Amylyx Pharmaceuticals, Inc. (AMLX) Earnings Call Transcript & Summary

Good afternoon, and thank you all for joining us today to discuss the treatment landscape for people living with Progressive Supranuclear Palsy or PSP, and our clinical development plans for AMX0035 and PSP. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs. Dr. Jamie Timmons, Head of Global Medical Strategy and Communications. Prof. Dr. Günter Höglinger, Director of the Department of Neurology at LMU Hospital in Munich, Germany and who will be our primary investigator on the Global Phase III clinical trial of AMX0035 and PSP. And Dr. Lahar Mehta, our Head of Global Clinical Development. Joining us for Q&A will be Jim Frates, our Chief Financial Officer. [Operator Instructions] Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to AMX0035, statements regarding the regulatory clinical developments and the expected timing thereof. Actual events and results could differ materially from those expressed or implied by any forward-looking statements. You are cautioned not to place any undue reliance on these forward-looking statements and Amylyx disclaims any obligation to update such statements unless required by law. Now I will turn the call over to Justin.

Thank you Lindsey, and good afternoon. As many of you on this call know, there is an enormous unmet need in relentlessly progressive and fatal neurodegenerative diseases. It is our mission at Amylyx to one day and the suffering caused by these diseases. AMX0035, also known as RELYVRIO in the U.S. is approved for the treatment of ALS by the FDA and approved with conditions by Health Canada. RELYVRIO is already being widely prescribed to people living with ALS. Our recent commercial launches in ALS enable us to not only invest in bringing RELYVRIO to more people living with ALS worldwide, but also to pursue research and development opportunities to further support our mission. There is tremendous scientific interest among the neurodegenerative disease community to further investigate AMX0035 in other diseases. When we originally developed AMX0035, we did designed it to target ER stress and mitochondrial dysfunction, two connected central pathways that lead to neurodegeneration. We are pleased to be on the call today to discuss AMX0035's role in neurodegeneration, its potential in PSP and the global Phase III PSP trial that we plan to kick off later this year. And we are so honored to be joined by Prof. Dr. Günter Höglinger, an expert in PSP. I will now turn the call to Dr. Jamie Timmons.

