Addex Therapeutics Ltd

Hello, everyone. I'd like to thank you all for joining our 2021 Full Year Financial Results Conference Call. I'm here with Roger Mills, our Chief Medical Officer, and Robert Lugins, our Head of Discovery Biology. 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 disclaimer. 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 achievements before handing over to Roger and Robert, who will review our clinical and preclinical pipeline. I will then review our 2021 full year financial results. Following that, we will open the call for Q&A. During 2021, we have continued to make excellent progress towards achieving our strategic objectives and now have three clinical programs dosing patients, which is a significant achievement. In September, we started dosing patients in our Phase IIa clinical trial of Dibrogluron for blepharospasm, a type of dystonia characterized by involuntary contractions or spasms of the eyelid muscles resulting in sustained eyelid closures. During 2021, we also continued to advance our pivotal program with Dibrogluron in Dyskinesia associated with Parkinson's disease. Our partner Janssen continued to make significant progress in executing their global phase two study in epilepsy patients. Due to the continued disruption caused by the global coronavirus pandemic, and in particular its impact on clinical research, we have revised our guidance for reporting data from our clinical studies. We now expect to report data from our blepharospasm study in Q2 of this year instead of the end of Q1, a six-week delay. We also expect our PD-LID study to report data in H1 of 2023 instead of the end of Q4 of 2022, a three to six month delay. While these delays are disappointing, we are focused on maintaining the integrity and quality of the study. We continue to expect our partner Janssen to report data from their epilepsy study in Q3 of 2022. We're also very excited by our preclinical pipeline. which has made spectacular progress with multiple clinical candidates rapidly advancing towards IND-enabling studies. In 2021, we announced the extension of our strategic collaboration on GABA-B-PAM with Indivio and their commitment of an additional $4 million of research funding to advance drug candidates through to the start of IND-enabling studies. We continue to make progress with an independent GABA-B-PAM program for Charcot-Marie-Tooth type 1a neuropathy and entered into a collaboration with the Charcot-Marie-Tooth Association of the United States. This collaboration is to evaluate selected drug candidates in preclinical models for Charcot-Marie-Tooth 1a neuropathy. We are on track to deliver multiple GABA-B-PAM drug candidates ready to start ion enabling studies. We continue to advance our other preclinical programs, in particular, our mGluR7 negative allostatic modulator program for post-traumatic stress disorder, which is progressing through clinical candidate selection funded by the Eurostars and InnoSwiss grant program. We also expect our mGluR2 negative allostatic modulator program for mild neurocognitive disorders associated with Alzheimer's disease, Parkinson's disease, and depression to enter clinical candidate selection phase in the second half of this year. On the financing side, The extension of our collaboration with Inivia and the additional $4 million of funding as well as the 10 million financing from Armistice Capital contributed to our completing the year with a cash position of 20.5 million Swiss francs or the equivalent of 22.5 million US dollars. So now I would like to hand over to Roger. So Roger, the floor is yours.

