Saniona AB (publ) (SANION) Earnings Call Transcript & Summary

[Audio Gap] while reducing the side effects that limit their chronic use. Later in this webinar, we will review the clinical data supporting this approach and our plans for clinical development. But before discussed SAN2668, it is important to understand the disease error we are aiming to address. Turning to this agenda. I'm delighted to welcome Dr. Nicola Specchio, Head of the Rare and Complex Epilepsy Unit and Bambino Gesu Children's Hospital in Rome. Please, next slide. So Dr. Specchio is a global recognized expert in pediatric epilepsy and has served as a principal investigator of enormous clinical studies in DEEs and other severe childhood epilepsies. Nicola will begin by discussing the DEE landscape, the burden of disease and the significant unmet medical need that remains despite current available therapies. Following Nicola's presentation, our Chief Scientific Officer, Karin Sandager Nielsen, will review the mechanism of action of SAN2668 and present the key critical data supporting the program. Our Chief Medical Officer, Pierandrea Muglia, will then discuss our clinical development strategy and the market opportunity for SAN2668. Following the presentation, we will open the session for questions and answers. And with that, Nicola, thank you again for joining us today and for sharing your expertise with us and the floor is yours.

Thank you very much, Thomas. Good day, ladies and gentlemen. It's a great pleasure to be part of this meeting today. So my topic is developmental and epileptic -- can follow up with this landscape and in the next 15 minutes, I will try to explain it and will try to summarize what are the major medical needs and the unmet needs that we do have in this specific need. So what DEE is? This is here the summary in one slide. So we're talking about a condition in which we do have patients, which can be pediatric, but also adolescents, but also time to time adults that they do present with epileptic seizures and/or a platform EEG activities together with development is slowing or refresh. So putting together these 2 concepts, so the slowing of the development and epilepsy is part of the definition. But what we do have is that we have one etiology. So the cause of epilepsy and developmental slowing and regression is exactly the same. So one etiology responsible for both situations. And this is exactly what we do mean with DEE. But moving forward, what we have in patients with DEE, we have, as I just mentioned, epilepsy, which is usually severe epilepsy and a lot of epilepsy for EEG abnormalities, but there are other clinical manifestations around the single patients and the single individual may present with other than development and delayed behavioral problems, psychiatric problems, speech impairment, sleep problems and other issues, including GI, gastrointestinal issues and high risk of more complex condition in which we do have so many morbidities in a single given patients. And you see here from this review of pay -- of different papers, you have here the evaluation of what are the most frequent and severe disability in different domains, including mobility, and use, feeing and communication. And you have here listed different 4 different DEEs, which are Dravet syndrome, KCNB1, KCNQ2 and Lennox-Gastaut syndrome. And you can appreciate that the recent high need of support for those patients in terms of disability, you have huge communication issues, pairing issues also are very relevant and also mobility. And there are some differences in between the different diseases. But overall, it's something that is affecting all patients diagnosed with DEE. One point that I want to make is what -- I mean, Again, just summarizing one concept which may help understanding how much is important having proper treatment of those patients. So this is the normal development of a given child. And when this child is affected by a given etiology, let's hypothize genetic etiology, so a genetic mutation, the development, it goes down due to etiology due to genetic mutation. But when on top of this genetic variant, you have difficult to beat epilepsy, you have still, you're losing much more in terms of development. So one step is due to the genetic variant and the second one is due to the epilepsy per se. Therefore, we have to think about how to interfere with this process. We have anti-seizure medications. And with anti-seizure medications, we can definitely improve epileptic EEG abnormalities, and we can improve epilepsy. And what we are doing with precision treatment and disease modifying treatment is acting on the cause of the situation. So the treatment goal for those patients, we have 2 major goals. One is treating the seizures. So -- and the second one tree is treating and improving more to morbidities. And you see that when we choose a drug for seizure control, we have to look at type of seizures, type of epilepsy syndrome. EEG abnormalities, very relevant. And we have also etiology gain and tolerability. So we need to choose a medication which can really improve the seizure control, not only in terms of number, but in terms of EEG abnormalities and the medication that should be well tolerated because those patients they do need almost long-life treatment. They do have chronic conditions. And what is the potential of the impact? If I have a drug that is able to modified epilepsy from this child and reduce seizures, I'm definitely improving cognition. Why? Because in the mechanisms of epileptic discharges, you can see here via different pathways, it affects cognition. So it acts on the brain disrupting the function. It ups acts on cells making alteration of neurodevelopment and it acts on the processing of information. So epileptic discharges are very bad for the brain of our patients. And