Welcome to Athira Pharma's virtual R&D event, Enhancing the HGF/Met Pathway to Fight Neurodegenerative Diseases. This webcast is being recorded today, December 7, 2022. I would like to turn the conference call over to Julie Rathbun, Head of Investor and Public Relations at Athira Pharma. Thank you, operator. Before we begin, I'd like to remind you that during this webcast, management will make forward-looking statements, including statements about Athira's platform technology and potential therapies, future development plans, clinical and regulatory objectives and the timing thereof, expectations regarding the potential efficacy and commercial potential of Athira's product candidates, the anticipated reporting of data, the potential learnings from the ACT-AD trial, and LIFT-AD unblinded interim efficacy and futility analysis, and their ability to inform and improve future clinical development plans, and Athira's ability to advance its product candidates into later stages of development. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described here and from time to time in our SEC filings. Our results may differ materials from these projected on today's call. We undertake no obligation to update statements regarding the future or to confirm those statements in relation to actual results unless required by law. Today's agenda will include opening remarks by Dr. Mark Litton, Athira's President and Chief Executive Officer, followed by a review of fosgonimeton's preclinical data by Dr. Kevin Church, Athira's Executive Vice President of Research. An overview of the compelling clinical data by Dr. Hans Moebius, Athira's Chief Medical Officer. Dr. Church will provide a review of the preclinical data in ALS. Rachel Lenington, Athira's Chief Operating Officer, will discuss the Alzheimer's disease landscape. Dr. Litton will rejoin with closing remarks. Following these prepared remarks, we'll open the call to questions. Please note that for today's event, we will be accepting all questions through the Q&A box. This box is located at the bottom of the screen. Please feel free to submit any questions you may have during the presentation. I'll now turn the webcast over to Dr. Mark Litton. Thanks, Julie, and thank you all for joining us today for what we will believe will be an engaging and insightful review of the potential and promise of enhancing the HGF/Met pathway to fight neurodegenerative diseases, which aligns with and supports our mission here at Athira. As we wind down the year and a look ahead to 2023, we took stock of the bolus of preclinical and clinical data published and presented throughout 2022. What we saw was a growing body of evidence that was consistent and correlative across multiple animal models in a broad range of neurodegenerative diseases, including Alzheimer's, Parkinson's, and ALS. In all cases, the data suggest that our small molecule product candidates are neuroprotective, neurotrophic, pro-cognitive, and potentially disease modifying. The totality of these data further strengthens our confidence in fosgonimeton, or Fosgo. For a favorable outcome from our phase 2/3 LIFT-AD study in Alzheimer's disease, but for the broader therapeutic potential of our small molecule product candidates across a variety of neurodegenerative diseases. There has been more than 30 years of research highlighting this naturally occurring repair mechanism known as HGF/Met. It has not been an easily druggable target. At Athira, we have spent considerable effort to discover a platform of small molecules designed with the appropriate therapeutic and pharmacokinetic properties to enhance this system. What gets us very excited is that through all of our research, we are beginning to elucidate the pathways and mechanisms for how our novel platform protects and repairs neural networks. We all know, neurodegenerative diseases are multifactorial. It is one of the reasons why these diseases have been so challenging to treat. To date, drug developers have been deploying approaches that address only a single factor of the cascade of pathologies that lead to neurodegeneration. As you will see from the review of our data, we are taking a multimodal approach that is impacting inflammation, protein pathology, synaptic connections, and more. Importantly, we are seeing the clinical results of this approach in improved biomarkers, cognition, function, and potentially disease modification. As I just noted, we believe our modulators are multimodal and are able to both protect and repair, which supports their potential to be disease modifying. Our first-in-class small molecules enhance the HGF/Met system, are able to cross the blood-brain barrier, and mechanistically provide a series of effects that support its therapeutic promise to reduce inflammation, promote regeneration, provide neuroprotection, and ultimately to slow disease progression. With that review of the HGF/Met system, let me now turn the call over to our Executive Vice President of Research, Dr. Kevin Church. For a more detailed discussion of the growing body of preclinical data that provide clear and consistent evidence of the potential of fosgonimeton to be beneficial in a number of neurodegenerative diseases. Kevin? Thank you, Mark. Happy to be here today to talk about the HGF/Met pathway and discuss some of the preclinical results from our work with HGF/Met positive modulators, including fosgonimeton or fosgo for short. First, I want to expand on what Mark was talking about regarding the HGF/Met system. HGF/Met is a critical neurotrophic and neuroprotective pathway, which has been well supported with over 30 years of literature describing its activity in the nervous system. This is 1 example of a figure from a comprehensive review by Dasari et al. that came out last year, which describes the neurotrophic and neuroprotective properties of HGF/Met, including protection of neurons from a variety of insults. This figure illustrates the neuroprotective pathways of HGF/Met that are activated downstream, including the activation of the AKT and ERK pathways, which play critical roles in protecting neurons from damage and death, including from oxidative stress, excitotoxicity, and apoptosis. As we've discussed before, at Athira, we have developed a series of small molecules that interact with HGF/Met to promote its activation and enhance signaling. Here we are showing signaling data from studies with our lead asset, fosgo, and for in vitro studies we use the active metabolite called fosgo-AM. When we treat cells with fosgo-AM, we see a significant enhancement in the levels of phosphorylated Met or activated Met, demonstrating our compounds work through the HGF/Met system. As I pointed out before, there are two key pathways, including ERK and AKT, that mediate neurotrophic and neuroprotective pathways downstream of Met. We see treatment with fosgo-AM here significantly enhances ERK and AKT activation. Also, I'd like to point out that AKT activation has been well described to block the activity of an enzyme called GSK-3β, which is a key enzyme responsible for hyperphosphorylation of tau, alpha-synuclein, and other pathological proteins in several neurodegenerative diseases like Alzheimer's and Parkinson's. To build upon what Mark was talking about regarding the HGF/Met system is that it has multimodal effects we believe are well-positioned to address the complex pathology in neurodegenerative diseases. We know that our small molecules can activate the system, and that leads to significant enhancement of downstream pathways that promote anti-inflammatory effects. They can help address protein pathology and promote neuroprotective and neurotrophic effects. All of these things together lead to improvement in function, whether it's motor function or cognition. We have a growing body of evidence to support the therapeutic potential of our compounds, which is highlighted in these presentations and publications listed here on the right. I'll walk through the data included in these presentations that support each of these aspects outlined here. We know from the literature that activation of HGF/Met can induce anti-inflammatory effects, and likewise, we've