Thank you, Justin. It's my pleasure to walk through the scientific rationale for AMX0035 in PSP with you today. The figure on this slide is taken from a review published and sell earlier this year. As shown, the authors summarized 8 hallmarks for neurodegenerative disease. Despite heterogeneous clinical presentation, these mechanistic hallmarks are seen across neurogenic diseases, such as ALS, Parkinson's disease, Alzheimer's disease and Tauopathies like progressive supranuclear palsy or PSP that we will talk the most about today. These hallmarks are synaptic and neuronal network dysfunction, [indiscernible], cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, neuronal cell death and finally, pathologic protein aggregation. As shown on the slide, these protein aggregates may be more disease-specific like in the case of TDP43 and SOD1 in ALS, or shared across diseases. As in tau, for ALS, Alzheimer's disease and PSP. While they are shown as separate hallmarks in the figure, another key conclusion of this paper is that these pathways are interconnecting, highlighting the need for therapies that can target different key pathways. So with the understanding that there are multiple shared pathways that can be targeted across neurodegenerative diseases, it follows that a drug that targets several of these pathways at once could show benefit in multiple neurodegenerative diseases. Shown on this slide is a high-level view of the Hallmark pathways that AMX0035, our fixed dose combination of Sodium Phenylbutyrate and Taurursodiol has been shown to impact. I'll go into more detail on in vitro, in vivo and clinical data specifically supporting the proposed mechanism in PSP shortly, but more generally. In vitro, AMX0035 has reduced neuronal cell death. Pathways -- include the back pathway of intrinsic apoptosis regulated via the mitochondria as well as the unfolded protein response. In vitro AMX0035 has also improved mitochondrial function, thus increasing energy production of the cell. This is important across neurodegenerative diseases where altered energy metabolism due to mitochondrial dysfunction is common. Finally, AMX0035 has reduced help, a key protein aggregate shared across ALS, Alzheimer's disease and PSP in cell and mouse models as well as in a Phase II Alzheimer's clinical trial. So let's move from the general rationale of AMX0035 in neurogenerative disease to PSP specifically. PSP is a rare but recognizable fatal neurodegenerative disorder that affects eye movement, walking and balance, speech and swallowing and cognitive function. It is typically fatal within just 6 to 8 years from system onset, and tends to be progressive during that time with people's disability becoming worse and worse. Globally, PSP's prevalence is 7 in 100,000 people worldwide, an incidence is roughly 1 in 100,000. So looking at the United States, PSP effects at least 20,000 people with around 3,000 people newly diagnosed every year. There are currently no disease-modifying treatments for PSP. Prof. Dr. Höglinger will discuss this more shortly, but the current standard of care is managing symptoms and ensuring that people living with PSP's quality of life is as high as can be. PSP as a tauopathy characterized by an aggregation of tau in specific areas of the brain. We hypothesized that impacting tau deposition will lead to a disease-modifying effect. So let's go into more detail about the pathways involved. The pathophysiologic changes underlying PSP are multifactorial and interconnected as summarized in this figure from a recent publication. Multiple pathways, including the activation of the unfolded protein response and mitochondrial dysfunction have been implicated as contributors to tau dysfunction. And as noted earlier, these are 2 of the hallmark neurodegenerative disease pathways, the AMX0035 is thought to target. I've highlighted the various mechanisms in yellow, where based on in-vitro, in-vivo and clinical data, AMX0035 may influence tau pathology and PSP. Starting on the left with mitochondrial dysfunction, which can feed back loop with oxidative injury and cause decreased energy for the cell, leading to tau aggregation and neuronal cell death. On the right, impairments in the unfolded protein response, a complex combination of signaling pathways aimed at protecting against cellular stress caused by misfolded proteins. Tau in this case, can lead to further tau aggregation and neuronal cell death, all of them leading to the devastating clinical manifestations seen in PSP. This figure also highlights that the proposed mechanisms AMX0035 impacts our upstream of tau aggregation. Again, suggesting that there are multiple potential targets for addressing tau pathology in PSP. Let's look at the data more closely that supports the pathways that AMX0035 can impact on PSP, starting with sodium phenylbutyrate or PB. In terms of proposed mechanism in a variety of in vitro experiments, sodium phenylbutyrate, upregulated and recruit chaperone proteins, stabilized protein folding, and reduced ER stress and the unfolded protein response, which can lead to apoptosis if the stress is overwhelming. To place this in context for PSP, it has been shown that the unfolded protein response is activated in disease affected regions in PSP. And genetic evidence indicates this activation is not a protective response but a risk factor for the development of PSP. In terms of data in mouse models of neurodegenerative disease, including the Tau35 PSP mouse model, sodium phenylbutyrate has reduced tau pathology and improved cognitive and motor functions as shown in the graphs. In the Morris Water Maze graph on the left, we can see that treatment with sodium phenylbutyrate improved cognition in this Tau35 PSP mouse model. Similarly, in Grip Strength test on the right, these Tau35 mice treated with sodium phenylbutyrate exhibited higher grip strength compared to Tau35 mice not treated with sodium phenylbutyrate. Moving now to Taurursodiol or TURSO. In terms of proposed mechanism here and in vitro experiments, TURSO stabilized the mitochondrial membrane by reducing the translocation of cell death regulator backs, which leads to improved mitochondrial function and energy production and an increased cell apoptotic threshold. So again, to place any context for PSP, impairment of mitochondrial function has been shown in [indiscernible] cell lines with mitochondria from patients with PSP as well as neurons derived from patients with PSP. In terms of TURSO data, in a cellular model where metabolic stress induced tau phosphorylation, TURSO inhibited tau phosphorylation caused by the stress. So in addition to preclinical data on PB and TURSO individually, we have a wealth of preclinical data on the synergistic effect that PB and TURSO combined have in targeting the hallmark pathways of neurodegeneration to simultaneously prevent or slow neuronal cell death. In the in-vitro experiment on the left, a structure that will cause cell death hydrogen peroxide was added to neurons, and we look to see if either PB, TURSO or the combination AMX0035 could prevent this cell death. Either PB or TURSO administration alone prevented a moderate percentage of neuronal cell death in this and future experiment. But the AMX0035 combination prevented nearly 100% of neuronal death in this model, indicating that the AMX0035 combination demonstrates synergistic protection, cortical neurons against peroxide-mediated neuronal cell death. As shown in the graph on the right, in a mouse model of ALS, the AMX0035 combination demonstrated synergistic slowing in motor function decline. This statistically significant benefit was seen only when using the AMX0035 combination of PB and TURSO, and not with the individual PB or TURSO treatment. These are just two examples of experiments, one in in-vitro cell model and one in a mouse model. But overall, 26 primary pharmacodynamic studies of AMX0035 support its effect and relevant mechanistic pathways for neurodegenerative diseases. The data support that the combination of PB and TURSO together shows an impact in each model that is greater than PB or TURSO individually. So moving from the cell and mouse studies into human clinical trials. Shown on this slide are biomarker results from our trial in Alzheimer's disease. This was the PEGASUS trial, a Phase II 24-week U.S. multicenter randomized placebo-controlled trial. In the PEGASUS trial, AMX0035 treatment demonstrated a statistically significant lowering of those p-tau181 and total tau in the CSF of people living with Alzheimer's disease compared to placebo. Total tau results are on the left and phospho tau results on the right. So based on this biomarker data from PEGASUS, we wanted to dig deeper to further characterize the effects of AMX0035 on pathways relevant to neurodegenerative disease. And so we performed proteomic analysis. So here are the results from an analysis using an Olink panel of 288 proteins, again, in the same 24-week PEGASUS trial. We see robust treatment effects across a variety of biological pathways, but primarily those related to tau and neurodegeneration. In fact, of 288 proteins measured in CSF of plasma, tau was the most significantly changed protein by AMX0035. This is one of the reasons we are so excited to study AMX0035 in PSP. We believe impacting tau deposition will lead to a disease-modifying effect. And in this trial in Alzheimer's disease, AMX0035 shows the potential to do just that by significantly lowering tau levels. We're also excited about AMX0035's potential impact on people living with PSP because we know AMX0035 slowed disease progression and prolonged survival in ALS. As shown, ALS and PSP share several mechanistic and phenotypic features, suggesting that a drug that is effective for ALS may be effective for PSP. So to summarize my section, PSP is a tauopathy associated with tau dysfunction and tau aggregation and widespread neurodegeneration. Multiple pathways, including activation of the unfolded protein response and mitochondrial dysfunction are implicated in tau pathology and PSP. And there is a variety of in vitro and in vivo evidence that AMX0035 impacts these pathways. In terms of clinical trials, in Alzheimer's disease, AMX0035 has been shown to target multiple pathways of neurodegeneration and significantly reduce CSF total tau and phospho tau levels. And an analysis measuring 288 proteins, tau was the most changed by AMX0035 treatment. And in ALS, AMX0035 slowed disease progression and improved survival. We are extremely excited about the science supporting the study of AMX0035 in PSP. We have seen significant and strong support from key opinion leaders in PSP and are excited to work with them to test AMX0035 and our Phase III ORION trial, which Dr. Mehta will describe later on during the presentation. We are hopeful we can potentially provide a new treatment option for this underserved community. Now I would like to turn it over to Prof. Dr. Günter Höglinger to discuss the PSP disease and treatment landscape.

