Good afternoon. 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 in 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, Professor 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 in PSP, and Dr. Lahar Mehta, our Head of Global Clinical Development. Joining us for Q&A will be Jim Frates, our Chief Financial Officer. If you would like to ask a question, you may do so at any point during the presentation by submitting a question in the Q&A panel on your browser.
If you do not see this panel, please click on the blue Q&A icon on the far right of the bottom bar of your screen, which will open up a chat window to submit your question. 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 end 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 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. We are so honored to be joined by Professor 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 and PSP with you today. The figure on this slide is taken from a review published in Cell earlier this year. As shown, the authors summarized eight hallmarks for neurodegenerative disease. Despite heterogeneous clinical presentation, these mechanistic hallmarks are seen across neurodegenerative 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, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, neuronal cell death, and finally, pathologic protein aggregation. As shown on this slide, these protein aggregates may be more disease specific, like in the case of TDP-43 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 interconnected, highlighting the need for therapies that can target different key pathways. 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. More generally, in vitro, AMX0035 has reduced neuronal cell death.
Pathways this can occur through include the Bax/Bak 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 tau, 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. Let's move from the general rationale of AMX0035 in neurodegenerative 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 six to eight years from symptom onset and tends to be progressive during that time, with people's disability becoming worse and worse.
Globally, PSP's prevalence is seven in 100,000 people worldwide, and incidence is roughly one in 100,000. Looking at the United States, PSP affects 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 is a tauopathy characterized by an aggregation of tau in specific areas of the brain. We hypothesize that impacting tau deposition will lead to a disease-modifying effect. 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. As noted earlier, these are two of the hallmark neurodegenerative disease pathways that 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 feedback 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 then leading to the devastating clinical manifestations seen in PSP.
This figure also highlights that the proposed mechanisms AMX0035 impacts are 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 in PSP, starting with sodium phenylbutyrate or PB. In terms of proposed mechanism, in a variety of in vitro experiments, sodium phenylbutyrate upregulated and recruited 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, in vitro experiments, TURSO stabilized the mitochondrial membrane by reducing the translocation of cell death regulator Bax, which leads to improved mitochondrial function and energy production and an increased cell apoptotic threshold.
Again, to place in context for PSP, impairment of mitochondrial function has been shown in cybrid 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 this stress. In addition to preclinical data on PB and TURSO individually, we have a wealth of preclinical data on the synergistic effects 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 stressor that will cause cell death, hydrogen peroxide, was added to neurons, and we looked to see if either PB, TURSO, or the combination AMX0035 could prevent this cell death.
Either PB or TURSO administration alone prevented a moderate % of neuronal cell death in this in vitro experiment. The AMX0035 combination prevented nearly 100% of neuronal death in this model, indicating that the AMX0035 combination demonstrates synergistic protection of 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 an in vitro cell model and one a mouse model. 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. Moving from 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 both phospho-tau 181 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. 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. We performed proteomic analyses.
Shown 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 and plasma, tau was the most significantly changed protein by AMX0035. This is one of the reasons we are so excited to study AMX0035 and 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. 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 in 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. In an analysis measuring 288 proteins, tau was the most changed by AMX0035 treatment. In ALS, AMX35 slowed disease progression and improved survival. We are extremely excited about the science supporting the study of AMX0035 in PSP.
We've seen significant and strong support from key opinion leaders in PSP and are excited to work with them to test AMX0035 in 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. I would like to turn it over to Prof. Dr. Günter Höglinger to discuss the PSP disease and treatment landscape.
The 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. This is the place where I'm currently working, and this is my disclosures. I work with a number of different companies, develop therapies for neurodegenerative diseases. 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 a neurologist and a neuropathologist working together and describing a small series of patients they had observed with a particular clinical phenotype, combining supranuclear gaze palsy 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. We have conducted 10 years ago, a 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 phosphorylated 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. The tau protein, which aggregates and which causes the degeneration of the neurons in the disease. The odds ratio to predispose for the disease is extremely high, much higher than any other predisposing gene associated with other neurodegenerative disease. This tells us that tau is really the key driver of neurodegeneration in PSP. As we can observe on neuropathological analyses in the brains of these patients, tau is aggregating both in neurons but also in glial cells, in astroglial cells and in oligodendroglial cells.