demonstrated these effects with our compounds. This is data from an in vitro study with glial-like immune cells, they're called THP-1, treated with LPS or lipopolysaccharide, which triggers production of inflammatory cytokines. We see a large increase in expression of IL-1β, which is an important cytokine for glial activation, and IL-6 and TNF-α, which are strong pro-inflammatory cytokines in the LPS group compared to normal controls. However, if we treat with LPS and fosgo-AM, we see a significant reduction in the secretion of these pro-inflammatory cytokines, indicating anti-inflammatory effects. We know activation of the HGF/Met system promotes neuroprotective pathways that may impact protein pathology. To investigate that, we utilized several in vitro models, and here we looked at cultures of cortical neurons treated with amyloid beta, which is toxic. It promotes tau hyperphosphorylation and aggregation and leads to neuronal death. In these images, we have the neuronal marker MAP2 in green, and the red is AT-100, labeling hyperphosphorylated tau. On the left, you're seeing a healthy control image with several neurons in green and little phosphorylated tau or p-Tau staining. In the middle, these are cultures treated with amyloid beta. You see a significant reduction in the number of neurons and substantial overlap of the p-Tau signal within the remaining neurons. On the right, these have been treated with fosgo-AM and amyloid beta. We see a significant protection from amyloid beta-induced degeneration. Results are quantified in the graphs on the right, where we see that fosgo-AM significantly protected these cortical neurons from amyloid beta-induced death. Contributing to that neuroprotection is this reduction in tau phosphorylation. We also looked at the effects of fosgo in cultures of dopaminergic neurons, which are relevant to Parkinson's. Here we treated dopaminergic neurons with rotenone, which is a neurotoxic pesticide that can cause Parkinsonism in humans. In these images, dopaminergic neurons are identified by tyrosine hydroxylase or TH in green, which is an enzyme important for dopamine production. The red color depicts immunostaining for alpha-synuclein, a neuronal protein whose aggregation is linked to Parkinson's disease. In the control, you see healthy dopaminergic neurons with minimal overlap or immunostaining for TH and alpha-synuclein. In the middle, these are treated with rotenone and vehicle. There's a substantial reduction in the number of dopaminergic neurons. Additionally, in the remaining neurons, substantial overlap of the immunostaining for TH and alpha-synuclein is observed in yellow. However, in cultures treated with rotenone and fosgo-AM, we see increased numbers of neurons, indicating treatment is preventing the dopaminergic neuron death. There is a reduction in the overlap of immunostaining for TH and alpha-synuclein, suggesting a decrease in alpha-synuclein aggregation in each cell. These results are quantified on the right, where we see fosgo-AM treatment significantly reduced alpha-synuclein pathology and protected neurons from death. We also see neurotrophic outcomes from activating this system, including synaptogenesis and neurite outgrowth. For synaptogenesis, we cultured hippocampal neurons and treated with either vehicle or fosgo-AM for several days and then immunostained for the synaptic marker synaptobrevin-2. Synaptic counts were collected and normalized to cell number. We observed that when combined with a subthreshold level of HGF, fosgo-AM significantly enhanced synaptic count compared to control, indicative of synaptogenesis. On the right, this is an example of a neurite outgrowth assay that we performed. The image on the left is from the control culture, on the right is a culture treated with fosgo-AM. Here we see a promotion of neurite outgrowth with fosgo-AM, that's quantified in the graph below, where we see a significant enhancement of neurite length per cell compared to controls. These results demonstrate stimulation of neurotrophic processes that are central to neuronal repair, supporting the potential of fosgo to promote synaptic connectivity and regeneration. All of these aspects, whether it's anti-inflammatory, reducing protein pathology, promoting neuroprotective and neurotrophic pathways, may ultimately result in improvement in function. We've been able to obtain evidence to support that in several models. One of them is the LPS-induced model of cognitive impairment. LPS, or lipopolysaccharide, induces a severe systemic inflammatory response that leads to neuroinflammation and can cause cognitive deficits. To assess the effects of Fosgo in this model, we used the T-maze. Normal mice have a natural drive to explore novelty in this T-maze, so they'll continue to alternate between each arm of the maze. Impaired mice, if they're exposed to LPS and have this severe neuroinflammatory state, they have poor working memory. They cannot remember which arm of the maze they just went into, so they won't alternate. The graph on the right is showing the level of spontaneous alternation for each group. Normal control mice have a high level of alternation. The LPS-treated animals have a significant reduction in their level of alternation. They basically cannot remember as well which arm of the maze they just went into. They're repeatedly going to the same arm. In the animals treated with fosgo and LPS, we see a reversal of that. fosgo significantly attenuated the cognitive deficits induced by LPS. That really indicated a couple things. One, this could be due to its anti-inflammatory effects, which I've talked about earlier. Two, it is indicative of pro-cognitive activity. A very different model that also demonstrates the in vivo activity of fosgo is the unilateral 6-OHDA rat model of Parkinson's. In this model, the animals receive a unilateral injection of 6-OHDA, which is a toxic form of dopamine, into the striatum. It kills the dopamine-producing cells in the striatum and substantia nigra, leading to significant motor impairment in these animals. Here we're looking at the forelimb grip strength, which is one of several behavioral assessments we use in this study. Rats in this model have consistently weaker grip strength because one half of their body is essentially compromised in terms of motor function. After surgery, sham control animals will initially have decreased grip strength, but that recovers over time since they did not receive 6-OHDA. That's the gray line. The red line is disease control. It has a fairly flat change or a low level of grip strength over time. Animals treated with fosgo here in the blue line were indistinguishable from the sham animals. They had significantly enhanced grip strength compared to disease control, indicative of recovery of motor function. We think it's likely due to the neuroprotective and repair properties of this system, and further studies are ongoing to elucidate the potential mechanisms in these models. In summary, we've been able to show through several lines of preclinical evidence that fosgo is able to promote protection and stimulate repair pathways. We believe this multimodal mechanism is well-positioned to address these multimodal diseases and has potential for disease modification. We've been able to demonstrate anti-inflammatory effects as shown in the LPS-induced model in vitro. We see reduction in protein pathology in vitro, including amyloid beta-induced tau phosphorylation and also with alpha-synuclein. We see protection of neurons from various insults. We see promotion of neurotrophic outcomes such as synaptogenesis and neurite outgrowth, which are important in repair. We believe all of these effects contribute to the improved function we've observed in several different models in vivo. Considering the mechanism of fosgo, I also want to mention that with regard to the potential interaction with fosgo and acetylcholinesterase inhibitors observed in the exploratory phase 2 ACT-AD study, we have since been able to replicate the mutual reduction of activity in certain preclinical model systems. Our leading hypothesis regarding this potential drug-to-drug interaction involves