their selective drug candidate for substance use disorders. As a reminder, under the terms of the agreement, ADDx is eligible for payments of up to $330 million US dollars and successful achievement of pre-specified regulatory clinical and commercial market as well as tiered royalties on the level of net sales from high single digits up to low double digits. Also under the terms of the agreement, we have the right to select compounds for development in a predefined list of reserved indications. We have selected a compound to advance our own independent recovery PAM programme for the treatment of chronic cough. We've substantially completed preclinical profiling of our selected drug candidate and recently published robust anti-TUSIV data in multiple preclinical models of COPS. Misha will speak about this exciting data later in our presentation. We also regained rights to our MGR2 positive alpha modulator program, including the Phase II asset ABX71149 from our partner, Johnson & Johnson. We're currently evaluating a number of therapeutic indications for the future development of this program. We've repositioned diprachloron, our NBR5 negative onset modulator program for brain injury recovery and recently entered into an option agreement giving us access to an exclusive license to intellectual property covering the use of NBR5 inhibitors in this interesting therapy indication. Misha will talk about this exciting program later in the presentation. On the financial side, we completed the year with 2.8 million Swiss francs of cash, which provides us with a cash runway through mid-2026. I'd like to highlight the cash burn has been significantly reduced following the Eurostaric spin-out transaction. The current cash does not fund the progress or the progression of our unpartnered program into the clinic. Now, for a quick review of our pipeline, We continue to believe in DIPAGRIL and are executing our plans to reposition the development in brain injury recovery. As mentioned, our partner DIPAGRIL has selected a GABB-B PAM, well-planned effort about immune substance use disorders, and has successfully completed R&D and AVM studies. We're advancing our independent GABB-B program, chronic health, and expect to start R&D and AVM studies this year, subject to experience financing. Neurotherics has made excellent progress in advancing its pipeline, including starting IMD and avian studies, sorry, completing IMD and avian studies with the 10-4 PAM program. Now I will hand over to Nisha, who will give you some more details about our exciting portfolio. Thanks, Tim. Hello, everyone. I will start by speaking about Depagluron and our plans for development in brain injury recovery. For termination of the development of Depragdorant in PD-LID, we embarked on a detailed evaluation of a number of potential indications for future development. We have completed this exercise and have identified brain injury recovery as an interesting indication for the future development. We believe the differentiated profile of Depragdorant makes it particularly suitable for enhancing the impact of rehabilitation in traumatic brain injury and stroke patients. There is a large number, large medical need in post-stroke recovery and rehabilitation. Stroke is among leading causes of chronic, often lifelong disability, as it leads to motor sensory cognitive impairment and multiple comorbidities. There are over 100 million stroke survivors worldwide, and the number is growing at the annual rate of 12 million. A variety of rehabilitation therapies are used with post-stroke patients, but the recovery is slow and often inadequate. there is an urgent need for pharmacological agents that can facilitate the recovery stimulated by rehabilitation therapies. MGOR5 receptor is a suitable target to address post-stroke recovery as it is densely expressed in the brain, involved in neuroplasticity, and modulates excitatory-intubatory equilibrium. In fact, activation of MGOR5 has been observed in range of neurological disorders, including stroke, where it plays a role in so-called maladaptive rewiring of the brain following stroke. Inhibition of MGOR5, on the other hand, can facilitate adaptive rewiring of the brain, promoting neuroplasticity and creating of new functional pathways moving the neural network towards the pre-lesion stage. Excited new evidence recently published in the journal Brain suggests that the negative ulcerative modulator of ANGLA-5, MPET, administered daily in rats following stroke results in a sustained and growing improvement in sensory motor function in comparison to vehicle treatment. Similar improvement in sensorimotor function was observed in animals treated with hour and gore-5 NAM depravulant. MRI imaging of the resting state functional connectivity in post-stroke rodents shows that daily administration of M-TEC also stimulates intra- and inter-hemispheric connectivity in the brain disrupted by stroke. It is important to note that improvement in brain connectivity after stroke is known to correlate with functional recovery and is observed across species. Dupragluron is ideally suited to be used in tandem with rehabilitation therapies in post-stroke patients as it has a fast onset of action and short half-life. It has shown good tolerability in healthy subjects and in Parkinsonian patients showing only mild to moderate CNS-related adverse effects. We have a drug product ready and a strong patent position and believe Depremurant can become a first-in-class drug to facilitate