AC Immune SA Study result

Hello, and a warm welcome to everyone joining this call, where we will discuss the results of part 1 of the VacSYn phase II trial, covering both the 18-month treatment period and the 6-month safety follow-up. Today, you will hear from Dr. Martin Zügel, AC Immune's Chairman of the Board and Interim CEO, Dr. Günther Staffler, Executive Vice President of Development, Dr. Kirsten Scott, a senior neurologist in the clinical team, and Professor Werner Poewe, Emeritus Professor of Neurology at the Innsbruck Medical University in Austria. Following the presentation and prepared remarks on today's call, we will open the call for a Q&A. Before getting into the presentation, let me first remind everyone of our disclaimer regarding any forward-looking statements. With that, I would now like to hand over to Martin for his comments.

Please go ahead. Thanks, Gary, and welcome to our web conference today.

I want to briefly introduce only very briefly the company. As you are aware, AC Immune is for 20 years in the field, and we are targeting the key pathological misfold proteins and pathways that drive neurodegenerative diseases. We have a deep expertise in the field, and you can see that by our strong partnerships we have formed, especially in the field of Alzheimer. We have licensed out all our Alzheimer compounds to Janssen, or J&J, Takeda, and Lilly. With this partnering, we have received lots of non-dilutive financing plus potential milestones. What we want to discuss today is our lead program. That's a compound, the ACI-7104.056, where we licensed in the predecessor formulation a couple of years ago from Affiris and this is different to all our Alzheimer compounds targets for Parkinson's disease. Go to the next slide.

What you see in the next slide is the overview of our pipeline. What you see there is we have Fast Track designation for our two Alzheimer active immunotherapy programs, and also received this year Fast Track designation for the 7104 Parkinson's disease alpha-synuclein program. We have also our NLRP3 program, which is end of phase I. Other interests that we're targeting is the tau from that we partnered with Lilly, and reinforced that partnership this year again. Let me now move to our 7104 program, which we'll discuss today in much more detail. The key thing you have to pay attention to during today's presentation is after we licensed the compound, we changed the formulation.

Based on the new formulation, we started the phase II trial with a part 1 with the key objective there to show safety and immunogenicity and also look for other signals that are important for that. What we have done in this small trial with 34 patients, 25 receiving ACI-7104.056 and 9 patients receiving placebo testing that in the trial over a 2-year period with primary endpoints with safety and tolerability, we achieved these primary endpoints and also 100% of the patients developed significant antibodies against the target antigen PD-L1 already after 3 immunizations. What was important there for us was extremely important also for the treatment there is that we saw a robust antibody penetration in cerebrospinal fluid, which is critical for the therapeutic effect. Last but not least, we also looked into exploratory correlations.

This can only be exploratory with 34 patients because with this disease, you need much more patients to truly see the effect there in a significant way. But we saw trends suggesting an association between antibody levels and disease activity. Let me now pass on to Günther, who will go more into detail and explain also the background of the development there.

Thank you, Martin. Now, with the next slide, I would like to briefly introduce Parkinson's disease to you. Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. It is the most common neurodegenerative movement disorder and is currently the fastest-growing neurological disease and affects about 1% of the population over 65 years. Most of the cases are so-called idiopathic cases, which means that the cause is unknown and just about 5%-10% of the cases can be attributed to a genetic mutation. On the cellular level now, Parkinson's disease is characterized by the loss of so-called dopaminergic neurons, and this loss in neurons then leads to all the symptoms listed here on the left side, including tremor, rigidity, and bradykinesia. Importantly, this loss in neurons is accompanied by the formation of pathological inclusions, so-called Lewy bodies, which are illustrated on the right side.

The main component of those Lewy bodies is the protein alpha-synuclein. Current evidence clearly suggests that alpha-synuclein pathology can spread across brain regions contributing to disease progression, which is basically illustrated on the right bottom figure. In the next slide, you can see an illustration about how alpha-synuclein exists under healthy conditions. Normally, alpha-synuclein is present as a monomer. For reasons that are not fully understood yet, alpha-synuclein can misfold, can aggregate, and these aggregates are then toxic to neurons, can escape into the extracellular space, and can spread to neighboring cells. This seeding and spreading of alpha-synuclein are the potential drivers of the disease. Therefore, I think it is also quite obvious that inhibiting the uptake and the propagation of this aggregated alpha-synuclein is expected to reduce downstream neurodegeneration and to slow disease progression.

This also means that targeting alpha-synuclein or aggregated species of alpha-synuclein offers the potential to develop a disease-modifying therapy, which is, of course, a major unmet need in Parkinson's disease. That is exactly what we aim, or what we aimed with the development of ACI-7104. ACI-7104 was designed to elicit an antibody response that specifically binds the aggregated species of alpha-synuclein. The reactivity of induced antibodies is illustrated now in the next slide. The data that are shown here come from the phase I trial where the ACI-7104 peptide was tested in the predecessor formulation as just mentioned by Martin. Here you can clearly see that the antibody show a high degree of specificity for aggregated alpha-synuclein. The data shown here on the left side come from a so-called surface plasmon resonance, SPR, analysis.

SPR enables a kinetic assessment of antibody-target interaction, which means an increase in the signal indicates that antibody bind to the target, while the maintenance of the signal over the time reflects the stability of this interaction between antibody and the target. So means this complex stability. As you can appreciate from the left upper figure, 7104 peptide-induced antibodies do not just bind the aggregates of alpha-synuclein, but these complexes are highly stable. On the other side, the figure below illustrates that there is no reactivity against the monomeric form of alpha-synuclein.

On top of that, this is shown on the right side, the induced antibodies do not just bind aggregated alpha-synuclein in vitro, but also bind to Lewy body pathology in postmortem PD brains, which also indicates that in case 7104-induced antibodies reach the brain, they have the potential to bind the target in the target organ. Now, going to the next slide. In the vaccine part 1 study, as communicated already by Martin earlier, the optimized formulation was tested, which means that the antigenic peptide sequence, the PD01 sequence, was attached to another carrier protein, which is now the CRM197. The advantages of using CRM197 is that it has been shown that this protein, this carrier protein, is highly immunogenic, is widely accepted by regulators, provides a well-established safety profile, and also provides advantages in manufacturing, including, for example, upscaling and analytical testing.

The important part is now that in the preclinical arena, many and extensive studies were performed to show that the reactivity of the antibodies induced by the optimized formulation are identical to the old formulation, which means they bind aggregated species with high specificity. So specificity and quality of induced antibody remains the same while antibody titers are higher, and this has been shown extensively in the preclinical arena. The goal of the part 1 of the vaccine trial was now to demonstrate the clinical safety, the safety and tolerability of this optimized formulation, and also to determine the immunogenicity of the improved formulation. Now, going to the next slide. Vaccine is a placebo-controlled biomarker phase II study divided in 2 parts.

In total, 34 subjects were enrolled with a 3-to-1 ratio, which means that finally, 25 subjects were randomized to the active arm and nine subjects were randomized to the placebo arm. The study comprises an 18-month treatment period with the main goal to show or to prove safety and immunogenicity, and of course, with exploratory readouts such as alpha-synuclein levels, biomarker analysis, and clinical readouts. At the end of the treatment period of 18 months was followed by a safety follow-up period of six months. The data we are showing today come from all 34 subjects. Data shown in the past just included two-thirds of the subjects, and now the data set is complete, and we can share data from all subjects. Going to the next slide, here you can see the primary readouts.