I'm Head of the Department of Neurology at LMU Hospital in Munich, Germany. I am clinical neurologist by training, and I have spent my scientific work mainly in studying PSP and related tauopathies. So this is the place where I'm currently working. And this is my disclosure. So I worked with a number of different companies, developed therapies for neurodegenerative diseases. So I will briefly introduce you to the disease and then discuss with you the treatment landscape that we have at present, which is very limited and the development pipeline for new therapies in PSP. The disease itself has been recognized only 60 years ago with the urologists and a neuropathologist working together and describing a small series of patients they had observed with a particular clinical phenotype combining supranuclear gaze process or eye movement problems with swallowing difficulties, rigidity similar to Parkinson's disease and a small degree of dementia. They coined the term progressive supranuclear palsy due to the prevailing clinical features of these patients. Now we have conducted, 10 years ago, the genome-wide association study in 2,000 patients who came to autopsy and were shown to have PSP. PSP is now defined by the presence of aggregated and cost-related tau in astrocytes and neurons in the brain, as you can see here in the image on top of the graph. In this genome wide association study, we pointed out one major risk factor, which predisposes for the disease, which is a common variation in the gene encoding the microtubule-associated protein tau. So the tau protein, which aggregates and which causes the degeneration of the neurons in the disease. The out ratio to predispose for the disease is extremely high, much higher than any other predisposing gene associated with other neurodegenerative disease. And this tells us that tau is really the key driver of neurodegeneration in PSP. As we can observe on neuropathological analysis in the brains of these patients tau is aggregating both in neurons, but also in glial cells in Astroglial cells and in oligodendroglial cells, now this is a major difference as opposed, for example, to Alzheimer's disease, where there is early neuronal tau aggregates and where we do also have a second protein tau aggregate, which is amyloid beta. So PSP and distinction is a primary tauopathy, there is only tau causing neurodegeneration, and it's all over the place in all kind of cell types in the brain. Now the clinical manifestation of these patients is quite easy to recognize. We do define the disease currently by the prevailing tau aggregation, as I have just outlined. And in the clinical space and the outpatients and inpatient wards, we can identify the patients primarily with a unique clinical combination of eye movement problems, so the inability to move with their eyes up and down in combination with a Parkinson syndrome and postural instability, which is prevalent early in the clinical course. Due to the original description, we coined the term Richardson's syndrome as the clinical -- the key clinical manifestation of the disease. Now we have elaborated diagnostic criteria in a work that was really a true international effort. We gathered together experts from North America, Europe, Asia, spanning expertise from clinical neurology, cognitive neurology, neuroimaging, neurogenetics, biomarker, and what we have elaborated is a very simple to use clinical grid. So this is clinical features from the domains ocular motor dysfunction, postural instability, akinesia and cognitive dysfunction, and it's, in principle, very simple to identify clinical features that neurologists all over the world are currently using to identify these patients. This criteria has been validated in clinical pathological case series, and we know that patients are identified with these criteria have a really, really high likeliness of having the underlying tau pathology. In other words, with these clinical features we can identify the presence of tau pathology without any other biomarker. I just show you a couple of videos to familiarize yourself with the key clinical features and to give you a flavor of what these patients are suffering from. Now this is eye movement problems. You can see here on that video, a patient following the finger of the examiner to the left and right, which is okay, but not to the top and to the bottom. This is the vertical gaze palsy, which can be overcome by a reflex maneuver. You can imagine that this patient has a difficult time to look down to the floor, for example, while walking and to identify obstacles to look down on the plate while eating, for example, and this is, of course, a very severe impact on the patient's activities of daily living. The second key feature is repeated unprovoked palsy postural instability. And you can see here a patient falling right without any stabilization into the eyes of the examining doctor. This, of course, is also a very severe predisposition for injuries, false head injuries and very treatment cause also bleeding in the brain and severe risk for mortality of these patients. One feature, which is also very prominent with these patients is dysphagia. You can see here on that video, a patient trying to swallow a glass of water, and you can virtually see how difficult the patient is actually finding that simple task. Dysphagia and aspiration pneumonia is the most risk factor for mortality in these patients. So this is a very severe aspect of the disease, predisposing them for early mortality. On average, these patients have a life expectancy of 6 to 7 years after symptom onset with a very severe impact on the patient's quality of life throughout the course of the disease. We have published an open access video at last, which you can have a look at in the Internet to familiarize yourself with the problems these patients are suffering from and then the impact is -- this sufferance also has on the families of these patients. Now we have jointly developed also a tool to use and to apply this diagnostic criteria. This is an open access Internet tool where you can just type in the features you observe in these patients and you get as a result, the diagnosis and the diagnostic certainty of these patients. What can be use in addition to the clinical examination in order to substantiate our clinical suspicion of PSP. First and foremost, we always do is a routine MRI of the patient's brain and you can appreciate here that there is a small degree of frontal lobe impairment, which leads to a mild degree of cognitive impairment in these patients. And then it's mainly the so-called mid-brain, which is located here right