Novel therapy

Abstract

Provided herein are methods of treating or preventing neurological or neurodegenerative diseases or disorders using ATH434 or a salt thereof, or using a pharmaceutical composition comprising ATH434 or a salt thereof.

Description

NOVEL THERAPY CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of US provisional application no.63 / 670,299, filed July 12, 2024, and US provisional application no.63 / 748,706, filed January 13, 2025; each of which is incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure relates to methods of treating or preventing neurological or neurodegenerative diseases or disorders using ATH434 or a salt thereof, or using a pharmaceutical composition comprising ATH434 or a salt thereof. BACKGROUND

[0003] Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability. Idiopathic Parkinson’s disease (PD) is the most common neurodegenerative cause of parkinsonism. Other causes of parkinsonism, such as Multiple system atrophy (MSA) and Dementia with Lewy bodies, are characterized as “atypical” as they have a poor response to dopaminergic therapy and comorbidities that greatly impair daily function and quality of life (Deutschländer et al 2018). These conditions are unified pathologically by the presence of aggregated α-synuclein in the central nervous system. Hence, they are commonly referred to as the synucleinopathies.

[0004] MSA is a rare, rapidly progressive and devastating neurodegenerative disorder affecting adults. It is characterized by diverse clinical manifestations, including parkinsonism, ataxia, and failure of the autonomic nervous system. The latter system regulates blood pressure, bowel function and bladder control. Parkinsonism in MSA either responds poorly to standard treatments such as levodopa, or the response is not sustained over time. Non-motor symptoms cause significant disability and may precede motor impairment in up to 75% of patients (Jecmenica- Lukic et al 2012, Vanacore et al 2001).The progression of MSA may vary, but the condition is unremitting and usually results in death within 6 to 10 years after symptom onset (Fanciulli and Wenning 2015, Coon et al.2015). The neuropathology of MSA involves the basal ganglia, a groupof subcortical brain regions that control voluntary movement and other critical functions, along with the thalamus, limbic regions, dentate nucleus of the cerebellum, and intermediolateral cell columns of the spinal cord.

[0005] Onset of MSA typically occurs between 50 and 60 years of age (Batla et al 2018). Current treatment of MSA is directed at symptom management and may be pharmacologic or nonpharmacologic in nature (Laurens et al 2017, Perez-Lloret et al 2015). There are no specific therapies for cerebellar symptoms, although benzodiazepines may be used empirically to treat myoclonus. With the exception of treatment for orthostatic hypotension, pharmacologic therapy in MSA is not based on scientific evidence but rather on expert opinion (Perez-Lloret et al 2015, Rey et al 2014). To the best of the inventors’ knowledge, there are no approved therapies that address the underlying pathology of the MSA (Poewe et al, 2022).

[0006] Alpha (α)-Synuclein is a 140-amino acid minimally phosphorylated protein, expressed predominately in neurons, that plays a vital role in the regulation of neurotransmission (Wong and Krainc 2017). In healthy neurons, α-synuclein is soluble and functions by reversibly binding to membranes and regulating the release of synaptic vesicles (Burré et al 2010). The synucleinopathies are characterized by intracellular aggregations of α-synuclein-filled neuronal inclusions in PD and Dementia with Lewy Bodies (DLB) or as glial cytoplasmic inclusions in oligodendroglial cells (ODGs) in MSA. Aggregation of α-synuclein in dopaminergic neurons in the presence of oxidative stress is thought to lead to dopaminergic cell loss and PD (Clayton and George 1998). The Lewy bodies observed in PD and DLB are comprised primarily of α-synuclein (Kaji et al 2020, Polymeropoulos et al 1997). In MSA, the α-synuclein in the ODGs becomes hyperphosphorylated and forms soluble fibrils. As fibrils bind increasingly to glial membranes, insoluble α-synuclein aggregates with other myelin-associated proteins to form glial cytoplasmic inclusions (GCIs) (Bleasel et al 2014). Oligodendroglial cells containing GCIs have reduced myelination capacity and hence trophic support for neurons is impaired (Song et al 2007, May et al 2014, Wong et al 2014). As a consequence, the α-synuclein-induced damage of ODGs leads to the neuronal degeneration that underpins disease pathogenesis.

[0007] Iron is essential for prokaryotic and eukaryotic cell function as it is required for energy production through the electron transport chain and for the function of numerous enzymes. To facilitate these actions, vanishingly small amounts of loosely bound iron is present within cells. Patients with PD and MSA have increased localized iron in regions of the brain that is thought topromote neurodegeneration. More specifically, increased levels of iron have been observed in the substantia nigra (SN) of PD patients and in the SN and lentiform nucleus of MSA patients, both on postmortem examination and MRI (Acosta-Cabronero et al 2017, Aquino et al 2014, Dexter et al 1991, Han et al 2013, Wang et al 2012).

[0008] In the pathogenesis of MSA and Parkinson’s disease, the progression from healthy to diseased cells is a complex process that is correlated with elevated iron and accumulation of aggregated α-synuclein. Through both increased translation (Uversky et al 2001) and post- translational modification (Hashimoto et al 1999, Souza et al 2000), iron directly increases the potential for soluble oligomers of α-synuclein to form insoluble fibrillar aggregates in dopaminergic neurons (Lewy bodies) and in ODGs (glial cytoplasmic inclusions).

[0009] Iron is a universal source of free radicals that form during oxidative phosphorylation and other normal cellular reactions. These free radicals damage DNA, lipid membranes, mitochondria, and other subcellular structures that contribute to cellular dysfunction and death (Crielaard et al 2017). Oxidative stress is evident in postmortem brain tissue from patients with PD and MSA, with higher levels of 4-hydroxy-2- nonenal, a marker of lipid peroxidation, as compared to age- matched controls (Giasson et al 2000, Kikuchi et al 2002, Shibata et al 2010). Oxidative stress in cells also promotes post translational modifications of α-synuclein such as phosphorylation that facilitates aggregation (Smith et al 2005, Lu et al 2011).

[0010] Redistributing excess iron represents a novel therapeutic approach for ameliorating MSA neuropathology through pre- and post-translational effects on α-synuclein and by eliminating important sources of oxidative stress.

[0011] ATH434 is a small molecule with moderate ferric and ferrous iron affinities (Kd10-10,Kd10-5respectively, Finkelstein et al, Acta Neuropathologica Communications, 2017, 5:53). Cl O

[0012] It binds iron with greater affinity than α-synuclein, but less than endogenous iron- trafficking proteins.

[0013] The development of new therapies is an extremely lengthy, challenging, uncertain and expensive task, involving extensive preclinical and clinical testing, with many agents failing for a variety of reasons, including for example lack of efficacy against the condition of interest, poor pharmacokinetic properties, and / or the presence of side effects / toxicity.

[0014] Further, in developing new agents for treatment of neurodegenerative diseases and disorders such as MSA, the situation is made all the more challenging since in many cases there is a need to provide therapeutically effective levels of active agent to the brain.

[0015] It would be desirable to provide a new therapeutic regimen which is effective in treating neurodegenerative diseases and disorders such as MSA, for example by modifying the underlying causes for the disease-related cellular damage. BRIEF SUMMARY

[0016] It has now been found that ATH434 has unexpected properties and can be administered at unexpectedly low dosage levels whilst maintaining therapeutically effective concentrations and resulting in good efficacy in the treatment of the neurodegenerative disorder MSA, whilst at the same time having a low incidence of side effects.

[0017] Accordingly, in a first aspect, there is provided a method of treating or preventing a neurodegenerative disease or disorder in a human subject, comprising administering ATH434 or a salt thereof OH , to the subject30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0018] In some embodiments, in each administration an amount of from 30 to 64 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 64 mg of ATH434.

[0019] In some embodiments, in each administration an amount of from 30 to 45 mg of ATH434 is administered, or in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 45 mg of ATH434.

[0020] In some embodiments, in each administration an amount of about 38 mg of ATH434 is administered, or in each administration an amount of ATH434 salt is administered which is equivalent to administering about 38 mg of ATH434.

[0021] In some embodiments, in each administration an amount of from 49 to 64 mg of ATH434 is administered, or in each administration an amount of ATH434 salt is administered which is equivalent to administering from 49 to 64 mg of ATH434.

[0022] In some embodiments, in each administration an amount of about 57 mg of ATH434 is administered, or in each administration an amount of ATH434 salt is administered which is equivalent to administering about 57 mg of ATH434.

[0023] In some embodiments, an ATH434 salt is administered.

[0024] In some embodiments, ATH434 methanesulfonate salt is administered.

[0025] In some embodiments, in each administration an amount of ATH434 methanesulfonate salt in the range of from 40 to 90 mg is administered.

[0026] In some embodiments, in each administration from 40 to 60 mg of ATH434 methanesulfonate salt is administered.

[0027] In some embodiments, in each administration 50 mg of ATH434 methanesulfonate salt is administered. In some embodiments, in each administration about 50 mg of ATH434 methanesulfonate salt is administered.

[0028] In some embodiments, in each administration from 65 to 85 mg of ATH434 methanesulfonate salt is administered.

[0029] In some embodiments, in each administration 75 mg of ATH434 methanesulfonate salt is administered. In some embodiments, in each administration about 75 mg of ATH434 methanesulfonate salt is administered.

[0030] In some embodiments, the neurodegenerative disease or disorder is multiple system atrophy (MSA).

[0031] In some embodiments, ATH434 or an ATH434 salt is administered twice per day for a period of at least 3 months, optionally for at least 6 months, or optionally for at least 1 year, or optionally for at least 3 years.

[0032] In some embodiments, the subject is at least 40 years old, optionally at least 50 years old, or optionally at least 60 years old.

[0033] In some embodiments, the method is for treating a neurodegenerative disease or disorder.

[0034] In some embodiments, ATH434 or a salt thereof is administered orally.

[0035] In some embodiments, the subject has an elevated plasma neurofilament light chain (NfL) level. In some embodiments, the subject has an elevated plasma neurofilament light chain (NfL) level before the administering of ATH434 or a salt thereof.

[0036] In some embodiments, the subject has a plasma NfL level of less than 30 pg / mL. In some embodiments, the subject has a plasma NfL level of less than 30 pg / mL before the administering of ATH434 or a salt thereof.

[0037] In some embodiments, wherein the subject has a plasma NfL level of less than 15 pg / mL, less than 20 pg / mL, less than 25 pg / mL, less than 30 pg / mL, less than 35 pg / mL, or less than 40 pg / mL. In some embodiments, wherein the subject has a plasma NfL level of less than 15 pg / mL, less than 20 pg / mL, less than 25 pg / mL, less than 30 pg / mL, less than 35 pg / mL, or less than 40 pg / mL before the administering of ATH434 or a salt thereof.

[0038] In some embodiments, the subject has a plasma NfL level of at least 5 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, or at least 25 pg / mL. In some embodiments, the subject has a plasma NfL level of at least 5 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, or at least 25 pg / mL before the administering of ATH434 or a salt thereof.

[0039] In some embodiments, the subject has a plasma NfL level of about 10-30 pg / mL, 15-30 pg / mL, or 20-30 pg / mL. In some embodiments, the subject has a plasma NfL level of about 10-30 pg / mL, 15-30 pg / mL, or 20-30 pg / mL before the administering of ATH434 or a salt thereof.

[0040] In some embodiments, the subject has a plasma NfL level of about 16.5-30 pg / mL. In some embodiments, the subject has a plasma NfL level of about 16.5-30 pg / mL before the administering of ATH434 or a salt thereof.

[0041] In some embodiments, the method comprises determining an NfL level in the subject before the administering of ATH434 or a salt thereof.

[0042] In some embodiments, the subject does not have orthostatic hypotension.

[0043] In some embodiments, the subject has a Unified Multiple System Atrophy Rating Scale Part I (UMSARS I) score of less than 14, less than 15, less than 16, less than 17, less than 18, less than 19, or less than 20 before the administering of ATH434 or the salt thereof.

[0044] In some embodiments, the subject has an UMSARS I score of less than 16 before the administering of ATH434 or the salt thereof.

[0045] In some embodiments, the subject has an UMSARS I score of 17 or lower before the administering of ATH434 or the salt thereof.

[0046] In some embodiments, the subject has an UMSARS I score of 1 to 16 before the administering of ATH434 or the salt thereof.

[0047] In some embodiments, the subject has an UMSARS I score of 1 to 17 before the administering of ATH434 or the salt thereof.

[0048] In some embodiments, the UMSARS I score of the subject does not increase by more than 3.0, 4.0, 5.0, 6.0, or 7.0 after the administering of ATH434 or the salt thereof for 52 weeks.

[0049] In some embodiments, the UMSARS I score of the subject does not increase by more than 6.0 after the administering of ATH434 or the salt thereof for 52 weeks.

[0050] In some embodiments, the UMSARS I score of the subject does not increase by more than 6.0 after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0051] In some embodiments, the UMSARS I score of the subject does not increase by more than 1.5 during a 13 week period throughout 52 weeks of the administering of ATH434 or the salt thereof. In some embodiments, the 13 week period starts with the administering of ATH434 or the salt thereof. In some embodiments, the 13 week period starts after the ATH434 or the salt thereof has been administered for 13 weeks, 26 weeks, 39 weeks, etc. In some embodiments, the 13 week period can start any time after the ATH434 or the salt thereof has been administered, e.g., after the ATH434 or the salt thereof has been administered for 10 weeks, 20 weeks, etc.

[0052] In some embodiments, the UMSARS I score of the subject does not increase by more than 0.5, 0.8, 1.0, 1.2, 1.5, 1.8 or 2.0 during a 13-week period throughout 52 weeks of the administering of ATH434 or the salt thereof.

[0053] In some embodiments, the UMSARS I score of the subject is at most 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 after the administering of ATH434 or the salt thereof for a period of 12 months.

[0054] In some embodiments, the UMSARS I score of the subject is at most 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 after the administering of ATH434 or the salt thereof for a period of 6 months.

[0055] In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 30% compared to placebo after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0056] In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, or at least 40% compared to placebo after 52 weeks.

[0057] In some embodiments, the relative treatment effect is determined according to the subject’s UMSARS I score.

[0058] In some embodiments, the relative treatment effect is determined according to one or more parameters of the UMSARS I score (such as speech, swallowing, cutting food, dressing, hygiene, etc.).

[0059] In some embodiments, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is speech.

[0060] In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the speech parameter of the UMSARS I score.

[0061] In some embodiments, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is swallowing.

[0062] In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the swallowing parameter of the UMSARS I score.

[0063] In some embodiments, the swallowing parameter comprises one or more sub-parameters selected from (i) Swallowing Disturbance Questionnaire Total score; (ii) Difficulty chewing; (iii) Food Residue; (iv) Chewed up food dribble from mouth; (v) Too much saliva; (vi) Need to swallow several times; (vii) Difficulty swallowing pureed food, (viii) Feel as though food is stuck in throat, (ix) Cough while swallowing liquids; (x) Cough while swallowing solid foods; and (xi) Difficulty breathing during meals. In some embodiments, the relative treatment effect of ATH434 or the saltthereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or at least 150% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the subitems in the Swallowing Disturbance Questionnaire described in this paragraph above.

[0064] In some embodiments, the relative treatment effect is determined according to a parameter of the motors score of the Parkinsons Plus Scale, and wherein the parameter is motor score (Bulbar / Pseudobulbar).

[0065] In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the motors score of the Parkinsons Plus Scale (Bulbar / Pseudobulbar) parameter of the UMSARS I score.

[0066] In some embodiments, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is fine motor skill.

[0067] In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the fine motor skill parameter of the UMSARS I score. In some embodiments, the fine motor skill parameter comprises one or more sub-parameters selected from (i) Cutting Food; (ii) Handling utensils; (iii) Dressing; and (iv) hygiene

[0068] In some embodiments, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is Orthostatic Hypotension.

[0069] In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 100%, at least 120%, at least 140%, at least 150%, or at least 160% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the Orthostatic Hypotension parameter of the UMSARS I score.

[0070] In some embodiments, the Orthostatic Hypotension parameter comprises one or more sub-parameters selected from (i) Orthostatic Hypotension Symptom Assessment (OHSA) total score; (ii) Dizziness; (iii) Problems with vision; (iv) Fatigue; (v) Trouble concentration; and (vi) Head and neck discomfort. In some embodiments, the relative treatment effect of ATH434 or thesalt thereof is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or at least 150% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the subitems in the Orthostatic Hypotension Symptom Assessment as described in this paragraph above.

[0071] In some embodiments, an MSA Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, an MSA Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

[0072] In some embodiments, an MSA Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, an MSA Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0073] In some embodiments, an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

[0074] In some embodiments, an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0075] In some embodiments, an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

[0076] In some embodiments, an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or thesalt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0077] In some embodiments, a composite Z-score of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, a composite Z-score of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

[0078] In some embodiments, a composite Z-score of the subject does not worsen by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, a composite Z- score of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0079] In another aspect, there is provided a method of treating of preventing a neurodegenerative disease or disorder in a human subject, comprising administering a pharmaceutical composition comprising ATH434 or a salt thereof OH , and awherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0080] In another aspect, there is provided ATH434 or a salt thereofOH , for use in a human subject,wherein and wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0081] In another aspect, there is provided a pharmaceutical composition comprising ATH434 or a salt thereof OH , and aneurodegenerative disease or disorder in a human subject, wherein ATH434 or ATH434 salt is administered to the subject twice per day, and wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0082] In another aspect, there is provided use of ATH434 or a salt thereofOH , for the disease ordisorder in a to the subject twice per day, and wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0083] In another aspect, there is provided a pharmaceutical composition in unit dosage form, comprising ATH434 or an ATH434 salt, and a pharmaceutically acceptable excipient, wherein the unit dosage form contains from 30 to 68 mg of ATH434, or wherein the unit dosage from has an amount of ATH434 salt which is equivalent to an amount of from 30 to 68 mg of ATH434.

