Emrusolmin for use in treating multiple system atrophy

Abstract

The disclosure provides methods of stabilizing one or more symptoms of Multiple System Atrophy (MSA), limiting the clinical progression of MSA, slowing the clinical progression of MSA, o stabilizing the clinical progression of MSA in a human or population of humans in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin to the human or humans. The disclosure also provide methods of improving overall survival in a human with MSA, improving progress-free survival in a human with MSA, or treating a human having Multiple System Atrophy (MSA) and in need of treatment thereof, comprising orally administering about 300 mg of emrusolmin to the human.

Description

EMRUSOLMIN FOR USE IN TREATING MULTIPLE SYSTEM ATROPHYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit to the priority of U.S. Provisional Patent Application No. 63 / 585,458, filed September 26, 2023 and U.S. Provisional Patent Application No. 63 / 683,752, filed August 16, 2024, the disclosures of which are incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure relates to methods for treating multiple systems atrophy (MSA).BACKGROUND

[0003] Multiple systems atrophy (MSA) is an adult-onset, fatal neurodegenerative disease characterized by progressive autonomic failure and parkinsonism, cerebellar, or pyramidal features in various combinations. MSA occurs in two different subtypes, either with predominant parkinsonism (MSA-P) (60% of cases in Caucasian populations) or with predominant cerebellar symptoms (MSA-C, 40%). MSA is an orphan disease with a prevalence of about 1 to 9 cases per 100,000 population.

[0004] A hypokinetic rigid parkinsonian syndrome is dominant in MSA-P but its presentation tends to be more symmetrical and less responsive to levodopa than in Parkinson’s disease (PD). In MSA-C, the most common symptom is gait ataxia with wide-based walking. Other common symptoms include limb ataxia, cerebellar oculomotor impairments, scanning dysarthria, and intention tremor. Extrapyramidal signs are seen in 30% to 50% of patients with MSA. Focal dystonia and posture abnormalities are also common. These signs and symptoms may help to distinguish MSA from other forms of atypical parkinsonism.

[0005] All common neurodegenerative diseases are characterized by pathological protein aggregation. Synucleinopathies like PD, Lewy body (LB) dementia, and MSA are characterized by deposits of the misfolded and aggregated protein a-syn. Such deposits are characterized by a beta-sheet based amylogenic fibrillary structure similar to that of protein deposits found in other neurodegenerative and prion diseases.

[0006] In MSA, pathologically aggregated a-syn is deposited not only in neurons, as is the case for PD and LB dementia, but also in oligodendrocytes, creating a more severe and inclusive phenotype. The affected brain areas are chiefly in the cerebellum and basal ganglia but also include the brainstem. Pathological a-syn aggregate formation and other subsequent processes such as neuroinflammation lead to neuronal dysfunction and death, a-syn pathology is believed to be spread in a prion-like fashion to other functionally connected brain areas.

[0007] The only available treatments for MSA are symptomatic, including levodopa, dopamine agonists, N methyl-D-aspartate receptor antagonists, botulinum toxin, antimuscarinic agents, and sympathomimetic agents. Most of the commonly used drugs are prescribed off-label. In about one-third of patients, treatment with levodopa will reduce the hypokinetic-rigid symptoms in MSA-P, although the degree of improvement is typically not to the extent seen in Parkinson’s patients. To date, no effective treatment exists for ataxia. Symptomatic treatment of autonomic dysfunction is recommended, as these notably impair patients’ quality of life (QoL). One on-label product (NORTHERA® [droxidopa]) is narrowly indicated for the treatment of orthostatic dizziness and lightheadedness in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure, such as MSA and PD, but not for the reduction of neurodegeneration.

[0008] Due to the paucity of effective and approved treatments, there is a high unmet medical need in MSA.SUMMARY

[0009] In some aspects, the disclosure provides methods of stabilizing one or more symptoms of Multiple System Atrophy (MSA) in a human in need of stabilization thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the stabilization is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof.

[0010] In other aspects, the disclosure provides methods of limiting the clinical progression of MSA in a human in need of limitation thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the limiting is determined as a change frombaseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof.

[0011] In further aspects, the disclosure provides methods of slowing the clinical progression of MSA in a human in need of slowing thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the slowing is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof.

[0012] In yet other aspects, the disclosure provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the clinical progression is determined as a change from baseline in the human’s total UMSARS score of part I and part II combined, or a modification thereof.

[0013] In still further aspects, the disclosure provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin, wherein the clinical progression is determined as a change from baseline in the human’s CGLS score.

[0014] In other aspects, the disclosure provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin, wherein the clinical progression is determined as a change from baseline in the human’s MSA-QoL score.

[0015] In further aspects, the disclosure provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population, wherein the clinical progression is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof, and wherein the change from baseline in the clinical progression is statistically significant, preferably statistically significant at a 1 -sided alpha of 0.05, as compared to a control population of humans.

[0016] In still other aspects, the disclosure provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population, wherein the clinical progression is determined as a change from baseline in the human’s CGI-S score, and wherein the change from baseline in the clinical progression is statistically significant, preferably statistically significant at a 1 -sided alpha of 0.05, as compared to a control population of humans.

[0017] In yet further aspects, the disclosure provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population, wherein the clinical progression is determined as a change from baseline in the human’s MSA-QoL score, and wherein the change from baseline in the clinical progression is statistically significant, preferably statistically significant at a 1 -sided alpha of 0.05, as compared to a control population of humans.

[0018] In other aspects, the disclosure provides methods of improving overall survival in a human with MSA comprising orally administering, on a daily basis, 300 mg emrusolmin to the human, wherein the improvement in overall survival is relative to a human with MSA who is not receiving treatment with emrusolmin.

[0019] In further aspects, the disclosure provides methods of improving progress-free survival in a human with MSA comprising orally administering, on a daily basis, 300 mg emrusolmin to the human, wherein the improvement in progress-free survival is relative to a human with MSA who is not receiving treatment with emrusolmin.

[0020] In yet other aspects, the disclosure provides methods of improving overall survival in a human with MSA, comprising orally administering, on a daily basis, 300 mg emrusolmin to the human, wherein the improvement in overall survival is relative to a human with MSA who is not

[0021] In still further aspects, the disclosure provides methods of treating a human having Multiple System Atrophy (MSA) and in need of treatment thereof, comprising a treatment period comprising orally administering to the human, once daily, for a period of treatment, about 300 mg of emrusolmin; wherein the administration results in a reduced rate ofprogression of the human’s MSA symptoms during the treatment period, wherein the reduced rate of progression is as compared to a placebo treatment; and wherein the rate of progression of MSA symptoms is measured using a Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof; total UMSARS score, or a modification thereof; CGI-S; and / or MSA-QoL.BRIEF DESCRIPTION OF THE FIGURES

[0022] FIG. 1 is a schematic of the study of Example 1.

[0023] FIG. 2 is a graph showing particle size distribution of nano milled anlel38b (emrusolmin). The Y axis is volume (%), the x axis is particle size (pm) on a log scale.

[0024] FIGs. 3A-3D are graphs showing PK Cmax profiles of each of the 3 rats in each group in the rat formulation study, described in example 1.2.

[0025] FIG. 4 is a logarithmic plot of plasma concentrations of anlel38b (emrusolmin) following single dose of DP in healthy volunteers.

[0026] FIGs. 5A and 5B are logarithmic plots of multiple dose plasma concentrations of anlel38b (emrusolmin) DP on Day 1 (4 A) and Day 7 (48) in healthy volunteers.

[0027] FIG. 6 is a logarithmic plot of food effect on single dose plasma concentrations of anlel38b (emrusolmin) DP.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0028] The present subject matter may be understood more readily by reference to the following detailed description which forms a part of this disclosure. It is to be understood that this disclosure is not limited to the specific methods, conditions or parameters described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention.Definitions

[0029] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understoodby those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0030] As employed above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings.

[0031] In the present disclosure the singular forms “a,” “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a compound” is a reference to one or more of such compounds and equivalents thereof known to those skilled in the art, and so forth. When a range of values is expressed, another embodiment includes from the one particular and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

[0032] As used herein, the terms “composition,” “compound,” “drug,” or “therapeutic” are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject induces a desired pharmacological and / or physiologic effect by local and / or systemic action.