in the center of the patient's brain which is shrinking and atrophic and some people have an association of seeing a Mickey-Mouse or a Kolibri or a Pinguin here in the brain of these patients, which gives rise to the name of Pinguin sign, Kolibri sign, Mickey-Mouse sign. This is features that we look out for in order to identify these patients diagnosis. The results on new diagnostic tools that are currently being developed, such as tau PET for example, we use radio tracers in order to identify the tau depositions in the brains of these patients. You see in the top row, for example, brain scanned with that particular tracer PI 2620 of a healthy control without neurodegenerative diseases and then you can see on the bottom row, for example, a brain of a patient with PSP where you can see your right in the core of the brain and the so-called basal ganglia, the aggregation of tau visualized on screen. This is not approved for clinical routine use, but it's widely used in clinical research and shows us actually that this disease is associated with tau aggregation in the brains of these patients and no other causes than that. So what can we offer to these patients currently in order to alleviate their clinical symptoms. There is actually very little we can do about that. We use neurotransmitter modulating substances as we do in Parkinson's and Alzheimer's disease, for example, in order to improve their symptoms. We use drugs that we use for Parkinson's like levodopa and amantadine in order to improve the akinesia and rigidity for the slowness and stiffness of their movements. We have a couple of other neurotransmitter modulating substances to improve their Oculomotor deficits, their sleep problems and their cognitive problems. But all of these effects are mild in impact and transient in that time. And all of these do actually not have any effect on the progressive nature of the disease. So they don't stop or reach out the progression to death. What is in the pipeline in the development for future therapies? First and foremost, we need tools in order to measure whether our drugs that we study have an impact of disease on disease progression. The foremost use tool is a clinical rating scale that has been developed by [ Larry Golby ] one of the key opinion leaders in that field. It's a 28 item clinical rating scale that actually rates all of the clinical features that I have just presented to you, incorporating daily activities, cementation, Bulbar exam, Ocular motor exam, link movement and gate and midline exam. And we raised a score from 0, meaning no impact on patients' activities of daily living and 100, which is very severely affected. And as you can see here on this graph, the scale actually progresses very linearly with time. It has been used in numerous clinical trials as a primary readout to monitor disease progression. This slide shows you a summary of the progression rate in the PSP rating scale as used and determined in a number of different clinical trials as they are cited here on the left. And you see that the progression rate measured with that scale is very reliable and predictable to be in the range between 11 and 12 points change within 12 months. So this reliable progression tool has then been used by us and others in order to calculate in a so-called power calculation, power analysis the number of patients that we require in a clinical trial in order to visualize a true clinical efficacy of a disease-modifying therapeutic interventions. And if you, for example, expect that our drug reduces the progression rate of the natural history of the patients by 25%, then we would require 200 patients per arms -- in orders of per arm, which means active treatment and placebo treatment in order to get a statistical significance of that difference. So this is a reasonable numbers that we can actually recruit in trials with PSP, we have demonstrated in positive clinical trials. We have also used MRI as a progression measure, an objective and greater independent quantitative tool in order to measure the progressive atrophy within 12 months of disease progression and the atrophy rate that we can visualize in particularly in well-defined regions of the brain, correlates well with the disease progression. It is therefore accepted as a surrogate parameter as a secondary endpoint or exploratory endpoint at least in clinical trials. Now what are the current therapeutic mechanisms that are being studied in disease-modifying therapeutic trials with PSP with an attempt to slow down the progression of the disease. We have learned in the past couple of years quite a bit about the mechanisms that are active and lead to cell death and dysfunction in the patient's brain. First and foremost, there is expression of the tau gene, which is probably encoded by the MAPT gene variants that I have previously introduced to you, but there is also epigenetic mechanisms and environmental mechanisms that lead to an altered the expression of the tau gene. Then we also know tau is expressed in 6 different isoforms, and there is specific isoforms, the so-called for repeat isoforms that are particularly prone to aggregate in the patient's brains and therefore, splice operating factors are also being currently debated and discussed and studied as a disease-modifying intervention. And then we do also know that tau protein is post translationally modified as there is, for example, glucosylation, there is phosphorylation. And these factors play in on the aggregation propensity of tau and ultimately modify also the rate of aggregation formation as we have seen on the histological slides that I have shown to you previously. So this is also a target for putative interventions, for example, to alter these disease -- this phos translational modifications or to disentangle the tau aggregates with anti-aggregational compounds. Then finally, we also know that the aggregates are oligomeric tau specimen leaf aggregation bearing cells and past the extracellular space in order to invade previously healthy cells in a prion-like propagation pattern and the release mechanisms, the uptake mechanisms are also subject to scientific studies in order to prevent the spreading. But by their passage through the extracellular space, there is also an opportunity to track the extracellular tau and to prevent the spreading from cell to cell, which is currently being studied with tau-targeting antibodies. Now, we and others have studied the putative efficacious effect of tau targeting antibodies to prevent the spreading from cell to cell in previous trials -- in previous clinical trials. One antibody that we had tried was the