This is a major difference as opposed, for example, to Alzheimer's disease, where there is only neuronal tau aggregates, and where we do also have a second protein to aggregate, which is amyloid beta. PSP, in 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 the 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 syndrome as the key clinical manifestation of the disease. 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. What we have elaborated is a very simple-to-use clinical grid. This is clinical features from the domains oculomotor dysfunction, postural instability, akinesia, and cognitive dysfunction. It's in principle, very simple to identify clinical features that neurologists all over the world are currently using to identify these patients. These criteria have been validated in clinical pathological case series, we know that patients identified with these criteria have a 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. 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. This is, of course, a very severe impact on the patient's activities of daily living. The second key feature is repeated unprovoked falls and postural instability. 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, falls, head injuries, and very frequent causes of bleedings in the brain and a severe risk for mortality of these patients. One feature which is also very prominent is these patients, is dysphagia.
You can see here on that video, a patient trying to swallow a glass of water. 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. This is a very severe aspect of the disease, predisposing them for early mortality. On average, these patients have a life expectancy of six to seven 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 atlas, which you can have a look at in the Internet, to familiarize yourself with the problems these patients are suffering from. The impact this suffering also has on the families of these patients.
We have jointly developed also a tool to use and to apply these 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 we use in addition to the clinical examination in order to substantiate our clinical suspicion of PSP? The first and foremost, we always do is a routine MRI of the patient's brain, 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. It's mainly the so-called midbrain, which is located here, right in the center of the patient's brains, which is shrinking and atrophic.
Some people have an association of seeing a Mickey Mouse sign or a colibri sign or a penguin here in the brain of these patients, which gives rise to the name of a penguin sign, colibri sign, Mickey Mouse sign. This is features that we look out for in order to identify these patients' diagnosis. There is also new diagnostic tools that are currently being developed, such as tau PET, for example. We use radiotracers in order to identify the tau depositions in the brains of these patients. You see in the top row, for example, a brain scanned with that particular tracer, PI 2620, of a healthy control without neurodegenerative diseases.
You can see on the bottom row, for example, a brain of a patient with PSP, where you can see here, 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. 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 their akinesia and rigidity, so 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. All of these effects are mild in impact and transient in their time, and all of these do actually not have any effect on the progressive nature of the disease, so they don't stop or retard 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 used tool is a clinical rating scale that has been developed by Larry Golbe, 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, mentation, bulbar exam, oculomotor exam, limb movement, and gait and midline exam. We rate a score from 0, meaning no impact on patients' activities of daily living, and 100, which is very severely affected. As you can see here on that graph, the scale actually progresses very linearly with time and 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 and the PSP Rating Scale, as used, and determined in a number of different clinical trials, as they are cited here on the left. 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. 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.
If we, for example, expect that our drugs reduces the progression rate of the natural history of the patients by 25%, then we would require 200 patients per arm, which means active treatment and placebo treatment, in order to get a statistical significance of that difference. This is reasonable numbers that we can actually recruit in trials with PSP. We have demonstrated in past clinical trials. We have also used MRI as a progression measure, a objective and rater independent, quantitative tool in order to measure the progressive atrophy within 12 months of disease progression.
The atrophy rate that we can visualize, and particularly in well-defined regions of the brain, correlates well with the disease progression, and is therefore accepted as a surrogate parameter, as a secondary endpoint or exploratory endpoint, at least in clinical trials. 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.
There is an altered 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 expression of the tau gene. We also know that tau is expressed in six different isoforms, and there is specific isoforms, the so-called four repeat isoforms, that are particularly prone to aggregate in the patient's brains, and therefore, splice altering factors are also being currently debated and discussed, and studied as a disease-modifying intervention. We do also know that tau protein is post-translationally modified.
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. This is also a target for putative interventions, for example, to alter these post-translational modifications, or to disentangle the tau aggregates with anti-aggregational compounds. Finally, we also know that the aggregates or oligomeric tau specimen, leave aggregation-bearing cells and pass the extracellular space in order to invade previously healthy cells in a prion-like propagation pattern. The release mechanisms, the uptake mechanisms, are also subject to scientific studies in order to prevent the spreading.
By their passage through the extracellular space, there is also an opportunity to trap 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 cells in previous clinical trials. One antibody that we had tried was the so-called tilanemap antibody, an N-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.
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 gozuranemab, and again, there was excellent target engagement, so a marked 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 two tau targeting antibody trials, and we and others think that probably the targeting epitope was a wrong epitope or not an appropriate epitope, because both of these antibodies target the N terminus of the tau protein, whereas the aggregation-prone domain is located in the middle region of the tau protein.
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 proteins. 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 this or identified this one key player of this mechanism in our genome-wide association study. One of the hits we identified is a gene called eIF2 alpha kinase 3.