[0033] As used herein, the terms “treatment” or “therapy” (as well as different forms thereof) include preventative (e.g., prophylactic), curative, or palliative treatment. As used herein, the term “treating” includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder. This condition, disease or disorder refers to MSA.

[0034] The term “administering” means either directly administering a compound or composition of the present disclosure, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.

[0035] The terms “subject,” “individual,” and “patient” are used interchangeably herein, and refer to a human. In some aspects, the human patient is an adult patient, i.e., 18 years of age of older.

[0036] The term “baseline” as used herein refers to the period of time just prior to administration of emrusolmin. The human’s condition prior to administration of emrusolmin is the human’s “baseline condition.”

[0037] The term “control population” as used herein refers to one or more humans participating in a research study, for example, a clinical trial study, who do not receive the test treatment and whose experience allows discrimination of outcomes caused by the test treatment from outcomes caused by factors other than the test treatment. Those of ordinary skill in the art can identify one or more humans participating in a research study who would be appropriate members of a control population. Guidance for selecting humans for a control population is provided in, for example, European Medicines Agency. (2002). ICH Topic E10: Choice of control group in clinical trials, https: / / www.ema.europa.eu / en / documents / scientific- guideline / ich-e-10-choice-control-group-clinical-trials-step-5 en.pdf.

[0038] “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit / risk ratio.

[0039] The term “emrusolmin” as used herein refers to 5-(l,3-benzodioxol-5-yl)-3-(3- bromophenyl)-lH-pyrazole and has the following chemical structure.Emrusolmin is also known in the art as anle-138b and TEV-56286.

[0040] Emrusolmin also refers to any tautomers thereof, such as the following tautomer:

[0041] The FDA characterizes CYP-inhibitors, for example CYP1A2 inhibitors, as “strong,” “moderate,” and “weak.” See, e.g, https: / / www.fda.gov / drugs / drug-interactions-labeling / healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter- systems#table%201. DIDB® Drug Interaction Database (Certara, USA) (https: / / www.druginteractionsolutions.org / solutions / drug-interaction-database / ) is a large, curated database focusing on drug-drug interactions and largely used by Life Science companies, pharmacokinetic (PK) experts and regulatory agencies. DIDB® includes a classification for CYP1 A2 inhibitors that is in addition to that provided by the FDA. As defined herein, "a strong CYP1 A2 inhibitor" is a CYP1A2 inhibitor that is defined as a strong CYP1A2 inhibitor in Table 1 below, which was derived from DIDB® in October 2023. As defined herein, "a moderate CYP1 A2 inhibitor" is a CYP1A2 inhibitor that is defined as a moderate CYP1A2 inhibitor in Table 1. As defined herein, "a weak CYP1A2 inhibitor" is a CYP1A2 inhibitor that is defined as a weak CYP1A2 inhibitor in Table 1. As defined herein, ciprofloxacin may be classified either as a strong CYP1A2 inhibitor as indicated in Table 1, or a moderate inhibitor as classified by the FDA (FDA in https: / / www.fda.gov / drugs / drug-interactions-labeling / healthcare-professionals- fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems#table%201also comment that " Ciprofloxacin is generally classified a moderate CYP 1 A2 inhibitor based on totality of evidence; however, it can sometimes behave like a strong inhibitor (i.e., increase AUC more than 5-fold) when it interacts with certain CYP1A2 substrates that are considered highly sensitive (e.g., tizanidine)."Table 1: CYP1A2 classification from DIDB® October 2023Methods

[0042] A. Individual Humans

[0043] The present disclosure relates to methods of using emrusolmin in humans diagnosed with Multiple System Atrophy (MSA). In certain embodiments, the disclosure provides methods of stabilizing one or more symptoms of Multiple System Atrophy (MSA) in a human in need of stabilization thereof. The methods include orally administering, on a daily basis, 300 mg of emrusolmin to the human.

[0044] “Multiple systems atrophy” refers to an adult-onset, fatal neurodegenerative disease characterized by progressive autonomic failure and parkinsonism, cerebellar, or pyramidal features in various combinations. In some embodiments, the MSA is multiple system atrophy-parkinsonian type (MSA-P). In other embodiments, the MSA is multiple system atrophy-cerebellar subtype (MSA-C).

[0045] Symptoms of MSA include hypokinetic rigid parkinsonian, gait ataxia, limb ataxia, cerebellar oculomotor impairment, scanning dysarthria, intention tremor, focal dystonia and posture abnormalities. An MSA patient may experience one or more of these symptoms, in any combination. In some embodiments, the MSA symptom is hypokinetic rigid parkinsonian. In other embodiments, the MSA symptom is gait ataxia. In further embodiments, the MSA symptom is limb ataxia. In yet other embodiments, the MSA symptom is a cerebellar oculomotor impairment. In still further embodiments, the MSA symptom is scanning dysarthria. In other embodiments, the MSA symptom is intention tremor. In further embodiments, the MSA symptom is focal dystonia. In still other embodiments, the MSA symptom is a posture abnormality.

[0046] The methods described herein may also include diagnosing the human with MSA. MSA may be diagnosed by one skilled in the art. In some embodiments, the MSA is “clinically possible” or “clinically probably” as determined by the Gilman criteria (2008). See, Gilman, Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71(9):670-6).

[0047] In some embodiments, the human is diagnosed with MSA-P. In other embodiments, the human is diagnosed with MSA-C.

[0048] The term “stabilizing” as used herein with reference to MSA symptoms refers to preventing the worsening of the one or more MSA symptom in a human. Thus, although the MSA symptoms may be still present, the methods herein prevent the symptoms from worsening. Stabilization may be assessed by a person skilled in the art using, for example, the Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof. In some aspects, stabilization may be determined as a change from baseline in the human’s UMSARS score, or modification thereof.

[0049] The disclosure also relates to methods of limiting the clinical progression of MSA, for example, limiting the clinical progression of one or more symptoms of MSA, in a human in need of limitation thereof. The methods include orally administering, on a daily basis, 300 mg of emrusolmin to the human. The term “limiting” as used herein with reference to MSA symptoms refers to limiting the progression of one or more MSA symptoms or in the human or the human developing one or more new MSA symptoms. The limiting may be determined by aperson of skill in the art, for example, by assessing the change from baseline in the human’s UMSARS score, or a modification thereof. In some embodiments, limiting the clinical progression comprises reducing or stopping the worsening and / or progression of one or more MSA symptoms.

[0050] The disclosure further provides methods of slowing the clinical progression of MSA in a human in need of slowing thereof. The methods include orally administering, on a daily basis, 300 mg of emrusolmin to the human. As used herein, the term “slowing the clinical progression of MSA” refers to reducing the deterioration experienced by a MSA patient. Slowing may be determined by a person of skill in the art, e.g., by assessing changes in UMSARS score. In some aspects, the slowing may be assessed as a comparison to the deterioration experienced by a control MSA patient not receiving emrusolmin over the same period of time. For example, in certain of these aspects, the slowing may be assessed by an average less worsening of the UMSARS at week 48 compared to baseline, e.g., comparing the UMSARS scores of treated and non-treated groups. In some embodiments, slowing the clinical progression comprises slowing the worsening of MSA symptoms, as determined by those skilled in the art.

[0051] The disclosure also provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof. The methods include orally administering, on a daily basis, 300 mg of emrusolmin to the human. The clinical progression can be determined by those skilled in the art, for example, by assessing changes in the human’s total UMSARS score of part I and part II combined, or a modification thereof, over time. For example, clinical progression can be determined by assessing a change in UMSARS from baseline, over time. In some embodiments, stabilizing the clinical progression comprises reducing or stopping the worsening of MSA symptoms, as determined by those skilled in the art.

[0052] The disclosure further provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof. The methods include orally administering, on a daily basis, 300 mg of emrusolmin to the human. In some aspects, those skilled in the art can determine clinical progression as a change in the human’s CGLS score over time, for example as a change from baseline over time.In some embodiments, stabilizing, limiting, or slowing the clinical progression comprises reducing or stopping the worsening of MSA symptoms, as determined by those skilled in the art.

[0053] The disclosure also provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof. The methods include orally administering, on a daily basis, 300 mg of emrusolmin to the human. Clinical progression may be determined as a change in the human’s MSA-QoL score over time, for example, as a change from baseline over time. In some embodiments, stabilizing, limiting, or slowing the clinical progression comprises reducing or stopping the worsening of MSA symptoms, as determined by those skilled in the art.