so-called tilavonemab antibody, and end terminal tau targeting antibody in a randomized placebo-controlled Phase II trial. This was a trial which used 1 placebo arm and 2 different dosing regimens of the antibody, observed patients for 1 year follow-up, demonstrated good target engagement, which meant a reduction in the free tau levels in CSF of these patients. But unfortunately, there was no effect on the clinical progression as measured with the PSP rating scale. A parallel study was also recruited to test in a placebo-controlled manner, the efficacy of an antibody called gosuranemab, and again, there was excellent target engagement. So market reduction in the tau binding or in the appropriate epitope in the CSF, but also again, no effect on the clinical progression rate in PSP patients. We and others have speculated about the causes of the possible failures of these 2 tau targeting antibody trials. And we and others think that probably the targeting epitope was a wrong epitope or not an appropriate epitope because it's -- both of these antibodies target the end terminus of the tau protein. Whereas the aggregation prone domain is located in the middle region of the tau protein. And now there is trials ongoing with antibodies hitting the mid-region of the tau protein. And we are quite optimistic that these might make a difference. Now other mechanisms that are active in PSP are mechanisms to harness the cells against aggregation of tau protein. So this is first and foremost, the unfolded protein response, which is a complex mechanism of both stabilizing and degrading misfolded tau proteins in a complex interplay of different proteins. We know that this mechanism is relevant to PSP because we have studied these or identified this 1 key player of this mechanism in our genome-wide association study. One of the hits we identified is a gene called EIF2AK3. And we have also identified patients, who have a mutation in this particular gene, which leads to a loss of function of the protein. So these patients live without functional protein encoded by this. The protein is called PERK. And if you do not have PERK expression, then these patients in their brains had an aggregation of the tau protein. So in other words, a misfunction of this protein leads to a tauopathy. In other words, we and others speculated that a activation of the encoded protein, which is called PERK could harness the cells to overcome the detrimental effects of tauopathy and we did that by stimulating both with genetic interventions and pharmacological interventions, the protein, and showed that this protected the cells. So this is one of the mechanisms that is also being served with AMX0035 and therefore, we think this is a very good intervention and of relevance for PSP. The second mechanism that I would wish to elaborate on is mitochondrial dysfunction. We have generated a lot of evidence in the past, together with many other scientists, that a primary mitochondrial defect might be at the origin of PSP at least in a subset of the patients. And this evidence comes mainly from a tropical island called Guadalupe, where there is an incredible high prevalence of PSP much more frequent than in other areas of the world. And we have conducted an epidemiological study, where we have linked the consumption and excessive consumption of these fruits or products derived from these fruits, the so-called graviola fruits to the onset of diseases. So if you have more of these, then you're at higher risk. In these fruits, we did identify toxic substances, which are called annonacin and related products and these are highly lipophilic complex 1 inhibitors, inhibitors of the mitochondrial respiratory chain. If we expose cultured neurons to these inhibitors, then we see a hyperphosphorylation and a somatic aggregation of the tau protein in these cultured neurons in a very dose-dependent manner at a low nanomolar concentration. Now we also seek to identify whether these mechanisms of primary energy metabolism defects might be active also in patients with sporadic diseases outside of Guadalupe and for that purpose, we quantified with MR spectroscopy, high-energy metabolite or ATP and phosphocreatine in the brains of these patients. And indeed, we identified these PSP patients have much reduced high energy phosphates as compared to controlled patients without neurodegenerative diseases. So that does indeed suggest that a primary energy deficit might be a basis, mitochondrial energy deficit might be at the basis of PSP in sporadic patients. And we use that as a rationale in order to study the efficacy, the potential efficacy of coenzyme Q-10 as a putative therapeutic intervention because coenzyme Q10 is counterbalancing the complex 1 deficit induced by these toxins. We did that in a small trial, in a small clinical trial, 6 weeks treatment only. And we observed that patients treated with coenzyme Q10, as opposed to placebo, had indeed an increased functionality, both in the motor functions, in the cognitive functions, and they had an increased level of high energy phosphates in their brains. So in summary, with the unfolded protein response and mitochondrial deficits, both of which are mechanisms that are being served by AMX0035 are of relevance to the pathophysiology of PSP. And I think there is preliminary evidence that targeting these 2 mechanisms might be a good thing to do in order to induce neuroprotection in PSP. So with that, I would like to summarize briefly that PSP, in my understanding, is an ideal disease to study tau-targeting, disease-modifying therapies for a number of reasons. First is primary tauopathy, not an amyloid beta-linked disease. It's frequent enough in order to study or to recruit for clinical trials, but it's still an orphan disease with all the advantages from a regulatory perspective. We have quite specific diagnostic criteria that are internationally accepted. We have validated clinical scales to measure disease progression. We have also natural history data to do solid power calculation. We have good surrogate biomarkers that can be simply and standardized -- used in a standardized manner internationally on classical MRI scanners. And there is no gold standard therapy, so the trials can be done in a placebo-compared manner. With that, I think I can conclude that the strongest argument to run clinical trials in the diseases that we have a very reliable and trusted international community of experts that are keen to study new therapeutic opportunities in that disease. And we are really looking forward to work with Amylyx in order to get the trial done. Thank you very much for your attention.

