AC Immune SA (ACIU) September 2026 Conference Transcript

Hello, and a warm welcome to everyone joining this call, where we will discuss the results of part one of the vaccine phase two trial, covering both the 18-month treatment period and the six-month safety follow-up. Today, you will hear from Dr. Martin Zügel, ACMUN's Chairman of the Board and Interim CEO, Dr. Gunter Staffler, Executive Vice President of Development, Dr. Kirsten Scott, a Senior Neurologist in the Clinical Team, and Professor Werner Purve, 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 Q&A. Before getting into the presentation let me first remind everyone of our disclaimer and regarding any forward-looking statements and 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 Moon 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 jansen or jnj takeda and lily and 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, where we licensed in the predecessor formulation a couple of years ago from Aferis. And it's different to all our Alzheimer compounds targets the Parkinson's disease. So 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's active immunotherapy programs, and also receive this for fast track designation for the 7104 Parkinson's disease AlphaSyn program. We have also our NLRP3 program, which is end of phase one. And other interest that we are targeting is the from that we partnered with Lilly and that partnership 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 and based on the new formulation we started the phase two trial with a part one with the key objective layer to show safety and immunogenicity and early look for also look for other signals that are important for that. So what we have done in this small trial with 34 patients, 25 receiving ACI 7.4, and nine patients receiving placebo testing, that in the trial over a two-year period, with primary endpoints, with safety and tolerability, that we achieve these primary endpoints, and also all 100% of the patients develop significant antibodies against the target antigen PD-01 already after 3 immunization. What was important there for us is, or is extremely important also for the treatment there, is that we saw a robust antibody penetration in spinal fluid, which is critical for the therapeutic effect. And 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 Günter, 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 now parkinson's disease is the second most common neurodegenerative disorder after alzheimer's disease is the most common neurodegenerative movement disorder and is currently the fastest growing neurological disease and affects about one percent of the population over 65 years now most of the cases are so-called idiopathic cases which means that the cause is unknown, and just about 5% to 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 predikinesia. Now, importantly, this loss in neurons is accompanied by the formation of pathological inclusion, so-called Lewy bodies, which are illustrated on the right side. And the main component of those Lewy bodies is the protein alpha-synoclein. And current evidence clearly suggests that alpha-synoclein pathology can spread across brain regions, contributing to disease progression, which is basically illustrated on the right bottom figure. Now, 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. And for reasons that are not fully understood yet, alpha-synuclein can misfold, can aggregate, and disaggregate are then toxic to neurons, can escape into the extracellular space and can spread to neighboring cells and this seeding and spreading of alpha-synuclein are the potential drivers of the disease and therefore i think it's also quite obvious that inhibiting the uptake and the propagation of this aggregated alpha-synuclein is expected to reduce downstream neural degeneration and to slow disease progression And 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. And that's exactly what we aim or what we aim to is the development of ACI-7104. ACI-7104 was designed to elicit an antibody response that specifically binds the aggregated species of alpha-synuclein. And the reactivity of in-used antibodies is illustrated now in the next slide. The data that are shown here come from the phase one trial where the ACI7104 peptide was tested in the predecessor formulation as just mentioned by Martin. And 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 kinetic assessment of antibody target