[0084] In some embodiments, the pharmaceutical composition contains ATH434 methanesulfonate salt.

[0085] In some embodiments, the pharmaceutical composition contains 50 mg ATH434 methanesulfonate salt.

[0086] In some embodiments, the pharmaceutical composition contains 75 mg ATH434 methanesulfonate salt.

[0087] In some embodiments, the unit dosage form is in the form of a tablet. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 shows a graph showing the mean pharmacokinetic profile (plasma concentration over time) of ATH434 methanesulfonate salt administered to mice at 3, 10 and 30 mg / kg.

[0089] Figure 2 shows an overlay of a summary of the pharmacokinetic data for the Cohort 1 subjects of study ATH434-202 administered ATH434 methanesulfonate salt at 75mg bid at a single dose and after bid dosing through week 2, overlaid with model predictions from Phase 1 data.

[0090] Figure 3 shows bar charts showing composite z-scores for subjects treated with either Placebo, ATH43450 mg BID, or ATH43475 mg BID, at each of 26 and 52 weeks. ATH434 treated subjects had, on average, smaller indicators of worsening brain atrophy at those time points, as measured by composite z-scores. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0091] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art.

[0092] The present disclosure may refer to the contents of certain documents being incorporated herein by reference. In the event of any inconsistent teaching between the teaching of the present disclosure and the contents of those documents, the teaching of the present disclosure takes precedence.

[0093] It is to be understood that if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art.

[0094] As used herein, the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0095] As used herein, the term “and / or”, e.g., “X and / or Y” shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning.

[0096] As used herein, the term about, unless stated to the contrary, refers to + / - 10%, of the designated value.

[0097] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes a single as well as two or more; referenceto "an" includes a single as well as two or more; reference to "the" includes a single as well as two or more and so forth.

[0098] Unless otherwise indicated, terms such as "first," "second," etc. are used herein merely as labels, and are not intended to impose ordinal, positional, or hierarchical requirements on the items to which these terms refer. Moreover, reference to a “second” item does not require or preclude the existence of lower-numbered item (e.g., a “first” item) and / or a higher-numbered item (e.g., a “third” item).

[0099] As used herein, the phrase “at least one of”, when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed. The item may be a particular object, thing, or category. In other words, “at least one of” means any combination of items or number of items may be used from the list, but not all of the items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination.

[0100] The term “about” means within a statistically meaningful range of a value, such as a stated concentration range, time frame, molecular weight, particle size, temperature, or pH. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, and even more typically within 3% of the indicated value or range. Sometimes, such a range can be within the experimental error typical of standard methods used for the measurement and / or determination of a given value or range. The allowable variation encompassed by the term “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Whenever a range is recited within this application, every whole number integer within the range is also contemplated as an embodiment of the invention.

[0101] Each embodiment of the present disclosure described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise or required otherwise by context. Therapeutic Methods

[0102] In a first aspect, there is provided a method of treating or preventing a neurodegenerative disease or disorder in a human subject, comprising administering ATH434 or a salt thereof OH N , to the subject from 30 to 68 mg ofATH434 is or an of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0103] There is also provided a method of treating of preventing a neurodegenerative disease or disorder in a human subject, comprising administering a pharmaceutical composition comprising ATH434 or a salt thereof OH , and awherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0104] There is also provided ATH434 or a salt thereof OH ,for use in treating or preventing a neurodegenerative disease or disorder in a human subject, wherein ATH434 or ATH434 salt is administered to the subject twice per day, and wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0105] The therapeutic methods and uses of the present disclosure involve the use of ATH434 or a salt thereof, or of a pharmaceutical composition comprising ATH434.

[0106] ATH434 has the structure: Cl O . ATH434 is also known asmolecular weight of 302.2 Da.

[0107] Any suitable form of ATH434 may be used. In some embodiments, ATH434 is used (i.e. the free base form of ATH434 is used). In some other embodiments, a salt form of ATH434 is used. ATH434 is capable of forming salts, e.g. with acid moieties.

[0108] In some embodiments, a pharmaceutically acceptable salt of ATH434 is used. Examples of salts include chloride, bromide, sulfate, fumarate, methanesulfonate, benzenesulfonate, and toluenesulfonate.

[0109] In some embodiments, the methanesulfonate salt of ATH434 is administered. The methanesulfonate salt of ATH434 has an average molecular weight of 398.3 Da. The methanesulfonate salt of ATH434 may be represented by the following structure: Cl O - O .

[0110] Those skilled in the art will appreciate that many organic compounds can form complexes in solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates, such as hydrates, exist when the compound incorporates solvent. It will be understood that ATH434 or a salt thereof, may be present in the form of solvates. Solvates which are suitable are those where the associated solvent is pharmaceutically acceptable. Suitable solvates include hydrates. It will be understood that the present disclosure encompasses the use of unsolvated forms of ATH434 and salts thereof, as well as solvated forms, such as hydrates.

[0111] ATH434 or salts thereof may exist in one or more crystalline or amorphous forms. It will be understood that all such forms are within the scope of the present disclosure.

[0112] ATH434 may be prepared by any suitable method known to a person of skill in the art. For example, it may be prepared as described in US 8,084,459.

[0113] Salt forms of ATH434 may be produced by any suitable method. For example, an acid (e.g. methanesulfonic acid) in a suitable solvent may be added gradually to a solution of the neutral form of the compound in a suitable solvent, leading to formation of the appropriate salt, which may be recovered by precipitation and / or crystallisation of the salt from the mixture, of by removal of the solvent (e.g. by evaporation, for example under reduced pressure).

[0114] As used herein, the terms “treatment” or “treating” include curing a disease or disorder, as well as alleviation of or reduction of symptoms associated with a disease or disorder or condition. The term treating also includes slowing the progression of a disease or disorder. The terms “treating”, “treatment” and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacologic and / or physiologic effect. It may include one or more of a) inhibiting the disease, i.e., arresting its development; or (b) relieving or ameliorating the effects of the disease, i.e., cause regression of the effects of the disease.

[0115] In some embodiments, ATH434 or a salt thereof is used for treating a neurological or neurodegenerative disease or disorder. In some embodiments, ATH434 or a salt thereof is used for treating MSA.

[0116] As used herein, the terms “prevention” or “preventing” include prophylaxis, and include reducing the likelihood of having a neurodegenerative disease or disorder or a symptom thereof. The effect may be prophylactic in terms of completely or partially preventing a disease or disorder or sign or symptom thereof.

[0117] In some embodiments, ATH434 or a salt thereof is used for preventing a neurological or neurodegenerative disease or disorder. In some embodiments, ATH434 or a salt thereof is used for preventing MSA.

[0118] The term “subject” as used herein refers to a human having a neurodegenerative disease or disorder. In some embodiments the subject is an adult human. In some embodiments, the subject is at least 40, or at least 50, or at least 60, or at least 70 years old. In some embodiments, the subject is male. In some embodiments, the subject is female.

[0119] It has unexpectedly been found that low dosages of ATH434, or of an equivalent amount of a salt thereof, provide beneficial therapeutic effects, with a good side effect profile. This is particularly surprising in view of previous studies which indicate that therapeutic concentrations of ATH434 were observed at dosing levels in humans of 200 mg bid or greater.

[0120] In each administration (e.g. in each of the two administrations per day), either an amount of from 30 to 68 mg ATH434 is administered, or an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434. It will be understood that an amount of ATH434 salt which is equivalent to administering a certain amount of ATH434, is an amount which provides the same quantity of moles of ATH434. For example, an amount of an ATH434 salt which is equivalent to 30mg of ATH434, is a quantity of ATH434 salt which provides the same number of moles of ATH434 as is present in 30mg of ATH434 free base.

[0121] In some embodiments, in each administration (e.g. in each of the two administrations per day), either an amount of from 30 to 64 mg ATH434 is administered, or an amount of ATH434 salt is administered which is equivalent to administering from 30 to 64 mg of ATH434.

[0122] In some embodiments, ATH434 (i.e. the free base) is administered. In such cases, in each administration an amount of from 30 to 68 mg ATH434 is administered (e.g. two doses of from 30 to 68 mg ATH434 are administered per day).

[0123] In some embodiments, in each administration an amount of from 30 to 45 mg of ATH434 is administered. In some embodiments, in each administration an amount of from 35 to 40 mg of ATH434 is administered. In some embodiments, in each administration an amount of about 38 mg of ATH434 is administered.

[0124] In some other embodiments, in each administration an amount of from 49 to 64 mg of ATH434 is administered. In some embodiments, in each administration an amount of from 54 to59 mg of ATH434 is administered. In some embodiments, in each administration an amount of about 57 mg of ATH434 is administered.

[0125] In some embodiments, a salt of ATH434 is administered.

[0126] In some embodiments, in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

[0127] In some embodiments, in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 64 mg of ATH434.

[0128] In some embodiments, in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 45 mg of ATH434. In some embodiments, an amount of ATH434 salt is administered which is equivalent to administering from 35 to 40 mg of ATH434. In some embodiments, an amount of ATH434 salt is administered which is equivalent to administering about 38 mg of ATH434.

[0129] In some embodiments, in each administration an amount of ATH434 salt is administered which is equivalent to administering from 49 to 64 mg of ATH434. In some embodiments, in each administration an amount of ATH434 salt is administered which is equivalent to administering from 54 to 59 mg of ATH434. In some embodiments, in each administration an amount of ATH434 salt is administered which is equivalent to administering about 57 mg of ATH434.

[0130] In some embodiments, the methanesulfonate salt of ATH434 is administered.

[0131] In some embodiments, in each administration an amount of ATH434 methanesulfonate salt in the range of from 40 to 90 mg is administered.

[0132] In some embodiments, in each administration from 40 to 60 mg of ATH434 methanesulfonate salt is administered. In some embodiments, in each administration from 45 to 55 mg of ATH434 methanesulfonate salt is administered. In some embodiments, in each administration about 50 mg, or 50 mg, of ATH434 methanesulfonate salt is administered.

[0133] In some embodiments, in each administration from 65 to 85 mg of ATH434 methanesulfonate salt is administered. In some embodiments, in each administration from 70 to 80 mg of ATH434 methanesulfonate salt is administered. In some embodiments, in each administration about 75 mg, or 75 mg, of ATH434 methanesulfonate salt is administered.

[0134] The methods and uses are for preventing or treating a neurological and / or neurodegenerative disease or disorder.

[0135] The term “neurological disease or disorder” refers to diseases or disorders in which various cell types of the nervous system are degenerated and / or have been damaged as a result of neurodegenerative disorders or injuries or exposures.

[0136] The term “neurodegenerative disease or disorder” as used herein refers to a condition in which cells of the central nervous system lose functioning and eventually die. A lack of functioning in living cells can be due to their inability to adequately perform typical functions. Cells involved in neurogenerative diseases herein refers to neurons and can also be non-neuronal cells that support neurons such as oligodendrocytes, astrocytes, or microglia. Causative agents in neurogenerative diseases herein may originate in neurons, originate in non-neuronal cells of the central nervous system, or from factors that penetrate the central nervous system.

[0137] In some embodiments, ATH434 or a salt thereof is used for the treatment and / or prevention of a neurological and / or neurodegenerative disorder such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amylotrophic lateral sclerosis, epilepsy, spinal cord disorders and / or injuries, dystrophy or degeneration of the neural retina (retinopathies), cerebral ischaemia, Creutzfeldt-Jacob disease and its variant associated with bovine spongiform encephalopathy disease, diabetic neuropathy, epilepsy, post-traumatic epilepsy, Friedreich's ataxia, frontotemporal dementia, Dementia with Lewy bodies, haemochromatosis, Hallerboden- Spatz disease, reperfusion injury after heart attack, Huntington's disease, macular degeneration, motor neuron disease, multiple sclerosis, MSA, myocardial ischaemia, Progressive supranuclear palsy, or traumatic brain injury (TBI).

[0138] More preferably, ATH434 or a salt thereof is used for the treatment or prevention of a disease or disorder selected from MSA, Parkinson’s disease, Friedreich’s ataxia, Progressive supranuclear palsy, and Dementia with Lewy bodies.

[0139] In some embodiments, ATH434 or a salt thereof (e.g. the methanesulfonate salt) is used for the treatment of a disease or disorder selected from MSA, Parkinson’s disease, Friedreich’s ataxia Progressive supranuclear palsy, and Dementia with Lewy bodies.

[0140] In some embodiments, ATH434 or a salt thereof is used for the treatment or prevention of MSA.

[0141] In some embodiments, ATH434 or a salt thereof is used for the treatment of MSA.

[0142] In some embodiments, ATH434 or a salt thereof is used for the treatment or prevention of Parkinson’s disease.

[0143] In some embodiments, ATH434 or a salt thereof is used for the treatment of Parkinson’s disease.

[0144] In some embodiments, ATH434 or a salt thereof is used for the treatment or prevention of Friedreich’s ataxia.

[0145] In some embodiments, ATH434 or a salt thereof is used for the treatment of Friedreich’s ataxia.

[0146] In some embodiments, ATH434 or a salt thereof is used for the treatment or prevention of Progressive supranuclear palsy.

[0147] In some embodiments, ATH434 or a salt thereof is used for the treatment of Progressive supranuclear palsy.

[0148] In some embodiments, ATH434 or a salt thereof is used for the treatment or prevention of Dementia with Lewy bodies.

[0149] In some embodiments, ATH434 or a salt thereof is used for the treatment of Dementia with Lewy bodies.

[0150] Determination of whether a subject has a particular neurological and / or neurodegenerative disorder can readily be carried out by those of skill in the art.

[0151] For example, in the case of MSA, determination of whether a subject has MSA can be carried out by one of skill in the art.

[0152] Typically, a subject having MSA will have clinical features of MSA, for example as elaborated in one or more of Gilman 1999, Gilman 2008 and Wenning 2022. Such features may include one or more of Autonomic impairment / failure, parkinsonism, cerebellar dysfunction, and corticospinal degeneration and combinations thereof (see Wenning, 2022). In some embodiments, MSA may be defined as Shy-Drager syndrome, olivopontocerebellar atrophy (OPCA), or striatonigral degeneration (SND). In some embodiments, MSA may be categorized with predominant parkinsonism (MSA-P, formerly SND) or predominant cerebellar ataxia (MSA-C, formerly OPCA) (Gilman 1999). In some embodiments, subjects having MSA have clinical features of MSA meeting criteria for ‘definite MSA’, ‘probable MSA’, or ‘possible MSA’, (Gilman 2008), or more recently classified as ‘clinically established’ or ‘clinically probable’ MSA (Wenning 2022). Autonomic impairment / failure may include neurogenic orthostatic hypotension, unexplained voiding difficulties with post-void residual, or unexplained urinary urge incontinence. Parkinsonism is a motor syndrome that includes tremor, rigidity, limb bradykinesia or axialbradykinesia. Cerebellar dysfunction, or cerebellar syndrome, is a motor syndrome of uncoordinated movement that includes ataxia, gaze-evoked nystagmus, abnormal knee-tibia test, abnormal finger-to-nose test, or unstable gait. In some embodiments, MSA patients may have or may also have supportive motor features or supportive non-motor features, but does not have an abnormal manifestation that excludes a diagnosis of MSA (see Exclusion criteria below). Supportive motor features include rapid progression within 3 years of motor onset, moderate to severe postural instability within 3 years of motor onset, craniocerical dystonia induced or exacerbated by L-dopa in the absence of limb dyskinesia, severe speech impairment within 3 years of motor onset, severe dysphagia within 3 years of motor onset, unexplained Babinski sign, jerky myoclonic postural or kinetic tremor, and postural deformities. Supportive nonmotor features include stridor, inspiratory sighs, cold discolored hands and feet, pathologic laughter or crying, erectile dysfunction (below age of 60 years for clinically probable MSA (Gilman 2008) / clinically probable MSA (Wenning 2022)). Exclusion criteria include substantial and persistent beneficial response to dopaminergic medications, unexplained anosmia on olfactory testing, fluctuating cognition with pronounced variation in attention and alertness and early decline in visuoperceptual abilities, recurrent visual hallucinations not induced by drugs within 3 years of disease onset, dementia according to DSM-V within 3 years of disease onset, downgaze supranuclear palsy or slowing of vertical saccades, brain MRI findings suggestive of an alternative diagnosis (eg, PSP, multiple sclerosis, vascular parkinsonism, symptomatic cerebellar disease, etc.), documentation of an alternative condition (MSA look-alike, including genetic or symptomatic ataxia and parkinsonism) known to produce autonomic failure, ataxia, or parkinsonism and plausibly connected to the patient’s symptoms.