Thank you. Before we go into Q&A, I would like to spend a few minutes on the design of the Phase III study. I will start by giving you a background on the previous clinical trials in order to provide context on Orion's design. First, there were 3 multicenter trials that employed similar designs to ORION. These trials selected the PSP rating scale or PSPRS as their primary endpoint. As you've heard, this is a 28-item scale that measures disease severity in people with PSP and measures disability across 6 domains, daily activities by history, behavior, bulbar function, ocular motor function, limb motor, gait and midline. Second, the PSP rating scale is a very reliable scale to detect disease progression. As you can see from these 3 trials, the PSPRS detects a consistent rate of disease progression, which is approximately 10 points for 52 weeks. Third, we can apply learnings from these trials to execute ORION. We seek to collaborate with a network of experienced trial investigators and scientists, who have participated in previous studies. Furthermore, ORION will require similar eligibility criteria employed in the previous studies to readily enroll the appropriate study population. The ORION Phase III trial was designed and planned in collaboration with key global academic leaders, people living with PSP and industry advocacy groups. ORION is a Phase III randomized double-blind, placebo-controlled clinical trial that will assess the impact of AMX0035 and compared to placebo on disease progression rate as measured by the PSPRS. We plan to enroll approximately 600 participants with clinically possible or probable PSP and those with Richardson's Syndrome phenotype and those with early onset of disease defined as having less than 5 years of symptom onset. This will likely be the largest PSP trial to date, and enrollment criteria are similar to previously conducted trials in PSP. After a screening period, Participants will be randomized in the 3 to 2 manner to receive AMX0035 for matching placebo twice daily for 52 weeks. Following the treatment period, all participants will have the opportunity to enroll in a 52-week open-label extension phase. This will provide us key insights on long-term safety and efficacy in this population. The primary endpoint is disease progression as measured by the total PSPRS score. As I mentioned, this is well established and validated. Our secondary endpoints include disease progression as measured by the modified 10-item PSPRS score and motor aspects of activities of daily living as measured by the Unified Parkinson's Disease Rating Scale Part II. In consultation with our global group of academic leaders on the additional endpoints, we have selected additional endpoints to encompass measures of brain atrophy, biomarkers, quality of life measures and survival. We plan to enroll participants across the globe in the United States, Canada, Europe and Japan. We look forward to initiating the study, which is anticipated to start by the end of this year. I will now turn it to Josh for closing remarks.

