Herantis Pharma Oyj (HRTIS) Earnings Call Transcript & Summary

Good morning, and welcome to the Herantis R&D Update Webinar. My name is Gabriela Urquilla, and I will be your moderator for today's event. Presenting today will be CSO, Henri Huttunen; and COO, Antti Vuolanto. We will give an update on -- an R&D update and information about Herantis' new biomarker program. Due to a family emergency, CEO, Craig Cook, will not be in attendance. The next slide shows our disclosure statement. As a quick reminder to listeners, during today's webinar, management may make forward-looking statements involving known and unknown risks, uncertainties and other important factors beyond the company's control that could cause the company's actual results, performance or achievements to be materially different from the expected results, performance or achievements expressed or implied by such forward-looking statements. Please note that the forward-looking statements made during this webinar speak only as of today's date, and the company undertakes no obligation to update them to reflect subsequent events or circumstances other than to the extent required by law. We will discuss our drug candidates and our biomarker programs, then conclude with a Q&A session. [Operator Instructions] As a reminder, this call is being recorded and will be available for replay soon after the event. And with that, I would like to turn the webinar over to Antti. You may begin.

Good morning, and thank you for joining. My name is Antti Vuolanto. I'm the COO of Herantis. We are delighted to give you an update of our development programs, including biomarkers, blood brain barrier crossing, neuroprotection, alternative administration routes and the commercial opportunity. And the objective of today is to share the progress with you. I will give you first a brief introduction of the company. So Herantis is a Finnish biotech company, fully focused in Parkinson's disease and other neurodegenerative diseases. We have been listed in Helsinki since 2014 and in Sweden since 2019. So far, we have collected dilutive and nondilutive funding worth of EUR 67 million to date. And recently, we have decided to fully focus now on the neurodegenerative franchise as we have had previously also other development programs. Our programs are based on CDNF, so Cerebral Dopamine Neurotrophic Factor, a natural protein whose role is to protect neurons. And we are looking to take that natural ability and harness that as a treatment of Parkinson's disease and potentially also other neurodegenerative diseases. We have 2 development programs. The first one is recombinant human CDNF, which we have completed Phase I clinical study last year. In that study, the drug was administered intracranially, using an invasive method involving also surgery. Now we are expanding the development of recombinant human CDNF into other less invasive routes of administration, so intranasal administration and subcutaneous administration, in order to address earlier-stage patients and also be more attractive as a partnering -- a potential partnering perspective. The second program, xCDNF, or HER-096, is peptidomimetic synthetic compound derived from the active fragment of the CDNF protein. And it captures the same mode of action as the CDNF protein. This slide illustrates the pandemic nature of Parkinson's disease. So some 30 years ago, there were approximately 3 million people suffering from Parkinson's. It's now close to 10 million, and it's projected to grow even beyond 10 million in the coming years. Parkinson's disease creates a massive burden for the patients, for the families and for the society. So only in European Union, over EUR 14 billion are annually used for the management of Parkinson's disease patients. The current treatments are insufficient because they can only treat the symptoms, but the disease is progressing regardless of the treatments. So there is a great unmet clinical need for developing new disease-modifying, disease-stopping treatments. And there are a lot of interest in the pharma industry to generate and create such new treatment modalities. However, so far, the attempts have not been successful. Due to our mode of action that covers the core pathology of Parkinson's disease, we are well positioned in the competitor space, with both the recombinant human CDNF and HER-096. The CDNF protein has been discovered by the researchers at University of Helsinki over 15 years ago. And the company has already a history of over 10 years of R&D with CDNF. So with the recombinant human CDNF, we have been able to create a very comprehensive preclinical data set. We have been able to run the first clinical study with the intracranial administration. We have completed the study, and we have been able to generate very compelling biomarker data. But at the same time, we have developed the xCDNF platform, so identifying the active part of the full protein and synthesized a library of different molecules; selected the lead compound, HER-096; filed the IPR; and now being able to create a comprehensive and compelling data set also with HER-096. So both of the assets derived from the CDNF protein, they target the core pathologies of Parkinson's disease, so proteostasis and unfolded protein response, UPR. So basically, proteostasis, it regulates the proteins in the cells, from synthesis to degradation. And as you know, proteins are the building blocks of all the cells and the body. So basically, the balance with the proteostasis is really important to -- or vital to have a functional cell and biological system. And the key reason for our excitement about our assets is that both CDNF and HER-096, they have, let's say, an effect on the whole proteostasis network, so not only part of that, but controlling and balancing the activity of these important pathways. And this is one of the differences with other attempts that there are in the industry to create disease-modifying treatments. As for example, Roche and Merck, which are big players in the space, they are focusing more on certain components of the network while we address the whole network. And really, the aim of CDNF and HER-096 is to return the normal function of the cells from a stressed situation that is linked with the pathology of Parkinson's disease. So as we have seen previously with cancer drug development, also in CNS, drug development is now shifting to biomarker-driven development. So previously, it has been very common that the development programs have been based on clinical results. And that has the consequence that the clinical studies are lengthy and requires a lot of patients to be recruited. Using biomarkers, that provides an earlier window for understanding the effect of the new treatment on the biology, and that enables the -- in the drug development, more rapid and efficient assessment of the effect. That shortens the development time lines. It saves cost as well. And it also provides the opportunity to provide important information for the drug approval. And there is a great example of BioGen. They delivered the new -- the first disease-modifying drug, aducanumab, for treating Alzheimer's. And the biomarkers -- or the biomarker's data was key for its approval. And a very similar manner, the CDNF platform is a disease-modifying drug for Parkinson's, and we aim at creating very strong biomarker data and also utilize that further on in the development and regulatory discussions. And as Henri will present today, we already have a unique set of biomarker data, which, to our knowledge, is -- it's currently in the forefront of the development of the field. So that provides a strong foundation to build upon, and it will be a key component of our programs moving forward. So Henri, please, if you'll take us through the R&D data.

