Welcome to Herantis Pharma's webcast. Delighted to have you here. Today, we will discuss about our phase II plans, FDA feedback related to the plans, and we also will have a chat with Indivi's Chief Medical Officer related to our partnership towards providing a digital readout for the phase II that will be very important for the trial execution. The session is being recorded, and you may submit questions throughout the webcast. We will have a dedicated Q&A session at the end. My name is Antti Vuolanto. I'm the CEO of Herantis, and together with me, I have here CSO Henri Huttunen and CFO Tone Kvåle. As you all probably know, Herantis is a Finnish clinical stage public company, and we develop disease-modifying therapies to stop the progression of Parkinson's disease. We have reported during this year great development with HER-096.
We have finalized the phase I clinical program with very strong results. Based on that, we believe that HER-096 is now very much derisked and ready for phase II clinical trial. The key achievements with HER-096 include the completion of the phase I clinical trials. We did two different trials, showing nice and supportive safety profile, blood-brain barrier penetration, and also biomarker data that showed a biological response to HER-096 treatment, which was also aligned with the mechanism of action. Also the previous CDNF program really validates the mechanism, and we have already received some clinical data from there and also very strong translational data. HER-096 is very differentiated asset. It is really designed to modify the disease progression and the mechanism of action derived from the CDNF, the neurotrophic factor, is first in class and unique for us.
We target the core drivers of Parkinson's pathology in a very broad way. That's why we believe that we have a very strong position with HER-096 now when we are ready to enter the phase II trial. The phase II design that we will disclose here on a high level is a proof of concept efficacy trial in approximately 100 patients, planned to be conducted in Europe. However, Henri will explain more details about that. On a high level, we have a very clear path forward, and we have very clear milestones that we are currently looking forward to achieving. We expect to submit the clinical trial application by the end of this year. Clinical trial application approval and the first patient is expected to be enrolled first half of next year, and then the efficacy data readout is expected early 2029.
We also have a very strong position related to financing. We have earlier this year announced that we got EU Horizon Grant of EUR 8 million that will be used for the phase II execution. In addition to that, as many times disclosed earlier, we have strong support from EIC Fund, who can support equity financing. We are currently in discussions with pharma and investors and also other organizations for the remaining funding that we need to finance the phase II. Of course, the important goal is to create long-term shareholder value and keeping up these different preparations in parallel, so maintaining the strategic flexibility and option for multiple paths forward until we have secured the financing. Henri, please take us forward with the clinical trial plans, FDA feedback, and then interview with Indivi's CMO. Thanks.
Thank you, Antti. After careful review of our target profile, existing data, available clinical trial designs, and continuous discussions with our scientific advisors, we have concluded that a signal finding phase II-A study design best balances the study objectives and potential risks. As mentioned, we will be enrolling approximately 100 patients. The participants will be so-called de novo Parkinson's patients. It means that they are recently diagnosed early stage disease without symptomatic medication. The participants will receive twice weekly injections of a single dose of HER-096 or placebo. The randomized placebo-controlled part of the study will be for six months, and this will be followed by a six-month open label extension, allowing all participants to receive active treatment. This will be a proof of concept study aiming to demonstrate a gradually developing symptomatic improvement.
For this purpose, we are planning to use a sensitive digital motor score as the primary outcome measure. I will be explaining a little bit of background and justification on that in a few minutes. In addition, we will include clinical symptom assessment, the standard conventional clinical rating scales such as UPDRS as secondary endpoints. There will be also multimodal brain imaging and also selected fluid biomarkers will be followed. These are, of course, based on our previously reported phase I-B data. Overall, the endpoint strategy is carefully considered and balanced and are fit for purpose for this type of a signal finding study. Importantly, two weeks ago, we had a pre-IND meeting with the U.S. Food and Drug Administration. Several areas of HER-096 development were covered, including the manufacturing and preclinical related items.
We also discussed the phase II-A trial design and whether it's appropriate with this stage of development. Moreover, the agency was very interested in the approach, applauded the approach, but also reminded that these type of digital endpoints, although there's a lot of activity in this area, there's still some work to do with their regulatory acceptance. Overall, the FDA feedback was very positive. It was a good milestone for the company, and clearly, the available data package and the study design is fit for purpose. The phase II-A study looks like this. We will first, of course, start with screening. There will be an extended baseline monitoring period before the first dose, and then the placebo-controlled randomized part will last for six months. The randomization ratio is 1 : 1, so about 50% active, 50% placebo, and the injections are done subcutaneously twice weekly.