the question is what are we really treating, the seizures, encephalopathy or both? Definitely, and I was mentioning a little bit earlier before, controlling the seizures does not mean controlling the full disease. Morbidities often are very relevant for the quality of life of those patients. And so we need to think about shifting from the antiseizures to disease modifying approaches, even if the definition and there is a discussion around what is a disease modification and how we should address the underlying neurobiological process, which is something that is not actually happening right now. All those patients, they do have a polytherapy. So drugs are used in combination because of different types of seizures because most of them, they do have drug-resistant epilepsy and they're used quite early in the disease progression and quite aggressively because we need to stop seizures. We need to reduce epileptic abnormalities. However, time to time, if we use too many drugs, if we use those drugs not appropriately, we may even worsen the developmental outcome because the side effects for some medications are heavy, and we need to protect our patients. So using many medications together, I mean, maybe 2, 3 medications together is fine but very carefully. We accept polytherapy, as I mentioned, because those patients, they do have uncontrolled seizures. But as mentioned here, time lived and regularly reviewed. We don't want to have effects which are against the development of our patients. And so trying to use antiseizure medications with different mechanism of actions with innovative mechanism of action and with the less possible side effects. I give you here a quick example of a condition in which we do have an increase of epileptic abnormalities during sleep, which is called developmental endopleptic and catalopaty with spike in wave activation during sleep. What the spike in wave activation during sleep, which was previously called thesis electrical stages of epileptic. What does in the brain of our patient, cognitive disturbances and you have language regression or regression of commissions. ADHD irritability, it's in some patients, they do present with autistic-spectrum disorder. And then what we can do. So we have to look at the modifiers. We have to look at how to improve the outcome of those patients. And you see it, the prognosis definitely is related to the etiology, but a delayed treatment or an effective treatment it will give a poor outcome in terms of cognition. So therefore, the intervention should be rapid, should be with proper medication. What are the best medications for these conditions. With this review, we look at that different results of studies. And for this DEE with spike and wave activation, the first-line treatment is corticosteroids and benzodiazepine. I mean it's the same group. Bringing corticosteroids a little bit earlier than giving the benzos, but the great majority of those patients, they are on benzos. And nowadays, what we use is Clobazam. But those medications can be effective on the SWI is the Spike and Wave index. But still, we have limited cognitive effects but -- and also a very relevant risk is the tolerance. So patients, they starts to not respond anymore to benzos and steroids after a while. And then there are the possibility of utilizing a gentive treatment with anti-tissue medication depending upon the number of seizures, avoiding polypharmacy when possible. And the last point is that some of those patients, they can be treated with surgery, but very, very few of them. So really, we have few options for those patients. Goal number two, morbidity management. And this is again in the list of some DEEs due to genetic mutations. And you can see here that the top priorities for families are the expressive communication, the blue bar, the gross motor function, the orange one. And at the end, you have the receptive communication behavior and other issues. So -- but you can see here that in several of those DEEs, you need to have similar issues for observations. We do have some amend needs for those patients, for patients with developmental epileptic encephalopathies. And this is the job that we're trying to do is trying to fulfill these needs to give hence. So firstly, we need to have much better biomarkers or progression of the disease. What I mean is that some of those patients, they may worsen over time if we're not able to control their epilepsy and their EEG epileptic abnormalities. And this is through the evaluation of the complexity of EEG, CSF markers and so on. We need to have better predictors of who are the responders to some even medications. So -- and this is the job that we're doing to using the genotype phenotype correlation and the deep phenotyping for those patients. Inclusion on non-seizure hand points in clinical trials. Again, this is another relevant point. And equity of an axis, so there is a quite global disparaties in the access and targeted therapies around the world. And then last but not least, of course, the transition from pediatric to adult medicine. So take home message is that seizure control is necessary in developmental and epileptic encephalopathy, but not really sufficient. We need to look behind seizures. We need to look at multi morbidities as far as they do drive the lifelong disability burden. We're now in the age of trying to have precision medicines which is shifting the care from seizures to non-seizure outcome, but also to treat the nonseizure count, to evaluate the nonseizure outcome, we need to develop good measurement tools. And depend definitely evolve with the child, evolves while the child is growing up. And so this is a moving target. The success is a moving target, depending upon the age of the patients. And this closes my talk, and I thank you very much for your kind attention.

