Good morning, and welcome to Day Two of the Jefferies London Healthcare Conference. My name is Lucy Codrington. I'm one of the European Pharma and Biotech team based here in London. It's my absolute pleasure to introduce Andrea Pfeifer, the CEO of AC Immune. Andrea is going to kick off with a short presentation, and then we'll move on to questions. If there are any questions in the room, please do raise your hand, and we will, I think, get a microphone to you. But with that, over to you.
Yeah, well, thank you very much, Lucy, for the introduction. I'm very happy to be here and give you a short introduction to AC Immune, and then move over to telling you the exciting news which we have in our company in 2024, so looking at the refocused investment highlights, our pipeline is very well balanced and diverse, balanced in terms of short-term versus long-term, balanced also in terms of partnered programs versus non-partnered programs. What is important is that we really stand apart in the field by our approach to precision medicine and, in fact, our leadership in active immunotherapy. Our pipeline is built by the two platforms which we have, a SupraAntigen technology and the small molecule Morphomer platform, and we generate constantly, continuously, breakthrough innovations.
One of the breakthrough innovations which we reported this year are actually more ADCs in analogy to cancer, to oncology, with enhanced brain penetration and enhanced efficacy, really leading potentially to a new class of molecules. We have several partnerships. The partnerships have generated about $450 million already, and with the potential to generate another more than $4 billion in milestones and also in royalties. Last but not least, we have our finance into 2027 in order to reach important catalysts, but also to invest in the acceleration of our active immunotherapy.
Now, going to our pipeline, as you can see here, we have active immunotherapy as one of the focuses of our pipelines. We have actually three active immunotherapies in phase II. One, the ACI-24, is now partnered with Takeda. I'm coming back to this deal in a second.
The second one is partnered with Janssen, and it's against the Tau protein. And the third one is on top, which is the 7104, which is our wholly owned Parkinson active immunotherapy, where we'll report important data which we just received recently. The clinical pipeline is, in fact, complemented by preclinical assets which reach high value, and this includes the small molecules against important targets in neurodegeneration, which includes alpha-synuclein, the Tau protein, and soluble and insoluble Tau, as well as the small molecule for NLRP3. I would also like to mention our diagnostic work. We have diagnostics to, in fact, enable our precision medicine. And here we have tracers for alpha-synuclein and for TDP-43, which are the first ones actually in the world.
Equally, we have seed amplification assays, so biomarkers which allow us to do actually what we intend to do in terms of precision medicine in neurodegeneration. Besides the ACI-24 and the ACI-35 active immunotherapy, we have a third important value driver, and this is our portfolio for Parkinson's. The portfolio of Parkinson's is consisting of three different therapeutics and one diagnostic you see on top on the left, the ACI-7104, which is our active immunotherapy in phase 2 development. It's specific for oligomeric alpha-synuclein and is, in fact, evaluated in a phase 2 study. On the top right, you see the alpha-synuclein small molecules. These are small molecules which can specifically bind structural different proteins in the brain. They are highly brain-penetrant, and we, in fact, will show the first clinical candidates in the near future. On the lower left, you see our new approach, which is ADC.
So it's really a combination of antibodies against the target, which is in this case alpha-synuclein, and a small molecule. And together, we achieve a much higher brain penetration, much higher brain exposure, as well as higher efficacy. And we believe that this could be really a new class of CNS molecules with enormous potential to combine also different targets, not just the same target. And last but not least, our two tracers. One, the first one is the 12589. It's in development, longitudinal studies for MSA. And the second one, the new one, is, in fact, in development for Parkinson. And we will have our first Parkinson data next year. Now, this shows you the development of our 7104, which is our alpha-synuclein active immunotherapy. You can see here that the study is done in two parts.