interference among shared intracellular signaling pathways, such as PKC and potentially SRC. We are currently testing this and other hypotheses to better characterize this potential interaction. With that, I'd like to turn it over to our CMO, Hans. Thank you, Kevin. I would now like to discuss how these preclinical findings translate into clinical data in our clinical development so far. We have made significant progress in further characterizing fosgo profile with the completion of the ACT-AD phase 2 study. Now, as you see here, we have always been focusing on the mild to moderate Alzheimer's disease population, and we are running all trials in a double-blind, placebo-controlled session. We have increased the observation period from 8 days, starting from phase 1B to 6 months in phase 2, and up to 18 months in addition in the open-label extension. We have multiplied the number of subjects observed to date. Also, in terms of background therapy, while our phase 1 did not allow concomitant medications, we were looking into both populations in the ACT-AD trial and found a potential interaction between fosgo and cholinergics, as mentioned just a moment ago by Kevin. Pharmacodynamic biomarker of neuroplasticity, namely P300 latency, was repeated as the primary outcome in ACT-AD. By not separating in the full population, it was complemented by various blood-based biomarkers, including the key hallmarks of Alzheimer's disease, Aβ and p-Tau. Of course, we did not measure cognition and function in phase one, but we did in phase two and continue to do so. Assessment of blood-based biomarkers that was not performed in phase one, but were collected in phase two and produced supportive data. Last but not least, we continue to see a favorable safety profile. With that, I'd like to pick up where Kevin kind of left with this mode of action, which is highly specific, yet multipronged. In the middle of the circle, you see the factors that can support the protection and repair of neuronal networks. How we can actually access that in the clinic is by blood-based biomarkers, which, for example, point to the status of neuroinflammation, like glial fibrillary acidic protein, GFAP, and YKL-40. I mentioned the protein pathology typical for Alzheimer's disease, Aβ42/Aβ40 ratio, p-tau181, and further neurofilament light chain for the current status of neurodegeneration. We were earlier talking about the neuroplasticity effect as assessed by P300 latency, and that importantly, we are now seeing ADAS-Cog 11 and ADCS-ADL functional data over 6 months double-blind from ACT-AD. I'd like to go now into a bit more details for each of these biomarkers around the circle. First, you see here the data supporting why we believe fosgo appears to improve neuroinflammation in our patients as well. You see on the left a nominal GFAP improvement and on the right YKL-40 improvement with a statistical trend. The magnitude of these decreases that we observe here below baseline for those on active treatment is encouraging in this continuously progressive neurodegenerative condition and supports the translation of the anti-inflammatory activity described by Kevin before. When we move to the Alzheimer's disease hallmarks, you see again a statistical trend for the Aβ42/Aβ40 ratio improvement and the descriptive improvement for p-tau181. These changes support the relevance of addressing this HGF/Met pathway for Alzheimer's disease progression and therefore support a disease-modifying potential of fosgonimeton. We were analyzing plasma samples for neurofilament light chain, which is an established objective marker of ongoing neurodegeneration. You see here that despite the limited numbers, there's a statistically significant difference favoring fosgo treatment. The data are concentration-controlled and not due to outliers. This decrease of neurofilament light chain actually below baseline levels is suggestive of repair in this continuously progressive condition and supports the potential for neuroprotective mechanism of fosgo. To put this effect into context, Madsen and colleagues have published earlier this year annual worsening of neurofilament light of 2.5 to 4.9 picogram per milliliter, depending on AD severity range. That was based on a sample of over 1,500 ADNI participants. A big public database, which speaks to this effect size of -6.49 picogram per milliliter after 6 months. When we now turn to the event-related potential biomarker P300 that we have presented earlier this year at AAIC, the latency improvement was not statistically significant, but congruently improving. We saw here a -28 millisecond reduction in latency in the population comparable to phase 1, hence without background cholinergics, which did not reach statistical significance in these limited numbers. A vast literature shows that P300 latency reduction goes hand in hand with cognitive improvement across many conditions. In terms of cognition, we saw a -3.3 points or 79% improvement on ADAS-Cog 11. You see below, again, those are not numbers that would allow to expect statistically significant differences. It is also important to mention that an improved function, as assessed by ADCS-ADL23 by +2.1 points descriptively, which corresponds to a 51% improvement over placebo in 6 months in the full study population. Again, I want to point out that to date, fosgo has shown a favorable safety and tolerability profile. Injection site reactions were the most frequent adverse event, which were generally mild in nature, reversible, and not reported as serious adverse event. Since LIFT-AD is utilizing a single primary composite endpoint, namely the Global Statistical Test, which is informed by ADAS-Cog 11 and ADL 23, you see here scatter plots from the full ACT-AD population with the change from baseline in the Global Statistical Test on the y-axis and change from baseline neurofilament light on the left and DSFV on the right respectively. Clinical and plasma biomarker improvements are significantly correlated despite the limited prior size, which supports the interpretation of our clinical results. Taking these insights together, we have amended the phase 2/3 LIFT-AD trial and defined a new target population without background medication. That led to further consecutive steps, which are outlined on the next slide. We reported the initial top line ACT-AD readout in June, and this was followed by additional analysis of ACT. In July, the Data and Safety Monitoring Board for LIFT-AD performed an unblinded adjudication of the safety data to date. This resulted in no adverse findings for both subjects on or off concomitant cholinergics. Additionally, we reported a first biomarker analysis of plasma neurofilament light at AAIC in August. We then conducted a blinded analysis of LIFT-AD and proactively amended LIFT-AD to exclude concomitant cholinergic medication in the future. That was followed by, in early October, by an independent unblinded interim analysis of LIFT-AD. Rather than fully unblinding the trial under the impression of the ACT-AD results, which we considered, we took a proven approach to maintain the integrity of LIFT and preserve the opportunity for it to play an important role in the potentially expedited development path for fosgo. There have been questions around this interim analysis. I'd like to go a little bit more into detail on the methodology. The objective of this approach was to set prospective criteria to avoid continuing a futile experiment and, if possible, to increase the probability of demonstrating a meaningful effect size of the primary outcome. The analysis itself was conducted by an unblinded independent data monitoring committee, which consisted of a neurologist and two biostatisticians, all accomplished experts in their fields. The method by Mehta and Pocock enables a sample size re-estimation based on actually observed interim data based on ADAS-Cog 11 and ADCS-ADL23 and their variants. Pre-specified constraints were protocoled in the interim statistical analysis plan, namely a sample size range with a maximum enrollment limit and a minimum target power. The formal efficacy analysis was then based on approximately 100 modified intent-to-treat