interaction, which means an increase in the signal indicates that antibody binds to the target, while the maintenance of the signal over the time reflects the stability of this interaction between antibody and the target, so it means this complex stability. And 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. And on the other side, the figure below illustrates that there is no reactivity against the monomeric form of alpha-synuclein. And on top of that, and this is shown on the right side, the induced antibodies do not just bind aggregated alpha-synuclein nitro, but also bind to Lewy body pathology in post-mortem 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 one study, as communicated already by Martin earlier, the new, the optimized formulation was tested, which means that the antigenic peptide sequence, the PD-L1 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 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 find 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, VAXIN is a placebo-controlled biomacrophage 2 study divided in two parts. Part 1, 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 9 subjects were randomized to the placebo arm. Now, 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 results. Now, at the end of the treatment period of 18 months was followed by a safety follow-up period of six months. And the data we are showing today comes 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. These were on safety and tolerability and immunogenicity, and then the exploratory readouts will be addressed later. On this slide, you can see on the left side the baseline characteristics of the patients in the study. There are 22 males and 12 females with a mean age of 62 years. So, the distribution between male and female, I think this mirrors also the prevalence of the disease, as the prevalence is higher in male compared to female. Importantly, patients are evenly split on the Hohen and Jahr scale between stage 1 and 2, which clearly indicates that early-stage PD subjects were recruited in the study. And this can also be seen when looking at the MDS-UPDRS scales that patients generally showed mild disease scores with a Part 3 score of 21 or Part 1 and 2 of about On the right side now, you can see basically a summary about the safety evaluation, and here we can clearly say that the product was safe and well-tolerated, so there is a very good benefit-risk ratio to date. The most commonly reported adverse events were injection site reactions, headache, and fatigue, and basically, and this is the important message as well, that the DSMB, the Data Safety Monitoring Board, clearly recommended that the trial may continue without modification to date. Now, with that, I will switch to the immunogenicity part. here in this slide you can see how titers developed over time the blue line as you can imagine represents the active arm and you can see that with each additional application you see an increase in titers a reboost in titers and the important message here is that already after three vaccinations for treatments, we have received or observed a 100% responder rate in the active arm, and titers with each individual application even went further up. And as expected, the placebo group did not show any detectable signal. So the key message from this slide here, the new formulation, the optimized formulation is highly immunogenic and induces the right antibody species in the humans. And at the next question, of course, we addressed whether the antibodies which are elicited in the periphery can also be found in the CSF, in the cerebrospinal fluid, in a compartment which is the closest compartment to the target organ to the brain. And as depicted here, already after treatment, a clear increase in antibody titers in CSF was observed at week 24 and this signal in further increases by one lock basically at week 76 at the end of the treatment period we saw a very strong increase in titers in csf importantly in all subjects antibodies could be detected in csf and this clearly illustrates that the titer, that the product is not just immunogenic, cannot just induce antibodies which circulate the body, but also that antibodies can penetrate into the center compartment and potentially can bind the aggregated alpha-senuclein, the target species in the brain. And with that, I will hand over to Kirsten, and Kirsten will guide you through the clinical, biomarker and clinical readouts.