The open label extension is optional. All patients are offered the opportunity to receive active treatment after completion of the randomized part, the study will end with a two-week follow-up. Altogether, the run-through time for a single participant will be a little bit over one year. As reported previously, we have received a EU Horizon Grant, together with some clinical sites. Our currently confirmed participating clinical sites for the phase II-A study are located in Finland, Sweden, Luxembourg, and Netherlands. We may also add additional sites, at least these are the sites that we will get started with, potential expansion within these countries is one option. We are currently negotiating with a few more sites to be included. Karolinska University Hospital, Lund University Hospital, and the Central Hospital of L uxembourg are members of the grant program consortium.
Going back to the rationale behind the study design. Historically, in Parkinson's disease, there has been symptomatic treatments available for decades. Because of that, there's also a certain historical divide and perhaps even burden in the clinical trial design. Many of the clinical outcome measures co-evolved with the symptomatic treatment development, and they were designed for detecting symptomatic effects. More recently, there's been a lot of activity developing disease-modifying drugs. Of course, the big difference here is how long it takes for the effect to start appearing. For symptomatic drugs, it is very rapid, acute effect that can be quite easily detected. For disease-modifying effects, the clinical benefits are expected to rise over time. This gives a little bit of a challenge for clinical trial design.
Looking at our data, what have we learned over the past 15 years or so about CDNF biology and HER-096 mechanism of action? The top image here shows tissue sections from a non-human primate Parkinson's disease model, and these animals were treated with intracranial CDNF infusions or placebo infusions for several months. What we actually observed at the end of the study is quite remarkable. All the dark staining seen here is actually showing dopamine neurons. The little dots are the cell bodies, the little fibers are the growing axons and terminals trying to reach their target region. The difference to placebo is quite remarkable. The CDNF treatment was associated with a very significant neurorestorative effect. This gradually will mean that there will be more dopamine terminals available, more dopamine secreted by these terminals, which is expected to result in a slowly appearing symptomatic effect.
This is exactly what we observed in this non-human primate study. Interestingly, in the CDNF phase I study with intracranial infusions, we also observed a few individuals that showed similar type of changes over a few months. Perhaps we shouldn't be so black and white about the two different types of effects. There actually may be a biologically founded, gradually developing symptomatic relief that is perhaps something that we could detect over a few months, and this is why the six-month randomized design. There's, of course, important questions on the patient population. Who are the ideal participants? The treatment time and outcome measures, and very importantly, we have made a decision to use a digital motor score as a primary endpoint to allow increased level of sensitivity for these type of effects.
The classical golden standard clinical rating scale for Parkinson's disease trials is so-called Unified Parkinson's Disease Rating Scale, UPDRS, and the revised version called MDS-UPDRS. This is a clinical rating scale, meaning that a clinician will observe the patient's symptoms and score them one by one. Typically, this type of assessment is done perhaps every three months in a study. There's a lot of room for day-to-day variation, inter-rater variation, et cetera. Typically, studies involving UPDRS as a primary endpoint, they seem to be very noisy. It's very hard to fish out the signal from the noise in these type of studies. There's a lot of interest in improved outcome measures. With disease-modifying therapies, we need to go beyond the UPDRS. We need increased sensitivity. We need continuity and also objectivity, and digital health technologies offer an excellent opportunity for this type of sensitivity.
Overall, if we summarize our phase I-B biomarker data showed very clear evidence over the four-week period of treatment on concordant biomarker changes that were consistent with the HER-096 mechanism of action. These signals are perhaps the first signs that appear before the gradual symptomatic relief starts occurring over time. There's also translational pre-clinical evidence from various animal models and animal studies using CDNF and HER-096 showing that there is truly this type of functional improvement, functional recovery effect, but it takes some time. A perfect partner in a way for a perfect endpoint strategy would be a sensitive, continuous, objective assessment of motor function for this type of signal-finding study. This is why we have recently announced a collaboration with a Swiss company called Indivi. Indivi is specialized in digital health technologies for objective real-world assessment, for example, of motor symptoms in Parkinson's trials.