completers at week 26 from LIFT-AD, hence at the end of the double-blind treatment period, of course, without background cholinergic medication. The primary analysis then used a mixed model for repeated measures to compare the change from baseline in GST between the pooled fosgo treatment arms and placebo. We pre-specified 2 potential outcomes of this interim analysis. One, to stop the study for futility if the results would not achieve the pre-specified lower boundary for conditional power or if the sample size required to reach the desired conditional power exceeds the pre-specified maximum. Second, to continue the enrollment within the pre-specified range to achieve an adequate target power for the primary endpoint. On this table, we show the pre-specified decision framework and potential outcomes for the primary composite endpoint of cognition and function. On the Y-axis, you see ADAS-Cog 11, on the X-axis, ADL 23. There is a futility zone, shaded area where the sample size would have exceeded Athira's pre-specified maximum recruitment number, and in green color, the GST combinations resulting in a decision to continue the study. On the right-hand side, the independent and unblinded analysis outcome was first, the data monitoring committee recommended in October to continue the LIFT-AD study. Second, the new sample size estimation was based on the actual effect size and the variance observed in these 100 first completers to achieve adequate power in this late-stage trial. As a result, less than 150 subjects are needed to complete the study with a well-powered primary endpoint, which will result in a total sample size of less than 300 for the new target population. The exact target recruitment number, however, remains unknown to all involved in trial conduct. Based on the findings from the exploratory ACT-AD study, the LIFT-AD protocol underwent two key changes. First, the amendment to exclude background therapy. Second, based on this interim analysis, the adaptation to the new target sample size to achieve a well-powered study. All randomized subjects with add-on therapy and those not completed yet will continue to week 26. The safety analysis will include all randomized sub-subjects. We will continue to analyze blood-based biomarkers in LIFT-AD, as well as in the open-label extension. To summarize, we believe this initial data that for both the repair and protect aspects of fosgo therapy, we have biological signals that are pointing us to a broad translation of the data that Kevin presented into clinical effects. They do so with a high degree of consistency. With that, I'd like to turn the discussion over to Rachel. Thank you, Hans, for that clear review of the Fosgo development program. There is little debate about the need for new innovation and therapeutic options for the millions of patients and families facing this progressive and ultimately fatal disease. The last widely available new Alzheimer's medicine approval was almost 20 years ago with Namenda. The good news is that we are seeing a supportive environment that creates potential opportunities to accelerate the development of novel therapies for neurodegeneration through biomarkers that are reasonably likely to predict clinical benefit. We saw the first use of this in Alzheimer's with the accelerated approval of aducanumab based on the reduction in amyloid plaque levels and supportive clinical evidence in June of 2021. Following that precedent, both Eisai and Lilly filed BLAs for accelerated approval based on their phase 2 study results that also demonstrated plaque reduction as well as supportive improvements on composite clinical endpoints, including ADCOMS for Eisai, Biogen and iADRS for Lilly. These approvals are anticipated in the coming months. In addition, in a rare form of ALS, SOD1, Biogen has submitted tofersen for accelerated approval based on effects on NFL as well as other supportive functional endpoints. This kind of regulatory flexibility has been instrumental to a significant progress in the fight against HIV and cancer. It is encouraging to see this type of innovation in neuroscience. People live a long time with Alzheimer's, there are limited treatment options, and even with the anticipated approvals of Aβ antibodies, there is significant room for continued innovation and for therapies that have the potential to provide meaningful improvements to both cognition and function. In looking at the competitive landscape today, the majority of development is focused on early Alzheimer's, when patients are still in the pre-dementia stage. In contrast, Fosgo is targeting the mild to moderate patient population, which comprises 81% of the currently diagnosed Alzheimer's patients today. Anecdotally, this aligns with feedback from treating physicians at the CTAD conference last week who shared that by the time they are seeing patients for the first time, it may be too late for monoclonal antibodies. While estimates vary, data from the Decision Resources Group using published epidemiology studies estimated in the United States in 2021 that 2.1 million patients were diagnosed with a mild, moderate stage of the disease. Using a claims data analysis, also from DRG, we also know that of those 2.1 million, around 50% are treated with cholinergic and Namenda, and that in less than a year, 75% of those treated will move on to a second-line therapy with either a new cholinergic, Namenda, an antidepressant, or some combination. This speaks to the significant opportunity for Fosgo Namenda as either a first or second-line therapy for mild to moderate patients, especially given its potentially differentiated and neuroprotective profile. Additionally, with the aging population and the anticipated monoclonal antibody therapy approvals, there is potential for increased diagnosis and treatment of this devastating disease. Following this year's CTAD, we are even more enthusiastic about the real potential for fosgo to be a first in a new class of therapies for Alzheimer's patients, one that is designed to protect and repair the neural networks, which we hope to demonstrate will result in improvements in cognition and function, and ultimately improve quality of life for patients and their caregivers by tackling this disease from many angles. At its core, no matter what the causative agent of AD pathology, the end result is the same: neurodegeneration. If a therapy can stop neurons and the neural networks from further damage and death, and repair and renew the remaining neurons, then we believe it could provide substantial benefit to Alzheimer's patients. Importantly, the data presented today encourage us that the enhancement of the HGF/Met pathway with fosgo may achieve just that. To conclude, what we have learned about the science, the ACT data supporting this potential translation to the clinic, the outcome of the interim analysis is that Fosgo is differentiated and the development path risk mitigated. The external environment is supportive. Our goal is to excite the development of this potential new option to patients and their families that need more tools to fight this progressive and fatal disease. We believe that we have the opportunity to transform the treatment paradigm for Alzheimer's and other neurodegenerative diseases. On that note, I'm going to turn it back to Kevin, who's going to share exciting data from a new molecule for ALS that also targets HGF/Met, called ATH-1105. Kevin, over to you. Thanks, Rachel. I'm going to now review preclinical data with another lead compound called ATH-1105 in models of ALS. There's a strong rationale from the literature to support HGF/MET as a potential therapeutic target in ALS. There's been reported beneficial effects of promoting HGF/MET activity in several preclinical models of ALS, including transgenic overexpression or direct injection of recombinant HGF, which has been shown to delay disease progression in ALS models. It can also reduce muscle impairment and motor neuron loss in these models. To explore the effects of our compounds in vivo, we focused on the TDP-43 mouse model of ALS. Approximately 90%, 97% of ALS patients have TDP-43 pathology. TDP-43 is a TAR DNA