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 a activation, an aggregation of the tau protein. 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. We did that by stimulating, both with genetic interventions and pharmacological interventions, the PERK protein, and showed that this protected the cell. This is one of the mechanisms that is also.
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. This evidence comes mainly from a tropical island called Guadeloupe, where there is an incredible high prevalence of PSP, much more frequent than in other areas of the world. 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 these diseases. If you eat 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 I 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. We also seek to identify whether these mechanisms of primary energy metabolism defects might be active also in patients with sporadic diseases outside of Guadeloupe. For that purpose, we quantified with MR spectroscopy, high energy metabolites or ATP and phosphocreatine in the brains of these patients. Indeed, we identified these PSP patients have much reduced high energy phosphates as compared to control patients without neurodegenerative diseases.
That does indeed suggest that a primary energy deficit, a mitochondrial energy deficit might be at the basis of PSP in sporadic patients. We use that as a rationale in order to study the efficacy, the potential efficacy of coenzyme Q10 as a putative therapeutic intervention, because coenzyme Q10 is counterbalancing the Complex I deficit induced by these toxins. We did that in a small trial, in a small clinical trial, six 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.
In summary, both 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. I think there is preliminary evidence that targeting these two, these two mechanisms might be a good thing to do in order to induce neuroprotection in PSP. 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, it's a primary tauopathy, not an amyloid beta-linked disease. It's frequent enough in order to study clinic 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 used in a standardized manner internationally on classical MRI scanners. 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 that disease is that we have a very reliable and trusted international community of experts that are keen to study new therapeutic opportunities in that disease. 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. There were three multi-center 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 six domains: daily activities by history, behavior, bulbar function, ocular motor function, limb motor, gait, and midline. The PSP Rating Scale is a very reliable scale to detect disease progression. As you can see from these three trials, the PSPRS detects a consistent rate of disease progression, which is approximately 10 points per 52 weeks.
We can apply learnings from these trials to execute ORION. We seek to collaborate with a network of experienced trial investigators and sites who have participated in previous studies. 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 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, those with Richardson syndrome phenotype, and those with early onset of disease defined as having less than five years of symptom onset.
This will likely be the largest PSP trial to date. Enrollment criteria are similar to previously conducted trials in PSP. After a screening period, participants will be randomized in a 3 to 2 manner to receive AMX0035 or 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 two.
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. 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 US 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. 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 impact of AMX0035 for people living with PSP. I would like to open it up for questions.
Thank you so much, Josh. As a reminder, you can submit your questions by clicking on the blue Q&A button on the far right of the bottom bar on your screen, which will open up a chat window to submit your question. 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. 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 high odds ratio, that common genetic variants predisposes for the disease, which is not observed, for example, in other tauopathies, such as Alzheimer's disease, provides a clear rationale. Tau is really a primary and key driver of the disease. I cannot answer the question, how much you need to know about 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 it's, from my perspective, for the scientific community, an undoubted fact.
Is there a point of intervention, this is still from Corinne, at which point we should anticipate a higher degree of clinical benefit? How will an understanding of the optimal point of intervention feature in the phase III?
Um, Doctor.
I'm not.
Yeah, Dr. Höglinger, you can take that.
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 course as possible into the disease so that the putative benefit for the patient is maximum.
Yeah, just adding, I think it stands to reason that, you know, the sooner you can get people on therapy, you know, the longer the period they have to potentially benefit. We did design this study to look fairly early in the course of PSP.
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. I think we showed a little bit about some of the literature on the powering during the presentation. You know, what you may have seen is that with about three patients, a 20% effect could be detected. You might presume that with 600 patients, even a much smaller effect could be detected. I think especially while we're running, you know, a single large phase III study, I think our goal is to get persuasive evidence that this, that this drug is effective.
I think we've designed this study to have strong power to do that and to detect, you know, even, you know, hopefully, you know, substantial effects, but even if the effects are smaller, to still be able to detect those.
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, then 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. 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. These two antibodies that were trialed were really focused on this N-terminal species of tau, which is a very specific subset of tau. That may be, you know, responsible for them not having the effect that they hope to. I'll pass to Dr. Höglinger to give more depth and insight on this.
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. If at all, then they act on the spreading of tau pathology. Still, if that mechanism is believed to be of true potential, then these two antibodies that have been tested in clinical trials were targeting the N-terminus. We know, meanwhile, that N-terminal tau is not prevalent to a high degree, at least in CSF of the patients, and the midregion 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.