The first part looking at immunogenicity, safety, and tolerability, and the pharmacodynamic effects, and the second part is looking into efficacy, and we are looking here at the expansion of a study to 150 people in Parkinson's, where we will really look for proof of concept in early Parkinson's disease, and we are really aiming in this study for an early identification of proof of concept and an early identification of biomarkers responsive to the disease and the treatment, which allows us into an early development into a pivotal study, and this shows you now the first data, which we just published last week, so this is part one. In part one, we have 34 patients. We are equally split into the stage one and stage two of a Hoehn and Yahr scale. On the UPDRS, you see that we have actually an early population.
Part one is below 10, part two below 12, and part three below 32 for the experts in the field. And on the right, you see that we have not seen any serious adverse events or severe adverse events. And we have basically only adverse events which are linked to the injection site irritations and to headaches. So it's a very safe product as it stands today. And this is now what we were hoping to see. On the left, you see the immune response after three injections. As you can see, all the patients responded after the second injections already. After three injections, we saw a 16-fold increase over placebo and a very high immune response of, on average, about 20,000 units per milliliter, which is higher than what was ever been seen before. And some of the patients reached even titers of 54 units per milliliter.
So again, the safety was excellent, already mentioned. Now, let me move to a fourth pillar of value-driving preclinical assets, which is our NLRP3 small molecule. As you know, the NLRP3 is a very promising target in neurodegeneration, but also in diseases like obesity, diabetes, IBD. In the figure on the left, you see how our small molecules actually of AC Immune intervene in the pathway, in the inflammasome pathway. And you see here that we have small molecules inhibiting the NLRP3 activation. And you see, in fact, that we have also antibodies binding the ASC protein, which is an extracellular protein released when the inflammasome gets activated. And there are quite some data out there which claim that if the ASC protein can actually lead to seeding of amyloid plaques in Alzheimer's disease.
We are using at the moment the ASC protein for developing the pharmacodynamic and biomarkers which we need to follow our precision medicine approach. And just one more data slide on the NLRP3, our lead molecule, it's ACI-19764. As you can see, it has a very competitive profile. It shows an excellent brain penetration of a KPU of 0.7 or 1, which is almost an ideal plasma-brain ratio. It shows excellent potency in preclinical mouse and human assay systems, as well as in vivo in the low nanomolar range. And last but not least, we see excellent safety. We have not seen any adverse effects up to 400 milligrams per kilogram in short-term mouse studies, as well as upon chronic treatment. Now, we would like to just review quickly where we stand in 2024 deliveries, as well as give a preliminary list of what we expect in 2024.
Starting with the ACI-24, what we have done in May, the very nice deal with Takeda, which was actually May 11. We are now for our reporting subject to the communication with Takeda, and we will communicate when available. At the same time, we still will, in fact, deliver on the milestone of 2024, which means completion of a third-dose cohort, as well as the first safety data on the Down syndrome part two. Going to ACI-35, our Tau vaccine or active immunotherapy partnered with Janssen, we had a fantastic year. We got fast-track designation. We injected the first patient into a potentially pivotal phase 2b study in preclinical Alzheimer's. In fact, we got an additional second milestone of $25 million due to the excellent pre-screening rates which were seen for this study. I mentioned already the ACI-7104.
We expect next year, early next year, to receive pharmacodynamic data. We hope, of course, that we follow the excellent titers which we have seen, which would justify a therapeutic response. Going down on our preclinical pipeline, we do hope and expect to see that several of our preclinical small molecules will move into preclinical candidates. Some of them, like the NLRP3 small molecule, will actually enter the clinic. For alpha-synuclein, we expect to see the lead candidate. For Tau, which is a collaboration with Lilly, we also hope to declare the clinical candidate. Now, not to forget that our two tracers, the first in the world against alpha-synuclein and TDP-43, will, in fact, deliver the first clinical data in 2025. With that, I'm already at the end. What I would like to say, the overarching goal of AC Immune has become even stronger.
We want to change the treatment paradigm towards prevention because we think that prevention has the highest potential when it comes to affordability, convenience, and safety for our patients. Thank you.