[0153] In some embodiments, a subject to be treated has MSA, and has one or more of the features of MSA discussed above.

[0154] In some embodiments, a subject having MSA will have one or more MRI markers for MSA, such as for example atrophy in subcortical brain structures, and / or increased iron content in subcortical structures. For example, a subject may have subcortical atrophy in one or more of the following subcortical brain structures: putamen, globus pallidus, brainstem or cerebellum. As a further example, a subject maty have increased iron content in one or more of the following subcortical brain structures: substantia nigra, putamen, globus pallidus or dentate nucleus of the cerebellum.

[0155] In some embodiments, a subject having MSA will have elevated concentration of neurofilament light chain (NfL) in plasma and / or cerebral spinal fluid samples.

[0156] In some embodiments, a subject having MSA has alpha-synuclein aggregates detectable in cerebral spinal fluid (see e.g. Gomez et al., 2023).

[0157] In some embodiments, a subject having MSA fulfils the Movement Disorder Society criteria for the diagnosis of multiple system atrophy (see e.g., Gilman 2008, Wenning et al, 2022).

[0158] In some embodiments, a subject having MSA fulfils criteria as set out in the relevant examples below.

[0159] The methods and uses disclosed herein provide for good therapeutic efficacy with low incidence of side-effects, such as CNS-related side effects.

[0160] Additionally, ATH434 or a salt thereof may also be used to potentiate the effects of other treatments.

[0161] In some embodiments, a subject may be evaluated for the presence of one or more features and / or symptoms, and a decision on whether to administer ATH434 or a salt thereof taken based on the outcome of the evaluation.

[0162] In some embodiments, a subject has an elevated plasma neurofilament light chain (NfL) level. In some embodiments, a subject has an elevated plasma neurofilament light chain (NfL) level before the administering of ATH434 or a salt thereof. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 10 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 15 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 15.5 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 16 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 16.5 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 17 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 17.5 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 18 pg / mL or higher. In some embodiments, the elevated plasma NfL level is determined partially based on the age of the subject. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 10 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 10 pg / mL or higher for subjects 18-50 years of age. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 15 pg / mL orhigher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 15 pg / mL or higher for subjects 51-60 years of age. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 20 pg / mL or higher. In some embodiments, an elevated plasma NfL level refers to plasma NfL level of 15 pg / mL or higher for subjects 61-70 years of age.

[0163] In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of less than 30 pg / mL. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of less than 15 pg / mL, less than 20 pg / mL, less than 25 pg / mL, less than 30 pg / mL, less than 35 pg / mL, or less than 40 pg / mL. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of at least 16.5 pg / mL. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of 16.5 pg / mL or higher. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of at least 5 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, or at least 25 pg / mL. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of about 10-30 pg / mL, 15-30 pg / mL. or 20-30 pg / mL. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of about 16.5-30 pg / mL. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of less than 30 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of less than 15 pg / mL, less than 20 pg / mL, less than 25 pg / mL, less than 30 pg / mL, less than 35 pg / mL, or less than 40 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of at least 16.5 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of 16.5 pg / mL or higher before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of at least 5 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, or at least 25 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of about 10-30 pg / mL, 15-30 pg / mL. or 20-30 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of about 10-30 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of about 15-30 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the subject has a plasma neurofilament light chain (NfL) level of about 16.5-30 pg / mL before the administering of ATH434 or a salt thereof. In some embodiments, the NfL level is determined at the patient screen. In some embodiments, the NfL level is determined as a baseline before the administering of ATH434 or a salt thereof. In some embodiments, the method further comprises determining an NfL level in the subject. In some embodiments, the method further comprises determining an NfL level in the subject before the administering of ATH434 or a salt thereof. In some embodiments, the method further comprises monitoring the NfL level in the subject after and / or during the administering of ATH434 or a salt thereof. In some embodiments, a subject having certain NfL level (e.g., 16.5-30 pg / mL, or less than 30 pg / mL) before the administering of ATH434 or a salt thereof is expected to receive a better treatment outcome.

[0164] In some embodiments, the subject does not have orthostatic hypotension. In some embodiments, the subject does not have orthostatic hypotension before the administering of ATH434 or a salt thereof. In some embodiments, the subject does not have protocol-defined orthostatic hypotension. In some embodiments, while efficacious in both subgroups, subjects without protocol-defined orthostatic hypotension before the administering of ATH434 or the salt thereof can have a better treatment outcome than those with orthostatic hypotension.

[0165] In some embodiments, the subject does not have orthostatic hypotension that is not otherwise explained (e.g., due to antihypertensive treatment). In some embodiments, this is defined as a decrease in one or more of systolic blood pressure and diastolic blood pressure at 3 minutes after a change in position (e.g. from lying to sitting; or sitting to standing). For example, this may be a change in systolic blood pressure (SBP) from ≥20 mmHg. As a further example, this may be a change in diastolic blood pressure (DBP) from ≥10 mmHg.

[0166] In some embodiments, the subject has orthostatic hypotension. In some embodiments, the subject has protocol-defined orthostatic hypotension.

[0167] In some embodiments, the subject has a Unified Multiple System Atrophy Rating Scale Part I (UMSARS I) score of less than 14, less than 15, less than 16, less than 17, less than 18, less than 19, or less than 20 before the administering of ATH434 or the salt thereof.

[0168] In some embodiments, the subject has an UMSARS I score of less than 40, less than 35, less than 30, less than 25, less than 20, or less than 15 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of less than 20, less than 19, less than 18, less than 17, less than 16, less than 15, less than 14, less than 13, less than 12, orless than 11 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of less than 16 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 17 or lower before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 1 to 16 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 0 to 16 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 1 to 17 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 0 to 17 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 1 to 20 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 1 to 25 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 1 to 30 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 1 to 35 before the administering of ATH434 or the salt thereof. In some embodiments, the subject has an UMSARS I score of 1 to 40 before the administering of ATH434 or the salt thereof. In some embodiments, while efficacious in various subgroups, subjects having certain UMSARS I score (e.g., 1-16, or 1-17) before the administering of ATH434 or the salt thereof can have a better treatment outcome than those with higher UMSARS I scores.

[0169] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 3.0, 4.0, 5.0, 6.0, or 7.0 after the administering of ATH434 or the salt thereof for 52 weeks. Experimental data has shown that, compared to placebo, administration of ATH434 salt has led to a slowing in progression of symptoms of MSA, as determined by UMSARS I score compared to placebo.

[0170] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 6.0 after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 7.0 after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 5.0 after the administering of ATH434 or the salt thereof for 52 weeks.

[0171] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 6.0 after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 5.0 after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 5.0 after the administering of ATH434 or the salt thereof for 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 7.0 after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 7.0 after the administering of ATH434 or the salt thereof for 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 4.0 after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 4.0 after the administering of ATH434 or the salt thereof for 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 3.0 after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 3.0 after the administering of ATH434 or the salt thereof for 12 months.

[0172] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 1.5 during a 13 week period throughout 52 weeks of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 0.5, 0.8, 1.0, 1.2, 1.5, 1.8 or 2.0 during a 13-week period throughout 52 weeks of the administering of ATH434 or the salt thereof. Changes of less than 1.5 are not considered clinically meaningful (Krismer et al 2016). In some embodiments, the UMSARS I score of the subject does not increase by more than 0.5, 0.8, 1.0, 1.2, or 1.5 during a 13 week period of the administering of ATH434 or the salt thereof.

[0173] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 1.5 during the first 13 weeks of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of thesubject does not increase by more than 2.5 during the first 13 weeks of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 0.2, 0.3, 0.4, 0.5, 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.5 or 3.0 during the first 13 weeks of the administering of ATH434 or the salt thereof.

[0174] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 1.0 from week 13- week 26 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 1.5 from week 13- week 26 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 2.5 from week 13- week 26 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 0.2, 0.3, 0.4, 0.5, 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.5 or 3.0 from week 13- week 26 of the administering of ATH434 or the salt thereof.

[0175] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 1.0 from week 26-week 39 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 1.5 from week 26-week 39 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 2.5 from week 26-week 39 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 0.2, 0.3, 0.4, 0.5, 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.5 or 3.0 from week 26-week 39 of the administering of ATH434 or the salt thereof.

[0176] In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 0.5 from week 39-week 52 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 1.5 from week 39-week 52 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 2.5 from week 39-week 52 of the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, the UMSARS I score of the subject does not increase by more than 0.2, 0.3, 0.4, 0.5, 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.5 or 3.0 from week 39-week 52 of the administering of ATH434 or the salt thereof.

[0177] In some embodiments, the UMSARS I score of the subject is at most 20 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 22 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 24 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 26 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 28 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 30 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject is at most 32 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 34 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 36 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 38 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 40 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, in a method described herein, the UMSARS I score of the subject is at most 20, at most 22, at most 24, at most 26, at most 28, at most 30, at most 32, at most 34, at most 36, at most 38, or at most 40 after the administering of ATH434 or the salt thereof for a period of 12 months. In some embodiments, the UMSARS I score of the subject is at most 20 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 22 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 24 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 26 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 28 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 30 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, in a method described herein,the UMSARS I score of the subject is at most 32 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 34 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 36 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, the UMSARS I score of the subject is at most 38 after the administering of ATH434 or the salt thereof for a period of 6months. In some embodiments, the UMSARS I score of the subject is at most 40 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, in a method described herein, the UMSARS I score of the subject is at most 20, at most 22, at most 24, at most 26, at most 28, at most 30, at most 32, at most 34, at most 36, at most 38, or at most 40 after the administering of ATH434 or the salt thereof for a period of 6 months. In some embodiments, in a method described herein, the UMSARS I score of the subject is at most 20, at most 22, at most 24, at most 26, at most 28, at most 30, at most 32, at most 34, at most 36, at most 38, or at most 40 after the administering of ATH434 or the salt thereof for a period of 3 months.

[0178] The term ‘relative treatment effect’, as used herein, represents an ATH434 treatment group Least Square Mean (LSM) Difference output from an ANCOVA model with treatment group (three levels) and sex as factors, and covariate adjustments for age and the baseline assessment value is divided by the LSM of a placebo group and expressed as a percentage. Improvement may be associated with lower numbers in some scales and with higher numbers in others. As a result, the absolute resulting percentage value is used.

[0179] In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 45%, at least 50% or at least 60% compared to placebo. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 20% compared to placebo after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 30% compared to placebo after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 40% compared to placebo after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the relative treatmenteffect of ATH434 or the salt thereof is at least 50% compared to placebo after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 20% compared to placebo after the administering of ATH434 or the salt thereof for 6 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 20% compared to placebo after the administering of ATH434 or the salt thereof for 12 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 30% compared to placebo after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 30% compared to placebo after the administering of ATH434 or the salt thereof for 6 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 30% compared to placebo after the administering of ATH434 or the salt thereof for 12 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 40% compared to placebo after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 40% compared to placebo after the administering of ATH434 or the salt thereof for 6 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 40% compared to placebo after the administering of ATH434 or the salt thereof for 12 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 50% compared to placebo after the administering of ATH434 or the salt thereof for 6 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 50% compared to placebo after the administering of ATH434 or the salt thereof for 12 months. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, or at least 40% compared to placebo after 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo after 26 weeks, 39 weeks, or 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 10% compared to placebo after 26 weeks, 39 weeks, or 52 weeks. In some embodiments, in amethod described herein, the relative treatment effect of ATH434 or the salt thereof is at least 20% compared to placebo after 26 weeks, 39 weeks, or 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 30% compared to placebo after 26 weeks, 39 weeks, or 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 40% compared to placebo after 26 weeks, 39 weeks, or 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 50% compared to placebo after 26 weeks, 39 weeks, or 52 weeks. In some embodiments, in a method described herein, the relative treatment effect of ATH434 or the salt thereof is at least 60% compared to placebo after 26 weeks, 39 weeks, or 52 weeks. In some embodiments, the relative treatment effect is determined by the UMSARS I score. In some embodiments, the relative treatment effect is determined by one or more parameters of the UMSARS I score (such as speech, swallowing, cutting food, dressing, hygiene, etc.). In some embodiments, the relative treatment effect is determined according to the parameter of swallowing. In some embodiments, the relative treatment effect is determined according to the parameter of cutting food. In some embodiments, the relative treatment effect is determined according to the parameter of dressing. In some embodiments, the relative treatment effect is determined according to the parameter of hygiene.

[0180] In some embodiments, the relative treatment effect is determined according to one or more of the efficacy endpoints provided in Example 2. In some embodiments, the relative treatment effect is determined according to the subject’s MRI. In some embodiments, the relative treatment effect is determined according to an imaging endpoint.

[0181] In some embodiments, in a method described herein, the treatment improves one or more parameters of the UMSARS I score. In some embodiments, in a method described herein, the treatment reduces the worsening of one or more parameters of the UMSARS I score. In some embodiments, in a method described herein, the treatment reduces the worsening of the UMSARS I score. In some embodiments, in a method described herein, the treatment improves the UMSARS I score.

[0182] In some embodiments, in a method described herein, the relative treatment effect is determined according to the subject’s UMSARS I score. In some embodiments, the relative treatment effect is determined according to one or more parameters of the UMSARS I score (such as speech, swallowing, cutting food, dressing, hygiene, etc.).

[0183] In some embodiments, in a method described herein, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is speech impairment, or dysarthria. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the speech parameter of the UMSARS I score.

[0184] In some embodiments, in a method described herein, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is disturbance of or impairment in swallowing. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the swallowing parameter of the UMSARS I score. In some embodiments, the swallowing parameter comprises one or more sub-parameters selected from (i) Swallowing Disturbance Questionnaire Total score; (ii) Difficulty chewing; (iii) Food Residue; (iv) Chewed up food dribble from mouth; (v) Too much saliva; (vi) Need to swallow several times; (vii) Difficulty swallowing pureed food, (viii) Feel as though food is stuck in throat, (ix) Cough while swallowing liquids; (x) Cough while swallowing solid foods; and (xi) Difficulty breathing during meals. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Swallowing Disturbance Questionnaire Total score. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to difficulty chewing. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to food residue. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Chewed up food dribble from mouth. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Too much saliva. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to the sub-parameter of Need to swallow several times. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Difficulty swallowing pureed food. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to the sub-parameter of Feel as though food is stuck in throat. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Cough while swallowing liquids. In some embodiments, therelative treatment effect of ATH434 or the salt thereof is determined according to Cough while swallowing solid foods. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Difficulty breathing during meals.

[0185] In some embodiments, in a method described herein, the relative treatment effect is determined according to a parameter of the motor score of the Parkinsons Plus Scale, and wherein the parameter is motor score (Bulbar / Pseudobulbar), which relates to swallowing. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the motor score (Bulbar / Pseudobulbar) parameter of the motor score of the Parkinsons Plus Scale score.

[0186] In some embodiments, in a method described herein, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is fine motor skill. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the fine motor skill parameter of the UMSARS I score. In some embodiments, the fine motor skill parameter comprises one or more sub-parameters selected from (i) Cutting Food; (ii) Handling utensils; (iii) Dressing; and (iv) hygiene. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Cutting Food. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Handling utensils. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Dressing. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to hygiene.

[0187] In some embodiments, in a method described herein, the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is symptoms related to Orthostatic Hypotension. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 100%, at least 120%, at least 140%, at least 150%, or at least 160% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the Orthostatic Hypotension parameter of the UMSARS I score. In some embodiments, the Orthostatic Hypotension parameter comprises one or more sub-parametersselected from (i) Orthostatic Hypotension Symptom Assessment (OHSA) total score; (ii) dizziness; (iii) problems with vision; (iv) fatigue; (v) trouble concentration; and (vi) head and neck discomfort. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Orthostatic Hypotension Symptom Assessment (OHSA) total score. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Dizziness sub-parameter. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to problems with vision. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to fatigue. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to Trouble concentration. In some embodiments, the relative treatment effect of ATH434 or the salt thereof is determined according to head and neck discomfort.

[0188] In some embodiments, in a method described herein, the relative treatment effect is determined according to the subject’s MRI.

[0189] In some embodiments, in a method described herein, one or more parameters of the UMSARS I score (such as speech, swallowing, cutting food, dressing, hygiene, etc.) does not worsen by more than 2 units after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, one or more parameters of the UMSARS I score does not worsen by more than 1.0, or 2.0 unit after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months. In some embodiments, in a method described herein, one or more parameters of the UMSARS I score does not worsen by more than 1.0 or 2.0 unit after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, the UMSARS I parameter is swallowing. In some embodiments, the UMSARS I parameter is cutting food. In some embodiments, the UMSARS I parameter is dressing. In some embodiments, the UMSARS I parameter is hygiene.

[0190] In some embodiments, in a method described herein, an MSA Atrophy Index, an index of the atrophy of the combined putamen, globus pallidus, cerebellum and brainstem regions of the brain relative to normal age-matched controls, of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, an MSA Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40%after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0191] In some embodiments, in a method described herein, an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0192] In some embodiments, in a method described herein, an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0193] In some embodiments, in a method described herein, a composite Z-score of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks. In some embodiments, a composite Z-score of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

[0194] In some embodiments, in a method described herein, the method further comprises determining and / or monitoring the subject’s UMSARS I score and one or more parameters thereof. In some embodiments, in a method described herein, the method further comprises determining and / or monitoring the relative treatment effect of ATH434 or a salt thereof on the subject. In some embodiments, in a method described herein, the method further comprises determining and / or monitoring the subject’s MSA Atrophy Index. In some embodiments, in a method described herein, the method further comprises determining and / or monitoring the subject’s MSA Volume Index. In some embodiments, in a method described herein, the method further comprises determining and / or monitoring the subject’s MRI Atrophy Index. In some embodiments, in a method described herein, the method further comprises determining and / or monitoring the subject’s composite Z-score.