I think there is reason to be optimistic for the midregion tau antibodies. This is primarily the reason why the N-terminal antibodies very likely did fail.
Also from Greg: How might you select AMX0035 dosing in the PSP study versus the other studies with AMX0035?
Justin and Dr. Mehta, 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. We've seen consistent efficacy and consistent safety profiles with our established dose. The same dose was shown to significantly lower tau in our AD trial. This is really the rationale why we want to use the same dose for PSP. In the active arm, AMX0035 will be administered twice daily.
I just add, you know, as we look at, you know, potential other indications, obviously we'll do a case-by-case analysis. I think as Dr. Mehta outlined, I think, you know, in this particular case, there's a very strong rationale on both the safety, biomarker engagement and efficacy in another disease that at this dose, it's got a very strong rationale behind it.
Just one more question from Greg: In PSP, which BMs do you think are most informative and correlative with clinical efficacy, NfL, GFAP, others?
Yeah. I assume by BM, you mean biomarkers.
Yeah.
-maybe going with that, probably best I'll pass to Dr. Höglinger to kind of go through that, in PSP.
I mean, there is quite good evidence that NfL is upregulated 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. 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 efficacy of an interventional drug.
Our next questions come 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?
Yeah, I'll pass over to Dr. Höglinger to talk about the kind of biology, and then maybe I can talk briefly about the label aspect you brought up. Yeah, Dr. Höglinger, do you want to share how the diagnostic criteria, you know, help us to select people who have tau pathology?
We have designed the diagnostic criteria in a way that we have stratified levels of diagnostic certainty. 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 a specificity in the order of more than 90%. 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 patients. 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 tested before have been developed for Alzheimer's disease and not for PSP.
it remains to be shown whether this would indeed increase the diagnostic specificity, and I think there is not even a need for that. It has nothing to do with labels. This is just a pure fact, actually, that the clinical diagnostic criteria are sufficient in nature in order to make the diagnosis.
Yeah, thanks, Dr. Höglinger. Yeah, I was going to say a very similar thing on the label side. We've designed this study, you know, based on the science. It's probably early to discuss label, but we're just trying to run the best scientific study we possibly can.
Excellent. 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, you want to take that one?
Yeah, very happy to, and great question. You know, I think in short, it's exactly what we were just presenting on, which is, I think first, there's a very strong rationale to run a study of AMX0035 in PSP based on both the mechanism, the preclinical work and the clinical work. 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 phospho-tau, all at the same dose. 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? The way to answer that is a phase III study.
Maybe the short way to answer is we've answered all the questions that one would want to answer in a phase II study. It makes sense to go to a phase III study. You know, I think in terms of the overall design of that, and I'll pass to Dr. Mehta, to share a little more about, you know, the, design of the study.
Sure. Thank you, Justin. As Dr. Höglinger and Josh mentioned before, you know, we're seeking to enroll 600 participants in the study with a diagnosis that has been well tested in previous clinical trials. This will be similar to our previous approaches, 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, you know, we're employing 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.
By using a similar set of design, we hope to capture a treatment effect with AMX0035.
Thanks. 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?
Yeah, maybe, I'll make a quick passing comment and then hand that over to Dr. Höglinger. When we've 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 two or three years, and so I wouldn't expect us to be markedly different. To talk about this study specifically and in terms of getting the right patients, you know, maybe I'll pass it to Dr. Höglinger.
Yeah, thank you. I mean, the previous two tau targeting antibody trials that I have shown to you were recruiting in 1.5 to two years, a similar number of patients. 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. I don't foresee any major issues with that recruitment.
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?
Sure. You know, maybe put briefly, you know, as we shared in the, in the slides, you know, previous published studies have shown that with about 300 patients, you're powered to detect, you know, a 20% effect. We here have approximately, you know, we'll recruit approximately 600 participants, which should give us substantially more power than that. Even the ability to detect a smaller effect or to show a very persuasive result on a, you know, on a 20% or larger effect. I'll talk to Dr. Mehta to, you know, talk a little bit about why we selected the duration of the trial we did, and to provide any other color on the powering, if you'd like to.
Sure. Thank you, Josh. Once again, we feel confident that 52 weeks would be sufficient to see a treatment effect. As the previous three trials have shown, all three have shown a 10-point change on the PSP Rating Scale, in terms of the natural history of decline. This consistency has given us confidence that when we designed the study, that if we can assess for at least a 20% effect, we would have sufficient power if we enrolled 600 patients. We believe that this sample size will give us, will give the study, well positioned to really detect a robust result.