Thank you, Winter. So we have some exploratory biomarkers, which just to remind you again, we're all exploratory measures on a very small sample size. Here you can see the total alphysnuclein levels in the CSF. And if you look first at the green line, which is the placebo, you can see a gradual decrease over time over the 76 weeks, which is what we see in some longitudinal cohort studies where there's a slow decline in alphysnuclein which is thought to represent the shift of alphysnuclein from the CSF into the intracellular space in the brain. You can see that in the ACI 7104 group there's stabilization of this pattern and there is no decrease. So we have seen this as being a potentially positive signal even though it's in a very small number and a possible measure of target engagement. Of course, as Gunther showed you in the very nice binding graph that the antibody, our induced antibodies bind the aggregated species of alphys nuclein and not all alphys nuclein. So if we had a drug that was binding all alphys nuclein, you might see a very dramatic effect on a measure of total alphys nuclein. But because we're only binding a very small proportion of the alphys nuclein, we never expected to see a big impact on this measure, but we were encouraged that there was possibly a trend there. We also looked at NFL and neurofilament light is a biomarker used across neurodegenerative and other neurological disorders and is a non-specific marker of neuronal death. So normally when nerves die, they release neurofilament into the circulation and the CSS and it can then be measured. And normally it gives a readout that gives it an idea of the turnover of nerve cells. So in very fast progressing diseases like motor neuron disease, it's very raised and gives a much clearer predictor of progressing in individual patients. Because Parkinson's disease is a much slower progressing disease, we see much smaller increases in NFL over time. There are many longitudinal cohorts that describe between 5% and 8% change over each year in PD cohorts. And you can see this size of change in the placebo group in green and in our ACI 7104 group. Again, we see that there is a stabilization of the trend. Of course, these are very small numbers, and this was an exploratory measure. But again, this gave us some enthusiasm to think that there was perhaps a downstream effect of the treatment. We were also encouraged by data looking at the relationship between the antibody titers and motor outcomes so this graph shows you on the y-axis the change in the UPDRS part 3 which is the motor score on the clinical scale and on the x-axis you can see the increase in the anti-PD-01 IgG titers and so what we saw overall was that there was a correlation that suggested that those patients who had higher levels of antibodies had smaller change on the UPDRS Part III. Again, we're limited by the variability of the clinical scale and the small sample size, but again this is one of the pieces of data that again encouraged us that there was something here and we were excited to move on to the next phase of the study. So to summarize the results so far, we were very happy to see that ACI 7104 was safe and induced significant antibody levels peripherally with robust antibody penetration into the CSF observed across all treated participants. We also saw and was presented in the last webinar, antibody reactivity against aggregated species of alpha nucleon and we saw at this time the twofold improvement in the immunogenicity over the previous formulation. We were encouraged by the signals on exploratory correlations between the biological and clinical parameters that we just showed you and we are excited and feel that these results support further clinical development of the program and discussion of our plans with regulators. So the next step that we're going on to is the extension. So initially we plan to recruit a further cohort in part one in order to increase the dosing so that we can see whether we can because you might remember from the graphs but it's unclear whether we've reached the ceiling so we have the possibility to increase the the number of doses so that we're dosing every three months in that initial period to see whether we can push up the titers even higher and and that will be done with an extension to the the part one of the study and then we will plan to move into part two which is essentially the main aim of part two is to provide us with data that would give us confidence to move into part two phase three studies at the end of part two So we've optimized the inclusion criteria for the Part 2 study and also enhanced the clinical outcome measures, focusing on digital measures of motor function as an important readout in order to have a clinically relevant measure that we can also use to power the We've also, of course, will focus on safety, tolerability, and immunogenicity as with this part of the study. And we also plan to include advanced MRI sequences measuring iron and neuromelanin in order to have other biomarkers of neurodegeneration. The protocol design and details are currently in the planning phase, but we plan to discuss this with the FDA under the FastTrack designation that we were recently awarded. So this shows you again a summary of where we are. Our plan is to design the Part 2 study in order to give us convincing evidence to allow for decision into Phase 3 at the end of the Part 2 study. This is going to involve an expansion of this part to approximately 250 patients with 24-month treatment periods and a six-month follow-up period. We know, of course, from other recent trials that the duration of treatment is important, and this allows us to potentially see a separation between the treatment and placebo, so this has been extended from the initial design. And we're also planning to have digital measures of motor function, which allow us to hopefully get around some of the variability that we see in the UPDRS scale, which means that we can reduce the sample size somewhat and still be powered to see a difference on those measures. And as I've mentioned before, we will continue to focus on safety and immunogenicity, but also using advanced MRI, measuring motor and non-motor function, and of course also both functional and patient-reported outcomes, which are important for both patients and the regulators.