[0195] In some embodiments, in a method described herein, a subject has onset of motor symptoms less than 4 years before the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, a subject has onset of motor symptoms less than 3 years before the administering of ATH434 or the salt thereof. In some embodiments, in a method described herein, a subject has onset of motor symptoms less than 2 years before the administeringof ATH434 or the salt thereof. In some embodiments, in a method described herein, a subject has onset of motor symptoms less than 1 years before the administering of ATH434 or the salt thereof.

[0196] In some embodiments, in a method described herein, the method comprises monitoring the movement of the subject (e.g., via a wearable movement sensor). In some embodiments, the movement includes Step count; bouts of walking; time walking, standing, sitting, or lying; mobility index; and sit-to-stand transitions. In some embodiments, in a method described herein, a subject has clinical diagnosis of MSA. In some embodiments, a subject has clinical diagnosis of MSA with a motor symptoms of ≤4 years duration and no evidence of severe impairment. In some embodiments, a subject has clinical diagnosis of MSA, motor symptoms of ≤3 years duration and no evidence of severe impairment. In some embodiments, a subject has one or more of the following findings on cerebellar examination: (a) Ataxic dysarthria, as determined by central rating (English-speaking countries only); and (b) Limb ataxia: dysmetria on exam (finger-nose-finger or finger-chasing assessment) AND / OR heel-knee-shin test with ataxic gait. In some embodiments, a subject exhibits the presence of unexplained pyramidal sign(s), e.g., Babinski with hyperreflexia. In some embodiments, a subject has increased iron in the putamen, globus pallidus or substantia nigra on Screening MRI, as confirmed by central reading. In some embodiments, a subject has reduced brain volume in MSA affected areas (putamen, globus pallidus, cerebellum and brainstem) as measured by the MSA-atrophy index. In some embodiments, a subject has elevated plasma neurofilament light chain (NfL) at screen. In some embodiments, a subject has an average modified UMSARS part I score (at Screening and Baseline) ≤17. In some embodiments, a subject is able to ambulate without assistance for at least 10 meters. In some embodiments, if subject is receiving dopaminergic therapy, the dose / regimen has been (i) optimized for control of parkinsonism; (ii) stable for at least 30 days before Screening and, and (iii) a change in therapy is not expected for 3 or more months. In some embodiments, if the subject is receiving drug treatment for neurogenic orthostatic hypotension, the dose / regimen has been (i) stable for at least 30 days; and (ii) a change in therapy is not expected for 3 or more months.

[0197] ATH434 or a salt thereof may be administered by any suitable means. Typically, ATH434 or a salt thereof is administered orally, for example in the form of a suitable oral composition, e.g. in a suitable unit dosage form such as a tablet.

[0198] The methods and uses involve administration of ATH434 or a salt thereof twice per day (i.e. bid or BID [bis in die] dosing). By twice per day is meant twice per 24 hour period.

[0199] In some embodiments, dosing is spaced approximately evenly across a 24 hour period. In some embodiments, doses are administered approximately every 12 hours.

[0200] In some embodiments, a dose of ATH434 or salt thereof is administered in the morning, and a further dose is administered in the evening.

[0201] In some embodiments, a dose of ATH434 or salt thereof is administered in the morning, within 2 hours of waking up, or within 1 hour of waking up.

[0202] In some embodiments, a first dose of ATH434 or salt thereof is administered in the morning, within 2 hours of waking up, and a further dose of ATH434 or salt thereof is administered between 10 hours and 14 hours after taking the first dose.

[0203] In some embodiments, a dose of ATH434 or salt thereof is administered in the morning with food, e.g. with breakfast.

[0204] In some embodiments, a dose of ATH434 or salt thereof is administered in the evening with food, e.g. with dinner / an evening meal.

[0205] In some embodiments, a dose of ATH434 or salt thereof is administered in the evening, at least 1 hour, or at least 1.5 hours, or at least 2 hours, or at least 2.5 hours, or at least 3 hours before sleep. In some embodiments, a dose of ATH434 or salt thereof is administered in the evening between 1 and 3 hours prior to sleep, or between 2 and 3 hours prior to sleep, or at about 2.5 hours prior to sleep.

[0206] The dosage regimen may be continued for as long as is desired, and for example may be continued indefinitely where administration of the active continues to provide beneficial effects.

[0207] In some embodiments, ATH434 or an ATH434 salt is administered twice per day for a period of at least 3 months, or for a period of at least 6 months, or for a period of at least 1 year, or for a period of at least 2 years, or for a period of at least 3 years, or for a period of at least 4 years, or for a period of at least 5 years, or for a period of at least 10 years.

[0208] In some embodiments, ATH434 or an ATH434 salt is administered twice per day for a period in the range of from 3 months to 6 months, or from 6 months to 1 year, or from 1 year to 5 years, or from 5 years to 10 years.

[0209] It will be understood that, where a medicine is being administered to a subject for a prolonged period of time, e.g. for a one- or multi-year period, there may be instances where a dose is missed occasionally, for example due to the subject forgetting to take a dose of the medicine. The present disclosure relates to bid dosing regimens, and it will be understood that the occasionalomission of a dosage (e.g. missing a few doses over a 6 or 12 month period), when the patient otherwise complies with the twice per day dosing regimen, is still encompassed by the present disclosure.

[0210] ATH434 or a salt thereof may additionally be combined with other medicaments to provide an operative combination. It is intended to include any chemically compatible combination of pharmaceutically-active agents, as long as the combination does not eliminate the activity of ATH434. It will be appreciated that ATH434 or salt thereof, and the other medicament, may be administered separately, sequentially or simultaneously. Pharmaceutical Compositions

[0211] The methods and uses of the present disclosure may involve administration of a pharmaceutical composition comprising ATH434 or a salt thereof and a pharmaceutically acceptable excipient (such as a diluent, carrier, or adjuvant). The excipient(s) (e.g. carrier, diluent, adjuvant) must be pharmaceutically “acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.

[0212] Compositions include those suitable for oral and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

[0213] The compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the excipient or excipients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid or solid carriers, diluents, adjuvants and / or other excipients.

[0214] Methods for preparation and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 20th Edition, Williams & Wilkins, Pennsylvania, USA.

[0215] As used herein, a “pharmaceutical carrier” includes a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the compound of formula I to the subject. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Each carrier must be pharmaceutically “acceptable” in the sense of being compatible with other ingredients of the composition and non-injurious to the subject.

[0216] ATH434 or a salt thereof may for example be administered orally in a formulation containing non-toxic pharmaceutically acceptable carriers, adjuvants, and / or vehicles. It may for example be administered orally in the form of tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc: Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0217] Where for example the composition is a tablet, the tablet may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating may also be performed using techniques described in the U.S. Pat. Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

[0218] The pharmaceutical composition is preferably prepared and administered in dose units. Solid dose units may for example be in the form of tablets, capsules or suppositories.

[0219] As discussed herein, it has been found that particular dosages of ATH434 or a salt thereof provide a particularly effective therapeutic regimen.

[0220] Accordingly, in another aspect, there is provided a pharmaceutical composition in unit dosage form, comprising ATH434 or an ATH434 salt, and a pharmaceutically acceptable excipient, wherein the unit dosage form contains from 30 to 68 mg of ATH434, or wherein theunit dosage from has an amount of ATH434 salt which is equivalent to an amount of from 30 to 68 mg of ATH434.

[0221] In some embodiments, the pharmaceutical composition in unit dosage form comprises ATH434 or an ATH434 salt, and a pharmaceutically acceptable excipient, wherein the unit dosage form contains from 30 to 64 mg of ATH434, or wherein the unit dosage from has an amount of ATH434 salt which is equivalent to an amount of from 30 to 64 mg of ATH434.

[0222] In some embodiments, the pharmaceutical composition contains ATH434 methanesulfonate salt.

[0223] In some embodiments, the pharmaceutical composition in unit dosage form contains 50 mg ATH434 methanesulfonate salt. In some embodiments, the pharmaceutical composition in unit dosage form contains about 50 mg ATH434 methanesulfonate salt.

[0224] In some embodiments, the pharmaceutical composition in unit dosage form contains 75 mg ATH434 methanesulfonate salt. In some embodiments, the pharmaceutical composition in unit dosage form contains about 75 mg ATH434 methanesulfonate salt.

[0225] In some embodiments, the unit dosage form is in the form of a tablet.

[0226] Those skilled in the art will appreciate that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. Examples

[0227] The disclosure is further illustrated by the following non-limiting examples. Example 1: Establishment of Human Dosage

[0228] Dose levels of ATH434, in the form of its methanesulfonate salt, were established for phase 2 studies, the dose level in one study being 75 mg BID, and in another study being 75 mg BID and 50 mg BID.

[0229] The selected doses were predicted to have systemic exposure because they met or exceeded efficacious concentrations in relevant animal models of disease, and were expected to be safe in relation to exposure in long term toxicology studies. Treatment rationale was based on targeting the iron-mediated pathological processes that underpin the neuropathology in MSA. Glial cytoplasmic inclusions (CGI)s, which are comprised primarily of phosphorylated α-synuclein,represent the cardinal histological finding in the brain of MSA subjects. Excess iron is implicated in this pathology, as it has been shown to directly promote α-synuclein oligomerization and aggregation as well as promote its phosphorylation. In addition to α-synuclein aggregation, brain tissue from MSA subjects demonstrates increased oxidative stress, as indicated by increased levels of 4-hydroxy-2-nonenal and increased expression of endogenous pro-oxidants such as myeloperoxidase. Beyond MSA, myeloperoxidase is a potent pro-oxidant implicated in important neurodegenerative conditions such as PD and Alzheimer’s disease. As excess iron generates reactive oxygen and free radicals that lead to oxidative stress, binding and distributing excess iron by ATH434 was also expected to have a beneficial effect on neuronal preservation and function.

[0230] Dose rationale was based on experience with animal studies. A transgenic mouse model of MSA (proteolipid protein-α-synuclein [PLP-α-syn]) was used to explore the effect of ATH434 on motor performance and neuropathology.

[0231] In the first study, ATH434 treatment as the hydrogen bromide salt (HBr) was initiated at doses of 3, 10, and 30 mg / kg / day several months after disease onset. Dose levels of 3, 10, and 30 mg / kg / day led to significant reductions in GCIs and significant preservation of neurons in the SN. Reduced levels of GCIs were observed in the pons at the tested dose of 30 mg / kg / day; lower doses were not tested. Improved motor performance was observed at 10, but not 3 and 30 mg / kg / day. Iron in the SN as measured by inductively coupled plasma mass spectrometry was reduced by 30, but not 10 or 3 mg / kg / day.

[0232] In a second, independent experiment in the PLP-α-syn mouse model, ATH434 HBr treatment at 30 mg / kg / day was also initiated several months after disease onset. ATH434 at the only tested dose, 30 mg / kg / day, reduced GCI counts in the SN, preserved neurons in the SN, reduced SN iron as measured by histochemical staining (Perl’s), and preserved neurons in the striatum. Lower doses were not tested.

[0233] The MPTP mouse model was used to investigate the activity of ATH434 on free radical- mediated neuropathology because MPTP causes acute oxidative injury in the SN. ATH434 HBr preserved SN neurons at doses of 3, 10, 30, and 80 mg / kg / day and improved motor function at doses of 30 and 80 mg / kg / day. ATH434 robustly reduced markers of lipid peroxidation, reduced midbrain iron, and increased markers of recovering synaptic processes at the single evaluated dose of 30 mg / kg / day. Lower doses were not tested.

[0234] Repeated twice-daily dose levels in the first-in-human Phase 1 clinical study in healthy volunteers (100mg bid to 250 mg bid) were selected with the goal of finding a dose that provided human exposure to ATH434 in plasma that was comparable to that in mice that had received ATH434 HBr doses of 30 mg / kg based on the pharmacologic efficacy described above (the well- characterized pharmacologically active dose in PD and MSA mouse models for neural preservation) and based on mouse pharmacokinetic study conducted with the single dose of 30 mg / kg. Results indicated that a dose between 100 mg and 200 mg bid would be required. Phase 2 Dose Selection

[0235] For dose selection in Phase 2, dose levels were selected that would provide human exposure to ATH434 in plasma that were similar to those in mice that received ATH434 HBr at the dose level of 10 mg / kg / day, or that exceeded that exposure by 3-4 fold. To achieve this, 4 additional studies were conducted that (1) characterized exposure in mice at 10 mg / kg / day at steady state, (2) compared the fraction of ATH434 bound to mouse and human plasma proteins, (3) compared the relationship between free (unbound) plasma concentrations and CSF concentrations as an index of brain penetration in mouse and human and (4) obtained human pharmacokinetic data at lower levels than those in the first-in-human study. Studies (1)-(4) are described in detail below. Study (1):

[0236] A mouse study conducted after the completion of the first in human clinical study investigated the pharmacokinetics of ATH434 methanesulfonate at doses of 3, 10, and 30 mg / kg provided for 4 days to C57Bl / 6 mice. Details of the study design are provided in the table below: Table 1 Group Test Dose LevelaDose Main Study CSF Animals No. Material (mg / kg / day) Concentration No. of No. of No. of No. of (mg / mL)bMales Females Males Females 1 ATH434 3 0.3 24 24 4 4 2 ATH434 10 1.0 24 24 4 4 3 ATH434 30 3.0 24 24 4 4CSF = cerebrospinal fluid; No. = Number a Presented as ATH434 methanesulfonate salt. When corrected for methanesulfonate salt (MW / FW:0.76), purity (99.53%) and water (0.30%) content with a correction factor of 1.33 the doses were 2.26, 7.6, and 22.56 mg / kg / day of the active substance ATH434. b Dose formulations were made to deliver the intended dose concentrations at a volume of 10 ml / kg in a vehicle of 0.5% (w / v) HPMC (Hydroxypropyl methylcellulose), 0.1% (v / v) Tween 80 in Deionized Water. Dose volumes were based on the most recent body weight measurement.

[0237] Main study animals had the following blood samples collected for the determination of ATH434 concentration (one sample per animal) in plasma on Day 4 from three animals per group / sex / time point: predose, 0.5, 1, 2, 4, 6, 10, and 18 hours postdose. Plasma concentration versus time profiles were generated for each dosing group for males, females, and combined by determining the average concentration at each time point for the respective population. The PK parameter of Area Under the Curve (AUC) was determined on Day 4 and was used for subsequent calculations for human dose calculations.

[0238] All animals designated for cerebrospinal fluid (CSF) collections had a terminal CSF collection for the determination of ATH434 concentration at 1-hour postdose. The average CSF concentration per dosing group for males, females, and combined was used.

[0239] The PK parameters AUClast, and AUClast / Dose were calculated using a non- compartmental analysis approach from the combined average plasma concentration-time profiles of ATH434 in Groups 1, 2, and 3 for females males, and combined. As there were no clear effect of sex, combined male and female data were used in evaluating results for human dose selection.

[0240] Nominal sampling times and nominal doses (in mg / kg) of ATH434 (see table above) were used for parameter calculations. The mean was calculated using Phoenix™. Concentration values that were below the limit of quantitation (BLQ) were set to 0 for descriptive statistics and analyses.

[0241] The ratio of 1-hour CSF to 1-hour plasma ATH434 concentrations was calculated for males, females, and combined for each dosing group.

[0242] A summary of the ATH434 PK parameter of AUC by dose is reported in the table below. ATH434 AUClast / Dose appeared similar between the 3 and 10 mg / kg dosing groups but was greater than proportional, at approximately 3-fold higher, in the 30 mg / kg dosing group. Table 2 Group Dose AUClast AUClast / Dose (mg / kg) (hr*ng / mL) (hr*kg*ng / mL / mg) 1 3 52.5 17.5 2 10 190 19.0 3 30 1680 56.1

[0243] Mean concentrations of ATH434 combined for both genders are depicted graphically on a semi-logarithmic scale in Figure 1.

[0244] An unexpected finding was that the steady state pharmacokinetic AUC parameter increased in a greater than dose-proportional manner across dose levels such that the increase in exposure between the 10 and 30 mg / kg dose level was approximately 9-fold as opposed to the expected 3-fold. The novel and surprising finding was applied to dose selection for the Phase 2 trials. Study (2):

[0245] ATH434 was shown to bind to approximately 94.4% of the proteins in human plasma such that approximately 5.6% was unbound (free). ATH434 was shown to bind the proteins in mouse plasma such that approximately 29% was unbound. Due to this difference, and because it is generally accepted that the unbound fraction of drug is pharmacologically active (Hammarlund- Udenaes et al 2008), interspecies exposure comparisons were based on free plasma concentrations of ATH434. Study (3):

[0246] In samples from the first in human study, CSF concentrations of ATH434 were strongly correlated (r2=0.72) with free plasma concentrations, indicating that ATH434 readily crossed the blood brain barrier to reach the site of action. At corresponding timepoints from the sameindividuals, ATH434 concentrations in CSF and in free plasma were within 2-fold of each other, indicating that free plasma concentrations were an adequate indicator of central exposure. A similar relationship between CSF and free plasma concentrations of ATH434 was observed in the mouse in results from Study (1) above. Thus, free plasma concentrations were used to compare exposure to ATH434 across species as an indicator of central exposure. Study (4):

[0247] Based on the findings in Study (1), a clinical healthy volunteer study conducted after the first in human study investigated steady state PK data at 75 mg BID, and used linear scaling of these data to estimate exposure at 50 mg BID.