binding protein. It's a nuclear protein under normal conditions, but in ALS it moves to the cytoplasm and forms these toxic aggregates, and this pathology is observed across the vast majority of ALS patients. TDP-43 mouse models have been developed that have a pathological version of this protein and exhibit significant motor neuron degeneration and motor deficits. ATH-1105 is a small molecule, orally bioavailable, positive modulator of HGF/Met that we've developed. I'll start with reviewing an in vitro experimental system we've used to assess the activity of ATH-1105. Here, we've challenged spinal motor neurons in culture with glutamate, as glutamate cytotoxicity likely plays a role in ALS pathology, and we explore the effect, protective effects of ATH-1105. In these images, spinal motor neurons are immunostained in green with MAP2, and cytoplasmic or extra-nuclear TDP-43 is immunostained in red. In the control image on the left with no glutamate, you see a healthy culture of the spinal motor neurons and little overlap of TDP-43 and MAP2 staining. In the middle image, this is a culture treated with glutamate, you can see a reduction in the number of neurons and an increase in the extra-nuclear TDP-43 staining. In the image on the right, these neurons were treated with ATH-1105 and glutamate. We see that ATH-1105 protects against neuron loss induced by glutamate and significantly reduces the amount of extra-nuclear TDP-43 accumulation in each cell. These results are quantified on the right, where we see a significant improvement in both measures with ATH-1105 treatment. We sought to evaluate ATH-1105 in vivo, and we utilized the TDP-43 model that I mentioned before. In this study, we had several groups, including controls. These are wild-type mice that do not have TDP-43 pathology. We have TDP-43 mice, referred to just simply as ALS mice here. These were treated once daily with oral vehicle. We had TDP-43 mice treated with once daily oral ATH-1105. Here we measured body weight over time and observed the ALS model mice did not gain much weight. They have significantly reduced body weight compared to normal mice, which we see here on the right, with wild-type mice in gray and ALS vehicle animals in red. We see that the animals treated with ATH-1105 here in blue are indistinguishable from the healthy controls. They continue to gain body weight, which suggests overall improved health. In keeping with other studies we've discussed, we explored the potential effects of ATH-1105 on inflammation. We know that in this model and in ALS, inflammation plays a significant role in the pathology. We measured plasma biomarkers of inflammation during the course of the study. We saw that the ALS mice had significant increases in TNF-α and IL-6, which are pro-inflammatory cytokines, compared to wild-type mice. Treatment with ATH-1105 resulted in significant reductions in both TNF-α and IL-6, demonstrating anti-inflammatory effects. These data are consistent with the reduction in TNF-α and IL-6 observed in vitro with fosgo-A M treatment, supporting that promotion of HGF/Met has anti-inflammatory effects. Given the neuroprotective effects we saw in vitro, we also looked at plasma NFL, since it is a marker of neurodegeneration. As expected in this model, we see a significant increase in plasma NFL in the ALS mice versus the wild-type controls. We see a significant reduction in NfL in animals treated with ATH-1105, which is indicative of neuroprotection and is consistent with the neuroprotective data that we've shown earlier. The reduction in NFL suggesting ATH-1105 is protecting motor neurons from degeneration. We performed histology to examine the sciatic nerves. Here, these images are cross-sections of the sciatic nerves stained with Toluidine blue. Now in the wild-type healthy control on the left, you see large diameter axon surrounded by healthy myelin sheath. In the middle image of the ALS mice, you see it's quite different. You see a reduction in axon size. You see degenerating axons, which are pointed out by the black arrows, and also examples of demyelination, which are pointed out by the red stars. In contrast, the image on the right, these are ALS Animals treated with ATH-1105. You see a significant preservation of the axon morphology. This is much more similar to the control. We see a healthy population of large diameter axons and what looks to be a normal level of myelin. These properties are quantified in the graphs below. On the left panel, there is a significant rescue of the number of axons in ATH-1105 compared to vehicle control treated ALS mice. In the middle panel, we see a significant increase in overall average axonal diameters for preservation of large diameter motor neurons. Finally, on the right panel, we see a normalization of the myelin g-ratio, which informs the relative thickness of the myelin versus the axon diameter. Next, analyses of electrophysiological and behavioral assessments indicated the protection of the motor neuron with ATH-1105 translated to improved nerve and motor function. We measured nerve function using sciatic nerve electrophysiology and looked at both compound muscle action potential on the left as well as nerve conduction velocity on the right, and observed consistent improvement in both measures with ATH1105 compared to vehicle. This improvement of nerve function likely contributes to the overall improvement in motor function that we observed across all behavioral measures. Here we are showing data from the balance beam test, an assessment of balance and motor function, and the grip test, an assessment of strength. ALS animals exhibit significant motor impairments compared to wild type, reflected in the significantly increased cross times on the balance beam and reduced grip strength. ATH1105 treatment in ALS mice led to significant improvements in both the balance beam and grip tests compared to the vehicle-treated ALS group, demonstrating improved motor function. In summary, in this TDP-43 mouse model of ALS, we observed that daily oral treatment with ATH-1105 resulted in maintenance or preservation of normal body weight. We saw reduced levels of plasma biomarkers of inflammation and neurodegeneration, which are very consistent with our in vitro studies and which also aligns with the ACT clinical biomarker data set. We believe this reduction in levels of NFL is because of the neuroprotective ability that was evident when we looked at the histology and we saw preservation of the nerve structure. These effects contribute to the significant improvements in nerve and motor function, including significant improvements in balance, coordination, and muscle strength across several measures. Together, these results highlight the therapeutic potential of ATH-1105 in ALS and support its further development. With that, I'll turn it back over to our CEO, Mark. Thanks, Kevin. As you can see from the body of work just presented by my colleagues, it has been a busy and productive year at Athira. All of the team's hard work and accomplishments aggregate to support the potential of our novel approach to bring a totally new paradigm to treat neurodegeneration. As Rachel discussed earlier, we are very excited to be advancing fosgo in Alzheimer's disease and believe there is a compelling rationale to invest in and support this very promising development program that has the potential to transform the treatment paradigm for mild to moderate Alzheimer's disease patients for whom there are few, if any, effective treatment options. Importantly, we feel we have mitigated development risk with the unblinded interim analysis of LIFT-AD and have a clear path to demonstrating Fosgo's therapeutic promise in a potentially pivotal study in mild to moderate Alzheimer's disease, where we believe no others are developing such a multimodal approach. 