Thank you, Antti. Good morning, everyone. My name is Henri Huttunen, the Chief Scientific Officer at Herantis. And first, I will walk you through the -- our new biomarker-driven strategy for CDNF and HER-096. And then I will give a brief update on the CDNF and HER-096 program status. So in -- generally speaking, there has been a clear paradigm shift towards precision medicine in health care widely. And this is, of course, also driving change in the biopharma industry. There's clearly now much more ability to develop mechanism-based targeted therapies in multiple therapeutic areas. And as Antti mentioned, oncology has been really paving the way for this change, and there are now several marketed drugs that are specifically developed to certain subtypes of cancer. And now, all therapeutic areas are transitioning to this type of biomarker-led development, and leading pharma companies worldwide have already adopted biomarker-driven trial models in their clinical development. And we know that in the space of neurodegenerative diseases, there has been a particularly poor success history so far, Alzheimer's, Parkinson's, of course, all others, frontotemporal dementia, ALS, these type of diseases, we have not been able to take potential disease-modifying therapies through the clinical proof-of-concept stage. And now, most companies in this space are shifting to biomarker-led development. This is expected to compress drug development time lines, increase patient response rates and reduce development costs. And in general, it has been estimated that success rates in clinical development are roughly 3x higher when a biomarker strategy is implemented. So this image compares the classical development strategy, where no -- biomarkers are not used to biomark the lead development, where particularly stratified patient populations are used so that we can actually tailor and target those patients which are believed to be most responsive to a particular treatment. This also gives much richer treatment efficacy data in the clinical trials, delivering deeper insights on the mechanism of action of the drug. And on average, the clinical trial success rates are roughly 3x higher as in the classical drug development approach. So Parkinson's disease is known to be a heterogeneous disease with multiple etiological subtypes. There's nearly 100 genetic associations now known for Parkinson's. And here, in this image, we've listed -- or we're showing 9 different types of molecular basis of disease that are known to be involved in Parkinson's. Now in the classical drug development approach, a drug would be tested in the broad population of patients where the patients are not stratified based on their molecular genetic type of disease. And this obviously results in much, much lower likelihood of showing efficacy. However, if we now choose patients smartly, and for example, we have a compound that targets mitochondrial function, and then we select patients based on biomarkers or their genetic profile who have this type of Parkinson's disease and then administer a drug. To these patients, it is much likelier to see good response rates and take the drug through the clinical proof-of-concept stage to Phase III and eventually to marketing authorization. There are many types of biomarkers also that can be used to support clinical development. We can use biomarkers to drive phenotyping and stratified clinical trial designs. We can also use the pharmacodynamic biomarkers to measure treatment response to a given therapy. Or we can use prognostic biomarkers to follow disease progression in trials. And of course, biomarkers are not something that are very new at Herantis. We have actually implemented biomarkers already in our CDNF Phase I study, particularly for the purpose of collecting biomarker data to support our future clinical development. In Parkinson's, there's a very specific degeneration of nigrostriatal dopamine neurons, and this can be very nicely visualized by brain imaging techniques, such as PET, Positron Emission Tomography. And we used dopamine transporter binding tracers and PET imaging in our CDNF Phase I study. And actually, we found that some subgroup of patients showed increased dopamine transporter tracer binding in their basal ganglia after being treated with CDNF. So this is, of course, one type of biomarker that we plan to also implement and incorporate in our future clinical studies. Now secondly, Parkinson's is a motor disorder. So patients are -- typically suffer from various types of motor symptoms. And these motor symptoms can be measured with digital devices, and Parkinson's has actually been leading the way for development of digital biomarkers for continuous, more objective measurement of motor symptoms as compared to the traditional clinical scores that have been used previously in clinical development. Also in the Phase I clinical study, we used a digital biomarker. We collected digital biomarker data using a device called Parkinson's KinetiGraph, PKG. And in this data, we did see clear differences between a placebo group and the CDNF-treated groups, particularly in terms of bradykinesia, the slowness of movements in these patients. And this is another type of biomarker that we plan to use also in our future clinical trials. Now the third modality of biomarkers are more classical biomarkers, proteomic biomarkers, based on bodily fluids. And in this Phase I study, we collected cerebrospinal fluid biomarker discovery data set to support our future development of very specific biomarkers, particularly related to pharmacodynamic responses of the drug. So this picture shows a heat map of 50 selected biomarkers in the cerebrospinal fluid, how they changed in the patients in the CDNF Phase I study, from baseline to 6 months and 12 months of treatment. And what we can see in this data set is that we have all 14 patients; we have 5 patients that share a very similar biomarker fingerprint in the cerebrospinal fluid. This is quite interesting in many ways. One is, of course, the fact that we have -- as you can see, the profile of these biomarkers is rather similar in all these 5 patients. Secondly, there are many patients that do not show this type of response. And of course, this raises a question, is there a correlation with the clinical stages of the patient or other metrics in the clinical study. And I will come to that in the next slide. The third important point here is that we have one patient here who was on placebo. And in the first 6-month treatment time period, the patient actually received just saline solution basically in the infusions. And at 6 months, there was no change in this cerebrospinal fluid biomanker profile. However, when the patient started receiving CDNF, after 6 months of receiving CDNF, the patient showed a very similar biomarker fingerprint in the CSF as did the other 4 patients who have been receiving CDNF throughout the whole study. Now we have actually just recently received and analyzed some follow-up study data from the CDNF Phase I study. And here, I show data from a single patient. There's actually several reasons for this. This is -- we have to keep in mind that this is really N-of-1. We should not jump into 2 strong conclusions, but there's some particularly interesting features in this patient. First of all, the patient was on placebo for the first 6 months. There was a little bit of a placebo effect in the Unified Parkinson's Disease Rating Scale scores. So this is the off-medication motor scores of the patient. And when the patient actually started receiving CDNF, there was a significant improvement in the motor symptoms, a 12-point improvement of the baseline. Now in the follow-up study, when