[0054] The disclosure further provides methods of improving progress-free survival in a population of humans with MSA. The methods include orally administering, on a daily basis, 300 mg emrusolmin to the human. The term “progress-free survival” refers to the time from random assignment in a clinical trial to disease progression or death from any cause. In some embodiments, the improvement in progress-free survival is relative to a population of humans with MSA that is not receiving treatment with emrusolmin.

[0055] The disclosure also provides methods of improving overall survival in a population of humans with MSA. The methods include orally administering, on a daily basis, 300 mg emrusolmin to the human. In some embodiments, the improvement in overall survival is relative to a population of humans with MSA that is not receiving treatment with emrusolmin.

[0056] The disclosure further provides methods of treating a human having MSA and in need of treatment thereof. The methods include a treatment period comprising orally administering to the human, once daily, for a period of treatment, about 300 mg of emrusolmin. In some embodiments, the administration results in a reduced rate of progression of the human’s MSA symptoms during the treatment period. In other embodiments, the reduced rate of progression is as compared to a placebo treatment. In further embodiments, the rate of progression of MSA symptoms is measured using a UMSARS score, or a modification thereof; total UMSARS score, or a modification thereof; CGI-S; and / or MSA-QoL. In yet other embodiments, the rate of progression of MSA symptoms is measured using a UMSARS score, or a modification thereof. In still further embodiments, the rate of progression of MSA symptoms is measured using a total UMSARS score, or a modification thereof. In other embodiments, the rateof progression of MSA symptoms is measured using CGI-S. In further embodiments, the rate of progression of MSA symptoms is measured using MSA-QoL.

[0057] As used herein, the term “reduced rate of progression” refers to reducing the deterioration experienced by a MSA patient or population of MSA patients, e.g., as quantified by UMSARS score, as compared to the deterioration experienced by a MSA patient or population of MSA patients not receiving emrusolmin, over a period of time. For example, the progression may be assessed by an average less worsening of the UMSARS at week 48 compared to baseline, e.g., comparing the UMSARS scores of treated and non-treated groups.

[0058] In certain aspects, emrusolmin reduces the clinical progression by at least about 20% relative to a treatment for MSA lacking emrusolmin. In some embodiments, emrusolmin reduces the clinical progression by at least about 30, about 40, about 50, about 60, about 70, about 80, or about 90% relative to a treatment for MSA lacking emrusolmin. In other embodiments, emrusolmin reduces the clinical progression by about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 90, about 70 to about 80, or about 80 to about 90% relative to a treatment for MSA lacking emrusolmin. In yet other embodiments, emrusolmin reduces the clinical progression by about 40 to about 60% relative to a treatment for MSA lacking emrusolmin. In still further embodiments, emrusolmin reduces the clinical progression by about 30 to about 40% relative to a treatment for MSA lacking emrusolmin.

[0059] In some aspects of the disclosure, treatment with emrusolmin reduces clinical progression of MSA, as measured by less worsening of the UMSARS scores, or a modification thereof, for example, modified UMSARS part I score, by 2 points (or more), from baseline, as compared to non-treatment with emrusolmin. In some aspects, there is a -2 point from baseline difference in UMSARS scores between those treated with emrusolmin and those not treated with emrusolmin. In some aspects of the disclosure, treatment with emrusolmin reduces the clinical progression of MSA, as measured by less worsening of the UMSARS scores, or a modificationthereof, for example, modified UMSARS part I score, by 2 points (or more), from baseline to week 48 of the emrusolmin administration, as compared to non-treatment with emrusolmin.

[0060] B. Human Populations

[0061] According to the disclosure, the stabilizing, limiting, or slowing is relative to a patient population with MSA that is not receiving treatment with emrusolmin.

[0062] The methods described herein are not only applicable to an individual human, but also are applicable to a population of humans. The term “population of humans” refers to a number of humans that can provide statistically relevant data that provides insight regarding the effectiveness of emrusolmin as applied to the general population. For example, a population of humans may include about 3 people, about 5 people, about 10 people, about 15 people, about 20 people, or more.

[0063] The disclosure, thus, provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof. The methods include orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population. The clinical progression is determined as a statistical change in the human populations’ UMSARS scores, or a modification thereof, for example, a statistical change from baseline in the human populations’ UMSARS scores, or a modification thereof. The change from baseline in the clinical progression is statistically significant. In some embodiments, the clinical progression is statistically significant at a 1 -sided alpha of about 0.05, as compared to a control population of humans. In some embodiments, the clinical progression is statistically significant at a 1 -sided alpha of about 0.1 , as compared to a control population of humans.

[0064] The disclosure also provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof. The methods includes orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population. In some embodiments, clinical progression is determined as a statistical change in the human population’s CGLS score, for example, a statistical change from baseline in the human population’s CGLs score. In other embodiments, the change in the clinical progression is statistically significant. In further embodiments, the change from baseline in the clinical progression is statistically significant at a 1 -sided alpha ofabout 0.05, as compared to a control population of humans. In further embodiments, the change from baseline in the clinical progression is statistically significant at a 1 -sided alpha of about 0.1, as compared to a control population of humans.

[0065] The disclosure also provides methods of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof. The methods include orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population. In some embodiments, the clinical progression is determined as a statistical change in the human population’s MSA-QoL score, for example, a statistical change from baseline in the human population’s MSA-QoL score. In other embodiments, the change in the clinical progression is statistically significant, preferably statistically significant at a 1 -sided alpha of about 0.05, as compared to a control population of humans. In further embodiments, the change from baseline in the clinical progression is statistically significant at a 1 -sided alpha of about 0.1, as compared to a control population of humans.

[0066] Desirably, administration of emrusolmin in any other methods of the disclosure does not result in a clinically serious adverse event in the human or the population of humans. In some embodiments, presentation of serious adverse events is not statistically significant as compared to a control human or a control population of humans.

[0067] The human may have received at least one therapy for the treatment of MSA prior to administration of emrusolmin. In some embodiments, the at least one therapy for MSA is levodopa. In other embodiments, the human is resistant to treatment with levodopa. In further embodiments, the human has acquired resistance to treatment with levodopa.

[0068] In some aspects, certain clinical assessments are utilized in performing the methods disclosure herein. Examples of such assessments include, without limitation, rating scales such as the Unified Multiple System Atrophy Rating Scale (UMSARS) score, a modified UMSARS score, a modified UMSARS part I (excluding question 11, item scoring rescaled 0-3), a total UMSARS score (part I and part II combined), a modified total UMSARS score (part I and part II combined), a CGI-S score, or a MSA-QoL score.

[0069] In some embodiments, the clinical assessment is the UMSARS. See, e.g., Wenning, “Development and validation of the Unified Multiple System Atrophy Rating Scale(UMSARS),” Mov. Disord. 2004; 19(12): 1391 -402, the entirety of which is incorporated by reference herein. The UMSARS is a multidimensional, validated scale for semi-quantitative clinical assessments of MSA patients. It is comprised of 4 parts: part I, historical review of disease-related impairments, 12 items; part II, motor examination, 14 items; part III, autonomic examination; and part IV, global disability scale. As UMSARS is a unified scale, each item in parts I and II achieves a single score using a range of 0 (no impairment) to 4 (severe impairment). To obtain the UMSARS part I score and UMSARS part II score, respectively, the values for the individual items are summed up with higher scores corresponding to a more pronounced clinical disease severity. A total UMSARS score includes the sums for parts I and II.

[0070] In other embodiments, the clinical assessment is a modified UMSARS, i.e., Unified Multiple System Atrophy Rating Scale - Modified Score (UMSARS-MS). The UMSARS-MS uses all data collected within part I and part II of the UMSARS. To obtain the classical total UMSARS score, values of 0, 1, 2, 3, or 4 (depending on the level of impairment) are assigned to each item of the UMSARS part I and part II and summed up, i.e., a modified total UMSARS score. For the UMSARS-MS, those values are transformed to reweighted and rescaled values before they are summed up. As the UMSARS-MS is a modified evaluation using different values assigned to the different levels of impairment within the items assessed, the source data for calculation of the score is identical to the data used for the calculation of the classical total UMSARS score. The range of scores (minimum to maximum) is preserved in UMSARS-MS compared to the classical UMSARS. In certain aspects, in a modified UMSARS part, I score, item 11 (sexual function) is omitted and the item scoring rescaled 0 to 0, 1 to 0, 2 to 1, 3 to 2, and 4 to 3.