'Cause at the end of the day, this is all about providing benefit to patients who have limited options today. All of this gets us really excited by the potential of what we're doing here at Athira. Turning now to where are we moving with these important programs. As Hans discussed in greater detail, we completed the independent unblinded interim analysis of LIFT-AD. Moving forward, we now expect to complete the enrollment in mid 2023 and have top-line data in early 2024. In addition, we plan to more formally engage with the FDA on the path forward for Fosgo. We completed enrollment of 28 patients in the exploratory phase 2 SHAPE study in Parkinson's disease and Lewy body dementia. Our plan is to complete the treatment of these 28 patients and evaluate the data to determine our next steps with this program. We now have very compelling preclinical data on the broader potential of Fosgo to improve motor function in Parkinson's disease, and we want to ensure that we design studies that will explore these questions in this complex and multimodal disease. We recently completed the phase 1 single ascending dose escalation cohort of ATH-1020, an orally bioavailable brain penetrant small molecule that is designed to enhance the HGF/Met system. ATH-1020 demonstrated a favorable safety profile and was well tolerated in this early test in healthy volunteers. Moving forward, we are going to evaluate our options with this compound and will consider its advancement in relation to other opportunities and available resources. Based on the very compelling preclinical data Kevin just reviewed for you, we have determined there is significant opportunity to pursue the clinical potential of ATH-1105 in ALS. Given the significant unmet need and the neuroprotective and neurotrophic effects of ATH-1105, we plan to file an IND in the coming year. As you would expect, we are very encouraged by the improvements in neuronal health and function, all of which suggest that enhancing the HGF MET system may benefit patients with ALS. In closing, we truly believe we are in a strong position to change the treatment paradigm for neurodegenerative diseases. As we've shown you today, we have preclinical evidence and corresponding signals in patients that our small molecule HGF enhancers have the potential to be neuroprotective, anti-inflammatory, and disease-modifying in a number of neurodegenerative diseases. We are currently seeking to demonstrate these clinical findings in larger numbers in the LIFT-AD study. Importantly, we believe we have mitigated development risk with the independent unblinded interim analysis of the LIFT-AD study in Alzheimer's disease and are in the position to have top-line data in early 2024. We have a talented and dedicated executive leadership team who have a successful track record of advancing product candidates through the development process, through regulatory approval, and through to successful commercial launch in the CNS space. Last but not least, we have a strong balance sheet to enable us to demonstrate the potential of Fosgo in Alzheimer's disease and to advance our other programs, such as ATH-1105 in ALS, through key inflection points. Before opening to your questions, I want to take a moment to recognize the hard work and dedication the Athira team brings to the fight against neurodegenerative diseases. Every single day, our team is passionate about tapping into the potential to bring new medicines to patients battling these devastating diseases. The excitement here at Athira is inspiring as we envision the prospect of potentially changing the course of debilitating neurodegenerative diseases. Our team recognizes that improving cognition and function can help restore lives for patients and their families, such as maintaining independence or simply recognizing their loved ones. This ambitious goal of ours is what drives the Athira team. We are incredibly proud of the progress we've made throughout 2022 and are looking forward to an even more promising 2023 for all of our stakeholders, but primarily for the neurodegenerative disease patients we seek to serve. Thank you all for taking the time to listen to our story today. Now, operator, let's open to your questions. As a reminder, please submit all questions by typing them in the Q&A box on the bottom of your screen. I will now turn the call back over to Dr. Mark Litton for the Q&A session. Okay. Let's start with our first question. This one's probably going to Kevin. Have you tried combining 1105 with riluzole to assess whether there may be any additional benefit or synergistical effects? Yeah. Thanks, Mark. Yeah, that's a great question. We have looked at that. We're starting to look at it in vitro. We have some preliminary results that say that there's really no interaction, that they don't seem to interfere with each other. And we're looking at expanding the dynamic range of these assays to see if there is additive effect. Early days with that, but it is something we're looking at. Great. Second question. Sorry, it's a long one. I'm gonna just try to sum it up here. It says: It's exciting to see growing evidence highlighting the potential of the HGF/Met across multiple neurodegenerative diseases and its potential in disease modification. Coming out of CTAD, what were your high-level takeaways? Personally, I'll start. The high-level takeaways that I personally was very excited by the potential of fosgo, both from the key focus on biomarker data, and the fact that we're gonna get some new therapies that are gonna help the marketplace. Hans, What was your takes on CTAD? I think bottom line of CTAD is there is a new invigoration of this field because everybody could clearly see that lecanemab has a shot on goal with their consistent data. On the other hand, of course, gantenerumab was negative. We may see two promising compounds in the near future, lecanemab, donanemab, that may make it. That said, I will add that there was less consistency than I was hoping for. For example, there is no effect at any time point by lecanemab on neurofilament light. Also, the phase two data showing progressive accelerated brain atrophy with lecanemab were not tabled at CTAD. In the future, there are two important movements that I would predict. One is an ever-stronger impact on blood-based biomarkers of all sorts. Second, the prospect of combination therapy in Alzheimer's disease. Thanks, Hans. Okay, I'm gonna go to our next question. It's gonna be one for you, Kevin. Any thoughts on the mechanism of change with the Aβ42/Aβ40 ratio? Yeah, that's a good question. There's several thoughts on the mechanism behind this. One of them is in the literature, there's a lot of competing but not mutually exclusive hypotheses is what causes the amyloid beta deposition. It can be oxidative stress. You know, generation of reactive oxygen species can actually generate amyloid beta pathology. HGF/Met activity has been shown to block it. It's actually in one of the figures that I showed early on when this is all from the review, is activation of these pro-survival pathways can block reactive oxygen species production, so it improves and protects against oxidative stress. That could actually reduce the protein pathology, including Aβ pathology. That could be reflected in the blood-based levels that we saw in ACT. Thanks, Kevin. Kevin, this might be another one for you. Is it known whether the HGF/Met level correlates with the severity of AD or other neurodegenerative diseases? Yeah, that's a good question. The CF levels of HGF can change over time in several diseases. Less is known. It's not as well characterized in Alzheimer's, in other diseases. There's a little bit more work, including MS, which in MS, it seems to be it follows patterns of relapsing. If there's active lesions following that, you see an increase in HGF, which is the activation of this repair mechanism. The cells secrete HGF to try to repair in response to those lesions. You see a pattern of that pretty well described in MS. Generally there is initially also in ALS, there's initially an increase in expression of HGF on initial injury. It's thought that the body is trying to repair itself. As the disease progresses, you see a loss of activity of that system, so a dysfunction in the natural repair mechanism. Really we think that promoting HGF/Met activity could push that further into the repair mechanism and then maintain it throughout the course of that disease. We're still very excited about the potential in ALS. Nice. There's