This enables high-frequency longitudinal monitoring, exactly what we need in a signal-finding study. Today, we have the pleasure of having Dr. Shibeshih Belachew, the Chief Medical Officer of Indivi, here with us for a brief interview. Dr. Belachew, welcome to the live webcast.
Pleasure to meet you, Henri. Pleasure to be with you.
First of all, thank you for joining us. Perhaps we can get started by a brief introduction of yourself and Indivi.
Yeah, Henri. Shibeshih Belachew. I'm a neurologist and the Chief Medical Officer of Indivi. In a nutshell, Indivi is a TechBio company, which means we're advancing precision medicine technologies to increase the probability of success of neuroscience drug development. We focus on those, I would say, hard-to-treat and hard-to-measure types of neurodegenerative disease like Parkinson's disease, the one you're trying to solve with HER-096. We know that Parkinson's disease is a hard area with historically low success rates. We believe part of the problem, part of the attrition, and the difficulty to go from first in human to proof of concept, as you stated it, Henri, is because the conventional endpoints are lacking precision and sensitivity to detect treatment effect. That's really where we play in Indivi.
We've built a battery of 18 instruments that constitute a multimodal deep phenotyping framework, meaning digital measurement tools embedded in a smartphone application that will more frequently, more continuously capture the most important motor and cognitive functions that we know are altered in Parkinson's disease.
For a participant, this would mean a smartphone-based continuous assessment. Can you tell us a little bit more on how the digital motor score, what are the different types of tests, the composite, how it's built? What does the digital motor score mean in practice?
No, it's trying to beat the MDS-UPDRS. You've summarized the limitation of MDS-UPDRS. It's poorly representative. It is subjective because this is the opinion in the Part III , so the motor examination. It's an opinion of a neurologist that determines the score. Because it depends on the neurologist, it's actually very infrequent over time. When you're actually using a smartphone with activities of daily living type of motor task, you can extract from that a digital motor score that will be a combination of objective performance of the patient measured with what I would call sensor-grade accuracy at a high frequency, for instance, on a weekly basis, like in your protocol, and at home in an ecological environment, and importantly, by patients themselves. You're actually putting the patients at the center of their self-measurement. You're excluding subjectivity.
We are developing and validating mostly four instruments for Parkinson's disease that will concentrate on the most meaningful aspect of how patient feel and function in the field of motor function, which could be, for instance, gait, balance, or upper limb bradykinesia. These are the type of tasks that will be at the source of the extraction of the measurement that will constitute that digital motor score.
Where would you say that the digital health technologies in general are? There are not many digital endpoints that have a regulatory acceptance or approval. Are there examples of clinical trials, for example, in Parkinson's, where digital motor score has been incorporated in the study design?
It's starting to become a reality, and we are not the first one to advance in that field. I think we have to be humble when it comes to regulatory adoption. You said it. That's what the FDA sort of summarized. We still have to prove ourselves to truly become a new standard. I think the jury is still out because the regulators have not yet seen the ultimate proof of superiority versus MDS-UPDRS Part III. This is the type of gap that we are actually trying to fill, and we do that thanks to the recent readout of a phase II trial in collaboration with Biogen and Denali Therapeutics, where our technology, and in particular for instruments that were assessing gait, the way you turn when you walk, the way you type on a smartphone.
Those type of instruments were longitudinally assessed vis-à-vis MDS-UPDRS to compare their responsiveness to decline, meaning their capacity to detect subtle progression of the disease, the type of progression where you hope that HER-096 will have an impact. This is what we have to put together. We will disclose the full comparative analysis of our digital measures and of our digital motor score versus MDS-UPDRS in an upcoming conference. We believe this is hitting the mark of providing more responsive measure of how patients function and how this may translate into how they feel. Ultimately, the regulators want to see that. They want to see more responsive but meaningful measures when it comes to what matters for patients. Again to convince them, you have to go after the proof.
The proof is in phase II trials, and we're very much looking forward to engaging with them ultimately after the full disclosure of the LUMA biomarker results.
Are there any other indications where digital health technology-derived endpoints have already been used for drug registration?