the patient did not receive CDN anymore -- CDNF anymore, the patient actually started only slowly coming back towards the previous stage of disease. For example, the UPDRS scores remained more or less on the improved level for several months after stopping the treatment. And the level of a dose was only increased more than 10 months after stopping CDNF treatment, suggesting that we may have had long-term effects in the brain function in this patient. Now if we look at the dopamine transporter PET data, there's also a very interesting finding here. As you can see in the first 6-month period, we can see that there's a decline in the dopamine tracer binding. This is expected to happen in the patients because of the continuous degeneration of the dopamine neurons. Now this period, the sort of like the blue-shaded period here, from 6 to 12 months, the patient received CDNF, and there was a clear slowing down of the degeneration. Perhaps you could say that there's even a small increase in the dopamine tracer binding here. Now at 12 months, when we stop CDNF treatment, we again start seeing the slope towards declined tracer binding. This is another second line of evidence suggesting that we do have a biological response to treatment that relates to the function of the dopamine system in the basal ganglia. And this patient was the one who also showed a CSF biomarker fingerprint change. So overall, a very, very interesting patient. And finally, and this was actually a little bit of a surprise to us, when we genotyped the patients, we found that the patient actually is a carrier over fairly common mutation causing Parkinson's called LRRK2-G2019S. So this indicates that this type of genetic subtype of Parkinson's could be particularly responsive after CDNF. It doesn't mean that this is selectively -- only CDNF is selectively working in this type of Parkinson's, but it clearly suggests that this type of subgroup of patients could be responsive also in our future studies. And this gives us now a way to explore further a stratification strategy for future clinical studies. Now moving on from the clinical data, looking at the biomarkers in the CSF, there's, of course, one more important question. And that is, do we have any functional commonalities between these markers that could be connected to the mechanism of action of CDNF? So the 20 markers in the cerebrospinal fluid that seem to change in response to CDNF treatment, we found, using pathway analysis, we found that they were roughly divided in 3 categories. The first one is lysosomal function in autophagy, a critical part of the proteostasis network. As Antti mentioned previously, CDNF is known to modulate proteostasis, particularly via modulation of the unfolded protein response pathway, which is closely connected to the autophagy pathways. Secondly, 1/3 of these 20 markers were associated functionally to various immune response and neuroinflammatory pathways, microglial activation, neutrophil activation and so on. This is again very tightly connected to the unfolded protein pathway. And we know unfolded protein response pathway, and we know from several preclinical studies that CDNF effectively modulates neuroinflammation. So we now have, in the clinical data set, also an indication of biomarkers related to neuroinflammation changing. And the third category was neuronal cell adhesion and synapse assembly. This could be related to changes in plasticity and perhaps regeneration of the neuronal networks in the basal ganglia. And these markers, of course, now generate a great basis for future biomarker development, particularly regarding the fluid-based biomarkers. So we are now launching a new program of biomarker development so that in the future disease-modifying clinical trials, we would be more successful. Key elements of this new biomarker program are to build on the existing biomarker discovery data that we generated in the Phase I study. We will do further verification and validation work. And we will build a multimodal biomarker approach for future clinical studies. A key element to this new strategy is also strengthening our team, with individuals with strong track record and vision to execute a biomarker-driven clinical development. And we'll come back to this in the next couple of slides. And finally, our goal to complete the biomarker development or take it to a stage where we can actually significantly benefit from it would be that, by 2024, when we estimate that we will be launching and initiating the Phase Ib, Phase IIa clinical studies in Parkinson's patients, with either HER-096 or CDNF, we would have a good multimodal biomarker strategy and set of biomarkers ready to be taken to the clinical development. Now there are 2 practical arms for our biomarker-led R&D work. One is, of course, we need to do a little bit of more preclinical biomarker research. We want to build a strong translational connection between our preclinical data and our future clinical data. We will develop ultrasensitive assays for selected markers. As you saw, there are some interesting candidates that we identified from the Phase I study. We will also explore these candidate biomarkers in existing Parkinson's brain banks to understand their natural variation in the early PD population. And importantly, we will be starting a new observational biomarker clinical study with a cohort of early Parkinson's patients, including a genetically defined subgroup. Also in this data, we will collect data -- we will collect more information on natural variation of markers in early-stage patients and verify candidate biomarkers in a clinically relevant cohort for our future studies. For this purpose, we have established a network of 4 clinical sites in Europe and key collaborators and partners. We are ready to start this clinical study hopefully by mid-'22. As of today, the company warmly welcomes Dr. Kira Holmström as our new Head of Biomarker Research. Kira will start at Herantis today, and she will take the responsibility for our biomarker development program. Kira has a very strong background in molecular neuroscience. She has held multiple research positions in the U.S.A., U.K., Germany, Finland. And most recently, she has worked at Orion Pharma as the preclinical and clinical biomarker lead in neurodegenerative disorders, so very well-matching exactly the things that we plan to do in the next 2 years and beyond. So the company warmly welcomes Kira. And also yesterday, we announced our new Scientific Advisory Board. Already, in September, we put out a release on Dr. Anders Gersel Pedersen, taking the chair of the Scientific Advisory Board. Anders is very well-known and a globally acknowledged figure in CNS drug development, was the Executive Vice President of R&D at Lundbeck for nearly 2 decades. And of course, he's a great person to chair our Scientific Advisory Board. Moreover, we welcome Drs. Daniele Bravi, Alberto Espay and David Dexter, all also internationally, globally acknowledged experts in Parkinson's disease and particularly in biomarker-driven clinical development in movement disorders. So we believe that this new Scientific Advisory Board will have a very important role in guiding our biomarker-driven development forward. So next, I will give a short update on our CDNF and HER-096 programs. As you may remember, about a year ago, the company announced that we will not be continuing development of intracranial CDNF. But instead, we are exploring new routes of administration and also some new indications potentially for CDNF. So this work, preclinical work, has been going on for now since early this year. We have particularly focused on 3 different aspects here. First, we've been working