Addex Therapeutics Ltd

Good day and thank you for standing by. Welcome to the Addicts Therapeutics Half Year 2024 Financial Results and Corporate Update Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be the question and answer session. To ask a question during the session, you need to press star 11 on your telephone keypad. You will then hear an intimate message advising your hand is raised. To withdraw a question, please press star 11 again. To ask a question via the webcast, please access the Ask the Question tab. Dear participants, due to the technical issues today, please use the download button to download the presentation from the download menu and follow it. Thank you so much. And now I would like to hand over the conference to your speaker today, Tim Dyer. Please go ahead.

Hello, everyone. I would like to thank you all for standing by and attending our half-year 2024 Financial Results Conference Call. I'm here with Misha Kalenchev, our Head of Translational Science, who will be providing an update on our R&D programs I draw your attention to the press release and the financial statements issued earlier today, which are available on our website. Unfortunately, there has been a technical issue with loading the presentation to the webcast system, so please use the download button in order to download the presentation. We will be indicating slide numbers so that you will be able to follow, hopefully. So on to slide three. the disclaimer slide, 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 them on our pipeline. I will then hand over to Misha, who will review in more detail some of our clinical and preclinical programs. I will then speak about the recent launch of NeuroSterix before reviewing a half-year 2024 financial results. Following that, we will open the call for Q&A. So moving to slide four, highlights. We launched NeuroSterics with a Series A of 63 million led by Perceptive Advisors. This is an innovative financing transaction that provides us with the resources needed to advance our preclinical portfolio without diluting our shareholders' interest in our clinical stage assets and partnered programs. As part of the transaction, we received 5 million Swiss francs and a 20% equity interest in NeuroSterics, securing the balance sheet and retaining significant upside in the programs for our shareholders. I will speak more about this innovative financing transaction later in the presentation. We have made excellent progress in our GABA v. PAM program, and our partner, Indivior, has selected a compound for development in substance use disorders and will now take over operational responsibility for development As a reminder, under the terms of the agreement, Addix is eligible for payments of up to $330 million on successful achievement of pre-specified regulatory, clinical, and commercial milestones, as well as tiered royalties on the level of net sales from high single digit up to low double digit. Under the terms of the agreement, we have exercised our right to select an independent compound to advance our own GABA-B PAM program for the treatment of chronic cough. We have some exciting data in cough with our lead compound, which Misha will be sharing with you later in our presentation. Janssen Pharmaceuticals' discontinued development of ADX71149 in epilepsy. Our partnership remains ongoing, while the full data set from the Phase II study as an adjunctive epilepsy treatment is analyzed. Now moving on to slide five, the pipeline slide. Now for a quick review of our pipeline. As mentioned, our partner Indivio has selected a GABA VPAM drug candidate for development substance use disorders and expects to start IND enabling studies in the first half of 2025. We are advancing an independent GABA VPAM program for chronic cough and expect to start IND enabling studies in 2025 subject to securing financing. We continue to believe and are executing our plans to reposition the development for brain injury recovery. NeuroAsterix has made excellent progress in advancing its pipeline, including starting IND-enabling studies with its M4PAM program. Now I will hand over to Misha, who will give you some more details about our exciting portfolio.