[0071] In further embodiments, the clinical assessment is the Multiple System Atrophy - Quality of Fife (MSA-QoL). The MSA-QoL is a patient-reported validated measure correlated with quality of life in a MSA population. The MSA-QoL shows internal consistency and construct validity (Schrag, “Measuring health-related quality of life in MSA: the MSA-QoL,” Mov. Disord. 2007; 22(16):2332-8). It was shown that MSA-QoL correlates negatively with disease progression in MSA (Schrag, “Health related quality of life in multiple system atrophy,” Mov. Disord. 2006; 21(6):809-15; Schrag 2007). The 40-item MSA-QoL questionnaire is selfadministered and each item is rated on a Likert type scale (0: No problem) to (4: Extremeproblem). It is comprised of 3 subscales relevant to MSA: motor (14 items), non-motor (12 items), and emotional / social (14 items). The MSA-QoL total score is the sum of all the items and lower scores indicate better QoL.

[0072] In yet other embodiments, the clinical assessment is the Clinical Global Impression Scale - Severity (CGI-S). The CGI-S scale permits a global evaluation of the patient’s current severity of illness on a Likert type scale ranging from 1 to 7, where l=normal / not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=among the most extremely ill patients (Guy 1976).

[0073] The methods may further include administering an additional therapeutic agent. As used herein, an additional therapeutic agent refers to an agent other than emrusolmin. In some embodiments, the additional therapeutic agent treats an aspect of the patient’s MSA symptom, such as, for example, hypokinetic-rigid symptoms, ataxia, orthostatic dizziness and lightheadedness. Exemplary additional therapeutic agents include, e.g., levodopa, droxidopa, dopamine agonists, N methyl-D-aspartate receptor antagonists, botulinum toxin, antimuscarinic agents or sympathomimetic agents. The additional therapeutic agent may be administering concomitant with, prior to, or following administration of emrusolmin.

[0074] As used herein, administration, "on daily basis, of 300 mg emrusolmin," or "emrusolmin 300 mg / daily,” or "emrusolmin 300 mg / daily," or "emrusolmin 300 mg / daily therapy," or "emrusolmin 300 mg given on daily basis," or "emrusolmin 300 mg / daily dose," or "emrusolmin 300 mg / daily regimen," or "emrusolmin 300 mg / day" or "emrusolmin in a 300mg daily regimen" or "emrusolmin in a 300 mg daily regimen therapy" all mean the same, and is contraindicated with the administration of strong and moderate CYP1 A2 inhibitors as defined herein.

[0075] As used herein, administration, "on daily basis, of 150 mg emrusolmin," or "emrusolmin 150 mg / daily,” or "emrusolmin 150 mg / daily," or "emrusolmin 150 mg / daily therapy," or "emrusolmin 150 mg given on daily basis," or "emrusolmin 150 mg / daily dose," or "emrusolmin 150 mg / daily regimen," or "emrusolmin 150 mg / day" or " emrusolmin in a 150 mg daily regimen" or "emrusolmin in a 150 mg daily regimen therapy" all mean the same, and is contraindicated with the administration of strong CYP1 A2 inhibitors as defined herein.

[0076] As used herein, "avoiding concomitant administration," " avoiding concomitant use," or "avoiding co-administration" of emrusolmin 300 mg / daily with one or more drug which is a strong CYP1 A2 inhibitor or a moderate CYP1A2 inhibitor, means that during the period of administration of emrusolmin 300 mg / daily, which may be one month, several months, a year or any period needed to treat the disease, disorder, or condition needing treatment, with emrusolmin, the one or more moderate or strong CYP1A2 inhibitor is not administered. In cases when the one or more moderate or strong CYP1 A2 inhibitor is already being administered to the patient, the one or more moderate or strong CYP1 A2 inhibitor should be discontinued prior to the administration of emrusolmin 300 mg / daily. In specific aspects of the disclosure, the one or more moderate or strong CYP1 A2 inhibitor should be discontinued at a time point that is sufficient so that the one or more moderate or strong CYP1 A2 inhibitor would be cleared from the blood of the patient before emrusolmin 300 mg / daily administration. In specific aspects of the disclosure, the one or more moderate or strong CYP1A2 inhibitor should be discontinued at least 4 days prior to emrusolmin 300 mg / daily administration. In other specific aspects of the disclosure, the one or more moderate or strong CYP1 A2 inhibitor should be discontinued at least a week prior to emrusolmin 300 mg / daily administration. In other specific aspects of the disclosure, the one or more moderate or strong CYP1 A2 inhibitor should be discontinued at least 2 weeks prior to emrusolmin 300 mg / daily administration. In other specific aspects of the disclosure, the one or more moderate or strong CYP1 A2 inhibitor should be discontinued at least 4 weeks prior to emrusolmin 300 mg / daily administration.

[0077] According to the disclosure, administration, "on daily basis, of 150 mg emrusolmin," or "emrusolmin 150 mg / daily,” or "emrusolmin 150 mg / daily," or "emrusolmin 150 mg / daily therapy," or "emrusolmin 150 mg given on daily basis," or "emrusolmin 150 mg / daily dose," or "emrusolmin 150 mg / daily regimen," or "emrusolmin 150 mg / day" is contraindicated with the administration of strong CYP1 A2 inhibitors as defined herein. As used herein, "avoiding concomitant administration," " avoiding concomitant use," or "avoiding coadministration" of emrusolmin 150 mg / daily with one or more drug which is a strong CYP1A2 inhibitor, means that during the period of administration of emrusolmin 150 mg / daily, which may be one month, several months, a year or any period needed to treat the disease, disorder, or condition needing treatment, with emrusolmin, the one or more strong CYP1 A2 inhibitors is notadministered. In cases when the one or more strong CYP1A2 inhibitor is already being administered to the patient, the one or more strong CYP1A2 inhibitor should be discontinued prior to the administration of emrusolmin 150 mg / daily. In specific aspects of the disclosure, the one or more strong CYP1 A2 inhibitor should be discontinued at a time point that is sufficient so that the one or more strong CYP1 A2 inhibitor would be cleared from the blood of the patient before emrusolmin 150 mg / daily administration. In specific aspects of the disclosure, the one or more strong CYP1A2 inhibitor should be discontinued at least 4 days prior to emrusolmin 150 mg / daily administration. In other specific aspects of the disclosure, the one or more strong CYP1A2 inhibitor should be discontinued at least a week prior to emrusolmin 150 mg / daily administration. In other specific aspects of the disclosure, the one or more strong CYP1 A2 inhibitor should be discontinued at least 2 weeks prior to emrusolmin 150 mg / daily administration. In other specific aspects of the disclosure, the one or more strong CYP1 A2 inhibitor should be discontinued at least 4 weeks prior to emrusolmin 150 mg / daily administration.

[0078] As used herein, “contraindicated” refers to the clinical situation for which the risk outweighs potential therapeutic benefit. A contraindication is reflected in the recommendation or instruction to avoid co-administration of the contraindicated drugs.

[0079] As used herein, an "adverse drug-drug interaction" between two drugs A and B means an adverse event or adverse reaction in the patient that is the result of increased exposure in the patient's blood to drug A (e.g., the treatment drug, e.g., emrusolmin), that is, in turn, the result of co-administration with drug B to the patient.

[0080] In some aspects of the disclosure, emrusolmin 300 mg / daily therapy is contraindicated with administration of, ciprofloxacin, rofecoxib, fluvoxamine, clinafloxacin, idrocilamide, enoxacin, viloxazine (high / supratherapeutic dose); oltipraz; pipemidic acid, mexiletine, fexinidazole, methoxsalen (8-methoxypsoralen), capmatinib, metamizole (dipyrone), vemurafenib, rucaparib, osilodrostat, ritlecitinib, etintidine, phenylpropanolamine, hormonal contraceptives, estrogen-containing medications, genistein, propranolol, or troleandomycin; or a combination thereof.