Thanks, Lahar. The next questions come from Mike DiFiore at Evercore. The only current FDA-approved tau tracer is fluorotaucipir F 18, which has demonstrated insensitivity in earlier stages. How do you intend to address these concerns in the phase III?
Yeah, maybe Dr. Höglinger, do you want to take that one?
Well, that particular tracer is approved for Alzheimer's, but not for PSP. There is no tracer approved for PSP, and we don't envision to use a tracer, as we have already elaborated, because the clinical diagnostic criteria are also already fit for purpose to identify the population that we need.
Could you elaborate on how and to what magnitude AMX0035 affects eIF2?
Good, good question. We have not clinically assessed eIF2 specifically. eIF2 is involved in ER stress pathways, and there is some literature on data with the components of AMX0035 against that target. Exactly the magnitude it affects eIF2 clinically, you know, we don't have data on at this time.
I'll just say in terms of preclinically, and from an ER stress perspective, there's, you know, significant interest right now in targeting different parts of the ER stress or unfolded protein response. eIF2 alpha is one of them, and I think there's compelling research around that. You know, our data and data previously, particularly with sodium phenylbutyrate, shows that it broadly helps across the ER stress pathway. It's not specific to any one pathway. That was one of the, you know, main rationales for studying it originally, preclinically, as per the rationale, as Dr. Timmons said, as well as I think the interest for PSP, giving Dr. Höglinger's and others work.
Great, thanks. The next set of questions comes from Ananda Ghosh at H.C. Wainwright. PSP, like AD, has diverse clinical presentations. What would be the patient eligibility criteria for ORION to maximize success?
I'll pass that over to Dr. Höglinger.
Yeah. We, I didn't elaborate on that too much in the presentation. I focused mainly on Richardson syndrome because this is the clinical predominance type that we will actually recruit for that trial. There is a broader spectrum, and this is well described in a number of publications and also in the PSP diagnostic criteria from the Movement Disorder Society. We focus mainly on PSP Richardson syndrome for patients to be recruited for a number of reasons. First, it's the most frequent clinical phenotype. Second, the natural history data are all available for PSP Richardson syndrome. The other phenotypes have diverse rates of disease progression. If we want to expand beyond Richardson syndrome, we would get a huge variability into the clinical data set, and that would probably spoil all of the possibilities to get outcomes.
We are fully aware also of the broader phenotypic spectrum of the disease, I think if we manage to get a signal in PSP Richardson syndrome, it will be a logical next step also to expand to the other phenotypes, foremost PSP of Parkinson's predominant and corticobasal syndrome, in order to demonstrate, probably in a phase IV clinical trial, efficacy also in the spectrum beyond Richardson syndrome.
Thanks. Just one more from Ananda. What is the general view in the field of how much tau aggregation has to be removed till one sees clinical effect?
I'll maybe pass that to Dr. Höglinger.
I think there is no feeling because we don't have a drug that actually managed to get clinical efficacy. In Alzheimer's disease, I think there is emerging consensus that the amyloid burden has to go down to 0 in order to get clinical efficacy. There is quite convincing evidence about that, recent brain papers to support that across clinical trials. In PSP, I think that kind of evidence has to be generated, and I don't want to make too courageous forward-looking statements on that regard.
Thanks. The next question comes from an investor. Are there any toxic effects of the drug from in vitro and in vivo studies?
I guess I would generally say no. You know, we've studied this clinically, and what we saw in terms of adverse events, the most common ones we saw were mild gastrointestinal AEs that generally resolved within a few weeks. As well as, you know, the drug naturally has a somewhat bitter taste, you know, which came up from time to time. Generally, this drug has been, you know, quite safe and well-tolerated. I'll pass it to Dr. Timmons to give any more color there as well.
I can't think of anything else. I know the question was pre-clinically. I was thinking back to the pharmacodynamic studies we mentioned, I can't recall any specific toxicity coming up with those. Of course, clinically is where, you know, safety is of the highest importance, and they're generally well-tolerated, diarrhea being the main adverse event.
Thanks. Another question from an investor: Dr. Höglinger, if approved, how would AMX0035 fit into your patient's current treatment plan?
Yeah, as I have outlined, we do have symptomatic treatments which provide temporary and limited relief to the patients. We do not have any drug that would slow down the disease progression. If approved, I think there would be a huge market for all types of PSP patients as a permanent baseline treatment in order to slow down disease progression. I think this is a very open market without any competition so far.