post-stroke recovery. We can also speculate that Depremurant-mediated adaptive rewiring and facilitation of recovery following brain damage would also be seen in traumatic brain injury patients. Let me now switch to our GABA-B positive allosteric modulator program, which is partnered with Indivio. The aim of this collaboration is to deliver a better baclofen for substance use disorders. As a reminder, GABA-B receptor activation has been clinically validated in a number of disease areas using Baclofen, a GABA-B orthosteric agonist. Baclofen is an FDA-approved for treatment of spasticity and is widely used or playable to treat numerous diseases, including substance use disorder. However, Baclofen has a short half-life and comes with significant side effects, hampering its wider use. there is a strong need for a better macrophage. We believe that this can be achieved with positive ulcer remodulators and their differentiated pharmacology, having the efficacy that is similar or better than that of macrophage, but longer half-life and improved side effect profile. Our partner, Indivior, has selected a GABA-B-PAM drug candidate for development in substance use disorders. and has started IND-enabling studies in H22024. As part of our agreement with Indivior, ADDx has exercised its right to select a compound to advance its own independent GABA-B PAM program for the treatment of chronic cough. I will now present this exciting opportunity. There is a strong rationale for developing GABA-BPAMs for chronic cough. Chronic cough is a persistent cough that lasts for more than eight weeks and can be caused by a variety of factors, including respiratory infections, asthma, allergies, and acid reflux, but also possibly by an overactive cough reflex. There is a large unmet medical need in novel antitrust drugs as current standards of care are ineffective in 30% of patients or only moderately effective in up to 60% of patients. In addition, the current treatments carry risks of serious side effects. On the next slide, we show that GABA-BPAMs are likely to have a superior tolerability profile in comparison to current standards of care and show no taste-related side effects, as seen with a newly-approved phyto-extra inhibitor, Kefabizab. Support for using GABA-B PAMs in treatment of chronic cough comes from the clinical evidence that Baclofen, a GABA-B agonist, is used off-label in cough patients, and from the anatomical evidence that GABA-B receptors are strongly expressed in airways and in the neural pathway regulating cough. Therefore, we believe that GABA-B PAMs could offer superior efficacy in cough patients. The pre-ING activities, including in vivo proof-of-concept studies, non-GLP talks, and CMC, have been completed. Our clinical candidate has shown favorable efficacy, tolerability, and developability profile. The compound has demonstrated a consistent minimum effective dose of 1 mg and ED50 or 6 mg in models of cough in vivo. No signs of tolerance were seen after subchronic dosing, and more than 60-fold safety margins were demonstrated based on respiratory depression as sedation biomarkers. The IND-needling studies are planned to start this year. The next set of slides describe the in vivo proof-of-concept studies in models of copygenetics where we evaluated efficacy and tolerability of our clinical candidate, compound A, and also characterized clinically active antitussive drugs, nalbufin, baclofen, codeine, and the P2X3 inhibitor in the same model. In the model of citric acid-induced cough in genetics, acutely administered compound A delivered a robust anti-tussive efficacy, reducing the cough number dose-dependently, and achieving 70% reductions at the maximum dose. The anti-tussive profile of compound A was similar to that of nalbufin, baclofen, and CODI. Compound A also increased the latency to first cough dose-dependently, thus delaying the onset of cough. The antitrusive profile of compound A in delaying cough onset was similar or better than that of reference trials. In the same experiment, compound A appeared well tolerated as there were no marked changes in respiratory rate at up to 60 mgs per kick. In contrast, nalbufin, baclofen, and codeine resulted in robust reduction of respiratory rate. at their highest dose indicative of sedative-like effects. When evaluation of the antidepressant efficacy across compounds was done at the respective highest doses free from respiratory effects, compound A was shown to be superior to reference drugs in both cost number and cost-laden measures. In the chronically administered compound A showed signs of improved efficacy and potency and no signs of tolerance in comparison to an acute treatment. In the model of ATP-potentiated citric acid COPs in guinea pigs in a head-to-head comparison experiment, acutely administered compound A exhibited a trend of better efficacy and potency. in comparison to that of P2X3 inhibitor, while showing signs of similar tolerability. In summary, we have selected a clinical candidate for chronic cold with a robust reproducible antitussive efficacy of 1 mcg per kick and good PKPD. The compound has the potential to have the best disease efficacy and tolerability profile and broad application in COVID patients. The compound showed a favorable developmental profile in non-GLB TOC studies performed in red dogs and non-human primates. We are on track to start IND-enabling studies this year. This concludes our prepared remarks on the progress of our R&D program. Now, I hand it back to Tim.