Great. Thank you for that, Andrea. Perfect. So obviously, your two more advanced Alzheimer's assets are now with big pharma partners. So I think it might make sense to start on some of the programs that have perhaps had less attention, specifically 7104, your vaccine for Parkinson's. You obviously had the encouraging data last week. Perhaps you could talk us through what defines success in this trial, both in the part one element and then assuming you move into part two.
Yeah, I think for us, it was extremely important to see that we have antibody titers which are close to our expectation to generate a therapeutic effect. And we did see that. Now, of course, the next step is to classify this antibody response, make sure that we are against the pathological species which we are doing right now. And we are really eager to look into H1 2025 to see if this very nice antibody response is followed by a significant reduction of alpha-synuclein aggregates in the brain. And if that is the case, when including our tracers, we will go into accelerated pivotal development.
And is that something that AC Immune would look to potentially do themselves? Or with that data, is that when you might think to partner, as you kind of have done in the past?
This is one of the key questions. We do hope that we can actually keep the molecule in clinical development at AC Immune for some time, at least to finish the part two of the study, which is a clinical proof of concept. We will see. But we also hope that with the availability of biomarkers which allow us to go potentially in an accelerated development and maybe less long and less costly studies, which is also what would facilitate our development in AC Immune. We'll see.
Okay. And then in the presentation, you talk through your approaches to alpha-synuclein. You've got four different modalities there. What is it about alpha-synuclein as a target that we should be thinking about when it comes to the development of those assets? And why do you need to have so many different modalities for it?
Yeah, I mean, I think one can say, and this is based on studies by others and our own clinical studies on alpha-synuclein, that if you modify alpha-synuclein, and we have published it also, you actually modify the clinical outcome. So we did see positivity after reduction of alpha-synuclein linked to the UPDRS3, so the motor function. So we have data, and there are quite some data out, also animal data, which actually identify alpha-synuclein as an important target in Parkinson's. Now, having said this, alpha-synuclein is an external, an extracellular target, as well as an intracellular target. So we believe eventually, in order to show a full-fledged response, you might also have to look intracellular or internal. And this is why we have small molecules which have an excellent brain penetration, can actually inhibit the initiation of the aggregation process early in the process.
Ideally, we think both together would give 80%-90% responsiveness, which we are, of course, all looking for.
Got it. Very clear, and then NLRP3, it's been getting a lot of attention lately, but perhaps more due to its potential, the excitement about its potential for use in obesity. When you think about your NLRP3 inhibitor, how is that differentiated from some of the other programs in development that you're aware of?
Yeah, this is a very good question. And I saw, it makes me, because obviously, the patent situation is very tough. So it took us quite some time to come with molecules which are patentable, have a very good patent position. So that's the first point I want to make. But then the second point is you really want to have the optimal brain penetration. And when you looked at the data which I showed, I mean, to come to these sort of plasma-brain ratios of one is a very, very good position. And I think, I mean, without actually saying anything about the competition, we are pretty close to the top here. Now, the next aspect is, of course, how do they work in different animal models? And we have shown in the classical inflammation models that it performs extremely well.
We see a 40%-60% reduction of all these downstream effectors, which is what you would aim for. Now, the next point is what about obesity? In animal models, we have seen a relatively rapid effect. After 24 days, we see a reduction of 10% of weight. But we also see that muscle mass is not affected, like in for the GLP-1 molecules, and we see that also microglial activation is mitigated, so there are some reasons where I would say it's interesting, and it should be maybe looked also on the obesity side. We have not decided yet.
Got it. And when you think, though, about kind of the commercial opportunity when it comes to developing such an asset for either obesity or Parkinson's disease, for instance, what do you think in terms of the potential there, and which do you think has the higher probability of success, if you can say at this stage?