Just a quick follow-up from that person: If AMX0035 was approved for PSP, how long would your patients tend to stay on it?
Yeah, big, good question. I think, as a, as a tendency, I would say that this is a lifelong treatment. If patients are diagnosed, they would probably get on treatment because this would be the first-in-class disease-modifying therapy. Unless there is any evidence to suggest that the treatment would lose its efficacy throughout the course of the disease, I think I would not see any reason to stop the treatment.
Thanks. Our next question, just one more from Charlie Yang at Bank of America. Has AMX0035 shown to prevent brain atrophy in ALS/Alzheimer's?
I'll pass that over to Dr. Timmons.
In ALS, we did not have imaging as part of our ALS clinical trial, so unfortunately can't answer that. From the Alzheimer's standpoint, we did have imaging there. Very difficult to draw a conclusion, just given the small sample size of the study. It was really more exploratory, looking at biomarkers and seeing the effect on tau that we saw. I would say verdict is still out, in both ALS and Alzheimer's in terms of brain atrophy.
The next question comes from an investor: Are you confident that the design and accuracy of the study could appeal to European authorization agencies?
Maybe I'll say briefly that, you know, we don't.
Yeah.
Oh, sorry. Go for it, Dr. Höglinger.
Go, go ahead.
I would say that, you know, we usually don't go into too much depth back and forth with the, you know, kind of regulatory interactions. Certainly, we intend for this to be a global study and certainly have, you know, attempted as best as possible to take into account thoughts and feedback, from global regulatory authorities. Obviously, we can't promise today whether or not this will be acceptable. We just, of course, design it as best as we possibly can to do so. Maybe Dr. Höglinger, if you want to add on that.
Yeah, the trial design is very classic. It's pretty much similar and related to the design as it had been used in previous trials that had passed by European medical agencies. I don't see any risk associated to the trial design.
Thanks. If time, two more minutes. Just one more from Ananda Ghosh at H.C. Wainwright. Given that AMX0035 acts at the execution phase of neurodegeneration, what kind of biomarkers might be critical concerning trial design that might capture slowing of neuronal death?
Maybe I'll pass that to Dr. Mehta.
Sure. Some of the markers that may reflect the slowing of neuronal death with AMX0035 could be gleaned from our results in our PEGASUS study. This would include lowering of various tau species that would be informative. Furthermore, we've also shown markers of inflammation that have been reduced, and so that would be another area of interest, as well as synaptic connectivity, and with looking at markers of neurogranin. These are, you know, this is the ability where we've been able to take our learnings from Alzheimer's and apply them in PSP. This is what tells us what the drug can do, and we hope to confirm this in PSP and expand the field.
Yeah, and I'd just add maybe to that, you know, just some of them, just for those who maybe haven't looked at the, you know, Alzheimer's data recently, some of the other markers we were interested in included YKL-40, you know, also known as chitinase-3-like-1, as well as neurogranin, and some inflammatory markers as well as Dr. Mehta shared. I think Dr. Höglinger shared earlier, too, there's also a lot of strong evidence that progression can be tracked through imaging in progressive supranuclear palsy. And that's certainly something we would measure as well.
Yeah, just one last thing to add on to this as well is that, you know, I think it's our view, and as Professor Dr. Höglinger was sharing, that many of these pathways are not just at the end of the disease, but in fact may be accelerants or even drivers of the disease. If when you look at ER stress, when you look at mitochondrial dysfunction, it's not just that they cause cell death, I think that's the end result. But it seems like these are present likely throughout the course of disease, which is why I think not. You know, we certainly are excited based on the biomarker results we have, but also the mechanistic rationales, I think why Professor Dr.
Höglinger and others in the PSP field are excited about the prospects of this treatment in PSP.
Excellent. Thanks so much. We have reached time, but if anybody has any further questions, please reach out to me, Lindsey Allen, at the company, and we're happy to help get you the answers you need. With that, I'll turn it back to Justin for closing remarks.
Thank you all very much for joining us. We hope that was informative and helpful. We really appreciate your attention and your great questions. Also, especially, thanks to Professor Dr. Höglinger, who's truly one of the world experts in progressive supranuclear palsy, in joining us and helping to answer questions and provide his perspectives both on PSP as well as in this trial in general. As Lindsey said, you know, we look forward to the continued discussions with you all, and we're very excited about the potential of AMX0035 for people with PSP. Thank you all very much, and hope you have a great rest of your day as well.