[0248] Based on Studies (1) and (2) above, the AUC for unbound mouse plasma concentrations of ATH434 after steady state dosing at 10 mg / kg / day was calculated to be 55 ng*hr / mL and an adequate representation of CSF exposure based on Study (3). An AUC of 55 ng*hr / mL represented the minimal target for a free plasma AUC in humans for the Phase 2 studies. The AUC of free ATH434 at the doses of 75 and 50 mg bid from (4) are summarized in Table 3. The dose level of 50 mg / kg / day was selected as the low dose for Phase 2 because the lowest estimated human exposure from Study (4) met the criteria of 55 mg / kg / day based on the minimal observed AUC. The dose level of 75 mg / kg / day was selected as the high dose for Phase 2 because the average human exposure from Study (4) met the criteria of exceeding 55 mg / kg / day by 3.8-fold. The selected Phase 2 doses were further supported by their estimated ability to avoid dose-limiting toxicities observed in toxicology studies based on comparison of free plasma AUC values and calculated safety margins. Table 3: Estimated Steady State Exposure of ATH434 at 50 mg BID and 75 mg BID unbound to plasma Dose Level of ATH434 Mean AUC0-24(ng*hr / mL) Minimum Observed methanesulfonate salt AUC0-24(ng*hr / mL) 75 mg BIDa209 83 50 mg BIDb139 55a Determined by taking free fraction (5.6%) of the geometric mean AUC0-24at steady state with 75 mg BID and adjusting for dosing with food (low-fat / fasting ratio of 93.4%). b Determined by linear scaling of data for 75 mg BID. Example 2: Phase 2 Open-Label Biomarker Study of ATH434 in Multiple System Atrophy

[0249] An open-label biomarker study was carried out to investigate ATH434, in the form of its methanesulfonate salt, in MSA in humans. Details of the study are set out below. Summary Protocol ATH434-202 Title An Open-Label Biomarker Study of ATH434 in Multiple System Atrophy Development Phase Phase 2 Indication MSA Number of Sites Single Center Objectives Primary: • To assess the efficacy of ATH434 in subjects with MSA Secondary: • To assess the safety and tolerability of ATH434 in subjects with MSA • To evaluate the pharmacokinetics (PK) of ATH434 and potential metabolites in subjects with MSA Study Design This was an open-label study conducted in 10 subjects. After Screening and Baseline assessments were complete, eligible subjects were enrolled to receive 12 months treatment with ATH434. Enrolment occurred in two consecutive groups to allow enhanced safety monitoring in a limited number of subjects before the study is expanded. The first 5 subjects (Cohort 1) were followed for at least two weeks and their safety and PK data reviewed by a Safety Review Committee before the remaining subjects (Cohort 2) were enrolled. All subjects were to receive 12 months of treatment. Subjects were assessed at in-clinic and remote (video [recommended] or telephone) visits over the course of the study. Following Screening and Baseline, in-clinic study visits occurred at Weeks 2, 6, 13, 21, 26, 39, 47 and 52 for safety assessments, including vital signs, routine laboratory testing, physical examination, and 12-lead electrocardiograms (ECG). Cohort 1 subjects had a 1-hour EEG at Screening and after 2 and 26 weeks of treatment. Remote visits to evaluate adverse events, concomitantmedication use, and study drug compliance were also performed at Weeks 4, 9, 17, 30, 34 and 43. A follow-up clinic visit for safety evaluation was to occur 2 weeks after completion of treatment. At the Week 13, 26, 39 and 52 clinic visits, disease-related clinical assessments were performed, including motor examination, autonomic symptom scales, activities of daily living scales, and patient / clinician impressions of change and / or severity. At Baseline and Weeks 26 and 52, biological specimens (blood and cerebrospinal fluid [CSF]) were collected for fluid biomarker assessments; optionally, a 24-hour urine collection (for analysis of iron and creatinine) could also be conducted. Magnetic resonance imaging (MRI) for structural analysis and imaging biomarkers (e.g., quantitative susceptibility mapping [QSM]) was to be performed at Screening and Weeks 26 and 52. Cohort 1 subjects provided blood samples for ATH434 concentrations through 4.5 hours post-dose at the Day 1 and Week 2 visits, with the addition of a pre-dose sample at Week 2. Cohort 2 subjects provided blood samples for ATH434 concentrations through 3 hours post-dose at the Day 1 and Week 2 visits, including a pre-dose sample at Week 2. A Safety Review Committee (SRC) periodically reviewed safety data during study conduct. The SRC first met after Cohort 1 (N=5) completed at least 2 weeks of treatment, and thereafter at intervals as specified in the Project Plan. Dosage and Dose ATH434 methanesulfonate salt was supplied as oval-shaped, white, Regimen coated 75 mg tablets. Subjects began dosing the morning of Day 1 and took study drug orally BID for 52 weeks. Study drug was to be taken with food; the evening dose was to be taken at least 2.5 hours before bedtime. The first dose and the Week 2 morning dose were administered in the clinic to facilitate pharmacokinetic assessment. All other doses were self-administered. Sample Size 10 subjects were enrolled Study Population Subjects with a clinical diagnosis of MSA Inclusion Criteria Subject had to meet all of the following criteria to be included: 1. Subject is 30 to 75 years old, inclusive, at the time of Screening. 2. Subject has provided written informed consent. 3. Subject has clinical features of parkinsonism. 4. Subject has at least two of the following features indicative of autonomic dysfunction: a. Urinary urgency / frequency with incontinence b. Incomplete bladder emptying that is not otherwise explained c. Significant orthostatic hypotension that is not otherwise explained 5. Subject has at least one of the following additional features of MSA:a. One or more abnormality on cerebellar examination b. Presence of unexplained pyramidal sign(s) 6. Subject has increased iron in basal ganglia (lentiform nucleus (putamen / globus pallidus) or substantia nigra) on Screening MRI, as confirmed by central reading. 7. Elevated plasma neurofilament light chain (NfL) at Screening. 8. If subject is receiving dopaminergic therapy, the dose / regimen has been stable for at least 30 days before Screening. 9. If subject is receiving drug treatment for neurogenic orthostatic hypotension, the dose has been stable for at least 30 days before Screening. 10. Subject has an identified, reliable study partner who either lives with the subject (e.g., spouse) or interacts with the subject on a daily basis. 11. Female subjects must fulfill at least one of the following conditions: a. Post-menopausal b. Surgically sterile c. Women of childbearing potential are using two methods of contraception from Screening through 2 weeks after the final IP administration. 12. Male subjects must be using an effective birth control method from Screening through 104 days after the final IP administration. Exclusion Criteria A subject meeting any of the following criteria was excluded: 1. Subject is unable to swallow study drug. 2. Subject has gait impairment that prevents attendance at study visits or completion of study procedures. 3. Subject has severe hyposmia not otherwise explained 4. Subject has evidence of Dementia with Lewy Bodies 5. Subject is cognitively impaired, based on Investigator assessment or as indicated by MMSE. 6.Evidence of disproportionate cortical atrophy, hippocampal / mesial temporal atrophy, or confluent white matter hyperintensities on Screening MRI, as determined by central reading. 7. Subject has evidence of any significant neurological disorder other than MSA 8. Subject has history of any neurosurgical procedure, including deep brain stimulation OR stereotactic surgery. 9. Subject has a contraindication or inability to tolerate brain MRI 10. Subject has a contraindication or inability to tolerate lumbar puncture 11. Use of prohibited concomitant medications 12. Subject has an unstable or serious illness that, in the Investigator’s opinion, may interfere with the subject's participation in study or adversely affect survival.13. Subject has an underlying medical condition that may confound interpretation of study results. 14. Female subject is pregnant or breastfeeding. 15. Subject resides at a skilled nursing facility or dementia care facility, or admission to such a facility is anticipated during the 54- week study period. 16. Consideration by the Investigator, for any reason, that the subject is an unsuitable candidate for the study. Study Duration The expected duration of participation for each subject was approximately 54 weeks, not including Screening. Efficacy Endpoints Primary Imaging Endpoint: Change from Baseline to Week 52 in the MSA Volume Index by T1-weighted MRI. The MSA Volume Index, or MSA-VI, is presented as a percentage of intracranial volume (ICV) and is calculated by summing the normalized volumes for the cerebellum, brainstem, putamen and globus pallidus. Secondary Imaging Endpoints: (assessed as change from Baseline to Week 52): • MSA Atrophy Index (MSA-AI, z-score) by T1-weighted MRI • Iron content in the substantia nigra by MRI QSM / R2* • Metabolic markers N-acetylaspartate [NAA] and myo- inositol [mI] by magnetic resonance spectroscopy (MRS) Fluid Biomarker Endpoint: • Neurofilament light chain levels in plasma and CSF. Key Clinical Endpoints: • UMSARS Part I Historical Review, total and modified1• Motor score of the Parkinson Plus Scale (m-PPS), total and modified2• Clinical global impression of severity (CGI-S) • Clinical global impression of change at Week 52 (CGI-C) (As CGI-C is a change score, there is no Baseline value) • Patient global impression of change at Week 52 (PGI-C) (as PGI-C is a change score, there is no Baseline value) Additional Clinical Endpoints: • Timed Up and Go • Levodopa dose equivalents • SF-36 Physical Functioning scaleAdditional Imaging Endpoints: • Volumetric assessments in the following regions: putamen, globus pallidus; lentiform nucleus (putamen + globus pallidus); cerebellum; and brainstem by T1-weighted MRI • Iron content in the following regions: putamen; globus pallidus; lentiform nucleus; dentate nucleus of cerebellum; and the combined region (substantia nigra + putamen + globus pallidus + dentate nucleus) by MRI QSM and R2* • Blood flow in lentiform nucleus by arterial spin labelling (ASL; mL / 100g / min) • Neuronal integrity in substantia nigra, assessed by volume and contrast ratio using neuromelanin-MRI 1 Modified UMSARS includes following items: Speech, swallowing, handwriting, cutting food / handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary function. 2 Modified motor score includes a subset of items from the motor examination of The Parkinson’s Plus Scale: bulbar / pseudobulbar (speech [motor examination], facial expression), tremor, rigidity, limb and axial bradykinesia, oculomotor function, and cerebellar function. Pharmacokinetic • Steady-state area under the curve over the dosing interval Endpoints (AUCtau) • Steady-state maximum plasma concentration (Cmax) • Steady-state time to Cmax (Tmax) Safety Endpoints • Incidence of AEs, SAEs, and AEs leading to withdrawal • Observed values and changes in clinical laboratory parameters (hematology, chemistry, urinalysis, and iron studies) • Observed values and changes in vital signs, including orthostatics • Observed values in ECG parameters and abnormal findings • Number of ECGs and subjects with 1) on-treatment QTcF values >450 ms, >480 ms, >500 ms and 2) QTcF change from baseline >30 ms and >60 ms. Pharmacokinetics Blood and CSF samples for measuring ATH434 (and potential metabolites) concentrations were collected as follows: • Cohort 1 (N=5) subjects provide 6 blood samples through 4.5 hours at the Day 1 visit (at 0.5, 1, 1.5, 2, 3, and 4.5 hours postdose) and 7 blood samples through 4.5 hours at the Week 2 visit (pre-dose and at 0.5, 1, 1.5, 2, 3, and 4.5 hours post-dose). • Cohort 2 (all subjects enrolled after Cohort 1) subjects provide 2 blood samples through 3 hours post-dose after the morning dose on Day 1 (1 and 3 hours post-dose) and 3 samples around the morning dose at the Week 2 visit (pre-dose and at 1 and 3 hours post-dose). • All subjects provide a single blood sample at the Week 13 and Week 39 visits, pre-dose if possible.• CSF was to be collected in all subjects at Week 26 and Week 52. This collection was paired with a blood sample taken within 15 minutes after CSF sampling. Statistical Efficacy Analyses Considerations Biomarker and clinical endpoints were to be summarized descriptively at baseline and at each subsequent time point. Changes from baseline were also to be summarized. Paired t tests were to be used to test the null hypothesis that the mean change from baseline is equal to zero. All statistical tests were to be two-sided and conducted at the alpha=0.05 level of significance, with no adjustment for multiplicity. Safety Analyses All subjects who have received at least one dose of study drug were to be evaluated for safety. All AEs were to be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Incidence of AEs by the severity, relationship to treatment, and outcome provided. Laboratory parameters, vital signs, and other safety parameters were to be listed by subject and presented using descriptive summary statistics. Treatment-emergent AEs and laboratory, vital sign, and safety 12- lead ECG parameters were to be summarized. In addition, change from Baseline were to be summarized for laboratory and vital sign parameters. Shift tables were to be provided for clinical laboratory results. Electrocardiogram results were to be classified as normal and abnormal and summarized. Cardiac intervals, including QTc, PR, and QRS, were to be analyzed for absolute outliers based on criteria set forth in the statistical analysis plan. PK Analysis In-study PK analysis ATH434 exposure in Cohort 1 (N=5) subjects was to be quantified on Day 1 and at Week 2, using a population PK model approach to determine mean PK parameters (Cmax and AUCtau), if feasible. If a population PK model was not feasible, ATH434 plasma concentrations from Cohort 1 participants was to be compared with the Phase 1 data to assess whether ATH434 in patients demonstrates PK characteristics as expected based on Phase 1 data. Population PK analysis Concentration data from all subjects were to be analyzed by population PK methods. The details of the analysis were to be described in a pharmacometric analysis plan and reported independently from the clinical study report.CSF concentrations For paired CSF and blood samples drawn for quantitation of ATH434 at Weeks 26 and 52, the ratio of CSF concentration to plasma concentration was to be reported and summarized descriptively by visit and dose level. Results:

[0250] A summary of the observed findings for MSA patients that were administered the 75 mg bid administration regime for the relevant administration time period is provided in Tables 4 through 7 below. The trial is ongoing and findings have been presented for study participants completing 6 months treatment, as well as a subset completing 12 months treatment.

[0251] The Clinical Global Impression of Severity (CGIS) is a single item scale administered by an investigator experienced in the diagnosis and management of MSA in order to make a global clinical judgment about the severity of the subject’s illness. The clinician rates the severity of subject’s illness at each visit, using a 7-point scale (see bottom of table), taking into account illness severity, the impact of the illness on function, the level of distress and any other aspects of impairment. Table 4: Clinical Global Impression of Severity Endpoint – Clinical Global Impression of Score Severity Subject Baseline 6 months 12 months 001 4 4 5 002 4 4 4 003 5 4 5 004 5 6 6 005 5 6 007 4 6 008 5 5 010 4 6 013 5 5 014 4 6 Prompt: How do you rate the severity of the patient’s illness over the past 28 days? 1 = Normal - not at all impaired 2 = Borderline impaired - subtle or suspected pathology 3 = Mildly impaired - clearly established symptoms with minimal, if any, functional impairment or distress 4 = Moderately impaired - overt symptoms causing noticeable, but modest, functional impairment or distress 5 = Markedly impaired - symptoms that distinctly impair function or cause significant distress 6 = Severely impaired - disruptive pathology, function is significantly impaired by symptoms, may require assistance from others 7 = Among the most extremely impaired subjects - pathology drastically interferes in many life functions

[0252] From the data in Table 4, it can be seen that 50% (5 / 10) of subjects had the unexpected finding of stabilized or improved disease severity at 6 months. To our knowledge, no treatment exists that has led to stabilization or improvement on this outcome measure in MSA.

[0253] The Clinical Global Impression of Change (CGIC) is a single-item scale in which the Investigator assesses a subject’s neurological symptoms at specific visits after initiating therapy. The CGIC uses a 7-point scale to assess overall response to therapy (see bottom of table). Because CGIC is a change score, there is no baseline value. Table 5: Clinical Global Impression of Change Endpoint – Clinical Global Impression of Score Change Subject BL to 6 mo BL to 12 mo 001 -1 0 002 +1 0 003 0 -1 004 -2 -2 005 -2 007 -1 008 -1 010 -1 013 0 014 -1 BL: Baseline Prompt: With respect to the subject’s overall neurological symptoms, how would you describe the subject now compared to immediately before starting treatment? -3 Very Much Worse -2 Much Worse -1 Minimally Worse 0 Not Changed 1 Minimally Improved 2 Much Improved

[0254] From the data in Table 5, it can be seen that, from the treating physician’s perspective, 30% (3 / 10) of subjects had the unexpected finding of stabilized or improved neurological symptoms at 6 months. To our knowledge, no treatment exists that has led to stabilization or improvement on this outcomes measure in MSA.