on developing a formulation for a nose-to-brain intranasal delivery of CDNF. There has been some delays early in the year, but now, the second half, there's been a great progress. And we have now developed more than 50 formulation candidates that are now in performance testing, using state-of-the-art methods for human nasal epithelium and towards the end of the year, also in vivo testing. By the end of the year, we will be in a situation where we'll have a very short list, 1 or 2 formulations, that we will then take to second round of formulation testing in vivo -- sorry, brain distribution testing in vivo. And by mid-next year, by end of first half '22, we will have this data set completed. We have also initiated a collaboration, a preclinical collaboration with an intranasal drug delivery device manufacturer that will be used in these in vivo studies. At the same time, we are exploring the utility of subcutaneous CDNF in new indications. And for intellectual property reasons, I will not disclose today what indications we are currently exploring. This will probably be a topic of an R&D update sometime next year. In September, we also announced that there has -- we have reached a process development proof-of-concept stage with the generation of CDNF protein nanoparticles together with Nanoform Finland. Now nanoparticles have been classically associated with small molecule drug development. And typically, biologicals, such as proteins, do not tolerate well these type of processes that are used for generation of nanoparticles. So it's a very interesting proof-of-concept data set that CDNF actually can tolerate a process that takes it into nanoparticles, and we are now further improving this process. And hopefully, early next year, we will also be able to take the CDNF nanoparticles to in vivo testing. We will then update -- give an update towards mid-next year on this program as well. On HER-096, this is the xCDNF preclinical candidate that we announced in May last year, a novel chemical entity, a peptidomimetic compound that is based on the active site, active fragment of CDNF. So we have now initiated a preclinical program in June this year for HER-096, and the progress during the second half of the year is listed here. So first of all, we have developed and selected the salt form for the compound. We have now contract manufacturers selected, and our first research-grade batch of the selected salt form has been manufactured and tested successfully. And we are now -- we have scaled also the manufacturing from milligram scale to hundreds of gram scale so that we can manufacture a larger batch for GLP toxicology studies, and this is currently ongoing. We have also initiated nonclinical toxicology studies. And there's -- actually, the first studies are just ongoing. The animals are in observation period. So far, we have not observed any signs of toxicity in terms of clinical observation. And in the next coming weeks, we will start a more thorough histopathological analysis of these first set of animals in the toxicology program. We also generated more data on target engagement, confirmed it in a very relevant preclinical model of Parkinson's. And we are now conducting dose finding and biomarker exploration studies in this model. And we are on track with our goal of initiating first-in-human studies with HER-096 in early 2023. So briefly, I will show a little bit of data here in the next few slides just to keep you updated. As you remember, HER-096 is a compound that effectively penetrates blood brain barrier, and this is a major advantage of this compound. This study used a dual microdialysis to analyze HER-096 levels in -- simultaneously in plasma and in brain interstitial fluid. And here, we gave the animals a single subcutaneous bolus dose of HER-096. And as you can see here in these graphs, we have a very good brain penetration, about 20 -- more than 20% of the compound entering the brain tissue. And also, importantly, the brain interstitial fluid half-life was longer than the plasma half-life of the compound. So when the compound gets to the brain, it stays there a little bit longer than it does in the circulation. We've also explored brain distribution of HER-096 using other approaches. Here is an example of a fluorophore conjugated compound, which was administered to healthy animals. And then we used microscopy to follow the compound in the brain and brain sections. And as you can see here, we have -- clearly, these animals are perfused before microscopy, and you can see that clearly, we have compound. The pink color showing compound in uptake in the endothelial cells. These are small brain capillaries, where we can see a compound. We can also see some co-staining with the astrocytes, the green one being an astrocyte marker. And also, we see some thin processes and also cells that are clearly parenchymal. So conclusion from these studies, which are still ongoing, is that HER-096 can be uptaken by multiple cell types of the brain following subcutaneous injection. Here, we have explored further the dosing of HER-096 in alpha-synuclein-based animal model of Parkinson's. And just to remind you, this is a mouse model based on aged 18-month-old black 6 mice. And the animals are injected with alpha-synuclein oligomers into substantia nigra. And then they are treated with daily injections of glucocerebrosidase inhibitors to promote development and propagation of alpha-synuclein pathology in the brain. And here, we have started subcutaneous HER-096 injections 1 week after the onset of pathology. We gave subcutaneous injections of HER-096 at 2 different dose levels for 5 weeks, after which, we analyzed the brain tissue for specific markers. The left graph here shows that we have reached nearly 70% protection of nigral dopamine neurons as compared to the vehicle-treated group here. So this is the model effect. So we have more than 50% drop in the number of nigral dopamine neurons and then about 70% increase in -- by a higher dose of CDN -- pardon me, HER-096. The middle graph shows alpha-synuclein deposition being also reduced significantly by about 35% with the higher dose level. And the right one shows microgliosis neuroinflammation in the basal ganglia of the animals. So this is a marker for activated glial cells called [ Ippa1 ]. And as you can see, animals treated with HER-096 for 5 weeks, subcutaneously, we have a complete normalization of neuroinflammation in this alpha-synuclein-based animal model, further suggesting that we have engaged our target pathways in the brain. We are currently also generating unfolded protein response macro pathway data in this model that's currently not available. The planned development time lines for HER-096 and CDNF are shown here. As mentioned previously, the HER-096 preclinical development is on track. And we plan to be IND-ready by end of '22, so that we can start a Phase I study in healthy volunteers early '23. And the observational -- the new observational biomarker clinical study is planned to start by mid-next year. And so that it would feed important biomarker data into the Phase Ib studies planned to start in 2024. This could be either with HER-096 or CDNF. And of course, data generated over the next 12 to 18 months will then guide that decision. At the same time, we will be continuing development of noninvasive CDNF, for example, the intranasal formulation, subcutaneous approaches and also exploring additional indications for CDNF. And for these, we have not made decisions yet which direction we will take the CDNF program. In the future, this is a decision that most likely will take place in the second half next year. Antti, will you tell us about the market opportunity?