Yeah, I mean, we obviously are also looking at Parkinson's because Parkinson's does show NLRP3 activation. I personally believe, and we have, of course, a lot of evidence from our work, that the driving disease factor in Parkinson's, or one of them at least, is alpha-synuclein. So without actually influencing the alpha-synuclein burden in the brain, I don't believe you will have the side effect with NLRP3 alone. So this goes clearly into a direction of combination therapy, and that's what we are looking at.
Got it. And you also have an antibody approach for NLRP3. What's the goal with that, and why is that, and how is that distinct from your small molecule approach?
Yeah, so the antibody approach is binding, as I mentioned. The ASC protein, which is the protein which is released outside the microglia cells and propagates, if you like, the inflammation. There is quite some literature out there that ASC might actually induce plaque formation in Alzheimer's. So if you inhibit the ASC protein with an antibody, you actually reduce the plaque load significantly in animals. The question is if this also plays a role in vivo or in people. We don't know that yet. We have decided that we concentrate on our NLRP3 small molecule because we think that's where the potential is. At the same time, we're using this ASC antibody to really develop the target engagement and the biomarker assays which we want to have in order to have the optimal NLRP3 development.
Again, this is in accordance with our precision medicine approach, and we are unique because we have these biomarkers which nobody else has.
Okay. I'll just use this opportunity. Any questions in the room before I carry on with mine? No? Okay. So ACI-24, your vaccine for Alzheimer's targeting Aβ. You obviously have now the opt-in agreement with Takeda, which somewhat limits what, I guess, we can talk about. But the phase 2 ABATE study, it's in Alzheimer's patients, but it does also include patients with Down syndrome. So what can we look forward to in terms of data from that study? And will we get the data from the patients with Down syndrome? Is that also tied up in your agreement?
As you might remember, we are testing different doses of ACI-24 in both Alzheimer's patients as well as in Down syndrome patients. It's always three doses. For the AD trial, we are completing the recruitment for the third highest dose this year, as we had planned. For the Down syndrome, we do hope to at least show safety data because that was a very important question. It's a very important population. We are extremely careful with this population because of the sensitivity. At the same time, it's a genetic population for Alzheimer's and might actually allow us to have quicker readouts or, in fact, even higher power in our readouts. But at the end of the day, it's really about making a treatment available to this population, which has nothing up to date.
At the end, it's also what can we learn from these Down syndrome cohorts for both, actually, for the Down syndrome cohorts as much as for the Alzheimer's. There should be a cross-learning, and hopefully, we can actually make this vaccine, which so far has not shown any safety issues, available to the Down syndrome population to start with because this population needs it, as well as to Alzheimer's.
Okay. And then ACI-35, your Tau-targeted vaccine that's partnered with Janssen. There's been some developments in the Tau space over the last few years, including your own assets. What's your thoughts on Tau as a target for Alzheimer's at the moment? And what do you think J&J has seen that has made them make such a significant investment as they have done with ACI-35?
Yeah. I mean, we will publish with data of our past phase I B2A study very soon. So this will give some of the explanations. I'm actually very happy about finally learning how Tau might work. I mean, what the Bepranemab updated clearly showed is that Tau spreading takes place, and Tau pathology can be treated with active immunotherapy. It also showed very clearly, not surprising to us, that if you go early in the development in the disease stage, meaning Tau concentration lower than 1.3, you have a much higher effect. In fact, we saw in a pre-specified analysis in Bepranemab that you go early enough, you actually see clinical benefits across, which was not seen for the main study. So I think we are finally understanding that Tau can be targeted with active immunotherapy.
You have to be early, and you have to potentially also use the right epitope. And since our epitope is exactly in this range where Randy Bateman thinks that this is where the soluble Tau, the most toxic Tau, is actually affected, we are pretty confident about this trial.
Perfect. Okay. We've run down the clock, so I'd like to take this opportunity to thank Andrea again for her time and for you all for attending. And with that, we'll move on. Thank you.