Good morning, good afternoon. My name is Karin Sandager Nielsen. I'm the Chief Science Officer of Saniona, and it's a great pleasure for me to walk you through the bullet of action and the preclinical data we have generated on 2668. Next slide, please. Now the GABAA receptor is the molecular target for SAN2668. The GABAA receptor is a ligand-gated ion channel that is activated by GABAA. And GABAA is the main inhibitor transmitter in the brain. And when GABAA binds to the receptor that opens up the channel and that allows chloride ions to flow in. That hyper polarizes the neuron and results in inhibition of neuronal activity. And that's believed to be the reason why drugs that potentiate the effects of GABAA such as the benzodiazepines and our own 2668 so robustly aborts the diseases. Now 2668 bites at the site where the benzodiazepines also bites. And this site is distant from where GABAA binds and that allows for positive allosteric modulation of the inhibitory action of GABAA without having any intrinsic activity, and this is a concept of a PAM, a positive allosteric modulator. The channel consists of 5 subunits that's normally composed of 2 alpha subunits, which can be 1 of either 1 and 2 and 3 to 5, 2 beta subunits and 1 GABAA subunit. And it's the identity of the Alpha subunit, which is either alpha 123 and 5 that determines the function of each receptor. Next slide. Now more than 30 years of scientific discovery using mice that have been equipped with genetic mutations, different benefit subunits have mapped out the function of each scale receptor subtype. And benzodiazepines nonselectively potentiate the effect of GABAA at receptors containing either for 1, 2, 3 and 5 subtypes. And Benzodiazepines are really, really effective medicines in general and in particular, antiepileptics. The nonselective action leads to side effects, like sedation, cognitive decline, falls in particular in elderly and addiction. And we know that all these adverse effects is primarily driven by 2 alpha-1 modulation, while most of the effects are mediated through GABAA alpha-2 and alpha-3 modulation. So subtype selectivity is very, very critical in order to obtain or maintain Benzodiazepines like seizure control while avoiding the Benzodiazepines-like limitations. Next slide, please. And the differentiator for oncology of 2668 is exactly designed to preserve the Benzodiazepines class efficacy without the Benzodiazepines class adverse effects. And the schematic you see on this slide outlines the relative functional activity of 2668 on the separate GABAA receptors. Now the strongest modulation is on alpha 3 containing receptors, targeting the thetomocotic circuits that are implicated in spike wave pathology in DEEs. Followed by robust modulation for potent control of convulsive seizures, both generalized and focused seizures. And then we have introduced a moderate or you can call it a balance alpha 1 modulation and it's intended to be high enough to preserve the Benzodiazepines class and sees efficacy, but low enough to minimize the limitations. So with this profile, we anticipate the 2668 is able to maintain the strong seizure control while avoiding the limitations of the Benzodiazepines. And I'll show you the preclinical data we have generated to demonstrate this in the next few slides. Next slide, please. So this slide demonstrates in mice that 2668 results in improved seizure control versus a Benzodiazepines, and here, we've chosen Clobazam, as Nicola alluded to, it's actually used in pediatric epilepsy and is likely due to achievement of higher receptor cumency of 2668. Now the animal model we have used here is the PTC special tests where higher numbers on the Y-axis corresponds to increased seizure threshold and accordingly, an increased seizure prevention. And we've selected a dose of 2668 targets approximately 30% receptor community, assuming that we'll be able to dose up to that and beyond in humans. And we have compared that to a human equivalent dose of Clobazam that results in approximately 40% receptor occupancy. And as you can readily see here on broth, the seizure protection by 2668 is increased versus that of Clobazam, and that's slightly due to the achievement of higher receptor occupancy by 2668. Next slide. Now spike wave discharges are apparent electrical activity in the brain that arises from pathological oscillations in part of the brain that is called the Cogeco telesystem. And there's a lot of converting evidence that links GABAA and the 3 containing receptor dysfunction to the generation of these spike wave discharges. GABAA alpha 3 contained receptors are the dominant GABAA receptor here in this part of the brain and also Benzodiazepines such as clonazepam that is active against absences suppresses back wave discharges. And this suppressant is actually absent in alpha 3-point mutated mice that are rendered insensitive for Benzodiazepines. And finally, we have shown with our own sensiML, it's now called ACP-711 as it was the molecule that was up licensed to Acadia. ACP-711 is a subtype selective GABAA -- and that markedly suppresses spike wave discharges in the growth model cost called the gas reads, finally confirming the alpha 3 mode of action pharmacologically. And as I will show you in the next slide, to 2668, which demonstrates a very high level of alpha 3 modulation also strongly suppresses spike wave discharges. Next slide, please. So this is the slide that depicts the very potent efficacy of 2668 against the generalized spike wave discharges. And they can be studied in gas rats, which is an inbred rat strain that presents with numerous spontaneous generalized spike wave discharges. And on the left-hand side is actually an example of such