Mikhail Kalinichev
Analyst
Thanks Tim. Hello everyone. I will start by speaking about our Phase 2 epilepsy study with ADX71149, which has been completed recently by Janssen. Epilepsy is a large multi-billion-dollar market opportunity where despite several available treatment options, many patients are still in need of improved therapies to their -- to treat their seizures. As a reminder, ADX71149 is a metabotropic glutamate receptor subtype 2 or mGluR2 positive allosteric modulator discovered in partnership with Janssen using Addex’s proprietary allosteric modulation platform. ADX71149 has demonstrated both standalone efficacy and a strong synergistic effect in combination with inhibitors of SV2A such as Keppra and Briviact. ADX71149 has also been thoroughly profiled in preclinical and clinical studies by Janssen demonstrating its good safety and tolerability profile in healthy volunteers and patients. Janssen responsible for development have just completed both the Phase 2 study and an open label extension study in epilepsy patients. Results are expected by mid-May this year. We have significant economics in our deal with Janssen with pre-launch milestones of €109 million, low double-digit royalties on net sales and Janssen is responsible for all development costs. To illustrate the synergistic effect, same with the combination of ADX71149 and levetiracetam, the active molecule in Keppra, here are the data obtained in the 6 hertz psychomotor seizure model widely recognized as having high translational value to characterize the efficacy of anti-epileptic drugs. As a reminder, ADX71149 given alone in this model produces a robust protection against 6 hertz induced seizures with an ED50 of approximately 20 mgs per kg. In combination studies with varying doses of levetiracetam, a fixed dose of ADX71149 increased the potency of levetiracetam leading to approximately 35-fold shift in its ED50 values. Conversely, using a fixed dose of levetiracetam with varying doses of ADX71149, it increased the potency of ADX71149 leading to approximately 14-fold shift in its ED50, suggesting a positive pharmacodynamic relationship or strong synergistic effect for the two molecules when given in combination. This extraordinary effect of a combination of an mGlu2-PAM with an SV2A antagonist has been patented, offering a strong protection for this program until 2035 without additional extension. This is the Phase 2 study design. The study is a double-blind placebo-controlled proof-of-concept study enrolling patients with focal onset seizures who have suboptimal response to treatment with levetiracetam, Keppra or brivaracetam, Briviact. In this Phase 2 study design, patients establish a 28-day seizure count over a 56-day baseline period prior to being randomized to receive either ADX71149 or matching placebo, the primary endpoint in this time taken to return to their monthly baseline seizure count. The study has two parts, Part 1 being the four-week acute efficacy phase and Part 2 being an eight-week maintenance phase of efficacy phase. Part 2 includes patients who did not reach their baseline seizure count during Part 1 of the study and continue on their randomized drug or placebo. An open-label extension study was ongoing in parallel, offering all patients the opportunity to get treated with ADX71149 in combination with levetiracetam or brivaracetam. As previously announced last year, an Independent Interim Review Committee convened by our collaboration partner recommended to continue the study following review of unblinded data from Part 1 of Patient Cohort 1. This was encouraging news, suggesting that ADX71149 is safe and well-tolerated and potentially offering benefit to epilepsy patients. We look forward to sharing the topline data of Cohorts 1 and 2 in mid-May this year. Following termination of the development of Dipraglurant in PD-LID, we embarked on a detailed evaluation of a number of potential indications of interest for future development, including substance abuse disorder, migraine and other forms of pain. We have completed this exercise and have identified post-stroke recovery as an interesting indication for the future development of Dipraglurant. We believe the differentiated profile of Dipraglurant makes it particularly suitable for post-stroke recovery. There is a large unmet medical need in post-stroke recovery and rehabilitation. Stroke is among leading causes of chronic often lifelong disabilities, 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. mGlu5 receptor is a suitable target to address post-stroke recovery, as it is densely expressed in the brain, involving neuroplasticity and modulates excitatory-inhibitory equilibrium. In fact, activation of mGlu5 has been observed in a range of neurological disorders, including stroke, where it plays a role in so-called maladaptive rewiring of the brain following stroke. Inhibition of mGlu5, on the other hand, can facilitate adaptive rewiring of the brain, promoting neuroplasticity and creating of new functional pathways, moving the neural network towards a pre-lesion state. Exciting new evidence recently published in the Journal Brain suggests that negative allosteric modulator of mGlu5, MPEP, 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 mGlu5 non-Dipraglurant. MRI imaging of the resting state functional connectivity in post-stroke rodents shows that daily administration of MPEP also stimulated intra- and interpenetratory 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. Dipraglurant 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 Dipraglurant can become a first-in-class drug to facilitate post-stroke recovery. We can also speculate that Dipraglurant-mediated adaptive rewiring and facilitation of recovery following brain damage can also be seen in traumatic brain injury patients. Let me now switch to GABAB positive allosteric modulator preclinical program, which is partnered with Indivior. The aim of this collaboration is to deliver a new treatment for substance use disorders. Indivior is supporting the research at Addex and has recently committed an additional CHF2.7 million funding for us to complete clinical candidate selection activities, in addition to CHF13.8 million total funding so far. As a reminder, GABAB receptor activation has been clinically validated in a number of disease areas using baclofen, a GABAB allosteric 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 a better baclofen. We believe this can be achieved with positive allosteric modulators and their differentiated pharmacology, having the efficacy of baclofen but longer half-lives and improved side effects profile. We are well on our way to meeting this objective, with multiple novel drug candidates rapidly advancing through clinical candidate selection phase, with the aim to nominate drug candidates ready to enter IND-enabling studies in H2 2024. As part of our agreement with Indivior, we have the right to select drug candidates from the funded research activities for our own independent GABAB PAM program. We have selected to focus our independent program on cough, and therefore, I will present this exciting opportunity. There is a strong rationale for developing GABAB 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 an overactive cough reflux. There is a large unmet medical need in novel anti-tumor drugs, as current standards-of-care are ineffective in 30% of patients and 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 GABAB PAMs 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 a newly approved P2X3 inhibitor, GABAB PAM. Support for using GABAB PAMs in treatment of chronic cough comes from the clinical evidence that baclofen, a GABAB agonist, is used off-label in cough patients and from anatomical evidence that GABAB receptors are strongly expressed in airways and in the neuronal pathway regulating cough. Therefore, we believe that GABAB PAMs could offer superior efficacy in cough patients. Therefore, we believe that GABAB PAMs could be an innovative new treatment of chronic cough, administered once daily via oral dosing and offering improved efficacy and tolerability with fewer non-responder patients suitable for chronic dosing, therefore significantly improving patients’ quality of life. We are working with multiple compounds progressing in late clinical candidate selection phase and we expect to move into IND enabling studies in H2 2024 in parallel to delivering compounds for our partner, Indivior. Now I hand it over back to Tim.