Thanks, Misha. Now for a view of our Q1 2025 financials.

Following the nearest direct transaction, we were required under the IFRS to identify continuing operations related to our retained business and discontinued operations related to the divested business . All incoming expense items related to the discontinued operations have been reclassed under a specific line. of the comprehensive loss called net loss from discontinued operations. Now, starting with the income statement, which relates to the continuing operations, we recognize 0.1 million of income in Q1 2025 compared to 0.2 million in Q1 2024. The decrease is primarily due to the completion of the funded research phase of our collaboration with Indivio in June of last year. Continuing R&D expenses of 0.1 million primarily related to our Gabbard and PAM programme and decreased by 0.1 million in Q1 2025 compared to Q1 2024 and again mainly due to the completion of the research phase of our collaboration with Invivior. Continuing G&A expenses of 0.5 million primarily related to corporate development activities and decreased by 0.3 million in Q1 2025 compared to Q1 2024 primarily due to decreased legal fees. The finance results lost in Q1 2025 primarily relates to US dollar currency exchange differences. The share of net loss of associates of 0.8 million relates to the 20% equity interest received as part of the consideration for the divestment of a part of our business in the US. which is being accounted for using the equity method. Under IFRS, we are required to recognize our share of their results. Now, to the balance sheet. Our assets are primarily held in cash, and we completed Q1 of 2025 with 2.8 million Swiss francs of cash held in Swiss francs and US dollars. Our current assets amount to 0.4 million, primarily related to prepaid R&D and G&A costs. Our non-current assets of £6.3 million as of 31st March 2025, primarily related to the 20% equity interest in your sales group recorded on the balance sheet under the Equity Method of Counting for Associates. Current liabilities of £1.1 million as of March 31, decreased by £0.3 million compared to December 31, 2024, and this primarily relates to accrued expenses and payables for the R&D and professional fees Long current liabilities of 0.1 million as of March 31, 2025 decreased to 0.1 million compared to December 31, 2024, primarily due to the reduction in retirement benefit obligations following changes in the financial assumptions. Now to the cash flow statement on March 31, 2025, the cash balance amounted to 0.8 million and decreased by 0.5 million compared to the beginning of the year. primarily due to the operating costs of continuing operations. Now, to summarize, we've made excellent progress in our GABB program with our partner in duty who are successfully completing IMD and ADM studies with their Select Compound for Developmental Substance Use Disorders. Neurosterics has made excellent progress with their lead M4 candidate successfully completing IMD and ADM studies in Q3-24. We have strengthened the IP in our MDR5 NAMM programme and Diploglarge is ready to start clinical development for brain injury recovery. Our GABBD PAM COG programme has demonstrated excellent pre-tensile efficacy and tolerability with the IV in every stage ready to start. We have validating partnerships with industry supported investors and a strong attitude which puts us on a solid position to deliver on our strategic objective. This concludes the presentation and we will now open for questions.

Thank you. Dear participants, as a reminder, if you wish to ask a question, please press star 11 on your telephone keypad and wait for your name to be announced. To withdraw a question, please press star 11 again. Alternatively, you can submit your questions via the webcast. Now we're going to take the first question on the line. And the question comes from H.C. Wainwright. Your line is open. Please ask your question.

Hi. Thanks very much for taking my questions. I was wondering if you could provide us with your updated thoughts on the current competitive landscape in chronic cough. And in particular, if you could comment on the relevance of preceding programs in terms of guiding what you expect to be the clinical development pathway for your asset in this indication?