As you know, there's a wonderful example in Duchenne muscular dystrophy, which is a rare genetically driven muscular dystrophies. It took 10 years to demonstrate that in Duchenne muscular dystrophy, the so-called 95th centile stride velocity is indeed meeting the bar of properties and longitudinal performance that could actually really convince regulators at the EMA level that it could become the primary endpoint during a registrational phase of drug development in that particular area. This serves for us as a blueprint. The stride velocity, maximum walking speed, passively quantified in one rare neuromuscular disease, serves as a blueprint for what we want to replicate in Parkinson's disease, continuously following the so-called V3 framework, so technical, analytical, and clinical validation to convince the regulatory bodies throughout the world.
Of course, in Parkinson's, there's a number of previous trials where digital motor score has been used in one way or another, Roche trials, NEULARK, LUMA, and so on.
I think exactly that's where we are currently. This is not new in Parkinson's disease. I think the Roche experimentation has been pioneering the field. The NEULARK trial is also using a similar combination of extracted digital measures. I think in PD, we just need a winner. We technically need a comparison with MDS-UPDRS to ultimately move the needle at the regulatory level. I think this is the field that is experimenting since 10 years, but we've not been catching up yet with Duchenne, for instance, where a single technology and a single endpoint, not a motor score, has actually demonstrated superiority. It's a bit easier there because there was no benchmark. In Parkinson's disease, there is an established endpoint, which represents something for regulators and which has been used in the last multiple decades.
The bar is higher and it's great to see that multiple technologies are now becoming more and more the standards in those early phase trials.
Thank you. Last question. You've recently started collaboration with Herantis. Any first impressions or feelings, or how do you feel about this?
I'm going to be very candid, Henri. I want to underscore the great thing about this collaboration with Herantis is that it is actually a partnership. We do not believe that this particular conundrum that we're trying to solve in Parkinson's disease, advancing transformative digital biomarkers can one day truly change probability of success of drug development without real joint development efforts between what I would call the deep science of the technology, which is complex, and the science of the drug asset itself, which is what you are championing. That's, I believe what we are putting together with you at Herantis from the inception of the study design to recently the opportunity to face the FDA and your pre-IND engagement.
We believe we have to be in it together, because detecting treatment effect on progression, especially with your biological target, a mix of symptomatic and disease modification paradigm, it is actually hard. It is a bit of a needle in a haystack. The magic can only happen if you create this symbiotic intersection of the knowledges, the signal processing engineering, the statistical science, and the clinical science all together. That's what we're so happy to do with you and with the HER-096 phase II study team.
Thank you, Shibe, for joining us today.
It's a pleasure.
Yes. Thank you, Henri, for the great presentation and interview with Shibe. I think we all agree that at least that we at Herantis, we are really enthusiastic about the phase II plan that we have put together and the parties that are currently involved. Of course, we believe that this is exactly the right step forward to increase the value of HER-096, taking it forward, and of course, it is also very instrumental for creating a long-term shareholder value. By these words, maybe the presentation part ends, and we can start the Q&A session.
Hello. We have got a lot of questions, but there's still room for more. Let's start. What are the specific trial design requirement and success metrics for the phase II-A study, and how do they differ from a standard phase II study?
I wouldn't say there is no standard phase II study. The study needs to be, first of all, designed to match the mechanism of action, and the type of effects that are expected to appear in response to the treatment. As we've just had a long discussion on challenges of some of the endpoints, also, the design has to balance various aspects, the endpoint strategy, the type of patients, the treatment duration, et cetera. My answer would be that there is no standard. As pointed out in the FDA discussion, the phase II is actually the time for exploring the future endpoint strategy, generating data that can eventually then be the foundation for pivotal studies and so on.
Thank you. We have been discussing the digital motor score, and so what is your assessment of that score sensitivity in detecting therapeutic responses relative to conventional clinical endpoints in Parkinson's disease?
Well, I think the key there is the continuity, and the objectivity that generates enough data to bring out the signal from the noise. I think we still have Shibe online. At least I see him on the screen. Maybe we ask Shibe to comment this question as well, because he's the true expert in these type of endpoints.