Let me now, I'd say, summarize again what we have shown you, and hopefully you, I'd say, fully understood all these topics, and we can then go to questions is the study showed what we intended to do. We have met our primary endpoints. The substance is safe. It's well-tolerated and strong immunogenic. What was extremely encouraging for us that we have a very robust antibody response against the target antigen plus a very robust penetration to the CSF, which is the most important information for us that the drug goes where it's supposed to do, and last but not least is the correlation analysis, which suggests to us an association between immunogenicity and antibody titers and disease activity measures. This gives us confidence that we can move forward to the expansion part two. With the continuation of the extension of the vaccine trial of the part one, we intend to generate further safety data than for a four-year period, which we think is essential because this is going to be a lifelong treatment then for patients as a disease-modifying drug, and their safety is of utmost importance. That's why we extend this from two years to four years. And with the expansion, the key objective will be there showing the clinical activity as a basis for entry into phase three trial we will take up the discussions with the sda and we assume that we can start the trial in the first half of next year so happy to take no questions and actually we'll um we'll invite before we go into the q a we'll invite comments from Professor Purve.

Please go ahead.

Well, thank you, Gary. I just want to briefly say that as someone who's been in the field of Parkinson's disease research for decades now and in numerous trials, I think this is an extremely important program. As has been pointed out, synuclein is a key target and key player in the pathogenesis of Parkinson's. It's even now an anchor most recently for biological disease concepts and definition, very much like we've seen with amyloid and tau in Alzheimer's disease. Immunotherapy is probably the most advanced in the field of studying interventions that could use this target to slow the spread and progression of pathology, and there have been signals already from passive immunotherapy trials in two synuclein areas, Parkinson's and multiple system atrophy. And, of course, being able to use an active immunization, as we've seen here in this trial, is an extremely attractive option in the scenario of disease-modifying strategies for Parkinson's disease. I find personally, I find it very reassuring and exciting to see the enhanced immunogenicity of the new formulation of this vaccine. I've been personally involved in a previous formulation of it when we did pilot work years back. So this is an important step forward while maintaining safety. As we heard, this particular part of the vaccine trial was, of course, not designed with 39 patients in total to detect statistically significant effects on efficacy measures. That's impossible with a disease like Parkinson's disease, which is slowly progressive in its early stages with these numbers. Nonetheless, there have been these signals that Kirsten has pointed out to us, and again, they're encouraging. And of course, it's exciting to see this program moving into the extension phase with larger numbers and a design that will use more biomarkers even to detect efficacy signals going along with this convincing rise in antibody titers that are seen over successive vaccinations and may even go higher with more frequent dosing of the vaccine. So all I can say is I'm excited about this, and I think the whole field is about this approach and look forward to the discussion that we're going to have now.

Thank you, Werner. And so now I will invite the operator to open the call for the Q&A session.

Of course, sir. We will now begin the question and answer session. Anyone who wishes to ask a question may press star and one on the telephone. You will hear a tone to confirm that you have entered the queue. If you wish to remove yourself from the question queue, you may press star and two. Questioners on the phone are requested to disable the loudspeaker mode and eventually turn off the volume of the webcast while asking a question. Webcast viewers may submit their questions in writing by the relative field. In the interest of time, please limit yourself to two questions. Anyone with a question may press star on 1 at this time. Our first question comes from Mark Goodman from Leering. Please go ahead.

Hi, good morning or good afternoon. This is Valentine for Mark Goodman. Thank you for taking my question. So my question relates to The data you presented today confirmed antibody reactivity against the aggregated alpha-synucine, but I was curious if you also assessed binding to the monomeric alpha-synucine in the human sample, and if so, was there any preferential binding to the aggregated species observed, and was it consistent across patients?

So, as I showed, we tested 7104 induced antibodies used in mice, induced in non-human primates, and also we tested antibodies derived from the phase one trial. And basically, we saw always the same result across all the species, including humans, that induced antibodies preferentially bind the aggregated species, by far, so they are specific. And there is, in principle, a light binding or a very low binding towards the monomer, but this interaction is of low affinity that de facto this complex falls apart immediately. So, that means the induced antibodies are specific for the aggregate. Now, in the 7104, in the vaccine trial, we are currently running the same analysis as previously done for phase one-derived sera or sera derived from the clinical arena. And, yeah, this data will be available soon, but I am absolutely convinced that the pattern of in-use antibodies will not change.

Great. Thank you so much.

The next question comes from Tom Schrader from VTIG. Please go ahead.

Good morning. Congratulations. I wanted to, do you have any sense of how long your antibodies last, what maintenance dosing would look like, and are antibodies antibodies? Is probably the maintenance dosing going to be the same as the A-beta vaccine, or do you have to determine it And then a quick follow-up, which was one of Andrea's favorite. Where are we in the world of alpha-syn imaging? Is there something close to an experimental tool that you might use, or are we still a ways away? Thank you.

Okay, so I think I will take on the first question on the half-life of the antibody. So a monoclonal antibody, when administered into the body, has a half-life time of about two weeks to up to four weeks. Now, the difference here in the active immunotherapy is basically that we do not talk about half-life of the antibody per se, but half-life of the cells producing the antibodies, which is, of course, a different kinetics or has a different kinetics. And here we can see that the half-life, the terminal half-life of antibodies then is about three to four months, which means that in part one, after the first priming period, we intended or we continued on a half, so every six months with scheduling. Now, we aim also to include another cohort in part one with a more frequent dosing, going from half-year dosing to a quarterly dosing. The reason for that is basically our goal is to, of course, increase the titers in general, but especially to increase the trough levels of the antibody response. And here, a quarterly administration of the product will certainly increase and has a huge impact in the trough levels of antibody titers. And for the second question on imaging, I will hand over to Gary.