spike wave discharges taken from the study from one of the rats that are enrolled in the study. And on your right-hand side of the slide, that shows the effect of 2668 on the spike wave discharges. The Y-axis depicts the cumulative duration of spike wave discharges while the X axis represents the time course after dosing. And as you can see by the black line, which is gas rats that has been dosed with vacant right after a baseline session, they show a very prolonged time spent in spike wave discharges. In contrast, the yellow lines which represents increasing doses of 2668, you can see they demonstrate a very potent and robust repression of spike waves with a minimal cases dose of 0.03 mg per kg and the highest dose of 0.1 mg per kg fully suppressing despite wave discharges. So we are actually get a full normalization of this apparent electrical activity by the highest dose of 2668. If you go to the next slide. So we've also tested a defect of 2668 on another seizure type, namely focal seizures, which arises in one part of the brain and can generalize to the entire brain. Now the bench chronic model for focal seizures in amygdala model, which replicates progressive epileptogenesis and on disease propagation up to the cortex. And it's offers -- it's known to our very strong predictive for clinical anti-seizure efficacy. And the seizures in this model are measured by a recording of the after discharges in seconds, and you see that on your left-hand side, and after discharges are abnormally prolonged electrical activity in the brain caused by the kindling. And it's also assessed by the observal severity done by visual observations behavioral score, you see that on your right-hand side. Now the white bars on this clearly represents measurements during baseline sessions where the reps are not treated with 2668 while the blue bars represents measurements after the reds have been dosed with increasing doses of 2668 or diazepam, that's the direct blue bar. So I think what is really evident here is the 2668 results in a very potent suppression present a focal seizures monitored after discharges on your left-hand side, and this marked suppression is also evidenced by a comparable reduction of the seizure severity seen on your right-hand side. And in both instances, the suppression is comparable to that of the nonselective Benzodiazepine, the comparator in this study, which is diazepam. Next slide. Now some of the DEs are genetically defined, and road models of many of those are difficult to get hold of and not necessarily developed. So we have turned to Cephagenix, which constitute a validated and very rapid way of assessing in vivo activity on genetically defined disease models. And this slide shows a snapshot of some of the data we have generated on defect of 2668 in one of the monogenetic DEEs called SNAP1B. And the data shows the strong effects of 2668 on seizure events on your left-hand side, aggressive behaviors in the middle and also on cognitive impairments caused by introduction of the SYNGAP1B mutations in sprains. And in each of the figures, the gray bar represents a mutated separatist without any treatment, and the black bar is the active comparator Clobazam, while the blue bars represents increase in concentration of 2668. And I think the data quite clearly shows the 2668 fully suppresses the number of seizure events on the left-hand side and also markedly reduces aggressive behaviors in the mid figure. And in both instances, the effect size are comparable to or may even be improved as back to Clobazam. And what I think is really interesting is when you look at the right-hand figure, that shows the 2668 also seems to rescue the cognitive deficits that is induced by this mutation. And in this instance, the comparator of Clobazam was non-efficacious, suggesting a potential benefit of 2668 over Clobazam. So in conclusion, based on this slide, 2668 not only demonstrated efficacy against seizures in this model of monogenetic epilepsy but the efficacy seems to extend beyond diseases supporting a potential benefit in behavioral disorders in DEEs where there is a great unmet need. Next slide, please. So this slide is just to show you that the differential profile of 2668 with this balanced for one modulation does not lead to the adverse effects such as motoric and stability of sedation in pharmacologically relevant dose levels in rodents as showed by the rotarod and locomotor activity. The left-hand side of the figure depicts a lag of effect of 2668 on motor performance evaluated by the accelerating rotarod while the right-hand side of the figure shows that increase in doses of 2668 does not affect locomotor activity of rodents, and that's a test that is very sensitive for sensitive effects. Next slide, please? So the key take home messages here is that 2668 shows quite strong preclinical and efficacy and good tolerability and that supports that it has a differentiated profile. And we've demonstrated superior seizure control and high receptor occupancy versus benzodiazepine versus clobazam. And also importantly, it shows broad efficacy across a number of chronic epilepsy models that displace different seizure types, spike wave discharges and progress. And benefit seems to extend to the behavioral comorbidities as well as evidenced by risk you of aggressive behavior and also amelioration of coins deficits. And all this is evident without any motor impairment or sensitive effects at pharmacological at irrelevant dose levels. So we do believe that those data supports the potential for 2668 as a safe effective treatment for pediatric DEEs that extends with potential extension beyond the seizure control. And with that, I will hand over the floor to Pierandrea.