another question that is asking like the specific power, and I just wanted to be clear that we've just only said that it would be well powered for a phase 2 and 3 study for LIFT-AD. Let's see. There's a question here, it's probably to you, Hans. The question is, the choice over ADCS-ADL23. Why did we choose this? What do we think going into the larger population? Historically it's been a challenging target. Maybe also talk a little bit, Hans, about, you know, our thoughts on the composite score of the GST. Yeah, that's a big topic. The question is of course well taken because so far, there has been very little evidence of improvement of ADCS-ADL23. I would like to translate that to the more colloquial instrumental activities of daily living. What we are really talking about here is independence of the subject, and that is a very important aspect. We did see a signal in ACT-AD. We have indirectly obtained replication of this notion that there is both procognitive effects and effects that are supporting independence from the unblinded interim analysis because the GST as an unweighted and unbiased composite score comprises of those two factors that feed into it. We feel encouraged by the result of the interim analysis to continue on that path. Maybe let's mention just a little bit, just to remind folks that, right, it's a composite score, both can actually be trending to actually hit stat sig when each of them are not stat sig. The goal for us is to have further interactions with the FDA on our pathway forward with fosgo. There was a question, Hans, about interim analysis and any interaction with the agency. Yeah. The agency is, of course, fully informed about every step that I showed on the slide with the time axis. On that basis, we will resume and continue our dialogue with the FDA next year once we have really the complete data. I should probably point out that our biomarker results are not yet exhaustive. We are continuing to run analysis, and that includes also the open-label extension, where the validity of the result is not hampered by the lack of placebo control. Based on this integral view, we will resume the dialogue with the FDA next year with various questions, of course, that we have and to determine the way in the future. Okay. There was one question, Hans, just to emphasize this, about what do you think the regulatory perspective will be about the interim analysis and how we approached it? There have been since the initial publication of the Mehta and Pocock method in 2000 and then supplemental publications later on, there has been also independent review papers, remember one by Edwards and colleagues, that have been looking into the application of this method, not only in neurology and psychiatry, but also across a number of other indications. The bottom line is that this is a well established and recognized way to adaptation of late-stage trials while preserving their data integrity. Thanks. This next question is going to you, Rachel. It's a question about Fosgo and how it will compete in the current marketplace, and how will it capture share. Thanks, Mark. It's a great question. I think there's a couple answers to the question. First of all, as we described, there are a lot of patients that are diagnosed and not treated at all today, and that is because of lack of perception of efficacy, or maybe they tried it and it didn't work for them. There's a tremendous population that are untreated or treatment naive. We saw that in ACT-AD and LIFT-AD because 40% of our patients, without trying, without seeking them out, were coming to the studies not on any type of treatment. I think that's a very clear patient segment. Also, I think that we also now know that a lot of people very quickly, in less than 1 year, are seeking other treatments, either a combination treatment or adding something or switching something. I think that that also gives us a lot of opportunity to have people want to try fosgo once it's approved. The other point that I'll make is that as we've seen in lots of other disease settings and that we experienced this certainly in my time working in oncology, that as new therapies become available after there's been nothing for even decades, the market dynamics change. There often are more patients treated because now there's a new option that may appeal to them. I think we have really compelling data, and I think because this drug is so differentiated in its mechanism of action and the potential for neuroprotection, there's no reason why this couldn't become a treatment of choice for all kinds of patients. Totally agree, Rachel. Okay, Kevin, another question coming your way. Of course, this is a question that a lot of people have been asking, right? The interaction. Kevin, can you just sort of summarize a little bit more on sort of the type of experiments you've been running and how we're approaching looking at the biology behind the interaction? Yeah. Yeah, it's a great question. As I mentioned before, we are investigating this. We have been able to replicate in certain conditions, in certain models. We have been able to replicate this essentially loss of activity when you combine Fosgo and acetylcholinesterase inhibitors. Some of those models have been in vitro, looking at expression of inflammatory cytokines or anti-inflammatory effects. Some of those models have been neuroprotective in vitro models. Also, we've now been able to replicate it in vivo in an animal model of a cognitive deficit. We're still exploring this. As I mentioned, we have several lines of evidence that points to the fact that this could be a real interaction. We're still investigating, trying to elucidate the exact mechanism, the point of interaction. We believe our leading hypothesis, as I mentioned, is some sort of downstream interference in the signaling pathway. There is several areas where they could cross over. One of those downstream effector proteins is PKC, so we're looking at that system, also the SRC pathway, and perhaps AKT. We're looking at that from several different angles, and we'll continue to see what we can find there. Thanks, Kevin. Really appreciate it. There's a question. Kevin, it's probably you. Do you see differences between 1105 and fosgo? Yeah, that's a great question. Absolutely. 1105 is a distinct compound from Fosgo. These two compounds have different physiochemical properties. while they both are able to activate HGF/Met, they do have different properties. They have different potencies. They have different tissue distribution. Really for these different, what really separates them in terms of why we're excited about Fosgo in Alzheimer's and 1105 in ALS is that it's about getting the drug at the right concentrations in the right tissues. 1105 seems to be particularly well suited to get to the areas of need in ALS, and that includes not only the spinal cord, but also to the muscles and to the neuromuscular junctions, the peripheral nerves, at concentrations that we think are efficacious. That's a really important feature of that compound. Likewise, fosgo seems particularly well suited to get into the CNS at concentrations that we think are efficacious in the CNS, not so much in the periphery. That's the primary difference is actually distribution and other physiochemical properties. Okay. There's. If I may add a small- Please go. You add, yes. Yeah. Just a tiny detail. ATH-1105 is already active. Right. That's another very large distinction between the two, yes. Okay. Another. This is another hypothesis for you, Kevin. What is your mechanistic rationale for the HGF/Met system in ALS? Your Talk a little bit about sort of the models and how does the community feel about the TDP-43 transgenic model? Sure. Maybe I'll start there, and then I'll go to the rationale. Regarding the models, yeah, typically historically, there's been most of the work done in the SOD1 model, which is a transgenic model that has a mutant form of superoxide dismutase, right? You have. That represents about 5% of ALS patients. They have pathology of oxidative stress, reactive oxygen species production, which can lead to neurodegeneration. Most of the work to date really has been primarily