Yes. Thank you, Henri, for the R&D update. So related to the market opportunity, this slide summarizes here both the market opportunity for the recombinant human CDNF and HER-096 as products and also the opportunity of the partnering of these assets for Herantis Pharma. So we have estimated that based on the prevalence of Parkinson's disease using a conservative estimate of the addressable market and assuming a price tag that has a small premium on the current symptomatic treatments, we have estimated that the annual market could reach EUR 8 billion if we would be able to bring this kind of a new disease-modifying drug into the market. And Herantis' main business model is focused on partnering with large pharma companies. And as a customer in the field, these discussions take long, and we are in a continuous dialogue with many potential partners. We discuss with them on an ongoing basis when we have more data and that we have great dialogue with these companies. A typical timing for a partnering agreement is normally between or when you have preclinical proof-of-concept through a clinical proof-of-concept after Phase Ib or Phase IIa clinical studies. And there are many good examples in the recent years of remarkable deals, sized anywhere between USD 0.5 billion to USD 1.5 billion, for example, Merck-Yumanity, Roche-Prothena and GSK-Alector. And as I already mentioned earlier, currently, the Parkinson's disease market is dominated by the symptomatic treatment, so levodopa drug and then lately also deep brain stimulation. However, there is an unmet clinical need to bring new types of drugs under the market. So this is modifying drugs that could potentially stop the progression of the disease. However, there have been some challenges with the field with some of the large pharma companies, which typically target one part of the pathology, for example, alpha-synuclein aggregation. And there has been some delays and challenges with that. However, we think that our candidates are very well-positioned in the space as our CDNF-based drug candidates, they target the whole proteostatic network by modulating it in a multiple way. So this is also something that we have learned with the discussion with big pharma companies, that our assets and the current data is very compelling. And as a conclusion, so this -- the slide summarizes our stage of development and the window of opportunity for partnering and also demonstrates that during the next 12 months, 18 months, we have a rich news flow related to our development towards the next clinical studies. So as a summary, we have unparalleled biomarker data, best in industry as far as we know. And we have a clear biomarker strategy and program ahead that will guide us through the clinical development and selecting and designing winning clinical studies and being able to create compelling data sets going forward. Our assets, they are really potent in neuroprotection, so they modulate the proteostasis. They normalize it, and that's needed for neuronal survival. And also for HER-096, we have shown an efficient crossing of blood brain barrier, which is very important. We have a significant market opportunity. So the pandemic nature of Parkinson's disease results in a multibillion need and opportunity for our drug candidates. And we have a rich potential news flow. We have several near- and medium-term milestones when we are now further creating our assets towards to the clinical studies. So our focus moving forward is to shape our development programs to identify biological- and biomarkers-based Parkinson's populations that would mostly benefit from the CDNF treatment and thereby establish new and innovative research paths, both for clinical purposes and also regulatory purposes. So thank you for listening to this update. And then it's time for the Q&A.