[0255] The Patient Global Impression of Change (PGIC) is a single item scale in which the participant assesses their neurological symptoms at specific visits after initiating therapy. The PGIC uses a 7-point scale to assess overall response to therapy (see bottom of table). Because PGIC is a change score, there is no baseline value. Table 6: Patient Global Impression of Change Endpoint – Patient Global Impression of Score Change Subject BL to 6 mo BL to 12 mo 001 -2 -2 002 +1 0 003 0 0 004 -2 -1 005 -1 007 -1 008 -2 010 -1 013 -1 014 -2 BL: Baseline Prompt: With respect to your overall neurological symptoms, how would you describe yourself now compared to immediately before starting treatment? -3 Very Much Worse -2 Much Worse -1 Minimally Worse 0 Not Changed 1 Minimally Improved 2 Much Improved 3 Very Much Improved

[0256] From the data in Table 6, it can be seen that, from the patient’s perspective, 20% (2 / 10) of subjects had the unexpected finding of stabilized or improved neurological symptoms at 6 months. To our knowledge, no treatment exists that has led to stabilization or improvement on this outcomes measure in MSA.

[0257] The Unified Multiple System Atrophy Rating Scale (UMSARS) is a clinical rating scale designed to assess the various functional impairments associated with MSA. Part I, or UMSARS- I, rates patient-reported functional disability in 12 different domains (see bottom of table). Scores range from 0 to 48, with higher scores indicating greater disability.Table 7: Unified MSA Rating Scale (Total) Endpoint – Unified MSA Rating Scale (Part I) Score Subject Baseline 6 months 12 months 001 16 18 21 002 16 11 13 003 21 18 19 004 30 29 30 005 29 32 007 20 29 008 24 31 010 24 29 013 26 30 014 14 25 Disease areas assessed: Speech, swallowing, handwriting, cutting food / handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary function, sexual function and bowel function

[0258] From the data in Table 7, it can be seen that 30% (3 / 10) of subjects had the unexpected finding of reduced disability from their MSA, as indicated by lower scores on the UMSARS-I at 6 months versus baseline. To our knowledge, no treatment exists that has led to improvement on this outcomes measure in MSA.

[0259] Taken together, the results indicate that ATH434 methanesulfonate salt, when dosed 75mg bid to human MSA patients, achieves beneficial results in stabilizing or even reversing the symptoms of MSA. Pharmacokinetic data

[0260] A summary of the pharmacokinetic data for the Cohort 1 subjects of Study ATH434-202 administered ATH434 methanesulfonate salt at 75mg bid at a single dose and after bid dosing through Week 2 in study ATH434-202 cohort 1 was overlaid with the applicable phase 1 study data modeled from studies including Study 4 above. Because the comparisons were within species (human), concentrations and PK parameter are presented without correction for plasma protein binding. Based on multiple Phase 1 pharmacokinetic studies, Week 2 is indicative of steady-state pharmacokinetic exposures. The overlay is provided in Figure 2.

[0261] A population PK model was previously developed based on Phase 1 studies of ATH434 which included single dose, steady state dosing, and the impact of a meal on ATH434 plasma concentrations and PK parameters. This was an interim model that will be further developed as more ATH434 concentration data become available during clinical development. Phase 2 ATH434 plasma concentrations were incorporated into the interim population PK model. A Bayesian post- hoc estimation step was performed using the interim PK model to derive individual predicted densely sampled ATH434 concentrations for each Phase 2 ATH434-202 subject based on the actual dosing history, including meal status. The modelled Phase 2 estimated PK parameters were compared to observed Phase 1 PK parameters in Table 8 below. Table 8 Parameter Single Dose, 75 mg Steady Stateb, 75 mg BID Phase 1aPhase 2 Phase 1aPhase 2 ATH434-202 ATH434-202 AUC tau 1223 1340 1867 1480 (ng*hr / mL) (Geometric Mean) a Study 4 above adjusted for effect of meal b Study 4: Day 7. Phase 2 Study ATH434-202: Week 2

[0262] These results demonstrate that 75 mg bid dosing at steady state (Week 2) in Phase 2 MSA subjects was similar to the phase 1 results from subjects receiving 75 mg BID at steady state (Day 7). This exposure was sufficient to exceed the minimum effective concentration required to achieve beneficial therapeutic effects by ~ 3-fold as intended. At the same time, measured concentrations were at levels which were expected to avoid significant side effects. Elevated plasma neurofilament light chain (NfL)

[0263] While efficacious in both subgroups, patients with plasma neurofilament light chain (NfL) less than 30 pg / mL at screening had a better treatment outcome than those with NfL greater than or equal to 30 pg / mL.Table 9 Modified UMSARS Part 1 Relative treatment All subjects NfL < 30 pg / mL NfL > 30 pg / mL effect 50 mg BID 48%a61%b26% 75 mg BID 30%b30%b9%a: P < 0.05b: Absolute Std error of Least Squares Mean > 0 Orthostatic hypertension

[0264] While efficacious in both subgroups, patients without protocol-defined orthostatic hypotension at screening had a better treatment outcome than those with orthostatic hypotension. Table 10 Modified UMSARS Part 1 Relative treatment All subjects No Orthostatic With Orthostatic effect hypotension hypotension 50 mg BID 48%a78% 15% 75 mg BID 30%b27% 45%a: P < 0.05b: Absolute Std error of Least Squares Mean > 0

[0265] While efficacious in both subgroups, patients without protocol-defined orthostatic hypotension at screening had a better treatment outcome than those with orthostatic hypotension. Modified UMSARS Part I at Baseline

[0266] While efficacious in both subgroups, patients with baseline modified UMSARS Part I score less than the median (16) had a better treatment outcome than those with baseline modified UMSARS Part 1 score greater than or equal to the median. Table 11 Modified UMSARS Part I Relative treatment All subjects Baseline Baseline effect mUMSARS P1 < mUMSARS P1 > Median Median 50 mg BID 48%a70%a27%75 mg BID 30%b43%b18%a: P < 0.05b: Absolute Std error of Least Squares Mean > 0 mUMSARS P1=Modified UMSARS Part 1 Change from Baseline for ATH43450mg BID and 75 mg BID versus Placebo, assessed using Modified UMSARS Part I Table 12 Modified UMSARS Part I at 52 weeks Placebo ATH43450 mg BID ATH434 75 mg BID Observed Change Observed Change Observed Change value from value from value from Baseline Baseline Baseline LSM (SE) 23.4 (1.21) 7.9 (1.21) 19.6 (1.09) 4.1 (1.09) 21.0 (1.41) 5.6 (1.41) LSMD Not appl. -3.8 (1.64)a-2.4 (ATH434- (1.67)bplacebo) Relative Not appl. 48%a30%btreatment effecta: P < 0.05b: Absolute Std error of LSM > 0 LSM=least squares mean; LSMD=least squares mean difference; SE=standard error Change from Baseline for ATH434 50mg BID and 75 mg BID over time, assessed using Modified UMSARS Part I Table 13Modified UMSARS Part I Least Change from baseline Change from baseline Change from baseline to Squares to 26 weeks to 39 weeks 52 weeks Means Placebo 4.4 6.4 7.9 50 mg BID 3.1 3.9 4.1 75 mg BID 2.0 4.4 5.6 Least Change from baseline Change from baseline Change from baseline to Squares to 26 weeks to 39 weeks 52 weeks Mean Difference from Placebo 50 mg BID -1.3 (1.30)b-2.5 (1.56)b-3.8 (1.64)a75 mg BID -2.4 (1.33)b-2.0 (1.59)b-2.4 (1.67)ba: P < 0.05b: Absolute Std error of Least Squares Mean > 0 Table 14 Modified UMSARS Part I Relative Change from baseline Change from baseline Change from baseline to treatment to 26 weeks to 39 weeks 52 weeks effect 50 mg BID 30% 39% 48%a75 mg BID 55% 31% 30%ba: P < 0.05b: Absolute Std error of Least Squares Mean > 0 Change from Baseline for ATH43450 mg BID and 75 mg BID versus Placebo, assessed Using Modified UMSARS Part I Table 15 Modified UMSARS Part I Change in Change in Change in Change in LSM LSM from LSM from LSM from 26 from 39 weeks to baseline to 13 13 weeks to weeks to 39 52 weeks weeks 26 weeks weeks Placebo 1.5 2.9 2 1.5 50 mg BID 2.2 0.9 0.8 0.2 75 mg BID 1.2 0.8 2.4 1.2a: P < 0.05b: Absolute Std error of Least Squares Mean > 0

[0267] Starting at 13 weeks, ATH434-treated subjects have changes of less than 1.5 in each 13 week period, with the exception of 26-39 weeks @75 BID, which was 1.6. Placebo subjects have changes that are equal to or greater than 1.5. Specific symptoms / effects treated by ATH434 in the UMSARS Part I Speech Table 16 Relative treatment UMSARS Part 1 effect item: Speech 50 mg BID 44%b75 mg BID 33%bbAbsolute Std error of Least Squares Mean > 0 Swallowing Table 17 Relative treatment UMSARS Part 1 Motor score of the PPS: effect item: Swallowing Bulbar / Pseudobulbar 50 mg BID 78%a46%a75 mg BID 44%b42%ba: P < 0.05b: Absolute Std error of Least Squares Mean > 0 Bulbar / Pseudobulbar (relates to swallowing) Table 18 Endpoints related to Swallowing- Subitems of Swallowing Disturbance Q. 50 mg BID 75 mg BID Swallowing Disturbance Questionnaire Total score 82%a27% Difficulty chewing71%b 14%Food Residue 73%a45%bChewed up food dribble from mouth 71%b57%bToo much saliva 117%a0% Need to swallow several times 50% 100%bDifficulty swallowing pureed food 100%b100%bFeel as though food is stuck in throat 100%b50% Cough while swallowing liquids 175%a0% Cough while swallowing solid foods 133%b0%Difficulty breathing during meals 100%a60%ba: P < 0.05b: Absolute Std error of Least Squares Mean > 0 Fine Motor Skills Table 19 Endpoints related to Fine Motor Skills- Subitems of modified UMSARS Part I 50 mg BID 75 mg BID Cutting Food / Handling utensils 69%a62%aDressing69%a 38%bHygiene 43%a50%aa: P < 0.05b: Absolute Std error of Least Squares Mean > 0 Orthostatic Hypotension Table 20 Relative treatment UMSARS Part I item: effect Orthostatic Symptoms 50 mg BID 50%b75 mg BID 100%bb: Absolute Std error of Least Squares Mean > 0 Table 21 Endpoints related to Orthostatic Hypotension- Subitems of Orthostatic Hypotension Symptom Assessment (OHSA). 50 mg BID 75 mg BID OHSA Total score 128%b110%bDizziness 113%b133%aProblems with vision 157%a50% Fatigue 1100%b400% Trouble concentration 73% 91%bHead and neck discomfort 85%b131%ba: P < 0.05b: Absolute Std error of Least Squares Mean > 0 MRI and MSA Volume Index, MSA Atrophy Index,

[0268] ATH434 treated subjects had, on average, smaller indicators of worsening brain atrophy as measured by composite z-scores of the putamen, globus pallidus, cerebellum and brainstem regions vs. healthy age-matched population by MRI. The results are shown in Figure 3. Example 3: Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATH434 in Multiple System Atrophy