Thanks, Tim. Good morning. Good afternoon, everybody. Let's start by speaking about our Dipragluron program for dyskinesia associated with Parkinson's disease. This indication represents a multi-billion dollar market opportunity. We announced the initiation of our 301 Pivotal Phase 2 B3 study during the second quarter of 2021. The study is intended to enroll 140 Parkinson's patients who are experiencing moderate to severe dyskinesia. and includes around 50 sites based in the United States. Let me remind you of the study design. This is a one-to-one randomized placebo-controlled study of 100 milligrams of dipreglorin taken three times daily in conjunction with the patient's L-DOPA dose. Duration of the study is 12 weeks. In parallel, we also initiated our 302 study. Patients who complete the 12 weeks of the 301 study are eligible to roll over into the 302 study, which is a 12-month open-label safety study where all patients received dipreglorant 100 milligrams three times daily, irrespective of the study arm they were randomized to in the earlier 301 study. 302 study provides six and 12-month treatment safety data to meet the regulatory requirements for an NDA submission. The primary endpoint to the 301 study is a change from baseline in the Unified Dyskinesia Rating Scale, or UDIS-RS. This scale was developed specifically to assess dyskinesia symptoms in Parkinson's patients. It's a scale recommended by the Movement Disorder Society and has regulatory precedent with the FDA approval of GoCovri for PD-LID. Secondary endpoints include the clinician's global impression of severity and standardized patients' diary-based assessments of on-time without troublesome dyskinesia and off-time. Importantly, we have included a number of measures to manage placebo response. These include the use of the UDIS-RS scale, which is less prone to placebo response than other scales for dyskinesia, the use of the brief psychosocial therapy adapted for dyskinesia to be used in a screening period of the study and the requirement that patients have moderate to severe symptoms both at the screening visit as well as at the study baseline visit. We are also using expert reviews of the ratings to ensure quality. In addition, the 12-week duration of the study will be expected to mitigate placebo response. For background, in a previous Phase IIa study, dipreglomerant met its primary endpoint by being generally well tolerated and showing no clinically significant safety issues. In addition, at day one and day 14, dipragorin showed statistically significant benefit on the PD-Lib's clinical symptoms as measured using the Modified Abnormal Involuntary Movement Scale, or MA. However, statistical significance was not achieved at day 28, due in part to an increasing placebo response. The registration or 301 study has an improved design, cooperating multiple methods to mitigate placebo response. We expect this study to read out top line data in the first half of 2023. In addition, we've initiated our second different clinical program. This is for the treatment of blepharospasm. Blepharospasm or BSP is a type of dystonia. which affects the muscles of the eyelids and can lead to sustained eyelid closure, resulting in substantial visual disturbance and functional blindness, and can involve other cranial or facial muscles in over half the patients. There are at least 50,000 BSP patients in the United States, about 2,000 new cases occurring every year. The main state of treatment is by injecting botulinum toxin, and this is the only treatment approved by FDA for BSP. With waning benefit or in more severe cases, patients may undergo surgical interventions often with limited benefit or resulting in poor cosmetic outcomes. There is a clear need for an improved therapy with an oral therapeutic. Study 203 is an exploratory placebo-controlled trial involving about 15 patients with moderate to severe blepharospasm randomized equally to either 50 milligrams or 100 milligrams of dipreglorant or matching placebo. Patients received three doses in total over a two-day period. Following baseline assessments, the first doses are administered in the clinic and the severity of the blepharospasm is assessed during dosing. Patients take a further dose at home, returning for a pre- and post-dose assessment in the clinic the following day. The outcome measures in this study include computerized motor objective rater, or CMOR, as well as standard efficacy scales of blepharospasm. We expect to report data from this study for blepharospasm in Q2 of this year. And now to ADX 71149 for epilepsy, which is partnered with Janssen Pharmaceuticals, a J&J company. In June, we announced that Janssen had started enrolling into a Phase II epilepsy study, evaluating 149 in treating patients with focal onset seizures. 149 is a selective metabotropic glutamate type II or NGluR2 receptor positive allosteric modulator. This is a Phase II double-blind placebo-controlled proof-of-concept study that is enrolling patients with focal onset seizures. who have suboptimal response to treatment with levotisirazepam or Keppra. Patients will establish a 28-day seizure count over a 56-day baseline period prior to randomization when they'll be randomized to receive either 149 at 50 milligrams BID or matching placebo. The primary endpoint is a time taken to return to their monthly baseline seizure count. The study will have two periods, period one being the four-week acute efficacy phase, and period two is an eight-week maintenance efficacy phase. Period two will include patients who did not return to their baseline monthly seizure rate during the first period of the study, and they will continue on their randomized drug or placebo. Data from this study is expected in Q3 2022. This study illustrates a continued commitment to our long-term collaboration partner, Janssen Pharmaceuticals, to this program and to pioneering novel ways to help epilepsy patients. As a reminder, Janssen is covering all the costs of development, and we have significant pre-launch milestones of 109 million euros and double-digit royalties on net sales. I'd now like to hand over to Robert, who will provide an update on some of our preclinical programs.