Yes. Thank you, Karin, and good morning, good afternoon to everybody. Pierandrea Muglia, the Chief Medical Officer at Saniona. So Dr. Specchio outlined on the significant unmet need of these severe conditions. Karin has presented this robust encouraging efficacy profile of the compound. My role is really to show how we plan to create all this into these findings into a human proof of concept in patients. We have defined a developmental strategy that thanks to validate biomarker is this really generate -- can generate air objective evidence of activity and allow rapid derisking of the program. The strategy is importantly, it's also been informed by my and other clinical team members and regulatory team members experienced in DEE, a recent successful story that we have been all part of. So that allow us to kind of anticipate some of the hurdles and put in place measures to minimize the risk of the program. And more importantly, I would think is really to focus on what is important for patients and family. And if we consider -- you heard the description of these conditions and from Dr. Specchio. This is like a multifactorial complex disorder. And our data indicates this robust effect in seizure, but also on nonseizure endpoints. And that's why -- and in addition to the nonseizure endpoints, we see this on this pathological EEG electrical activity. So altogether, the efficacy can translate in a kind of a broad disease control. This is why we say that we have a potential disease control that could go beyond seizure. Clearly, seizure is the primary thought for patient and for their development. And this is like the efficacy side, on the tolerability on the left side, you see that, as you saw and illustrated by Karin, the design on the pharmacology and the data support a reduced sedative effect and also preserve motor function that is quite compromised in this subject and with the current treatment, particularly benzodiazepine. We further compromise them the function. And for example, induced hypotonia and very severely affected the hydric kids. And the other big important differentiating factors that we put in a lot of attention is the fact that all benzodiazepine and all other antiseizure medications, they have profound CNS effect and particularly a cognitive impairment in of the kids. So we attract less that with our compounds and to a neutral effect on cognition. So all this should translate into a potential impact -- clinical impact as you see on the right side. So we will have good chronic news with the reduced tolerability and reduced tolerance means that we expect to maintain the effect because of the pharmacology and the data and improve the development of these kids, they are compromised by seizure, EEG activity and all these behavioral issues. In the longer term, as you heard from Dr. Specchio, these kids are on polytherapy. That's kind of more a rule than an exception. They take 2, 3 antiseizure medication. And if you have a new agent that has robust seizure control, you have the option to reduce this bargain that is given by antiseizure medication, and therefore, improve the long-term outcome. So that's kind of the ultimate ambition and the opportunity we see ahead of us with the clinical profile. And if you look in the next -- on this slide is really the key differentiating feature that we expect based on the pharmacology data. And when I say the pharmacology, this is a selective data pharmacology that parents and teams are working for a couple of decades. So we really understand the nuances on the selectivity and what to expect by all this selectivity. And this is likely resulting differentiating profile we expect versus benzodiazepine but also versus a most of the antiseizure medication. They all have a sedative effect and impaired cognition and have mostly impairment and for sure, tolerance means that the efficacy goes away with time. So 2668 is expected to have an improvement on these factors. And as you see in this slide, I have delineated here at a high level, our development strategy. And this has been designed -- of course, we will have to measure PK safety in health frontiers as the first aim. But thanks to this biomarker that we can use, and they are a validated biomarker for target engagement and pharmacodynamic readouts. We have defined this product that can objectively determine if this compound is truly differentiated as we publicized based on the preclinical data. And so that we will have defined different clinical studies a component that will address key question that you see listed there. We will have a biomarker for target engagement. So are we engaging the target, is it PET and selective GABAA selected tracer, we can say, are we engaging the target and what doses and what those limits we should impose based on this readout. The biomarkers that I'm going to illustrate in a second will tell us, it isn't truly differentiated versus benzodiazepine. And the other key component to the program is the ability to utilize an early inpatient study, the relies very well-established paradigm that I wouldn't be illustrating in more details, but basically, this is being used with multiple antiseizure medication and development. If you're exposed to flickering light, a susceptible epileptic individual, you will see an EEG readout with our compound, we can suppress that effect or test if the compound suppressed that effect at what doses. So we can end by early on doses that are expected to be in the critical range. And eventually, we will do a phase out study in pediatric to efficacy. This slide is a fundamental one to understand how sophisticated is going to be our Phase I program. Well, first of all, we're going to be -- we are partnering with the CSBR Phase 1 specialized unit in the Netherlands has a lot of experience in testing this pharmacology as defined as a comprehensive battery of tests that you see on the left side that they are all computerized and use and implement it regularly. And so what it allows us to do is to define the effect of the drug on motor function, on EEG and eventually on tolerability issue and cognition. And on the right side, for illustrative purpose, I was showing you what type of output we can -- we will generate. You see the red line is the typical benzodiazepine test in all these measures, and you see where it sits on this radar clot. The green dash line is what we expect for 2668 and how it differs from historical benzodiazepine testing in the same paradigm. So this early readouts in Phase I will really allow us the differentiated profile of the compound and its differentiating potential. And now if the other biomarker that, as I said, we will be able to utilize is this PET tracer that will allow us to test different exposure of the drug and what type of target engagement. This will be very important to define the dose strategy for the -- during Phase I, but more importantly, to pick up the best and optimal dose to progress into Phase II in patients. And this information will be matched with this paradigm that we'll be using during the Phase I right after the single ascending dose in a single dose setting as traditionally done, we will expose susceptible subject to this intermittent like stimulation that will generate these EE trace that you see here indicated. The paradigm is developed so that you can test the condition with our drug and then the effect of our drug is suppressing this EEG activity. This is like as I said, is predictive of antiseizure efficacy, but also predictive of which dose are expected to give antiseizure efficacy. So this early readout combined with the patent of other data will allow us to rapidly progress in an efficient way to the study in patients. This pediatric study that we have delineated also based on our experience, as previously said, we will first do an open-label study in few subjects to understand the equivalent dose in pediatric patients. They will be modeled upfront, and then that study will tell us if the modeling will be correct. And that will allow us to move into the randomized placebo-controlled study, second phase of the study that we will measure seizure effect on EEG and an effect on seizure endpoint. So now what is the size of the problem? We have consensus figures that are coming from the field that everybody accepted and adopt based on a number of epidemiological study and treatment phase and we have quite precise numbers. And so with that, we define our potential revenue. And I think everybody has those numbers and they have the validity of whatever is forecast as a validity. But what I think is most important to the value of the program that we illustrate recent transaction in this space because they clearly illustrate the pharma company that acquired this asset -- single asset for single disorder, single DEE or group of DEE revision acquisition, the value that they have been given. So those are all multibillion transactions for compounds that have some differentiated features that can manage seizure in these difficult conditions. So that's by itself on the potential value of such programs. And so we are really enthusiastic about embarking on this program. And we are really planning to get in human later this year and with the submission and potentially dosing first human subject early next year. So in essence, what we have for '26. So we have a robust preclinical data, not only in seizure, on nonseizure endpoints. They are critical for patients and families as you heard, irritability, aggressivity they need to be managed, and there is a potential here for some of the preclinical data. We have then defined this developmental strategy that based on established biomarker, we'll do early derisking, early objective readout and differentiation. And you see here the key listed value inflection point, we will see in the program, the early programs that will be, as I said, starting by the next year. So with that, I complete my part and over to Thomas for his wrap up of the session.