Hi, Tom. So you know well that we have a number of alpha-syn PET imaging agents in development. Our first generation was ACI-12589, which has proven to be extremely good at imaging and detection of patients with MSA. We have a second-generation candidate, which is currently in Phase 1, and I think it is our early indications are that it performs relatively well in Parkinson's disease. But I think more than that, in the field generally, we are kind of a little bit starved of good imaging agents, and indeed, more broadly, for alpha-syn-specific biomarkers.

As a reminder, if you wish to register for a question, please press star followed by We have now a question from Alina Famuzzi from Jefferies. Please go ahead.

Hi, thank you for taking my question.

I was wondering if you could provide a bit more detail on the relationship between the antibody levels and the MDS-UP-DRS progression and if this relationship observed was consistent across the treated population i understand it was a small population but any detail would would be helpful thank you i think this is a good question so i think the the first message to say here in this context is basically that no correlation was observed in the first year which also is clear that first of all a certain time is needed and required to elicit a profound antibody response and on the second part also there is a certain need for disease progression in order to see a correlation. The first time when a correlation became visible was at week 48 where we have observed a weak correlation but this correlation then became stronger and a moderate to good correlation at the treatment end, which is at the week 76. And if we now talk about correlation, it's not just that we have observed a correlation between PD-1 titers and MDS Part 3 score, but we also have observed a correlation with titers, PD-1 titers, with other clinical scores such as MDS Part 2. And this correlation was observed when looking at the active arm only, and also when including the placebo arm. But again, I think we are excited to see, of course, this correlation, and I think this is also a foundation for the next step. The variability is large, but still, we have observed this correlation, which was actually not expected to this extent.

Thank you.

Ladies and gentlemen, so far there are no further questions. Back over to you for the written questions.

Thanks, Sandra. So we have a question submitted online, which was, did we measure that spec? And for this, I'll hand over to Gunther.

So, that spec was used, of course, first of all, to include the subjects, you know, to stratify, of course, for the pathology. I think this was important. It was also used in follow-up analysis. Here, again, I think the important part is that the study was not powered to see a difference in this imaging readout, as it was also the case for other biomarker readouts or for clinical readouts. So that means we need to interpret the data with caution. At week 48, until week 48, now all data from all subjects included, we have not observed any decrease in the signal, but at a later time point, we saw a decline in the signal, in the DAPSPEC signal. Again, I think we need to interpret the data with caution at week 48 and at a later time point as well.

Thanks, Quinter. I think that's it for all the questions we've received online and via the phones. So if there are no further the questions. I think now is a good time to close the call, to thank you all for participating in your time, and invite any, if there are any further questions that arise after the, well, hang on, there is just one further question that has come in. Correlations between alpha-syn levels and immunogenicity. For clarification, the assay is based on lower alpha-syn suggest aggregation, much like a beta-42 to 40 ratio. Is that something?

So I think there are two questions included here. First of all, the analysis of aggregated alpha-cynuclein, if I understood it correctly. So we did this analysis. We used a measurement which is based on the infrared biosensor. We have observed an effect here. But again, I think due to the low number of subjects included, we need to be, and to treat this data with a caveat, we also, of course, saw the stabilization of total alpha cyanuclein, and I think when we did the correlation, no real correlation between antibody titers and total alpha cyanuclein levels was observed.

Okay.

But again, I think this is something based on the low end and on the variability of the data on those measures, which cannot be expected.

And the fact that we're measuring, we're not measuring the aggregated species.

Exactly, I think this is.

Well, so we had hoped to find that relationship because, indeed, it would be more elegant. But I think based on the fact that the total alphysnuclein is measuring all of the species, the small percentage that's aggregated, the signal is lost in the total ASIN measurement. And our other assays, in an exploratory way, trying to measure oligomeric alphysnuclein, I think we don't have enough faith in the assay to really put it into a correlation.

Okay, I think that now is the final questions that we've had. So thank you all again for participating, and I would invite anyone to reach out and contact us if there are further questions they have following this call. But thank you all, and goodbye.