Ladies and gentlemen, Welcome to the AC Immune conference call and live webcast. I am Sandra, the conference call operator. I would like to remind you that all participants have been in listen-only mode and the conference is being recorded. The presentation will be followed by a Q&A session. You can register for questions at any time by pressing star and one on your telephone. Webcast viewers may submit their questions in writing by the relative field. For operator assistance, please press star and zero. The conference must not be recorded for publication or broadcast. At this time, it is my pleasure to hand over to Gary Waanders, Senior Vice President, Investor Relations and Communications. Please go ahead, sir.
Thank you, Sandra. Hello, and a warm welcome to everyone joining this call, where we will discuss the results of part one 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 Eli 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 ACI-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 ACAI-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 one 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 nine patients receiving placebo testing that in the trial over a two-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 PD01 already after three 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, ACI-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 ACI-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 two 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.
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. 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 Hoehn and Yahr scale between stage one and two, which clearly indicates that early-stage PD subjects were recruited in the study. This can also be seen when looking at the MDS-UPDRS scales that patients generally showed mild disease course with a part III score of 21 or part I and II of about IV.
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. There is a very good benefit-risk ratio to date. The most commonly reported adverse events were injection site reactions, headache, and fatigue. 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. With that, I will switch to the immunogenicity part. Here in this slide, you can see how titers develop 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.
The important message here is that already after three vaccinations or treatments, we have received or observed a 100% responder rate in the active arm and titers with each individual application even went further up. As expected, the placebo group did not show any detectable signal. 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. As a 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. As depicted here, already after three treatment, a clear increase in antibody titers in CSF was observed at week 24.
This signal even further increases by one lot, 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 product is not just immunogenic, cannot just induce antibodies which circulate the body, but also that antibodies can penetrate into the central compartment and potentially can bind the aggregated alpha-synuclein, the target species in the brain. With that, I will hand over to Kirsten, and Kirsten will guide you through the clinical biomarker and clinical readouts.
Thank you, Günther. We have some exploratory biomarkers, which just to remind you again, were all exploratory measures on a very small sample size. Here you can see the total alpha-synuclein levels in the CSF. 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 alpha-synuclein, which is thought to represent the shift of alpha-synuclein from the CSF into the intracellular space in the brain. You can see that in the ACI-7104 group, there is stabilization of this pattern and there is no decrease. 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 Günther showed you in the very nice binding graphs of the antibody, our induced antibodies bind the aggregated species of alpha-synuclein and not all alpha-synuclein. If we had a drug that was binding all alpha-synuclein, you might see a very dramatic effect on the measure of total alpha-synuclein. But because we're only binding a very small proportion of the alpha-synuclein, 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. Normally when nerves die, they release neurofilament into the circulation and the CSF, and it can then be measured. Normally, it gives a readout that gives an idea of the turnover of nerve cells.
In very fast-progressing diseases like motor neuron disease, it's very raised and gives a much clearer predictor of progression 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. 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.
This graph shows you on the y-axis the change in the MDS-UPDRS Part III, which is the motor score on the clinical scale. On the x-axis, you can see the increase in the anti-alpha-synuclein IgG titers. 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 MDS- UPDRS Part III. Again, we're limited by the variability of the clinical scale and the small sample size. 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.
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-synuclein, and we saw this time a 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. We are excited and feel that these results support further clinical development of the program and discussion of our plans with regulators. The next step that we're going on to is the extension.
Initially, we plan to recruit a further cohort in Part 1 in order to increase the dosing so that we can see whether we can, because you might remember from the graph, but it's unclear whether we've reached the ceiling. We have the possibility to increase 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. That will be done with an extension to the Part 1 of the study. Then we will plan to move into Part 2. The main aim of Part 2 is to provide us with data that would give us confidence to move into phase III studies at the end of Part 2.
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 study. 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 their Fast Track designation that we were recently awarded. 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 III 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 six-month follow-up periods. We know, of course, from other recent trials that the duration of treatment is important, and this allows us to tend to see a separation between the treatment and placebo. This has been extended from the initial design. We are 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.
As I have 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 would say, summarize again what we have shown you and hopefully you, I would say, good understood all these topics, and we can then go to questions as the study showed what we intended to do. We have met our primary endpoints. The substance is safe. It is well-tolerated and strongly 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 most important information for us that the drug goes where it is supposed to do. 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 1, we intend to generate further safety data then for a four-year spirit, 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 is why we extend this from two years to four years. With the expansion, the key objective will be there showing the clinical activity as a basis for entry into phase III trial. We will take up the discussions with the FDA, and we assume that we can start the trial in the first half of next year. Happy to take now questions and-
Actually, before we go into the Q&A, we will invite comments from Professor Poewe. Please go ahead.