[0081] In some aspects of the disclosure, emrusolmin 150 mg / daily therapy is contraindicated with administration of, ciprofloxacin, rofecoxib, fluvoxamine, clinafloxacin,idrocilamide, enoxacin, viloxazine (high / supratherapeutic dose); oltipraz;; or a combination thereof.

[0082] In some aspects of the disclosure, emrusolmin 300 mg / daily or 150 mg / daily is contraindicated with administration of ciprofloxacin. In some aspects of the disclosure, emrusolmin 300 mg / daily or 150 mg / daily is contraindicated with administration of rofecoxib. In some aspects of the disclosure, emrusolmin 300 mg / daily or 150 mg / daily is contraindicated with administration of fluvoxamine. In some aspects of the disclosure, emrusolmin 300 mg / daily or 150 mg / daily is contraindicated with administration of clinafloxacin. In some aspects of the disclosure, emrusolmin 300 mg / daily or 150 mg / daily is contraindicated with administration of idrocilamide. In some aspects of the disclosure, emrusolmin 300mg / daily or 150 mg / daily is contraindicated with administration of enoxacin. In some aspects of the disclosure, emrusolmin 300 mg / daily or 150 mg / daily is contraindicated with administration of viloxazine (high / supratherapeutic dose). In some aspects of the disclosure, emrusolmin 300 mg / daily or 150 mg / daily is contraindicated with administration of oltipraz.

[0083] In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of pipemidic acid. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of mexiletine. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of fexinidazole. In some aspects of the disclosure, emrusolmin 300mg / daily is contraindicated with administration of methoxsalen (8-methoxypsoralen). In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of capmatinib. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of metamizole (dipyrone). In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of vemurafenib. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of rucaparib. In some aspects of the disclosure, emrusolmin 300mg / daily is contraindicated with administration of osilodrostat. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of ritlecitinib. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of etintidine. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of phenylpropanolamine. In some aspects of the disclosure, emrusolmin 300mg / daily is contraindicated with administration of hormonal contraceptives. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of estrogen- containing medications. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of genistein. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of propranolol. In some aspects of the disclosure, emrusolmin 300 mg / daily is contraindicated with administration of troleandomycin.

[0084] In some aspects, the CYP1A2 inhibitor is fluvoxamine, ciprofloxacin, enoxacin, viloxazine, clinafloxacin, idrocilamide, or a combination thereof. In some aspects, the CYP1 A2 inhibitor is genistein, methoxsalen (8-methoxypsoralen), mexiletine, vemurafenib, osilodrostat, phenylpropanolamine, pipemidic acid, an estrogen-containing medication, or a combination thereof.

[0085] In some aspects of the disclosure, emrusolmin therapy is not contraindicated with administration of one or more CYP1A2 inhibitors that are defined as weak CYP1A2 inhibitors in Table 1.

[0086] Subjects in need of emrusolmin therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to emrusolmin. Subjects "in need of one or more moderate or strong CYP1A2 inhibitors" or "in need of one or more moderate or strong CYP1 A2 inhibitor therapy" include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to certain one or more moderate or strong CYP1 A2 inhibitors. Subjects "in need of one or more moderate CYP1 A2 inhibitors" or "in need of one or more moderate CYP1 A2 inhibitor therapy" include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to certain one or more moderate CYP1A2 inhibitors. Subjects "in need of one or more strong CYP1 A2 inhibitors" or "in need of one or more strong CYP1 A2 inhibitor therapy" include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to certain one or more strong CYP1 A2 inhibitors. For example, subjects in need of pipemidic acid therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to pipemidic acid. Subjects in need of mexiletinetherapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to mexiletine. Subjects in need of fexinidazole therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to fexinidazole. Subjects in need of methoxsalen (8-methoxypsoralen) therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to methoxsalen (8-methoxypsoralen). Subjects in need of capmatinib therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to capmatinib. Subjects in need of metamizole (dipyrone) therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to metamizole (dipyrone). Subjects in need of vemurafenib therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to vemurafenib. Subjects in need of rucaparib therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to rucaparib. Subjects in need of osilodrostat therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to osilodrostat. Subjects in need of ritlecitinib therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to ritlecitinib. Subjects in need of etintidine therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to etintidine. Subjects in need of phenylpropanolamine therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to phenylpropanolamine. Subjects in need of hormonal contraceptives therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to hormonal contraceptives. Subjects in need of vemurafenib therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to vemurafenib. Subjects in need of genistein therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to genistein. Subjects in need of propranolol therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to propranolol. Subjects in need of troleandomycin therapy includethose having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to troleandomycin.

[0087] Subjects in need of fluvoxamine therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to fluvoxamine. Subjects in need of ciprofloxacin therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to ciprofloxacin. Subjects in need of rofecoxib therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to rofecoxib. Subjects in need of clinafloxacin therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to clinafloxacin. Subjects in need of idrocilamide therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to idrocilamide. Subjects in need of enoxacin therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to enoxacin. Subjects in need of viloxazine - high / supratherapeutic dose therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to viloxazine - high / supratherapeutic dose. Subjects in need of oltipraz therapy include those having a disease, disorder, or condition that is suggested or indicated to be therapeutically responsive to oltipraz.

[0088] For even more clarity, Doctors and / or other health practitioners, according to their discretion, may prescribe the patient a different drug or more than one drug, that is not a moderate or strong CYP1 A2 inhibitor, and that is / are useful to treat the same disease, disorder, or condition as the one or more moderate or strong CYP1A2 inhibitors.

[0089] In some aspects, the disclosure is directed to methods wherein the patient is being administered one or more moderate or strong CYP1 A2 inhibitors, wherein the treatment comprises (a) first discontinuing administration of said one or more moderate or strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin. In some aspects, the disclosure is directed to methods wherein the patient is being administered one or more moderate CYP1 A2 inhibitors, wherein the treatment comprises (a) first discontinuing administration of said one or more moderate CYP1 A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin. In some aspects, the disclosure is directed tomethods wherein the patient is being administered one or more strong CYP1 A2 inhibitors, wherein the treatment comprises (a) first discontinuing administration of said one or more strong CYP1 A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0090] In some aspects, the disclosure is directed to methods wherein the patient is being administered one or more strong CYP1 A2 inhibitors, wherein the treatment comprises (a) first discontinuing administration of said one or more strong CYP1 A2 inhibitors, and then (b) administering to the patient, on a daily basis, 150 mg of emrusolmin.

[0091] In some aspects, the disclosure is directed to methods wherein the human is in need of administration, on daily basis, of 300mg emrusolmin and also in need of one or more moderate or strong CYP1 A2 inhibitors, wherein the treatment comprises (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong CYP1 A2 inhibitors. In some aspects, the disclosure is directed to methods wherein the human is in need of administration, on daily basis, of 300 mg emrusolmin and also in need of one or more moderate CYP1 A2 inhibitors, wherein the treatment comprises (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate CYP1A2 inhibitors. In some aspects, the disclosure is directed to methods wherein the human is in need of administration, on daily basis, of 300 mg emrusolmin and also in need of one or more strong CYP1 A2 inhibitors, wherein the treatment comprises (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1 A2 inhibitors.

[0092] In some aspects, the disclosure is directed to methods wherein the human is in need of administration, on daily basis, of 150 mg emrusolmin and also in need of one or more strong CYP1 A2 inhibitors, wherein the treatment comprises (a) administering, on a daily basis, 150 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1A2 inhibitors.

[0093] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin to a patient in need thereof and also in need of one or more moderate or strong CYP1A2 inhibitors, comprising (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strongCYP1 A2 inhibitors. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin to a patient in need thereof, and also in need of one or more moderate CYP1A2 inhibitors, comprising (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate CYP1A2 inhibitors. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin to a patient in need thereof, and also in need of one or more strong CYP1 A2 inhibitors, comprising (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1 A2 inhibitors.

[0094] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 150 mg of emrusolmin to a patient in need thereof, and also in need of one or more strong CYP1A2 inhibitors, comprising (a) administering, on a daily basis, 150 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1A2 inhibitors.