[0269] A randomized, double-blind, placebo-controlled study of ATH434, in the form of its methanesulfonate salt, in MSA in humans was carried out. Details of the study are set out below. Summary Protocol ATH434-201 Title A Randomized, Double-Blind, Placebo-Controlled Study of ATH434 in Multiple System Atrophy Development Phase Phase 2 Indication MSA Number of Sites Approximately 25 Objectives Primary: • To assess the efficacy of ATH434 in subjects with MSA Secondary: • To assess the safety and tolerability of ATH434 in subjects with MSA • To evaluate the pharmacokinetics (PK) of ATH434 and potential metabolites in subjects with MSA Study Design This was a randomized, double-blind, placebo-controlled, multinational study in approximately 75 subjects with MSA enrolled at up to 30 sites. Subjects were required to provide written informed consent prior to undergoing any study procedures. After Screening and Baseline assessments were complete, eligible subjects were randomized 1:1:1 to 12 months treatment with two dose levels of ATH434 or placebo. Enrollment occurred in two consecutive cohorts to allow enhanced safety monitoring in a limited number of subjects. The first 15 subjects (Cohort 1) were followed for at least two weeks and their safety and pharmacokinetic data reviewed by the Data Monitoring Committee before the remaining 45 subjects (Cohort 2) were enrolled. All subjects were to receive 12 months of treatment. Subjects were assessed at in-clinic and remote (video [recommended] or telephone) visits over the course of the study.Following Screening and Baseline, in-clinic study visits occurred at Weeks 2, 6, 13, 21, 26, 39, 47 and 52 for safety assessments, including vital signs, routine laboratory testing, physical examination, and 12-lead electrocardiograms (ECG). Cohort 1 subjects had a 1-hour EEG at Screening and after 2 weeks of treatment. Remote visits to evaluate adverse events, concomitant medication use, and study drug compliance were also performed at Weeks 4, 9, 17, 30, 34 and 43. A follow-up clinic visit for safety evaluation was to occur 2 weeks after completion of treatment. At the Week 13, 26, 39 and 52 clinic visits, disease-related clinical assessments were performed, including motor examination, autonomic symptom scales, activities of daily living scales, and patient / clinician impressions of change and / or severity. Wearable wireless motion sensors were provided to the subject at the Screening, Baseline, Week 13, Week 26 and Week 39 visits to monitor physical activity (gait parameters, postures [e.g., standing or sitting] and postural transitions) for 2-week periods every 3 months during the study. At Baseline and Weeks 26 and 52, biological specimens (blood and cerebrospinal fluid [CSF]) were collected for fluid biomarker assessments. Magnetic resonance imaging (MRI) for structural analysis and imaging biomarkers (e.g., quantitative susceptibility mapping [QSM]) was to be performed at Screening and Weeks 26 and 52. Cohort 1 subjects provided blood samples for ATH434 concentrations through 4.5 hours post-dose at the Day 1 and Week 2 visits, with the addition of a pre-dose sample at Week 2. Cohort 2 subjects provided blood samples for ATH434 concentrations through 3 hours post-dose at the Day 1 and Week 2 visits, with the addition of a pre-dose sample at Week 2. A Data Monitoring Committee (DMC) reviewed unblinded safety data during study conduct. The DMC was independent from the sponsor and first met after Cohort 1 (N=15) have completed at least 2 weeks of treatment, and thereafter met at intervals as specified in the DMC Charter. The DMC was to be notified of serious adverse events (SAEs) and PSAEs throughout the study in accordance with the DMC Charter. Dosage and Dose ATH434 methanesulfonate salt was supplied as oval-shaped, Regimen white, coated 75 mg and 50 mg tablets. The 75 mg tablet is larger than the 50 mg tablet. The placebo tablets are identical in appearance and weight to corresponding active drug. Each dose of study drug comprised two tablets to maintain blinding. At randomization (Day 1), eligible subjects were assigned to one of the following treatment arms in a 1:1:1 ratio in a double-blind manner as follows: • ATH434 methanesulfonate salt 75 mg BID• ATH434 methanesulfonate salt 50 mg BID • Placebo BID Subjects began dosing the morning of randomization and took study drug orally BID for 52 weeks. Study drug should be taken with food; the evening dose should be taken at least 2.5 hours before bedtime. The first dose and the Week 2 morning dose were to be administered in the clinic to facilitate pharmacokinetic assessment. All other doses were to be self-administered. Suspension of dosing was at the discretion of the Investigator. Following suspension, if the Investigator believes that resumption of dosing is warranted, agreement from the Medical Monitor had to be sought before dosing is resumed. Sample Size Approximately 75 subjects were enrolled. Study Population Subjects with a clinical diagnosis of MSA, motor symptoms of ≤4 years duration and no evidence of severe impairment. Inclusion Criteria Subject had to meet all of the following criteria to be included: 1. Subject is 30 to 75 years old, inclusive, at the time of Screening. 2. Subject has provided written informed consent. 3. Subject has clinical features of parkinsonism. 4. Subject has at least one of the following features indicative of autonomic dysfunction: a. Urinary urgency / frequency with incontinence b. Incomplete bladder emptying that is not otherwise explained c. Significant orthostatic hypotension that is not otherwise explained 5. Subject has at least one of the following additional features of MSA: a. One or more abnormality on cerebellar examination b. Presence of unexplained pyramidal sign(s) 6. Subject has increased iron in basal ganglia (lentiform nucleus (putamen / globus pallidus) or substantia nigra) on Screening MRI, as confirmed by central reading. 7. Elevated plasma neurofilament light chain (NfL) at Screening 8. If subject is receiving dopaminergic therapy, the dose / regimen has been stable for at least 30 days before Screening. 9. If subject is receiving drug treatment for neurogenic orthostatic hypotension, the dose has been stable for at least 30 days before Screening. 10. Subject is able to ambulate without assistance for at least 10 meters 11. Subject has an identified, reliable study partner who either lives with the subject (e.g., spouse) or interacts with the subject on a daily basis. 12. Female subjects must fulfill at least one of the following conditions: a. Post-menopausalb. Surgically sterile c. Women of childbearing potential are using two methods of contraception from Screening through 2 weeks after the final IP administration. 13. Male subjects must be using an effective birth control methods from Screening through 104 days after the final IP administration Exclusion Criteria A subject meeting any of the following criteria was excluded: 1. Subject had onset of motor symptoms >4 years before Screening. 2. Subject has swallowing impairment as indicated by choking more than once a week. 3. Subject falls one or more times per week. 4. Subject has severe hyposmia not otherwise explained 5. Subject has evidence of Dementia with Lewy Bodies 6. Subject is cognitively impaired, based on Investigator assessment or as indicated by MMSE score. 7. Evidence of disproportionate cortical atrophy, hippocampal / mesial temporal atrophy, or confluent white matter hyperintensities on Screening MRI, as determined by central reading. 8. Subject has evidence of any significant neurological disorder other than MSA 9. Subject has history of any neurosurgical procedure, including deep brain stimulation OR stereotactic surgery. 10. Subject has a contraindication or inability to tolerate brain MRI 11. Subject has a contraindication or inability to tolerate lumbar puncture 12. Use of prohibited concomitant medications 13. Subject has an unstable or serious illness that, in the Investigator’s opinion, may interfere with the subject's participation in study or adversely affect survival. 14. Subject has an underlying medical condition that may confound interpretation of study results. 15. Female subject is pregnant or breastfeeding. 16. Subject resides at a skilled nursing facility or dementia care facility, or admission to such a facility is anticipated during the 54- week study period. 17. Consideration by the Investigator, for any reason, that the subject is an unsuitable candidate for the study. Study Duration The expected duration of participation for each subject was approximately 54 weeks, not including Screening. Efficacy Endpoints Primary Endpoint: Change from Baseline to Week 52 in iron content / deposition in substantia nigra (SN) by MRI QSM / R2*Key Secondary Endpoint: Change from Baseline to Week 52 in modified UMSARS Part I Historical Review1Additional Secondary Endpoints: Assessed as change from Baseline to Week 52 Clinical • Total UMSARS Part I Historical Review • Condensed total score of the UMSARS Part I Historical Review • Modified motor score of the Parkinson Plus Scale (m-PPS)2• Total motor score of the Parkinson Plus Scale (m-PPS) • Levodopa dose equivalents • Clinical global impression of severity (CGI-S) • Clinical global impression of change (CGI-C) (As CGI-C is a change score, there is no Baseline value) • Patient global impression of change (PGI-C) (As PGI-C is a change score, there is no Baseline value) • Timed Up and Go • SF-36 Physical Functioning scale Additional Imaging biomarkers • Iron content / deposition in the following regions: putamen; globus pallidus; lentiform nucleus (globus pallidus + dentate nucleus); dentate nucleus of cerebellum; and the combined region (substantia nigra + putamen + globus pallidus + dentate nucleus) by MRI QSM and R2* • Volumetric assessments in the following regions: putamen, globus pallidus; lentiform nucleus (putamen + globus pallidus); cerebellum; and brainstem by T1-weighted MRI • Neuronal integrity in substantia nigra, assessed by volume and contrast ratio as assessed by neuromelanin-MRI Fluid biomarkers • Neurofilament light chain in CSF • Neurofilament light chain in plasma Wearable movement sensors Step count; bouts of walking; time walking, standing, sitting, or lying; mobility index ((Standing time + Walking time) / (Sitting time + Lying time)); sit-to-stand transitions.1Modified UMSARS includes following items: Speech, swallowing, handwriting, cutting food / handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary and bowel function. 2 Modified motor score includes a subset of items from the motor examination of The Parkinson’s Plus Scale: bulbar / pseudobulbar (speech [motor examination], facial expression), tremor, rigidity, limb and axial bradykinesia, oculomotor function, and cerebellar function. Safety Endpoints • Incidence of AEs, SAEs, and AEs leading to withdrawal • Observed values and changes in clinical laboratory parameters (hematology, chemistry, urinalysis, and iron studies) • Observed values and changes in vital signs, including orthostatics • Observed values in ECG parameters and abnormal findings • Number of ECGs and subjects with 1) on-treatment QTcF values >450 ms, >480 ms, >500 ms and 2) QTcF change from baseline >30 ms and >60 ms. Pharmacokinetics Blood and CSF samples for measuring ATH434 (and potential metabolites) concentrations were collected as follows: • Cohort 1 (N=15) subjects provide 6 blood samples through 4.5 hours at the Day 1 visit (at 0.5, 1, 1.5, 2, 3, and 4.5 hours postdose) and 7 blood samples through 4.5 hours at the Week 2 visit (pre-dose and at 0.5, 1, 1.5, 2, 3, and 4.5 hours post-dose). • Cohort 2 (N=45) subjects provide 2 blood samples through 3 hours post-dose after the morning dose on Day 1 (1 and 3 hours post-dose) and 3 samples around the morning dose at the Week 2 visit (pre-dose and at 1 and 3 hours post-dose). • All subjects provide a single blood sample at the Week 13 and Week 39 visits, pre-dose if possible. • CSF collected in all subjects at Week 26 and Week 52. This collection was to be paired with a blood sample taken within15 minutes after CSF sampling. Statistical Primary Efficacy Analysis Considerations The change from Baseline to Week 52 in the primary endpoint (iron content / deposition in the substantia nigra) is to be analyzed using mixed-model for repeated measures (MMRM) model with treatment group (three levels) as a factor and the Baseline value of iron content / deposition and age as covariates. The primary analysis was to compare the high-dose group to the placebo group using a two-sided test at the alpha=0.05 level of significance. If the primary analysis was statistically significant, then the following additional hypotheses were to be tested in order, using a two-sided test at the alpha=0.05 level of significance.1. Comparison of high dose to placebo for change from Baseline to Week 52 for key secondary endpoint (modified UMSARS I) 2. Comparison of low dose to placebo for change from Baseline to Week 52 for the primary efficacy endpoint (iron content in substantia nigra (SN)) 3. Comparison of low dose to placebo for change from Baseline to Week 52 for key secondary endpoint (modified UMSARS I) The analysis of the change from Baseline to Week 52 for the key secondary efficacy endpoint of modified UMSARS I was to be conducted using an analysis of covariance (ANCOVA) model with treatment group (three levels) and the randomization stratification variable (screening plasma NfL) as factors and the Baseline value of the modified UMSARS I and baseline CSF NfL as covariates. If the primary analysis or any secondary analysis is not statistically significant, the subsequent comparisons will be exploratory rather than confirmatory. This fixed-sequence testing procedure will control the overall level of significance. Safety Analyses All subjects who have received at least one dose of study drug will be evaluated for safety. All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Incidence of AEs by the severity, relationship to treatment, and outcome will be provided. Laboratory parameters, vital signs, and other safety parameters will be listed by subject and presented using descriptive summary statistics. Treatment-emergent AEs and laboratory, vital sign, and safety 12- lead ECG parameters will be summarized. In addition, change from Baseline will be summarized for laboratory and vital sign parameters. Shift tables will be provided for clinical laboratory results. Electrocardiogram results will be classified as normal and abnormal and summarized. Cardiac intervals, including QTc, PR, and QRS, will be analyzed for absolute outliers based on criteria set forth in the statistical analysis plan. PK Analysis In-study PK analysis For the initial DMC meeting, ATH434 exposure in Cohort 1 (N=15) was quantified on Day 1 and at Week 2, using a population PK model approach to determine mean PK parameters (Cmax and AUCtau). As a complementary approach, ATH434 plasma concentrations from Cohort 1 participants were compared with the Phase 1 data to assess whether ATH434 in patientsdemonstrated PK characteristics as expected based on Phase 1 data. Population PK analysis Concentration data from all subjects were to be analyzed by population PK methods. The details of the analysis were to be described in a pharmacometric analysis plan and reported independently from the clinical study report. CSF concentrations For paired CSF and blood samples drawn for quantitation of ATH434 at Weeks 26 and 52, the ratio of CSF concentration to plasma concentration will be reported and summarized descriptively by visit and dose level. Pharmacokinetic data

[0270] A population PK model was previously developed based on Phase 1 studies of ATH434 which included single dose, steady state dosing, and the impact of a meal on ATH434 plasma concentrations and PK parameters. This was an interim model that will be further developed as more ATH434 concentration data become available during clinical development. Phase 2 ATH434 plasma concentrations from ATH434-201 were incorporated into the interim population PK model. A Bayesian post-hoc estimation step was performed using the interim PK model to derive individual predicted densely sampled ATH434 concentrations for each Phase 2 ATH434-201 Cohort 1 subject based on the actual dosing history, including meal status. The modelled Phase 2 estimated PK parameters at Week 2 were compared to observed Phase 1 PK parameters in Table 8 below. Table 22 Parameter Steady Stateb, 50 mg Steady Stateb, 75 mg BID Phase 1aPhase 2 Phase 1aPhase 2 ATH434-201 ATH434-201 AUC tau 1245 1380 1867 2510 (ng*hr / mL)(Geometric Mean) a Study 4 above adjusted for effect of meal and adjusted linearly for dose b Study 4: Day 7. Phase 2 Study ATH434-201: Week 2

[0271] These results demonstrate that 50 and 75 mg bid dosing at steady state (Week 2) in Phase 2 MSA subjects was similar to the phase 1 results from subjects receiving 75 mg BID at steady state (Day 7) and dose adjusted estimates at 50 mg BID. These exposures were sufficient to exceed the minimum effective concentration required to achieve beneficial therapeutic effects by ~ 3-fold as intended. At the same time, measured concentrations were at levels which were expected to avoid significant side effects. Example 4: A Randomized, Double-Blind, Placebo-Controlled Study of ATH434 in Multiple System Atrophy

[0272] A randomized, double-blind, placebo-controlled clinical study of ATH434, in the form of its methanesulfonate salt, in MSA in humans will be carried out. Details of the study are set out below. Summary Protocol ATH434-301 Title A Randomized, Double-Blind, Placebo-Controlled Clinical Study of ATH434 in Multiple System Atrophy Indication MSA Number of Sites Approximately 45 Objectives To assess the efficacy and safety of ATH434 in subjects with MSA Study DesignThis is a randomized, double-blind, placebo-controlled, multinationalstudy in approximately 180 subjects with MSA enrolled at up to 45 sites. Subjects will be required to provide written informed consent prior to undergoing any study procedures. After Screening and Baseline assessments are complete, eligible subjects will be randomized 1:1 to 12 months treatment with ATH434 or placebo. Randomization will be stratified based on the Screening level of plasma neurofilament light chain (low / high) and degree of orthostatic blood pressure change at Baseline (<30 mmHg change / ≥30 mmHg change). Subjects will be assessed at in-clinic and remote (video [recommended] or telephone) visits over the course of the study. Following Screening and Baseline, in-clinic study visits will occur at Weeks 13, 26, 39 and 52 for safety assessments, routine laboratory testing, physical examination, and 12-lead electrocardiograms (ECG). Remote visits to evaluateadverse events, concomitant medication use, and study drug compliance will be performed at Weeks 6, 20, 33 and 45. A follow-up clinic visit for safety evaluation will occur 2 weeks after completion of treatment. At the Week 13, 26, 39 and 52 clinic visits, disease-related clinical assessments will be performed, including the UMSARS Part I activities of daily living scale, motor examination, assessment of swallowing, orthostatic hypotension symptom assessment, and patient / clinician global impressions of change and / or severity. Wearable movement sensors will be used to monitor physical activity (gait parameters, postures [e.g., standing or sitting] and postural transitions) at the Baseline, Week 13, Week 26 and Week 39 visits for 1-week periods. At Baseline, biological specimens (blood and cerebrospinal fluid [CSF]) will be collected for fluid biomarker assessments. Magnetic resonance imaging (MRI) for assessing iron content and volume will be performed at Screening and Weeks 26 and 52. A Data Monitoring Committee (DMC) will review unblinded safety data during study conduct. The DMC will be independent from the sponsor and will first meet periodically as specified in the DMC Charter. The DMC will be notified of serious adverse events (SAEs) and PSAEs throughout the study in accordance with the DMC Charter Dosage and DoseRegimen ATH434 methanesulfonate will be supplied as oval-shaped, white,coated 75 mg tablets. The placebo tablets are identical in appearance andweight to the 75 mg tablet. The tablets will be packaged into uniquely identified blister cards. An initial supply of blister cards will be shipped to each site prior to the start of study enrollment. • ATH434 methanesulfonate salt 75 mg BID • Placebo BID Subjects will begin dosing the morning of randomization and will take study drug orally BID for 52 weeks. Study drug should be taken with food; the evening dose should be taken at least 2.5 hours before bedtime. Suspension of dosing is at the discretion of the Investigator. Following suspension, if the Investigator believes that resumption of dosing is warranted, agreement from the Medical Monitor must be sought before dosing is resumed. Sample Size Approximately 180 subjects will be enrolled. Study Population Subjects with a clinical diagnosis of MSA, motor symptoms of ≤4 years duration and no evidence of severe impairment. Optionally, subjects with clinical diagnosis of MSA, motor symptoms of ≤3 years duration and no evidence of severe impairment. Inclusion Criteria Subjects meet one or more of the following criteria to be included. In some cases, subjects can meet all of the following criteria: 1. Subject is 30 to 75 years old, inclusive, at the time of Screening. 2. Subject has provided written informed consent. 3. Subject has clinical features of parkinsonism.4. Subject has at least one of the following features indicative of autonomic dysfunction: a. Urinary urgency / frequency with incontinence b. Incomplete bladder emptying that is not otherwise explained (i.e. BPH) c. Significant orthostatic hypotension that is not otherwise explained (e.g., antihypertensive treatment), defined as a decrease in either SBP and / or DBP at 3 minutes after a change in position (from lying to sitting; or sitting to standing). i. systolic blood pressure (SBP) ≥20 mmHg ii. diastolic blood pressure (DBP) ≥10 mmHg Note: A history of neurogenic orthostatic hypotension with current use of approved pharmacologic treatment (i.e., droxidopa, midodrine, fludrocortisone, atomoxetine) or non- pharmacologic treatment (i.e., salt tablets, abdominal binders, leg compression stockings) will satisfy this criterion if the above thresholds were met prior to initiating therapy. 5. Subject has at least one of the following additional features of MSA: a. One or more of the following findings on cerebellar examination: i. Ataxic dysarthria, as determined by central rating (English-speaking countries only) ii. Limb ataxia: dysmetria on exam (finger-nose- finger or finger-chasing assessment) AND / OR heel-knee-shin test with ataxic gait b. Presence of unexplained pyramidal sign(s), e.g., Babinski with hyperreflexia 6. Subject has increased iron in the putamen, globus pallidus or substantia nigra on Screening MRI, as confirmed by central reading. 7. Subject has reduced brain volume in MSA affected areas (putamen, globus pallidus, cerebellum and brainstem) as measured by the MSA- atrophy index. 8. Subject has elevated plasma neurofilament light chain (NfL) at Screening 9. Subject has an average modified UMSARS part I score (at Screening and Baseline) ≤17. 10. Subject is able to ambulate without assistance for at least 10 meters Note: Use of a cane is permitted but stabilization of one arm from an assistant OR a walker is not permitted. 11. If subject is receiving dopaminergic therapy, the dose / regimen hasbeen a. optimized for control of parkinsonism b. stable for at least 30 days before Screening and c. the Investigator does not anticipate a change in therapy for 3 or more months after Screening. 12. If subject is receiving drug treatment for neurogenic orthostatic hypotension, the dose / regimen has been a. stable for at least 30 days before Screening and b. the Investigator does not anticipate a change in therapy for 3 or more months after Screening. 13. Subject has an identified, reliable study partner who either lives with the subject (e.g., spouse) or interacts with the subject on a daily basis. 14. Female subjects must fulfill at least one of the following conditions: a. Post-menopausal b. Surgically sterile c. Women of childbearing potential are using two methods of contraception from Screening through 2 weeks after the final IP administration. 15. Male subjects must be using an effective birth control methods from Screening through 104 days after the final IP administration Exclusion Criteria A subject meeting any of the following criteria will be excluded: 1. Subject had onset of motor symptoms >4 years before Screening. 2. Subject has swallowing impairment as indicated by choking more than once a week. 3. Subject falls one or more times per week. 4. Subject has severe hyposmia not otherwise explained 5. Subject has evidence of Dementia with Lewy Bodies 6. Subject is cognitively impaired, based on Investigator assessment or as indicated by MMSE score <26. 7. Evidence of disproportionate cortical atrophy, hippocampal / mesial temporal atrophy, or confluent white matter hyperintensities on Screening MRI, as determined by central reading. 8. Subject has evidence of any significant neurological disorder other than MSA 9. Subject has history of any neurosurgical procedure, including deep brain stimulation OR stereotactic surgery. 10. Subject has a contraindication or inability to tolerate brain MRI 11. Subject has a contraindication or inability to tolerate lumbar puncture 12. Use of prohibited concomitant medications 13. Subject has an unstable or serious illness that, in the Investigator’s opinion, may interfere with the subject's participation in study or adversely affect survival. 14. Subject has an underlying medical condition that may confound interpretation of study results. 15. Female subject is pregnant or breastfeeding.16. Subject resides at a skilled nursing facility or dementia care facility, or admission to such a facility is anticipated during the 54-week study period. 17. Consideration by the Investigator, for any reason, that the subject is an unsuitable candidate for the study. Study Duration The expected duration of participation for each subject was approximately 54 weeks, not including Screening. Efficacy Endpoints Primary Endpoint: Change from Baseline to Week 52 in modified UMSARS Part I Historical Review1Secondary Efficacy Endpoints: Assessed as change from Baseline to Week 52 Clinical • Orthostatic Hypotension Symptom Assessment (OHSA) • Swallowing Disturbance Questionnaire (SDQ) • Speech, as assessed by Items 3 and 6 of the Bulbar / Pseudobulbar subscale of the Parkinson’s Plus Scale2• Fine motor skills, optionally as assessed by the Promis upper extremity item bank or other suitable scale • Activity in the outpatient setting, as assessed by wearable movement sensors: total walking time, step count , bouts of walking; sit-to- stand transitions • Clinical global impression of severity (CGI-S) • Timed Up and Go Biomarker endpoints • Brain volume in MSA-affected regions (putamen, globus pallidus, cerebellum; and brainstem) by T1-weighted MRI, optionally, as assessed with the MSA-atrophy index • Iron content / deposition in the putamen, globus pallidus; lentiform nucleus (globus pallidus + dentate nucleus); dentate nucleus of cerebellum; and the combined region (substantia nigra + putamen + globus pallidus + dentate nucleus) by MRI QSM and R2* • Neurofilament light chain in CSF • Neurofilament light chain in plasma 1 Modified UMSARS includes following items: Speech, swallowing, handwriting, cutting food / handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary and bowel function. 2 Modified motor score includes a subset of items from the motor examination of The Parkinson’s Plus Scale: bulbar / pseudobulbar (speech [motor examination], facial expression), tremor, rigidity, limb and axial bradykinesia, oculomotor function, and cerebellar function. Safety Endpoints • Incidence of AEs, SAEs, and AEs leading to withdrawal• Observed values and changes in clinical laboratory parameters (hematology, chemistry, urinalysis, and iron studies) • Observed values and changes in vital signs, including orthostatics • Observed values in ECG parameters and abnormal findings • Number of ECGs and subjects with 1) on-treatment QTcF values >450 ms, >480 ms, >500 ms and 2) QTcF change from baseline >30 ms and >60 ms. Pharmacokinetics Blood and CSF samples for measuring ATH434 (and potential metabolites) concentrations will be collected as follows: • All subjects will provide 2 blood samples through 3 hours post-dose after the morning dose on Day 1 (1 and 3 hours post-dose) and 3 samples around the morning dose at the Week 2 visit (pre-dose and at 1 and 3 hours post-dose). • All subjects provide a single blood sample at the Week 13 and Week 39 visits, pre-dose if possible. • CSF collected in all subjects at Week 26 and Week 52. This collection will be paired with a blood sample taken within15 minutes after CSF sampling. Statistical Considerations Primary Efficacy Analysis The analysis of the change from Baseline to Week 52 for the primary efficacy endpoint of modified UMSARS I will be conducted using an analysis of covariance (ANCOVA) model with treatment group (two levels) and the randomization stratification variables (Screening NfL and degree of orthostatic blood pressure change at Baseline (<30 mmHg change / ≥30 mmHg change) as factors and the Baseline value of the modified UMSARS I as covariate. If the primary analysis is statistically significant, then the following additional hypotheses were to be tested in order, using a two-sided test at the alpha=0.05 level of significance. 1. Comparison of ATH434 treatment to placebo for change from Baseline to Week 52 on the OHSA 2. Comparison of ATH434 treatment to placebo for change from Baseline to Week 52 on the SDQ (Swallowing Disturbance Questionnaire) 3. Comparison of ATH434 treatment to placebo for change from Baseline to Week 52 on indices of fine motor performance (applicable sub-items from the modified UMSARS I) 4. Comparison of ATH434 treatment to placebo for change from Baseline to Week 52 on indices derived from wearable sensors . 3. Comparison of low dose to placebo for change from Baseline to Week 52 for key secondary endpoint (modified UMSARS I) If the primary analysis or any secondary analysis is not statistically significant, the subsequent comparisons will be exploratory rather than confirmatory. This fixed-sequence testing procedure will control the overall level of significance. Safety AnalysesAll subjects who have received at least one dose of study drug will be evaluated for safety. All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Incidence of AEs by the severity, relationship to treatment, and outcome will be provided. Laboratory parameters, vital signs, and other safety parameters will be listed by subject and presented using descriptive summary statistics. Treatment-emergent AEs and laboratory, vital sign, and safety 12-lead ECG parameters will be summarized. In addition, change from Baseline will be summarized for laboratory and vital sign parameters. Shift tables will be provided for clinical laboratory results. Electrocardiogram results will be classified as normal and abnormal and summarized. Cardiac intervals, including QTc, PR, and QRS, will be analyzed for absolute outliers based on criteria set forth in the statistical analysis plan. PK Analysis Population PK analysis Concentration data from all subjects were to be analyzed by population PK methods. The details of the analysis were to be described in a pharmacometric analysis plan and reported independently from the clinical study report. CSF concentrations For paired CSF and blood samples drawn for quantitation of ATH434 at Weeks 26 and 52, the ratio of CSF concentration to plasma concentration will be reported and summarized descriptively by visit and dose level.References Acosta-Cabronero et al 2017 Acosta‐Cabronero J, Cardenas‐Blanco A, Betts MJ, Butryn M, Valdes-Herrera JP, Galazky I, et al. The whole‐brain pattern of magnetic susceptibility perturbations in Parkinson's disease. Brain.2017;140:118‐131. Aquino et al 2014 Aquino D, Contarino V, Albanese A, Minati L, Farina L, Grisoli M, et al. Substantia nigra in Parkinson's disease: a multimodal MRI comparison between early and advanced stages of the disease. Neurol Sci.2014;35:753‐758. Batla et al 2018 Batla A, De Pablo-Fernandez E, Erro R, et al. Young-onset multiple system atrophy: clinical and pathological features. Mov Disord.2018;33(7):1099-1107. Bleasel et al 2014 Bleasel JM, Wong JH, Halliday GM, Kim WS. 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Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating or preventing a neurological or neurodegenerative disease or disorder in a human subject, comprising administering ATH434 or a salt thereof OH ,to the subject twice per day, wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