Thank you, Pierandrea, and before we open up for questions, I would like to briefly summarize the key messages from this webinar. So first, development in epileptic encephalopathies remains among the areas of highest unmet medical need in neurology. And despite the availability of treatment options, many patients continue to experience severe seizures, development impairment, behavior issues and a substantial burden on both patients and their families. And second, while benzodiazepine remain among the most effective antiseizure medications available today, long-term use is limited by side effects such as sedation, cognitive impairment, motion impairment. And third, SAN2668 as is specifically designed to maintain the powerful antiseizure associated with benzodiazepine, while we're producing the side effects that limit their chronic use. The clinical data presented to date demonstrate robust seizure control across multiple markets, activity against by wave discharges with potential to increase cognition, efficacy in behavioral endpoints and a differentiated tolerability profile. Finally, we have aligned clinical development strategy designed to rapidly generate human data, through the use of translational biomarkers, pit emitting and an early proof of mega started in photosynthesis epilepsy. Before we advance into patients with DEEs, SAN2668 represents this exciting opportunity to address a significant unmet medical and we look forward to advance the program into clinical development around year-end this year. With that, we will be happy to take your questions. Thank you. So we open up for Q&A now.

Yes, Thomas. Just pull on some questions that have come in through the audience here. First question that's come in. Can you talk about why SAN2668 is ultimately the right focus for Saniona's next chapter?