[Operator Instructions] Our first question, what is the rationale behind having both CDNF and xCDNF in development? Still one is further ahead in development, but given that the time line is now more aligned for entering preclinical, will you solely focus on xCDNF as the lead selection?

So Henri, please?

Thank you. This is, of course, a very important question. I would start by saying that there's actually 2 important things here. One is risk management, and the second one is opportunity. So first of all, HER-096 is a peptidomimetic. It's a novel chemical entity, a compound that doesn't exist in the human body. So there is a certain level of inherent risk in developing novel chemical entities in terms of toxicology. Secondly, related to safety, CDNF is a natural protein that's produced in all of our bodies. So the body can most likely tolerate a little bit better than any novel compounds. So that being said, it's important that until we have completed our preclinical toxicology program and get human safety data as well, it's important that we have a good fallback position in case there would be unexpected toxicology findings for HER-096. And CDNF because it's already observed to be clinically safe in humans is actually an optimal fallback position. Secondly, because we -- CDNF, I mean, we have to be realistic and also acknowledge the fact that we -- it's possible that we don't know everything about CDNF yet. There may be properties that we were just not aware of. And maybe HER-096 doesn't share all, exactly all those properties. So for that reason, CDNF could actually provide potential other opportunities. And this is exactly why we are exploring novel indications for CDNF. So there's a risk management perspective, and there's also an opportunity perspective. And I would believe that when we have completed the preclinical toxicology and have human safety data, then we are in a much better position to say which one is the #1 priority for Parkinson's.