Thank you. Before we go into Q&A, I would like to spend a few minutes on the design of the Phase III study. I will start by giving you -- sorry, -- thank you, Dr. Mehta. To conclude, we are looking forward to launching our global Phase III study in PSP later this year. PSP represents a clear unmet need with no disease-modifying treatments. There is a strong scientific rationale for AMX0035 and PSP, including compelling biomarker evidence of AMX0035 significantly reducing tau, the hallmark protein of PSP. Additionally, there are adjacencies and synergies with ALS, and RELYVRIO received full FDA approval from the U.S. FDA for the treatment of ALS. There is an existing and robust understanding of the natural history of disease. PSP has a well-validated and highly consistent measure of progression. We have the ability to rapidly determine if this drug is effective in PSP. And we have interest and support from KOLs and are collaborating with key global academic leaders like Professor Dr. Höglinger, people living with PSP and advocacy groups on our development program. We're excited about the potential of AMX0035 for people living with PSP. Now I would like to open it up for questions.

[Operator Instructions]. Our first question comes from Corinne Jenkins at Goldman Sachs. What is the available evidence that reduction of tau protein could lead to clinical benefit in PSP?

Thanks, Corinne. So I'll pass that one over to Dr. Höglinger to discuss a little bit why we believe that tau reduction would be important and have a clinical benefit in PSP.

I mean there is a number of lines of evidence that strongly provide rationale to lower the tau aggregation in the brains of these patients. I think what is very convincing is that there is tau and only tau aggregates in the brains of these patients, no other protein. Secondly, the clinical progression is also linked to the progression of tau aggregation. And I think the genetic evidence that I have demonstrated to you with the clear genetic predisposition at the [ highest ] ratio that common genetic variants predisposes for the disease, which is not observed, for example, in other tauophaties, such as Alzheimer's disease provides a clear rationale. Tau is really a primary and key driver of the disease. So I cannot answer the question how much you need to know tau in order to get a clinical improvement. I think this is to be shown by the clinical trials. But the fact that tau lowering is the key mechanism, I think, from my perspective, for the scientific community and undoubted effect.

And is there a point of intervention, this is still from Corinne, at which point we should anticipate a higher degree of clinical benefit? And how will an understanding of the optimal point of intervention feature in the Phase III?

Okay. I'm not quite sure what is meant by point of intervention, whether this is the disease duration, for example, disease severity or whether that relates to the burden of tau in the brain. I think we have no evidence to suggest that any such point does actually exist and whether there is a critical point beyond which an intervention would not make sense and would not be justified. I think with the clinical criteria that we have used to actually define the inclusion criteria into the trial, we try to make sure to get patients as early in the clinical, of course, as possible into the disease so that the putative benefit for the patient is maximum.

Yes. And just adding, I think it stands to reason that the sooner you can get people on therapy, the longer the period they have to potentially benefit. So we did design this study to look fairly early in the course of PSP.

And then just one other question from Corinne. What benefit of RELYVRIO was assumed in the powering decision to enroll 600 patients in the Phase III study?

Sure. I'm happy to take that. So I think we showed a little bit about some of the literature on the powering during the presentation. What you may have seen is that with about 300 patients, a 20% effect could be detected. So you might presume that with 600 patients, even a much smaller effect could be detected. But I think especially where we're running a single large Phase III study, I think our goal is to get persuasive evidence that this drug is effective. And so I think we've designed the study to have strong power to do that and to detect even, hopefully, substantial effects, but even if the effects are smaller, to still be able to detect those.

And then our next set of questions come from Graig Suvannavejh at Mizuho. What's your view on why prior anti-tau-specific MAb approaches have failed in the clinic?

Sure. Maybe I'll say a sentence on it and pass it to Dr. Höglinger to give a little further. At least from my perspective, I think, first, it's important to note, antibodies are generally extracellular acting agents. So I think the general goal of these is to prevent the spread of tau. But it doesn't necessarily address the tau within a cell. And these 2 antibodies that were trialed, we're really focused on this end terminal species of tau, which is a very specific subset of tau. And that may be responsible for them not having the effect that they hope to. But I'll pass to Dr. Höglinger to give more depth and insight on this.

Yes, there is not much more I have to add, actually, to that statement. First, I think one can reconsider whether tau antibodies are actually the right thing to do because they only target the extracellular compartment, whereas the major aggregation is actually taking place intracellularly. So if at all, then they act on the spreading of tau pathology. But still, if that mechanism is believed to be of true potential than these 2 antibodies that have been tested in clinical trials were targeting the end terminals, and we know meanwhile that in terminal tau is not prevalent to a high degree, at least in CSF, the patients and the mid-region tau antibodies are more efficacious in adequate cellular models and animal models, as we know by now. And is also more prevalent in human patients. So I think there is reason to be optimistic for the mid region to antibodies, and this is primarily the reason why the internal antibodies very likely did fail.

And also from Graig, how might you select AMX0035 dosing in the PSP study versus the other studies with AMX0035?

Justin and Dr. Mehta, do you want to take that one?

Sure, Josh. I can start first. First, we established the dose in our Phase II CENTAUR trial in ALS as well as our Phase II PEGASUS trial in AD. And we've seen consistent efficacy and consistent safety profiles with our established dose. And the same dose was shrunk to a significantly lower tau in our AD trial. So this is really the rationale why we want to use the same dose for PSP. And in the active arm, AMX0035 will be administered twice daily.