[0095] In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, and being administered one or more moderate or strong CYP1A2 inhibitors, comprising (a) first discontinuing administration of said one or more moderate or strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin. In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, and being administered one or more moderate CYP1A2 inhibitors, comprising(a) first discontinuing administration of said one or more moderate CYP1A2 inhibitors, and then(b) administering to the patient, on a daily basis, 300 mg of emrusolmin. In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, and being administered one or more strong CYP1 A2 inhibitors, comprising (a) first discontinuing administration of said one or more strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0096] In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, and being administered one or more strong CYP1A2 inhibitors,comprising (a) first discontinuing administration of said one or more strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 150 mg of emrusolmin.

[0097] In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, wherein the patient is also in need one or more moderate or strong CYP1 A2 inhibitors, comprising (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong CYP1 A2 inhibitors. In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, wherein the patient is also in need one or more moderate CYP1 A2 inhibitors, comprising (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate CYP1A2 inhibitors. In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, wherein the patient is also in need one or more strong CYP1 A2 inhibitors, comprising (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1A2 inhibitors.

[0098] In some aspects, the disclosure is directed to methods of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, wherein the patient is also in need one or more strong CYP1A2 inhibitors, comprising (a) administering, on a daily basis, 150 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1A2 inhibitors.

[0099] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is being administered one or more moderate or strong CYP1 A2 inhibitors, comprising (a) discontinuing administration of said one or more moderate or strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is being administered one or more moderate CYP1A2 inhibitors, comprising (a) discontinuing administration of said one or moremoderate CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is being administered one or more strong CYP1 A2 inhibitors, comprising (a) discontinuing administration of said one or more strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0100] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 150 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is being administered one or more strong CYP1 A2 inhibitors, comprising (a) discontinuing administration of said one or more strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 150 mg of emrusolmin.

[0101] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need one or more moderate or strong CYP1A2 inhibitors, comprising (a) administering to the patient, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong CYP1A2 inhibitor. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need one or more moderate CYP1 A2 inhibitors, comprising (a) administering to the patient, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate CYP1 A2 inhibitors. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need one or more strong CYP1A2 inhibitors, comprising (a) administering to the patient, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1A2 inhibitors.

[0102] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 150 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need one or more strong CYP1 A2 inhibitors, comprising (a) administering to the patient, on a daily basis, 150 mg of emrusolmin and (b) avoiding concomitant administration of said one or more strong CYP1 A2 inhibitors.

[0103] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate or strong CYP1A2 inhibitors, comprising avoiding or discontinuing concomitant use of said one or more moderate or strong CYP1 A2 inhibitors. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate CYP1 A2 inhibitors, comprising avoiding or discontinuing concomitant use of said one or more moderate CYP1 A2 inhibitors. In some aspects, the disclosure is directed to methods of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more strong CYP1 A2 inhibitors, comprising avoiding or discontinuing concomitant use of said one or more strong CYP1A2 inhibitors.

[0104] In some aspects, the disclosure is directed to methods of administering, on a daily basis, 150 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more strong CYP1A2 inhibitors, comprising avoiding or discontinuing concomitant use of said one or more strong CYP1 A2 inhibitors.

[0105] In some aspects, the disclosure is directed to of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate or strong CYP1A2 inhibitors, comprising administering to the patient 300 mg / day of emrusolmin while avoiding co-administration with said moderate or strong CYP1A2 inhibitors and advising the patient that the CYP1 A2 inhibitor should be avoided or discontinued; advising the patient that co-administration of emrusolmin with said moderate or strong CYP1 A2 inhibitor can alter the therapeutic effect or safety profile of emrusolmin; advising the patient that use of emrusolmin with said moderate or strong CYP1 A2 inhibitor is contraindicated; advising the patient that co-administration of emrusolmin and said moderate or strong CYP1A2 inhibitor can result in an increase in exposure to the emrusolmin; and / or advising the patient that said moderate or strong CYP1 A2 inhibitor should be used with caution in patient receiving emrusolmin due to the potential for reduced emrusolmin clearance.

[0106] In some aspects, the disclosure is directed to of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate CYP1A2 inhibitors, comprising administering to the patient 300 mg / day of emrusolmin while avoiding co-administration with said moderate CYP1A2 inhibitors and advising the patient that the CYP1 A2 inhibitor should be avoided or discontinued; advising the patient that co-administration of emrusolmin with said moderate CYP1 A2 inhibitor can alter the therapeutic effect or safety profile of emrusolmin; advising the patient that use of emrusolmin with said moderate CYP1 A2 inhibitor is contraindicated; advising the patient that co-administration of emrusolmin and said moderate CYP1 A2 inhibitor can result in an increase in exposure to the emrusolmin; and / or advising the patient that said moderate CYP1 A2 inhibitor should be used with caution in patient receiving emrusolmin due to the potential for reduced emrusolmin clearance.

[0107] In some aspects, the disclosure is directed to of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more strong CYP1A2 inhibitors, comprising administering to the patient 300 mg / day of emrusolmin while avoiding co-administration with said strong CYP1A2 inhibitors and advising the patient that the CYP1 A2 inhibitor should be avoided or discontinued; advising the patient that co-administration of emrusolmin with said strong CYP1 A2 inhibitor can alter the therapeutic effect or safety profile of emrusolmin; advising the patient that use of emrusolmin with said strong CYP1 A2 inhibitor is contraindicated; advising the patient that co-administration of emrusolmin and said strong CYP1 A2 inhibitor can result in an increase in exposure to the emrusolmin; and / or advising the patient that said strong CYP1 A2 inhibitor should be used with caution in patient receiving emrusolmin due to the potential for reduced emrusolmin clearance.

[0108] In some aspects, the disclosure is directed to of administering, on a daily basis, 150 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more strong CYP1A2 inhibitors, comprising administering to the patient 150 mg / day of emrusolmin while avoiding co-administration with said strong CYP1A2 inhibitors andadvising the patient that the CYP1 A2 inhibitor should be avoided or discontinued; advising the patient that co-administration of emrusolmin with said strong CYP1 A2 inhibitor can alter the therapeutic effect or safety profile of emrusolmin; advising the patient that use of emrusolmin with said strong CYP1 A2 inhibitor is contraindicated; advising the patient that co-administration of emrusolmin and said strong CYP1 A2 inhibitor can result in an increase in exposure to the emrusolmin; and / or advising the patient that said strong CYP1 A2 inhibitor should be used with caution in patient receiving emrusolmin due to the potential for reduced emrusolmin clearance.

[0109] In some aspects, the disclosure is directed to emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1 A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1A2 inhibitors.

[0110] In some aspects, the disclosure is directed to emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate inhibitors of CYP1 A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate CYP1A2 inhibitors.

[0111] In some aspects, the disclosure is directed to emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more strong inhibitors of CYP1 A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more strong CYP1A2 inhibitors.

[0112] In some aspects, the disclosure is directed to emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1A2, while avoiding an adverse drug-drug interaction in said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1 A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient. In some aspects, the disclosureis directed to emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate inhibitors of CYP1A2, while avoiding an adverse drugdrug interaction in said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate CYP1A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient. In some aspects, the disclosure is directed to emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more strong inhibitors of CYP1 A2, while avoiding an adverse drug-drug interaction in said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more strong CYP1 A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient.

[0113] In some aspects, the disclosure is directed to emrusolmin in a 300 mg daily regimen for use in a treating a patient in need of emrusolmin in a 300 mg daily regimen therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1 A2 inhibitors.

[0114] In some aspects, the disclosure is directed to emrusolmin in a 300 mg daily regimen for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate inhibitors of CYP1 A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate CYP1A2 inhibitors.

[0115] In some aspects, the disclosure is directed to emrusolmin in a 300mg daily regimen for use in treating a patient in need of emrusolmin in a 300mg daily regimen therapy, and in need of therapy with one or more strong inhibitors of CYP1A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co- administration of said one or more strong CYP1A2 inhibitors.

[0116] In some aspects, the disclosure is directed to emrusolmin in a 300mg daily regimen for use in treating a patient in need of in a 300mg daily regimen emrusolmin therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1 A2, while avoiding an adverse drug-drug interaction in said patient, characterized in that the treatingcomprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1 A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient. In some aspects, the disclosure is directed to emrusolmin in a 300 mg daily regimen for use in treating a patient in need of emrusolmin in a 300mg daily regimen therapy, and in need of therapy with one or more moderate inhibitors of CYP1 A2, while avoiding an adverse drug-drug interaction in said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate CYP1 A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient. In some aspects, the disclosure is directed to emrusolmin in a 300mg daily regimen for use in treating a patient in need of emrusolmin in a 300mg daily regimen therapy, and in need of therapy with one or more strong inhibitors of CYP1 A2, while avoiding an adverse drug-drug interaction in said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more strong CYP1A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient.