Thank you. And a follow-on question to that is xCDNF is slightly less-developed than its parent CDNF. Have you been able to optimize its development based on what you have learned during the development of CDNF?

Definitely, we have -- there's a lot of synergies between these programs. I mean as far as we know, HER-096 shares all the important pharmacodynamic effects of CDNF. It engages with the same targets. It has the same effects on the proteostasis and information. And if the CDNF program didn't exist, we would be -- we would have significantly less data to understand the biology of HER-096. So there's a lot of synergy there. And this also accelerates development of HER-096.

Thank you. Another question is, you mentioned the genetic link that you saw in the Phase I trial. How does that affect the impact on the market potential? And will you focus on targeting those patients with a genetic mutation?

A very important question. And I would say that we have a lot of parallels in oncology again. So the short-term strategy here would be to find a patient population where we can demonstrate efficacy for the drug. And this is why the stratified clinical trial designs are so important. We want to get through the most difficult challenge and barrier in CNS disease-modifying drug development. And that's a demonstration of efficacy in a relevant group of patients. Of course, in the long term, it matters how big the market size is. And here, I would say, that the strategy is a little bit like trying to colonize a new continent. So here, we're trying to first establish a firm strong settlement on the new continent, and then we would like to colonize the rest of it. So in other words, if we have a marketed therapeutic that's approved for only a subgroup of disease, it's much easier then to explore the rest of the disease with this therapeutic than doing it as the developmental compound.