Yes, of course. There are a number of compounds that are in development currently. One that I can mention in particular is nalbufin, and that's actually the reason we wanted to benchmark it against our compound. So nalbufin has shown very promising efficacy profile in patients with IPF-related calls. By the same time, there were clear signs that were indicative of central mediation. So that tolerability profile will be challenging once you move into the patient population that has refractory chronic calls that are markedly younger and overall healthy in their early to mid-50s instead of early to mid-70s as in IPF. And their level of tolerability is very different. So that's where we see a significant opportunity to deliver similar efficacy with markedly improved tolerability profile and have the compound that can be applied those to IPF related and refractory chronic cough. So that would be my answer to your first part of the question. In terms of our plans for development, we are planning to perform SAD and MAD in healthy volunteers and quickly go and perform a so-called challenge study, which can be done both in healthy controls and in chronic cough patients. That can be done even at the end of SAD or at the end of MAD as 1B. This offers an opportunity to have a quick and straightforward efficacy readout relatively early in development. This will, of course, follow by a phase 2 study in clinical patients. So this will be a refractory clinical patient. We are also considering to have a more in-depth evaluation of chronic cough in these patients using more advanced technologies that are now being developed and already approved by FDA that allow 24-7 monitoring of cough. That gives an opportunity for much more precise monitoring of cough, but also better selection of chronic cough patients. So that will be another innovation on our side. So that's the answer to your question. So maybe I can just add a little bit to what... Can you also... Yes. Sorry, can you also comment on... Go ahead, go ahead, please. Yeah, I just want to add to what Misha is saying, Graham. So I think... What is so exciting about this program of ours is that we know that P2X3 inhibitors, which are peripherally restricted, are showing about a 30% reduction in chronic cough. And what was really exciting about the NABUFIN data that came out from Trevi is they were over 50% reduction in chronic cough patients. And this really supports our hypothesis that you need to have a molecule that's both central and peripheral. And that's what we have with our compound A, our GABA-B positive allosteric modulator. What you can clearly see from the data that we've generated preclinically is we have a much better therapeutic margin. So we have reason to believe that we're going to see more than 60%. We'll see a sort of an efficacy readout more similar to now but a tolerability profile closer to P2X3 inhibitors, which will give us a very, very clear competitive advantage over not only standard of care today, but what's coming through in the pipeline.

Can you also comment on the potential applicability of this agent to treatment of chronic painful cough in indications outside of IPF, particularly pulmonary sarcoidosis?

Actually, painful cough could be another possibility. indication in particular based on the large body of evidence suggesting that GABA-B activation reduces pain across multiple pain conditions, including chronic pain. So this could be absolutely one of the very suitable indications for chronic cough reduction with GABA-B PAM. Yeah, we are thinking about that indication as potentially a

path forward in phase two.

And then with respect to Dipraglurant, specifically in the post-stroke rehabilitation context, can you give us a little bit more detail on two aspects? The first would be what an appropriate control arm would look like in a potential registration quality study in this setting. What patients in the control arm would likely be receiving in terms of therapy, whether behavioral or physical or otherwise. And then secondly, if you could talk a little bit about what the efficacy bar might look like in this indication, given the fact that, as far as I'm aware, there are no pharmacotherapies currently approved in this context.

Yeah. Yeah, it's a very good question. The way we see it now, we are planning to use, to tell you the wrong in tandem with physiotherapy. Because of its short half-life, it can be given multiple times per day and be well-tolerated. We are thinking that we need to perform a few studies, including clinical pharmacology studies, to learn more about how to probably modulate plasticity in both healthy, to start with, and then in patients with stroke. This will really help us in better designing the proper phase two study. So this is what we are planning, performing to evaluating measures of plasticity in sensory motor cortex, in the midbrain and spinal cord. We are also interested in exploring whether it's best to give the compounds before the exercise or immediately after. So there are a few components of the design that can be explored in a dedicated clinical pharmacology study before we move forward into a phase two.

Thank you. Thank you.

Dear participants, as a reminder, if you wish to ask a question, please press star one one on your telephone keypad. Alternatively, you can submit your questions via the webcast. Dear speakers, we'll just give one moment to our participants to submit any questions on the webcast or to press star one one. Dear speakers, there are no further questions for today. Thank you, ladies and gentlemen. This brings our main part of the conference to the close, and I would like now to hand back to Tim Dyer for any closing remarks.

Well, thank you very much, everyone, for attending the conference call today, and we look forward to speaking to you again soon. I wish you a very nice day.

This concludes today's conference call. Thank you for participating. You may now disconnect. Have a nice day.