Yes, I would take that one. So SAN2668 is an excellent fit with our strategy. It combines in our view, a relative attractive risk profile with significant commercial potential in an area with high unmet medical need. So the biology is well understood in this case. And we believe SAN2668 is differentiated both from benzodiazepine and previous subtype selective GABAA moderators. And the goal here is to retain the benzodiazepine plus efficacy while we reduce the side effects that limit their chronic use. And the clinical data support this. Now focus on severe pediatric epilepsies, which represents a substantial commercial opportunity in an area where we potentially have the opportunity to take the program significantly further ourselves. And therefore, we believe that this program that could fit very well into our strategy of advancing selected assets through late-stage development and potential consultation, allowing us to retain substantial more value than just a introducing a partnering model. So this is why we are so happy with this program.

Awesome. The next question from the audience is, can you talk about what is the most promising aspects of 2668 in respect to the DEE opportunity?

Would I mean to take this one, guys?

If you feel you heard enough.

Okay. yes. What heard? I mean, what I've explained to you guys about DEEs, this drug seems addressing net for dysfunction and developmental burden also behind the seizure reduction. What is really exciting for us as a clinician is that targeting the spike wave pathology has been very just showed a little bit. It's something that is very interesting in terms of clinical output as far as what I -- what we do actually know and we are very sure about this is that many DEEs are characterized by persistent epileptic form activity that contribute definitely to cognitive and behavioral impairment. And therefore, if we're able to complete the -- to have a complete suppression of the spike and wave discharges through the mechanism of action via the alpha 3 subunits. This is going to improve definitely several aspects, including reducing the sleep-related platform activities because these receptors are very highly expressed in the thalamus and the thalamus is relevant for the sleep, and it's relevant for the spreading the seizures from one hemisphere to the other. Some seizures are really maybe -- I mean the platform activities, some seizures really mediated by thalamus. So it's -- this is a really potential impact, not only on seizures, but there is a potential impact on behavioral communications very, very high.

The next question is again -- is can you talk about what does 2668 selectivity profile enable that earlier alpha 2 or alpha 3 selective positive allosteric modulators couldn't achieve?