Thanks, Tim. Hello, everyone. I will start by speaking about depraglurant in our plans for development in brain injury recovery. Following termination of the development of depraglurant in Pedulit, we embarked on a detailed evaluation of a number of potential indications of interest 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 Depragnoliran makes it particularly suitable for enhancing the impact of rehabilitation in traumatic brain injury and stroke patients. Please move to slide seven. There is a large unmet medical need in post-stroke recovery and rehabilitation. Stroke is among the 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 therapy. Slide eight. 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-inhibitor equilibrium. In fact, activation of MGOR5 has been observed in a range of neurological disorders, including stroke. where it plays a role in maladaptive rewiring of the brain following stroke. Inhibition of AMGOR5, on the other hand, can facilitate adaptive rewiring of the brain, promoting neuroplasticity and creating of new functional pathways, moving the neural network towards pre-lesion state. Exciting new evidence recently published in the journal Brain suggests that the negative ulcerative modulator of NGOR5, MTEP, 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 sensory motor function was observed in animals treated with our NGOR5 NAM depragolant. Please move to slide 10. MRI imaging of the resting state functional connectivity in post-stroke rodents shows that daily administration of M-TEF also stimulates intra- and inter-hemispheric connectivity of 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. Slide 11. Depragluant 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 Depremulone can become a first-in-class drug to facilitate post-stroke recovery. We can also speculate that Depremulone-mediated adaptive rewiring and facilitation of recovery following brain damage would also be seen in traumatic brain injury patients. Please move to slide 12. Let me now switch to our GABA-B positive allosteric modulator program, which is partnered with Indivia. The aim of this collaboration is to deliver a better baclofen for substance use disorders. Slide 13. As a reminder, GABA-B receptor activation has been clinically validated in a number of disease areas, including baclofen, a GABA-B autosteric agonist. Baclofen is FDA-approved for treatment of spasticity and is widely used off-label to treat numerous diseases, including substance use disorders. However, Baclofen has a short half-life and comes with significant side effects, hampering its wider use. Thus, there is a strong need for better Baclofen. We believe this can be achieved with positive autosteric modulators and their differentiated pharmacology, having the efficacy of Baclofen, but longer half-life and improved side effect profile. Our partner in DVR has selected a GABA-B-PAM drug candidate for development in substance use disorders and expects to start IND-enabling studies in H1 2025. Please move to slide 14. Part of our agreement with Indivior, ADEX 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. Slide 15. There is a strong rationale for developing GABA-B PAMs 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 overactive cough reflux. There is a large unmet medical need in novel antitrusive 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. Slide 16. On the next slide, we show that GABA-BPAMs are likely to have a superior tolerability profile in comparison to the current standards of care and show no taste-related side effects as seen with newly approved P2X3 inhibitor, gefapixone. Please move to slide 17. Support for using GABA-B PAM 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 anatomical evidence that GABA-B receptors are strongly expressed in airways and in the neuronal pathway regulating cough. Therefore, we believe that GABA-B PAMs could offer superior efficacy in cough patients. Slide 11. The pre-IND activities, including in vivo proof of concept, non-GLP talks, and CMC have been completed, and our clinical candidate has shown favorable efficacy, tolerability, and developability profiles. Our clinical candidate has demonstrated a consistent minimum effective dose of 1 mcg and ED50 of 6 mcg in call frequency. Noise signs of tolerance were seen after subchronic dosing, and a tenfold safety margin was demonstrated based on tolerability biomarkers. The IND-enabling studies are planned to start in 2025. Slide 19. The next set of slides describe the in vivo proof-of-concept studies in models of COF. In a model of citric acid-induced cough in GeneFix, acutely administered compound A delivered a robust antitrusive activity profile, reducing the cough number and increasing the latency to the first cough. The antitrusive profile of Baclofen, the same model, was more modest as cough latency remained largely unchanged. Slide 20. In the same experiment, Compound A was better tolerated than Baclofen as there were no marked changes in respiratory rate, body temperature, and plasma concentration of growth hormone at up to 60 mgs per kick. In contrast, Baclofen suppressed respiratory rate, reduced body temperature by near 22 degrees Celsius, and increased growth hormone concentration in plasma starting at 3 mgs per kick dose. we believe we achieved our goal to discover a better baclofen for chronic cough. Please move to slide 21. In a model of citric acid-induced cough in guinea pigs, subchronically administered compound A showed signs of improved efficacy and potency and no signs of tolerance in comparison to an acute treatment. Slide 22. As expected, signs related to safety and tolerability of compound A remained largely unchanged under subchronic versus acute treatment regime. Slide 23. In the model of ATP-potentiated citric acid cough in guinea pigs, in a head-to-head comparison experiment, acutely administered compound A and the P2X3 inhibitor had similar efficacy and tolerability profiles. Please move to slide 24. In summary, we have selected a clinical candidate for chronic cough with a robust, reproducible, antitrusive efficacy of 1-mgpK and a good PK-PD. The compound showed a favorable developability profile in non-GLP toxic studies performed in rats, dogs, and non-human primates. We are on track to start IND-enabling studies early H1 2025. This concludes our prepared remarks on the progress of our R&D programs. Now, I hand it back to Tim. Thanks, Misha.