What we aim at here is a material increase in sensitivity to change. Signal finding studies like the one of HER-096 are a signal-to-noise ratio optimization type of problem. How do you measure signal-to-noise ratio of an endpoint is generally by the capacity of the endpoint to change from baseline when the disease is progressing with a limited noise. We believe at Indivi that we should develop digital biomarker the way we develop drugs, so defining a product profile, defining what success look like. I can just tell you without disclosing the LUMA results, which will be published at the upcoming MDS conference in October, that our product profile for success means a twofold increase in signal-to-noise ratio.
That is when you kind of get to that margin of superiority, that it translates into the capacity to design really smaller and shorter trials without compromising the statistical power.
Thank you. Next follow-up question there. If successful in the phase II-A, do you believe that the DMS could support late-stage development and potentially serve as endpoint in the registration trial?
I would say the field is moving forward, trial- by- trial. It's perhaps a little bit premature to speculate on that. We did have a little bit of a discussion with the FDA on this topic as well. I think what's important is that there's very broad interest also from that side, so the regulatory authorities also see the need for improved outcome measures. The availability of the digital technologies is a great opportunity, but it takes time to get there. There's still some work to be done.
Maybe to continue, as Shibe already mentioned, that it's important that also we create evidence that aligns the digital motor score with the current clinical measures. Of course, that correlation will then take the whole measurement of digital motor score forward towards a regulatory endpoint.
Good. Is a six-month follow-up long enough for early-stage patients?
Depends on what you're looking at. In this phase II-A study, we tried to balance the objectives with the potential risks and also with the potential patient burden. 12-month study with injectables is a lot to ask. For this stage, we believe that this is the right design. This will not be the last clinical study with HER-096. We all know that. This will be a key moment to find that signal, and this design is designed for that.
Maybe continue that, of course, first we have this six months randomized part, but all the participants will get the next six months also treatment. Some of the patients will get 12 months treatment, some of the patients will get first six months placebo and then six months treatment. It's not only six months data that we will get, we will also get 12 months data point. As Henri mentioned, we believe that this is a very good design to find the signal and giving us the guidance what would be then the registration trials look like. This is in a way very much also aligned with the discussions that we have had with pharma.
Very good. Assuming that the phase II-A results is positive, what will be the expected development and commercialization path for HER-096?
Yeah, that's a very good question, of course, the most important thing is what kind of data we will get from the phase II-A. Of course, based on those data, we will discuss with regulatory authorities, of course, at that stage, we very likely will have a large pharma partner taking those discussions with regulatory authorities like FDA and EMA to design the pivotal, so the registration trials towards commercialization.
I think it's the last question that's a really important one. We have been talking about the trial now, and we are all excited about starting that, but there's funding needed. The question is, with more than 50% of the phase II funding now secured or identified, how is management prioritizing the remaining funding options across strategic partnership, equity financing, and further non-dilutive sources? In particular, would Herantis prefer to start a study independently and partner after the interim or full phase II-A data, or secure a partner before trial initiation?
That's of course an important question, and I would say that there are a couple of very important things. One thing is that we need to ensure that HER-096 is advanced to the phase II trial as soon as possible. We have great study design, and it is the benefit for all the stakeholders, including the patients, including Herantis, including our shareholders, that we can timely start the trial and get to the efficacy data point. That's very important. Then of course, the second thing is how we build the long-term shareholder value. There, of course, we have already earlier said that we will keep the options open until we know what is the exact right path.
This is still the case that we are advancing the operational capabilities, but at the same time, we are looking at strategic discussions which are still ongoing, and also looking at equity financing and non-dilutive financing. As mentioned, we are in a strong position as over half of the required financing is already secured. The coming months will show what is the ideal path. However, the most important thing is to get to the phase II-A data point, because of course, during this first signal-finding trial, that's the biggest increase in the HER-096 value during the development path. As mentioned, we believe that we have now designed the best possible trial, and we are really looking forward to execute that.
Mm-hmm. Thank you. I think that concludes the Q&A session. I don't know if you have some more key messages or takeaways in the end or.
Yeah. Thank you for joining us today. It is always a pleasure to update our progress as we have had very good progress during the past years. Thank you, Shibe, for joining the webcast, and thank you for the management also joining me here today. We will keep you updated about the progress in the coming months. I wish you all very nice summer, at least in Finland, we have sunshine so it's a great moment to have spent half an hour here with you. Thanks.