Well, thank you, Gary. I just want to briefly say that as someone who has 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, alpha-synuclein is a key target and key player in the pathogenesis of Parkinson's. It is even now an anchor, most recently for biological disease concepts and definition, very much like we have 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 alpha-synuclein areas, Parkinson's and multiple system atrophy.
And of course, being able to use an active immunization as we have seen here in this trial is an extremely attractive option in the scenario of disease-modifying strategies for Parkinson's disease. Personally, I find it very reassuring and exciting to see the enhanced immunogenicity of the new formulation of this vaccine. I have 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 is 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 are encouraging.
And of course, it is 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 am excited about it, and I think the whole field is about this approach and look forward to the discussion that we are going to have now.
Thank you, Werner. I will invite the operator to open the call for the Q&A session. Thank you.
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 a 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 and one at this time. Our first question comes from Marc Goodman from Leerink. Please go ahead.
Hi, good morning or good afternoon. This is James from Marc Goodman. Thank you for taking my question. My question relates to the data you presented today confirm antibody reactivity against the aggregated alpha-synuclein. I was curious if you also assessed binding to the monomeric alpha-synuclein in the human sample, and if so, was there any preferential binding to the aggregated species observed, and was it consistent across patients?
As I showed, we tested 7104 induced antibodies used in mice, induced in non-human primate, and also we tested antibodies derived from the phase I trial. 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. This interaction is of low affinity that de facto this complex falls apart immediately. That means the induced antibodies are specific for the aggregate. In the 7104 in the vaccine trial, we are currently running the same analysis as previously done for phase I derived sera or sera derived from the preclinical arena. Yeah, this data will be available soon, but I am absolutely convinced that the pattern of induced antibodies will not change.
Great. Thank you so much.
The next question comes from Thomas Shrader from BTIG. Please go ahead.
Good morning. Congratulations. Do you have any sense of how long your antibodies last, what maintenance dosing would look like, and are antibodies? Is probably the maintenance dosing going to be the same as the amyloid-beta vaccine, or do you have to determine it here? Then a quick follow-up, which was one of Andrea's favorite. Where are we in the world of alpha-synuclein imaging? Is there something close to an experimental tool that you might use, or are we still a ways away? Thank you.
Okay. I think I will take on the first question on the half-life of the antibody. A monoclonal antibody, when administered into the body, has a half-life time of about two weeks to up to four weeks. 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 kinetic or has a different kinetic. Here we can see that 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. 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. Here, a quarterly administration of the product will certainly increase and has a huge impact in the trough levels of antibody titers. For the second question on imaging, I will hand over to Gary.
Hi, Tom. You know well that we have a number of alpha-synuclein 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 I, and I think our early indications are that it performs relatively well in Parkinson's disease. 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-synuclein specific biomarkers. Any other comments from the team? No.
Okay, thanks.
Thank you.
As a reminder, if you wish to register for a question, please press star followed by one. We have now a question from Alyna Shamsi 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-UPDRS progression, and if this relationship observed was consistent across the treated population. I understand it was a small population, but any detail would be helpful. Thank you.
I think this is a good question. I think 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. 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.
If we now talk about correlation, it is not just that we have observed a correlation between PD01A titers and MDS-UPDRS Part III score, but we also have observed a correlation with PD01A titers with other clinical scores such as MDS-UPDRS Part II. This correlation was observed when looking at the active arm only and also when including the placebo arm. 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 no further questions. Back over to you for the written questions.
Thanks, Sandra. We have a question submitted online, which was, did we measure that DaTSCAN? For this, I will hand over to Günther.
Yes. That DaTSCAN was used, of course, first of all, to include the subjects 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 readout or for clinical readout. That means we need to interpret the data with caution. 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 DaTSCAN signal. Again, I think we need to interpret the data with cautions at week 48 and at a later time point as well.
Thanks, Günther. I think that's it for all the questions we've received online and via the phones. If there are no further questions, I think now is a good time to close the call, to thank you all for participating and your time and invite if there are any further questions that arise after the Oh, hang on. There is just one further question that has come in. Correlations between alpha-synuclein levels and immunogenicity. For clarification, the assay is based on lower alpha-synuclein suggest aggregation, much like A-beta 42 to 40 ratio. Is that something?
I think there are two questions included here. First of all, the analysis of aggregated alpha-synuclein, if I understood it correctly. 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 treat this data with a caveat. We also, of course, saw the stabilization of total alpha-synuclein, and I think when we did the correlation, no real correlation between antibody titers and total alpha-synuclein levels was observed.
Okay.
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.
The fact that we're not measuring the aggregated species-
Exactly. I think this is-
Well.
Yeah.
We had hoped to find that relationship because indeed it would be more elegant. But I think based on the fact that the total alpha-synuclein is measuring all of the species, the small percentage that's aggregated, the signal is lost in the total alpha-synuclein measurement and our other assays in an exploratory way, trying to measure oligomeric alpha-synuclein. 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. 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.
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