done in that model in terms of testing the therapeutic potential of experimental compounds in vivo. Recently there has been development of other models, particularly this TDP-43. A lot of interest here in the last 10 years. It's gaining a lot of momentum. We think that's because it could be considered perhaps more representative of a pathology seen in the vast majority of patients as opposed to a small percentage. As I said, the 97% of ALS patients have this pathology that can be caused by several reason, several different reasons. In the end, they have this pathology. They have this TDP-43 moving out of the nucleus into the cytoplasm, causing, forming these toxic aggregates. That leads to a lot of the neurodegeneration that we see in ALS. That was something we're really interested in terms of choosing models. The rationale for targeting HGF met in ALS is very strong. As I mentioned, there's been several preclinical studies done by other groups looking at overexpressing HGF either with plasmids, intrathecal injections of recombinant HGF. Really proof of concept studies that showed overexpressing or increasing HGF Met activity has beneficial effects in different models, in models of ALS. However, intrathecal injections of plasmids or recombinant proteins is not really a developable drug. We think the small molecule has distinct advantages to that. We've learned, or we've used the rationale from those prior studies, as part of our foundation, scientific foundation to look at our compounds in ALS. Also the, you know, a lot of the aspects we talked about, the neurotrophic aspects, particularly the neuroprotective aspects, could be critical, we think is really supports the rationale for looking at our system, or promoting HGF/Met in ALS. ALS is the neurodegeneration is caused by a lot of different things. It's oxidative stress, it's glutamate cytotoxicity, it is these toxic proteins. We have evidence and a growing body of evidence to suggest that or that demonstrate that 1105 and our compounds can block degeneration from those different insults. From oxidative stress, we have glutamate cytotoxicity data. I showed that we see a reduction in TDP-43, pathology and also in the TDP-43 mouse we had really, robust neuroprotective activity. We think the rationale is strong, and we're really excited about continuing to investigate and explore, and develop this program. There's considerable clinical confidence that these results will translate into humans. Not to mention NFL. Yes. Talk about the NFL again. The NFL, the plasma NFL we saw in vivo, obviously in ALS patients, they have, you know, significant increase in plasma and CSF NFL. We think this is a really important piece of evidence too, that could be translatable. Kevin, I have a specific question about the ALS mice. The question is the body weight gain shown receiving that are getting 1105? Is it achieved by increasing food intake or in other ways? A change in metabolism, locomotor activity or et cetera? That's a really good question. I don't have a specific answer. I don't believe it's locomotor activity because actually they perform better. We're able to do more activities. Yeah than the ALS vehicle mice. It could be we can't say for sure exactly what it is. It could be appetite, it could be metabolism. That's a great question and something we can look at in the future. But what we do know is that it was indistinguishable from control. Whatever was the reason, it was essentially normalized their body weight gain over time. We think that's an important marker of overall health, regardless of what is the mechanism behind it. It's a great question. Can I, yeah, just to ask another question, and maybe it's Hans or Kevin, but Hans, you know, in the clinic, do you see this atrophy in patients losing weight? Well, that is one of the notorious problems with Alzheimer's disease as it evolves over the years, that people are becoming more and more underweight and they're losing weight. We will need to increase our database in order to provide a definitive answer on the influence of Fosgo on body weight, you know, in the trials. Yeah. Let me just... Just to kind of expand on my previous answer, it could also be due to inhibition of muscle atrophy. We didn't measure that specifically here, but we do know that, and Hans mentioned, that is a, you know, a major problem for ALS patients, right? As you lose the neuromuscular junctions, right, the innervation of the muscles, the muscles atrophy. That could be playing a part here. Actually we have evidence to support that. The compound muscle action potential data is suggestive of preservation of neuromuscular junction. Innervation of that muscle, that's how you get that measure. It could also be suggestive of inhibition of muscle atrophy. Okay, I got another question, I think coming your way, Hans. It's about GFAP and NFL in your poster, and the improvements on GST. The question was, would you select a minimum criteria for the GFAP and the NFL as selecting patients? Or, what was it... Now, that hasn't been done, I don't think, before, but what would be your thoughts about running a trial where you use that as a selection criteria? I'm understanding that the question points at the use of NFL and or GFAP as inclusion criteria. Yes. I think that's what the question is. That would be novel. That has not been done, to the best of my knowledge, ever. It's also not part of the experimental diagnostic criteria by IWG-2 criteria, 18. However, we have shown that N-NFL is an independent predictor of the future decline. The baseline value predicts the decline, and I think it will take more efforts to try and establish these blood-based biomarkers. Remember, it's not that long ago that it was shown that they are highly congruent with the new Simoa analytical method in plasma as compared to CSF. The diagnostic ATN criteria I just cited from 2018 were still entirely based on CSF. That requires large series of lumbar punctures plus, of course, PET scanning. Here we have now, a situation where more and more data has been accrued, to show that, there's a tight correlation between CSF and plasma. I think it will continue to evolve, this field. Whether one day they might be utilized as an inclusion criteria in trial, I would not speculate. Hans, there's another question. Again, this is asking the question, the difference between being on background therapy and not. Was there a difference between the correlation from the full body or focused on mono? Let me say the ACT-AD, LIFT- AD, by the way, is stratifying by severity. We did not have a pre-hoc stratification by other factors. We did protocol subgroup analysis by severity, by APOE genotype, and by add-on therapy, so whether the group does or does not have background cholinergic medication. We found that there was a trend to improve NFL in the full population and that signal became statistically significant in those without background cholinergic medication. Hans, here's another question for you. I mean, have you seen what happens when you stop the therapy after a while? First of all, there is no tapering off. The medication can be stopped at any time because we have not observed any withdrawal effects of stopping, fosgo medication. I think that answers the question. Okay. There's a lot of questions I'm just gonna answer as in general. We're just putting together our protocol and clinical development plan for 1105, we don't have specific answers to that at this moment. We will do your typical file the IND and single ascending dose, multiple ascending dose while we're working on that. May I add, Mark, also that, since ALS is an orphan indication, we will be very careful to discuss with the agency how to go about this development. I think we've gone through most of the questions. I think that concludes our questions for now. I'd like to thank everybody. I know it's been almost 90 minutes. We truly appreciate you, all the questions, taking the time, and we remain very excited about this pathway, fosgo 1105, and the next year. We're looking forward to seeing everybody at J.P. Morgan. Happy Holidays. Thank you again. Be safe. Thanks again for the time. Thank you. Bye-bye.