[0117] In some aspects, the disclosure is directed to emrusolmin in a 150 mg daily regimen for use in treating a patient in need of emrusolmin in a 150 mg daily regimen therapy, and in need of therapy with one or more strong inhibitors of CYP1A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co- administration of said one or more strong CYP1A2 inhibitors.

[0118] In some aspects, the disclosure is directed to emrusolmin in a 150 mg daily regimen for use in treating a patient in need of emrusolmin in a 150 mg daily regimen therapy, and in need of therapy with one or more strong inhibitors of CYP1A2, while avoiding an adverse drug-drug interaction in said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more strong CYP1A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient.

[0119] In those aspects of the disclosure wherein one or more moderate or strong CYP1 A2 inhibitors is avoided, contraindicated, or concomitant use or co-administration is discontinued, the patient in need of emrusolmin therapy and one or more weak inhibitors of CYP1 A2 may be administered the emrusolmin and the one or more weak CYP1 A2 inhibitors. Inthose aspects of the disclosure wherein one or more moderate CYP1A2 inhibitors is avoided, contraindicated, or concomitant use or co-administration is discontinued, the patient in need of emrusolmin therapy and one or more weak inhibitors of CYP1 A2 may be administered the emrusolmin and the one or more weak CYP1 A2 inhibitors. In those aspects of the disclosure wherein one or more strong CYP1 A2 inhibitors is avoided, contraindicated, or concomitant use or co-administration is discontinued, the patient in need of emrusolmin therapy and one or more weak inhibitors of CYP1 A2, may be administered the emrusolmin and the one or more weak CYP1A2 inhibitor.

[0120] In aspects of the disclosure wherein one or more moderate or strong CYP1 A2 inhibitors is discontinued, the one or more moderate or strong CYP1 A2 inhibitors is discontinued for at least 4 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more moderate CYP1A2 inhibitors is discontinued, the one or more moderate CYP1 A2 inhibitors is discontinued for at least 4 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more strong CYP1A2 inhibitors is discontinued, the one or more strong CYP1A2 inhibitors is discontinued for at least 4 weeks before the emrusolmin is administered.

[0121] In aspects of the disclosure wherein one or more moderate or strong CYP1 A2 inhibitors is discontinued, the one or more moderate or strong CYP1 A2 inhibitors is discontinued for at least 2 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more moderate CYP1A2 inhibitors is discontinued, the one or more moderate CYP1 A2 inhibitors is discontinued for at least 2 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more strong CYP1A2 inhibitors is discontinued, the one or more strong CYP1A2 inhibitors is discontinued for at least 2 weeks before the emrusolmin is administered.

[0122] In aspects of the disclosure wherein one or more moderate or strong CYP1 A2 inhibitors is discontinued, the one or more moderate or strong CYP1 A2 inhibitors is discontinued for at least 4 days before the emrusolmin is administered. In aspects of the disclosure wherein one or more moderate CYP1A2 inhibitors is discontinued, the one or more moderate CYP1 A2 inhibitors is discontinued for at least 4 days before the emrusolmin is administered. In aspects of the disclosure wherein one or more strong CYP1 A2 inhibitors is discontinued, the one or morestrong CYP1A2 inhibitors is discontinued for at least 4 days before the emrusolmin is administered.

[0123] In aspects of the disclosure wherein one or more moderate or strong CYP1 A2 inhibitors is avoided, the one or more moderate or strong CYP1 A2 inhibitors is avoided for at least 4 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more moderate CYP1 A2 inhibitors is avoided, the one or more moderate CYP1A2 inhibitors is avoided for at least 4 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more strong CYP1A2 inhibitors is avoided, the one or more strong CYP1 A2 inhibitors is avoided for at least 4 weeks before the emrusolmin is administered.

[0124] In aspects of the disclosure wherein one or more moderate or strong CYP1 A2 inhibitors is avoided, the one or more moderate or strong CYP1 A2 inhibitors is avoided for at least 2 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more moderate CYP1 A2 inhibitors is avoided, the one or more moderate CYP1A2 inhibitors is avoided for at least 2 weeks before the emrusolmin is administered. In aspects of the disclosure wherein one or more strong CYP1A2 inhibitors is avoided, the one or more strong CYP1 A2 inhibitors is avoided for at least 2 weeks before the emrusolmin is administered.

[0125] In aspects of the disclosure wherein one or more moderate or strong CYP1 A2 inhibitors is avoided, the one or more moderate or strong CYP1 A2 inhibitors is avoided for at least 4 days before the emrusolmin is administered. In aspects of the disclosure wherein one or more moderate CYP1 A2 inhibitors is avoided, the one or more moderate CYP1A2 inhibitors is avoided for at least 4 days before the emrusolmin is administered. In aspects of the disclosure wherein one or more strong CYP1A2 inhibitors is avoided, the one or more strong CYP1 A2 inhibitors is avoided for at least 4 days before the emrusolmin is administered.Aspects

[0126] Aspect 1. A method of stabilizing one or more symptoms of Multiple System Atrophy (MSA) in a human in need of stabilization thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the stabilization is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof.

[0127] Aspect 2. A method of limiting the clinical progression of MSA in a human in need of limitation thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the limiting is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof.

[0128] Aspect 3. A method of slowing the clinical progression of MSA in a human in need of slowing thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the slowing is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof.

[0129] Aspect 4. A method of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, comprising orally administering, on a daily basis, 300 mg of emrusolmin, wherein the clinical progression is determined as a change from baseline in the human’s total UMSARS score of part I and part II combined, or a modification thereof.

[0130] Aspect 5. A method of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin, wherein the clinical progression is determined as a change from baseline in the human’s CGLS score.

[0131] Aspect 6. A method of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin, wherein the clinical progression is determined as a change from baseline in the human’s MSA-QoL score.

[0132] Aspect 7. The method of any one of the preceding Aspects, wherein the emrusolmin administration does not result in a serious adverse event in the human.

[0133] Aspect 8. A method of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population, wherein the clinical progression is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof, and wherein the change from baseline in the clinical progression isstatistically significant, preferably statistically significant at a 1 -sided alpha of 0.05, as compared to a control population of humans.

[0134] Aspect 9. A method of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population, wherein the clinical progression is determined as a change from baseline in the human’s CGI-S score, and wherein the change from baseline in the clinical progression is statistically significant, preferably statistically significant at a 1 -sided alpha of 0.05, as compared to a control population of humans.

[0135] Aspect 10. A method of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a population of humans in need thereof, comprising orally administering, on a daily basis, of 300 mg emrusolmin to each human in the population, wherein the clinical progression is determined as a change from baseline in the human’s MSA-QoL score, and wherein the change from baseline in the clinical progression is statistically significant, preferably statistically significant at a 1 -sided alpha of 0.05, as compared to a control population of humans.

[0136] Aspect 11. A method of improving overall survival in a human with MSA comprising orally administering, on a daily basis, 300 mg emrusolmin to the human, wherein the improvement in overall survival is relative to a human with MSA who is not receiving treatment with emrusolmin.

[0137] Aspect 12. A method of improving progress-free survival in a human with MSA comprising orally administering, on a daily basis, 300 mg emrusolmin to the human, wherein the improvement in progress-free survival is relative to a human with MSA who is not receiving treatment with emrusolmin.

[0138] Aspect 13. A method of improving overall survival in a human with MSA, comprising orally administering, on a daily basis, 300 mg emrusolmin to the human, wherein the improvement in overall survival is relative to a human with MSA who is not receiving treatment with emrusolmin.

[0139] Aspect 14. The method of any one of the preceding Aspects, wherein the emrusolmin administration does not result in statistically significant serious adverse events in the population of human, as compared to a control population of humans.

[0140] Aspect 15. The method of any one of Aspects 1-7, wherein the stabilizing, limiting, or slowing is relative to a patient population with MSA that is not receiving treatment with emrusolmin.

[0141] Aspect 16. The method of any one of Aspects 2-6, wherein emrusolmin reduces the clinical progression by at least about 20%, such as about 40 to about 60%, or about 30 to about 40% relative to a treatment for MSA lacking emrusolmin.