Great. Thank you. Another question, I think this one, how will the biomarker program improve the possibility of success?

This is, of course, impossible to exactly predict, but what we can look -- what we can do is look back in the history of, for example, on the therapeutic area, oncology. It's -- there are a number of reviews that help us to understand how biomarker-led development actually increases the success rate. But again, one of the important ways is to be able to better demonstrate the effects of the drug in the human body connected to the clinical changes. And the second one is being able to stratify patient populations, stratify clinical trials, have selected patient populations that are more likely to respond to the treatment.

Brilliant. Next question is how can companies and regulators create consensus around surrogate endpoints such as biomarkers? Given the heterogeneity of the disease, will it be harder than, for example, Alzheimer's? How willing are regulators when it comes to using biomarkers in PD today in your view?

Yes. This is a very interesting question, of course, a broad question for the whole field. And of course, our -- we -- our hands are a little bit limited in how we can influence the regulators. But then again, the FDA approval of aducanumab is a major milestone. And this, I would say, significantly facilitates similar approaches for other companies developing CNS -- disease-modifying therapies in CNS diseases. So it shows, first of all, that regulators are perhaps more ready and willing to go to this route. And perhaps that the fields are sufficiently advanced with the understanding of the basic biology of the disease, with the development of biomarkers, validation of the biomarkers. In general, I would say that Parkinson's actually could be even easier than Alzheimer's in terms of biomarkers. I think we have great tools already for brain imaging. Digital biomarkers are also very strong in Parkinson's, coming very strong. And there's a lot of history that actually helps and facilitates Parkinson's going fairly rapidly into this direction. Of course, I mean, it's something that will still take years before these projects are widely adopted. And -- but again, going back to the example of oncology, we can expect that something similar is going to happen in the CNS space as well.

Thank you, Henri. Another question is if a drug is approved based on an effect in a genetic subgroup, do hospitals or clinicians have enough tools to effectively divide patients into subgroups? If not, what type of advancements are needed?

Yes, this is something where I think the health care in general is progressing fairly rapidly. And again, this is something that oncology has paved the way for. We know that the -- nowadays, we can target therapies very effectively to genetic molecular subtypes of -- based on what we can know on an individual tumor, individual patient's tumor, we can tailor the therapy based on that. And in a similar way, somewhat similar tools would be used also for characterization or subtyping of Parkinson's patients. We would likely use genetics as one tool. We would probably use fluid-based biomarkers. Already, there are development on -- around alpha-synuclein, for example, as a potential biomarker in Parkinson's, somewhat similar to what we've seen in the Alzheimer field with amyloid beta and tau. And of course, the brain imaging markers will be something that's not -- I mean, PET, PET centers are not broadly available. But for example, Finland, which is a fairly small country, we have one PET center in Turku. But that's also, when needed, also used by other hospitals for generating PET data for patients.

Thank you. And the last question in queue, just to confirm, should we interpret the time line slide that HER-096 is closer to clinical and now more prioritized?

Yes, that's a very good question. So for HER-096, the development program is pretty straightforward and clear. So we have the proof-of-concept in preclinical setting available. And now, we are working with the safety and toxicology part. So basically, that's a very well-defined path and that we are now taking it towards the clinic, the IND-enabling studies, and then to the clinic. For the recombinant human CDNF, we are currently mostly working with the international delivery or administration. And there, as Henri explained, we have major milestones coming in the first half of next year. And of course, based on these data that we will get from those studies, we will then decide how we continue with those developments. So that's why -- that's the priorities of the company.

Thank you. At this time, that will conclude our Q&A session. I would like to turn the call over back to Antti and Henri for some closing remarks.

All right. Very much appreciated that you joined the update today. I hope that we were able to provide you a good summary of what has happened since the previous update in May this year. We will continue our work towards the clinical studies again. And we will provide, on a continuous basis, new updates to the market to understand our development and advances. So I really much thank Henri as well for the presentation, and I wish you all a very good day.

Thank you all. That concludes today's webinar. And I hope you have a nice day.