Thanks, Roger. Good morning and good afternoon to everyone. We have made significant progress over the year, and today I will highlight three programs, starting with our GIB-positive out-of-state modulator program. As a reminder, this program is partnered with Indivio, who is funding the research at ADDx, and their primary interest is substance use disorder. GIB receptor activation is a well-validated approach. benefiting from the wealth of scientific and clinical data generated with Baclofen, the FDA-approved Gabi agonist. The aim of this program is to use the differentiated pharmacology of allosteric modulation to discover novel drug candidates with the efficacy of Baclofen without its side effect, in other words, a better Baclofen. We're well on our way to meeting this objective with multiple novel drug candidates rapidly advancing through clinical candidate selection phase. We announced in 2021 the extension of our research collaboration with an additional 4 million US dollars of funding committed by Endivio to advance development of the drug candidates discovered by ELIX. We are currently profiling several candidates in non-GLP studies with the aim to nominate drug candidates for IND enabling studies this year. In addition, candidates are being profiled in alcohol use disorder models in order to identify one candidate that in Divio will progress into the clinic for substance use. In parallel, we are progressing multiple differentiated drug candidates for our independent Charcot-Marie-Tooth 1A program. We announced in September 2021 a collaboration with the American Charcot-Marie-Tooth Association. This collaboration will provide us access to significant resources and expertise in the field of CMT1A. As mentioned earlier, there is strong data supporting the GERB receptor activation mechanism coming from clinical studies that reported the beneficial effect of baclofen in patients with CMT1A. In addition, we have robust preclinical data with our own drug candidates in highly translational models of CMT1A. In these studies, we have demonstrated a robust effect both on biomarkers and behavioral measures suggesting we can slow and possibly stop the progression of the disease with this approach. Our candidates are completing studies in CMT1A models and other non-GLP preparatory studies as we get ready to select a candidate to enter IND-enabling studies by the end of 2022. The second program I want to highlight today is the MV7 negative allosteric modulator program for post-traumatic stress disorder, or PTSD. PTSD is a psychiatric disorder that may occur in people who have experienced or witnessed a traumatic event, such as a serious accident, natural disaster, or war. Current treatments are mostly relying on behavioral therapy, as most pharmacological treatments show poor or insufficient benefit. We're developing mGlu7 negative allostatic modulators as a novel approach to addressing fear memory consolidation and retrieval. We have generated robust preclinical data in multiple in vivo models of the disease. The program is supported by Eurostar's industries grant of 4.85 million euros, which is financing a consortium led by us. We are advancing drug candidates through clinical candidate selection and expect to enter IND enabling studies in H2 2022. And finally, a few words on our mGlu2 negative allosteric modulator program for mild neurocognitive disorders, or MCI. MCI is the stage between expected cognitive decline of normal aging and the more serious decline of dementia. Besides being potentially the early sign of Alzheimer's disease, MCI is also often experienced by patients suffering from depression. Developing mGlu2-NAM offers the exciting opportunity to address cognitive impairment while also providing an antidepressant effect. Both these effects have been demonstrated in relevant preclinical models with our mGlu2-NAM candidate compounds. We are now progressing through the final stages of lead optimization and expect to enter clinical candidate selection phase with multiple compounds in the second half of the year. In summary, we have made spectacular progress in our preclinical portfolio with multiple drug candidates rapidly advancing towards IND-enabling studies. The renewed commitment of our partner, Indivio, and additional funding is a further validation of the quality and productivity of ADDx's drug discovery platform and the significant achievements made in our GERB-EPAM program. This concludes my prepared remarks, and I hand back to Tim.