2. A method as claimed in claim 1, wherein in each administration an amount of from 30 to 64 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 64 mg of ATH434.

3. A method as claimed in claim 2, wherein in each administration an amount of from 30 to 45 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 45 mg of ATH434.

4. A method as claimed in claim 3, wherein in each administration an amount of about 38 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering about 38 mg of ATH434.

5. A method as claimed in claim 2, wherein in each administration an amount of from 49 to 64 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 49 to 64 mg of ATH434.

6. A method as claimed in claim 5, wherein in each administration an amount of about 57 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering about 57 mg of ATH434.

7. A method as claimed in any of claims 1-6, wherein an ATH434 salt is administered.

8. A method as claimed in claim 7, wherein ATH434 methanesulfonate salt is administered.

9. A method as claimed in claim 8, wherein in each administration an amount of ATH434 methanesulfonate salt in the range of from 40 to 90 mg is administered.

10. A method as claimed in claim 9, wherein in each administration from 40 to 60 mg of ATH434 methanesulfonate salt is administered.

11. A method as claimed in claim 10, wherein in each administration 50 mg of ATH434 methanesulfonate salt is administered.

12. A method as claimed in claim 8, wherein in each administration from 65 to 85 mg of ATH434 methanesulfonate salt is administered.

13. A method as claimed in claim 12, wherein in each administration 75 mg of ATH434 methanesulfonate salt is administered.

14. A method as claimed in any of claims 1-13, wherein the neurological or neurodegenerative disease or disorder is multiple system atrophy (MSA).

15. A method as claimed in any of claims 1-14, wherein ATH434 or an ATH434 salt is administered twice per day for a period of at least 3 months, optionally for at least 6 months, or optionally for at least 1 year, or optionally for at least 3 years.

16. A method as claimed in any of claims 1-15, wherein the subject is at least 40 years old, optionally at least 50 years old, or optionally at least 60 years old.

17. A method as claimed in any of claims 1-16, wherein the method is for treating a neurological or neurodegenerative disease or disorder.

18. A method as claimed in any of claims 1-17, wherein ATH434 or a salt thereof is administered orally.

19. A method of treating or preventing a neurological or neurodegenerative disease or disorder in a human subject, comprising administering a pharmaceutical composition comprising ATH434 or a salt thereof OH , and ato the subject twice per day, wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

20. ATH434 or a salt thereofOH , for use in or disorderin a human subject twice per day, and wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

21. A pharmaceutical composition comprising ATH434 or a salt thereof OH , and afor use in treating or preventing a neurological or neurodegenerative disease or disorder in a human subject, wherein ATH434 or ATH434 salt is administered to the subject twice per day, and wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

22. Use of ATH434 or a salt thereofOH , for the oror ATH434 salt is administered to the subject twice per day, and wherein in each administration an amount of from 30 to 68 mg of ATH434 is administered, or wherein in each administration an amount of ATH434 salt is administered which is equivalent to administering from 30 to 68 mg of ATH434.

23. A pharmaceutical composition in unit dosage form, comprising ATH434 or an ATH434 salt, and a pharmaceutically acceptable excipient, wherein the unit dosage form contains from 30 to 68 mg of ATH434, or wherein the unit dosage from has an amount of ATH434 salt which is equivalent to an amount of from 30 to 68 mg of ATH434.

24. A pharmaceutical composition in unit dosage form as claimed in claim 23, wherein the pharmaceutical composition contains ATH434 methanesulfonate salt.

25. A pharmaceutical composition in unit dosage form as claimed in claim 24, wherein the pharmaceutical composition contains 50 mg ATH434 methanesulfonate salt.

26. A pharmaceutical composition in unit dosage form as claimed in claim 25, wherein the pharmaceutical composition contains 75 mg ATH434 methanesulfonate salt.

27. A pharmaceutical composition in unit dosage form as claimed in any of claims 23-26, wherein the unit dosage form is in the form of a tablet.

28. The method of any one of claims 1-19, wherein the subject has an elevated plasma neurofilament light chain (NfL) level before the administering of ATH434 or the salt thereof.

29. The method of any one of claims 1-19 or 28, wherein the subject has a plasma NfL level of less than 30 pg / mL before the administering of ATH434 or the salt thereof.

30. The method of any one of claims 1-19 or 28-29, wherein the subject has a plasma NfL level of less than 15 pg / mL, less than 20 pg / mL, less than 25 pg / mL, less than 30 pg / mL, less than 35 pg / mL, or less than 40 pg / mL before the administering of ATH434 or the salt thereof.

31. The method of any one of claims 1-19 or 28-30, wherein the subject has a plasma NfL level of at least 5 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, or at least 25 pg / mL before the administering of ATH434 or the salt thereof.

32. The method of any one of claims 1-19, wherein the subject has a plasma NfL level of about 10-30 pg / mL, 15-30 pg / mL, or 20-30 pg / mL before the administering of ATH434 or the salt thereof.

33. The method of any one of claims 1-19, wherein the subject has a plasma NfL level of about 16.5-30 pg / mL before the administering of ATH434 or the salt thereof.

34. The method of any one of claims 1-19 or 28-33, further comprising determining an NfL level in the subject before the administering of ATH434 or a salt thereof.

35. The method of any one of claims 1-19 or 28-34, further comprising monitoring the NfL level in the subject after the administering of ATH434 or a salt thereof.

36. The method of any one of claims 1-19 or 28-35, wherein the subject does not have orthostatic hypotension before the administering of ATH434 or the salt thereof.

37. The method of any one of claims 1-19 or 28-36, wherein the subject has a Unified Multiple System Atrophy Rating Scale Part I (UMSARS I) score of less than 14, less than 15, less than 16, less than 17, less than 18, less than 19, or less than 20 before the administering of ATH434 or the salt thereof.

38. The method of any one of claims 1-19 or 28-36, wherein the subject has an UMSARS I score of less than 16 before the administering of ATH434 or the salt thereof.

39. The method of any one of claims 1-19 or 28-36, wherein the subject has an UMSARS I score of 17 or lower before the administering of ATH434 or the salt thereof.

40. The method of any one of claims 1-19 or 28-36, wherein the subject has an UMSARS I score of 1 to 16 before the administering of ATH434 or the salt thereof.

41. The method of any one of claims 1-19 or 28-36, wherein the subject has an UMSARS I score of 1 to 17 before the administering of ATH434 or the salt thereof.

42. The method of any one of claims 1-19 or 28-41, wherein the UMSARS I score of the subject does not increase by more than 3.0, 4.0, 5.0, 6.0, or 7.0 after the administering of ATH434 or the salt thereof for 52 weeks.

43. The method of any one of claims 1-19 or 28-41, wherein the UMSARS I score of the subject does not increase by more than 6.0 after the administering of ATH434 or the salt thereof for 52 weeks.

44. The method of any one of claims 1-19 or 28-41, wherein the UMSARS I score of the subject does not increase by more than 6.0 after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

45. The method of any one of claims 1-19 or 28-44, wherein the UMSARS I score of the subject does not increase by more than 1.5 following 13 weeks of the administering of ATH434 or the salt thereof.

46. The method of any one of claims 1-19 or 28-44, wherein the UMSARS I score of the subject does not increase by more than 0.5, 0.8, 1.0, 1.2, 1.5, 1.8 or 2.0 following 13 weeks of the administering of ATH434 or the salt thereof.

47. The method of any one of claims 1-19 or 28-46, wherein the UMSARS I score of the subject is at most 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 after the administering of ATH434 or the salt thereof for a period of 12 months.

48. The method of any one of claims 1-19 or 28-46, wherein the UMSARS I score of the subject is at most 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 after the administering of ATH434 or the salt thereof for a period of 6 months.

49. The method of any one of claims 1-19 or 28-48, wherein the relative treatment effect of ATH434 or the salt thereof is at least 30% compared to placebo after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

50. The method of any one of claims 1-19 or 28-48, wherein the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, or at least 40% compared to placebo after 52 weeks.

51. The method of claim 49 or 50, wherein the relative treatment effect is determined according to the subject’s UMSARS I score.

52. The method of claim 49 or 50, wherein the relative treatment effect is determined according to one or more parameters of the UMSARS I score (such as speech, swallowing, cutting food, dressing, hygiene, etc.).

53. The method of claim 52, wherein the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is speech.

54. The method of claim 53, wherein the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the speech parameter of the UMSARS I score.

55. The method of claim 52, wherein the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is swallowing.

56. The method of claim 55, wherein the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the swallowing parameter of the UMSARS I score.

57. The method of claim 55 or 56, wherein the swallowing parameter comprises one or more sub-parameters selected from (i) Swallowing Disturbance Questionnaire Total score; (ii) Difficulty chewing; (iii) Food Residue; (iv) Chewed up food dribble from mouth; (v) Too much saliva; (vi) Need to swallow several times; (vii) Difficulty swallowing pureed food, (viii) Feel as though food is stuck in throat, (ix) Cough while swallowing liquids; (x) Cough while swallowing solid foods; and (xi) Difficulty breathing during meals.

58. The method of claim 52, wherein the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is motor score (Bulbar / Pseudobulbar).

59. The method of claim 58, wherein the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relativetreatment effect is determined according to the motor score (Bulbar / Pseudobulbar) parameter of the UMSARS I score.

60. The method of claim 52, wherein the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is fine motor skill.

61. The method of claim 60, wherein the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the fine motor skill parameter of the UMSARS I score.

62. The method of claim 60 or 61, wherein the fine motor skill parameter comprises one or more sub-parameters selected from (i) Cutting Food; (ii) Handling utensils; (iii) Dressing; and (iv) hygiene 63. The method of claim 52, wherein the relative treatment effect is determined according to a parameter of the UMSARS I score, and wherein the parameter is Orthostatic Hypotension.

64. The method of claim 63, wherein the relative treatment effect of ATH434 or the salt thereof is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 100%, at least 120%, at least 140%, at least 150%, or at least 160% compared to placebo after 52 weeks, and wherein the relative treatment effect is determined according to the Orthostatic Hypotension parameter of the UMSARS I score.

65. The method of claim 63 or 64, wherein the Orthostatic Hypotension parameter comprises one or more sub-parameters selected from (i) Orthostatic Hypotension Symptom Assessment (OHSA) total score; (ii) Dizziness; (iii) Problems with vision; (iv) Fatigue; (v) Trouble concentration; and (vi) Head and neck discomfort.

66. The method of any one of claims 1-19 or 28-65, wherein an MSA Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

67. The method of any one of claims 1-19 or 28-65, wherein an MSA Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

68. The method of any one of claims 1-19 or 28-67, wherein an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

69. The method of any one of claims 1-19 or 28-67, wherein an MSA Volume Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

70. The method of any one of claims 1-19 or 28-69, wherein an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

71. The method of any one of claims 1-19 or 28-69, wherein an MRI Atrophy Index of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

72. The method of any one of claims 1-19 or 28-71, wherein a composite Z-score of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 52 weeks.

73. The method of any one of claims 1-19 or 28-71, wherein a composite Z-score of the subject does not worsen by more than 10%, 20%, 30%, or 40% after the administering of ATH434 or the salt thereof for 3 months, 6 months, 9 months, or 12 months.

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