Yes. And I'd just add, as we look at potential other indications, obviously, we'll do a case-by-case analysis. But I think as Dr. Mehta outlined, in this particular case, there's a very strong rationale on both the safety, biomarker engagement and efficacy in another disease at this dose. So it's got a very strong rationale behind it.

And just one more question from Graig. In PSP, which BMs do you think are most informative and correlate with clinical efficacy, NfL, GFAP, others.

Yes. So I assume by BM, you mean biomarkers. And maybe going with that, probably best, I'll pass to Dr. Höglinger to kind of go through that in PSP.

Yes. So I mean there is quite good evidence that NfL up-regulated in the CSF of patients as a reflection of ongoing cell death. And therefore, if we would manage to reduce NFL levels, this would be a quite strong argument that we are protecting cells. I think I would probably not only refer to fluid biomarkers, but also imaging biomarkers and we are also incorporating MRI atrophy, which has been shown, as I've shown you in my slides, as a very reliable progression parameter, which can also be used with high power as a parameter to determine because of an interventional drug.

And our next question comes from Neena Bitritto-Garg at Citi. Without the use of tau PET for screening, how confident are you that you will enroll a true PSP population? Is lack of tau PET and inclusion intended to maintain the ability to avoid a label restriction?

Yes. I'll pass over to Dr. Höglinger to talk about the kind of biology, and maybe I can talk briefly about the label aspect you brought up. But yes, Dr. Höglinger, do you want to share how the diagnostic criteria help us to select people who have tau pathology?

Yes. So we have designed the diagnostic criteria in a way that we have stratified levels of diagnostic certainty. And the certainty level of probable PSP that we will apply for the inclusion criteria into this particular trial have been validated in clinical pathological case areas of a substantial size. And we know that these criteria have specificity in the order of more than 90%. So there is no need for any other aspects than the clinical criteria to predict that these patients have tau pathology in the brains of the patient. With regard to the tau PET, I think there is no demonstration as of so far whether this would increase the specificity of the diagnostic criteria since the tau PET ligands that we have attended before has been developed for Alzheimer's disease and not for PSP. So it remains to be shown whether this would increase the diagnostic specificity. And I think there is not even a need for that. That has nothing to do with labels. This is just pure fact actually that the clinical diagnostic criteria are sufficient in nature in order to make the diagnosis.

Yes. Thanks, Dr. Höglinger. And yes, I was going to say a very similar thing on the label side. We've designed this study based on the science and it's probably early to discuss label, but we're just trying to run the best scientific study we possibly can.

Excellent. And our next question comes from Charlie Yang at BofA. Can you discuss the rationale for conducting a large Phase III trial without doing a smaller Phase II trial first?

Justin, do you want to take that one?

Yes, very happy to. And great question. So I think in short, it's exactly what we're just presenting on, which is, I think, first is a very strong rationale to run a study of AMX0035 in PSP based on both the mechanism, the preclinical work and the clinical work. Then in terms of dose, we have a dose that was found to be safe and efficacious in ALS, safe in Alzheimer's and lower tau as well as possible tau all at the same dose. So there's -- in short, there's a very strong data package supporting the rationale to test in PSP. The question now is, will this be an effective therapy. And the way to answer that is a Phase III study. So maybe the short way to answer is we've answered all the questions that one would want to answer in a Phase II study. So it makes sense to go to a Phase III study. And I think in terms of the overall design event, pass to Dr. Mehta to share a little more about the kind of design of the study.

Sure. Thank you, Justin. So as Dr. Höglinger and Josh mentioned before, we're seeking to enroll 600 participants in the study with a diagnosis that has been well tested in previous clinical trials. And so we -- this will be similar to our previous impressions, where we will have sufficient power to detect a treatment effect on the PSP rating scale and essentially provide evidence that this treatment can be beneficial for this community. We believe that we're deploying the same type of design as the previous trials, and we're also leveraging natural history data where there has been a consistent 10-point change or decline in the PSP rating scale over 52 weeks. And so by using this -- by using a similar set of design, we hope to capture a treatment effect with AMX0035.

And our next question comes from Marc Goodman at Leerink. How long does it take to enroll a 600 PSP patient study? How do you ensure you are enrolling the right patients?

Yes. Maybe I'll make a quick passing comment and then hand that over to Dr. Höglinger. So when we looked at the past Phase II and Phase III studies that have been run in PSP, they've generally been conducted over a time period of about 2 or 3 years. And so I wouldn't expect us to be markedly different. But to talk about this study specifically and in terms of getting the right patients, maybe I'll pass it to Dr. Höglinger.

Yes. Thank you. I mean the previous 2 tau targeting antibody trials that I have shown to you were recruiting in 1.5 to 2 years a similar number of patients. So in parallel, both studies were actually recruiting in parallel. And both studies were actually seeking the same type of patients as we have defined as per our inclusion criteria. So I don't foresee any major issues with that recruitment.

And then one more from Marc. Can you talk about the powering of ORION and what gives you confidence that 42 weeks is the right duration for treatment?