Yes. I think I should take that one. Now as I said in the presentation, this entire field and this program rests on the shoulders of more than 30 years of scientific discovery. And when it was discovered, back then that the majority of the adverse effects of the benzodiazepine was mediated by too high alpha 1 modulation. Most of the companies, including the one that I was working at, at the moment, no such trial to dial out alpha 1 activity entirely. And that resulted in improved tolerability, but it might have been at the expense of efficacy. So what differentiates 2668 is that, apart from the fact that we have pretty high modulation on the beneficial 2 and 3 receptors, we have introduced a balanced or calibrated or whatever you would like to call it, alpha 1 modulation. And that's explicitly designed to preserve the benzodiazepine like efficacy and in the hope that it's low enough not to cause adverse effects. And I think it's readily evident in our animal models that this balanced alpha 1 modulation contributes to a stronger seizure protection. So we might have hit the right balance that is, of course, to be seen in the clinic. But at least we see that the additional alpha 1 activity shows increased seizure prevention. And we don't see the benzodiazepine effect would like adverse effects, at least in our rodent models. So I think that's the critical point, the critical differentiator for 2668 versus the other 2, 3 PAMs.

Awesome. Thank you. And then the next question is, can you talk about which preclinical beta are the most important in supporting 2668's potential in pediatric DEEs and EES?

Should I go for that one as well? Yes, I can do that. As Dr. Specchio says seizure prevention is of essence. That's the most important thing. So I think it's quite compelling, the data we have demonstrated that 2668, very robustly, very potently suppresses fully suppresses seizures in a range of not only the acute seizure models, but also in the chronic epilepsy models that present different types of seizures. So that's the first thing. I think the preclinical data are quite impressive. The second thing is that there's a great unmet need on the behavioral disturbances in the DEEs and the data we have generated so far actually does suggest that 2668 may have a benefit beyond seizure protection in that it could ameliorate or risk some of the behavioral disturbances that is seen such as aggressive behavior, cognitive impairments in particular. So from my side of the table, I think that's the most compelling data. Thank you.

A couple of additional questions here that have come in. But can you talk about the significance of using the quantitative EEG biomarkers in the planned Phase I state.

Yes, I can take that one. Thank you because that's a slide for brevity, I couldn't expand on this very critical aspect of our Phase I program. So we have, well, we in the field has quite a bit of experience on what we call pharma called EEG. That means like understanding what the specific pharmacology does on the EEG trace. We recently completed the Phase I of alpha 3 selected compound that we partner out to Acadia, we really understand what to expect. And this is going to be very helpful biomarker to respond to one critical question, question on the program is is 2668 induced has a sedative effect. And if it does, at what doses. So of course, when you do that as a question, you're going to be asking the patient actually this is going to a -- you look and feel a little bit sticky and you see and you observe it. But that's not very objective. The EEG can objectively tell you, if the sedative effect is relevant. If you use a benzodiazepine, you have specific waves in the EEG that they are called delta waves that increase because you're sleeping. So basically, just to give you one example, we will be looking for the lack of an increase in delta waves, there will be an objective way to demonstrate that the compound is not associated with a sedative effect or is a typical very reduced sedative effect. So that's the activity of the EEG of pharmacopeias we call it during our Phase I program. And just to say that we will do that during the synthase or multiple doses. So multiple dose level we'll have all that readout. So we will compare effect dose and exposure.

And then kind of a follow-up here, but can you talk about the added value of the photosensitivity study as well?

Yes. This is like -- I would say, in the CNS, that's what I've been doing is a unique opportunity that you can do a test in patients early on. And the testing in patient as I described, is something that has been extensively used and validated. So there's a lot of -- it's a great predictive value. You see this effect on the EEG and suppression of this EEG activity, and then you will expect and you will see antiseizure effect. So basically, it's a very early readout of efficacy in patients. And so that will be tremendously important to correlate that exposure where you see efficacy with everything else we do in the program.

I think that concludes the Q&A, and it looks like we're at the top of the hour. So I'll turn it back to Thomas for any closing remarks.

Thank you. So yes, so speaking about -- a little bit about the financing then. So today, we -- based on our current plans, we have funding into the second half of '28, while advancing all 3 internal price programs through Phase I development and initiating Phase II study for at least 2 of them. For SAN2668, this includes the planned Phase I study, the PET study and biomarker and the anticipated photosensitivity study, which could provide the early evidence of antiseizure activity in humans as Pierandrea just mentioned. A larger Phase II study in DEEs would require additional funding. And this could come through partnering, financing, all our regularization of our sources or a combination of those 3. Our focus today is to generate clinical data that will maximize the value of the program and expand our strategic option in this context. Thank you.