[0142] Aspect 17. The method of any one of Aspects 1-7, wherein the clinical progression comprises worsening MSA symptoms.

[0143] Aspect 18. The method of any one of the preceding Aspects, wherein the human received at least one therapy for the treatment of MSA prior to administration of emrusolmin.

[0144] Aspect 19. The method of any one of the preceding Aspects, wherein the human is resistant to treatment with levodopa or has acquired resistance to treatment with levodopa.

[0145] Aspect 20. A method of treating a human having Multiple System Atrophy (MSA) and in need of treatment thereof, comprising a treatment period comprising orally administering to the human, once daily, for a period of treatment, about 300 mg of emrusolmin; wherein the administration results in a reduced rate of progression of the human’s MSA symptoms during the treatment period, wherein the reduced rate of progression is as compared to a placebo treatment; and wherein the rate of progression of MSA symptoms is measured using a i. Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof; ii. total UMSARS score, or a modification thereof; iii. CGI-S; and / or iv. MSA-QoL.

[0146] Aspect 21. The method of any one of Aspects 2-6, wherein emrusolmin reduces the clinical progression by at least about 20%, such as 40-60%, or about 30-40% relative to a treatment for MSA lacking emrusolmin.

[0147] Aspect 22. The method of any one of the preceding Aspects, wherein the MSA is multiple system atrophy-parkinsonian type (MSA-P).

[0148] Aspect 23. The method of any one of Aspects 1-21, wherein the MSA is multiple system atrophy- cerebellar subtype (MSA-C).

[0149] Aspect 24. The method of any one of the preceding Aspects, comprising diagnosing the human with MSA-P or MSA-C.

[0150] Aspect 25. The method of any one of the preceding Aspects, wherein the patient is being administered one or more moderate or strong CYP1 A2 inhibitors, wherein the treatment comprises (a) first discontinuing administration of said one or more moderate or strong CYP1 A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0151] Aspect 26. The method of any one of the preceding Aspects, wherein the patient is being administered one or more moderate CYP1 A2 inhibitors, wherein the treatment comprises (a) first discontinuing administration of said one or more moderate CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0152] Aspect 27. The method of any one of the preceding Aspects, wherein the human is in need of one or more moderate or strong CYP1 A2 inhibitors, wherein the treatment comprises (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong CYP1 A2 inhibitors.

[0153] Aspect 28. The method of any one of the preceding Aspects, wherein the human is in need of one or more moderate CYP1 A2 inhibitors, wherein the treatment comprises (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate CYP1A2 inhibitors.

[0154] Aspect 29. A method of administering, on daily basis, 300 mg of emrusolmin to a patient in need thereof, wherein said patient is also in need of one or more moderate or strong CYP1A2 inhibitors, comprising (a) administering to the patient, on daily basis, 300 mg ofemrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong CYP1A2 inhibitors.

[0155] Aspect 30. A method of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, and being administered one or more moderate or strong CYP1A2 inhibitors, comprising (a) first discontinuing administration of said one or more moderate or strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0156] Aspect 31. A method of stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, wherein the patient is also in need one or more moderate or strong CYP1 A2 inhibitors, comprising (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong inhibitors CYP1 A2.

[0157] Aspect 32. The method of any one of Aspects 25-31, further comprising administering to the patient a weak CYP1 A2 inhibitor, wherein the patient is also in need of said weak CYP1A2 inhibitor.

[0158] Aspect 33. A method of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is being administered one or more moderate or strong CYP1A2 inhibitors, comprising (a) discontinuing administration of said one or more moderate or strong CYP1A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0159] Aspect 34. A method of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is being administered one or more moderate CYP1 A2 inhibitors, comprising (a) discontinuing administration of the one or more moderate CYP1 A2 inhibitor, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

[0160] Aspect 35. A method of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need one or more moderate or strong CYP1A2 inhibitors, comprising (a) administering to the patient a therapeutically effective amount of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong CYP1 A2 inhibitor.

[0161] Aspect 36. A method of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate CYP1 A2 inhibitors, comprising (a) administering to the patient a therapeutically effective amount of emrusolmin and (b) avoiding concomitant administration of said one or more moderate CYP1A2 inhibitors.

[0162] Aspect 37. A method of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate or strong CYP1A2 inhibitors, comprising avoiding or discontinuing concomitant use of said one or more moderate or strong CYP1A2 inhibitors.

[0163] Aspect 38. A method of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate CYP1 A2 inhibitors, comprising avoiding or discontinuing concomitant use of said moderate CYP1A2 inhibitors.

[0164] Aspect 39. A method of administering, on a daily basis, 300 mg of emrusolmin therapy to a patient in need thereof, wherein the patient is also in need of one or more moderate or strong CYP1A2 inhibitors, comprising administering to the patient 300 mg / day of emrusolmin while avoiding co-administration with said moderate or strong CYP1A2 inhibitors and advising the patient that the CYP1 A2 inhibitor should be avoided or discontinued; advising the patient that co-administration of emrusolmin with said moderate or strong CYP1A2 inhibitor can alter the therapeutic effect or safety profile of emrusolmin; advising the patient that use of emrusolmin with said moderate or strong CYP1 A2 inhibitor is contraindicated; advising the patient that co-administration of emrusolmin and said moderate or strong CYP1 A2 inhibitor can result in an increase in exposure to the emrusolmin; and / or advising the patient that said moderate or strong CYP1 A2 inhibitor should be used with caution in patient receiving emrusolmin due to the potential for reduced emrusolmin clearance.

[0165] Aspect 40. Emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1A2,characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1 A2 inhibitors.

[0166] Aspect 41. Emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate inhibitors of CYP1 A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or coadministration of said one or more moderate CYP1A2 inhibitors.

[0167] Aspect 42. Emrusolmin for use in treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1A2, while avoiding an adverse drug-drug interaction in said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1 A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient.

[0168] Aspect 43. The method of any one of Aspects 25, 26, 30, 33, 34, 37, or 38 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate or strong CYP1 A2 inhibitors is discontinued for at least 4 weeks before the emrusolmin is administered.

[0169] Aspect 44. The method of any one of Aspects 25, 26, 30, 33, 34, 37, or 38 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate CYP1 A2 inhibitors is discontinued for at least 4 weeks before the emrusolmin is administered.

[0170] Aspect 45. The method of any one of Aspects 25, 26, 30, 33, 34, 37, or 38 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate or strong CYP1 A2 inhibitors is discontinued for at least 2 weeks before the emrusolmin is administered.

[0171] Aspect 46. The method of any one of Aspects 25, 26, 30, 33, 34, 37, or 38 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate CYP1 A2 inhibitors is discontinued for at least 2 weeks before the emrusolmin is administered.

[0172] Aspect 47. The method of any one of Aspects 25, 26, 30, 33, 34, 37, or 38 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or moremoderate or strong CYP1 A2 inhibitors is discontinued for at least 4 days before the emrusolmin is administered.

[0173] Aspect 48. The method of any one of Aspects 25, 26, 30, 33, 34, 37, or 38 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate CYP1A2 inhibitors is discontinued for at least 4 days before the emrusolmin is administered.

[0174] Aspect 49. The method of any one of Aspects 27, 28, 29, 31, 35, 36, 37, 38, or 39 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate or strong CYP1A2 inhibitors is avoided for at least 4 weeks before the emrusolmin is administered.

[0175] Aspect 50. The method of any one of Aspects 27, 28, 29, 31, 35, 36, 37, 38, or 39 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate CYP1A2 inhibitors is avoided for at least 4 weeks before the emrusolmin is administered.

[0176] Aspect 51. The method of any one of Aspects 27, 28, 29, 31, 35, 36, 37, 38, or 39 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate or strong CYP1A2 inhibitors is avoided for at least 2 weeks before the emrusolmin is administered.

[0177] Aspect 52. The method of any one of Aspects 27, 28, 29, 31, 35, 36, 37, 38, or 39 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate CYP1A2 inhibitors is avoided for at least 2 weeks before the emrusolmin is administered.

[0178] Aspect 53. The method of any one of Aspects 27, 28, 29, 31, 35, 36, 37, 38, or 39 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate or strong CYP1 A2 inhibitors is avoided for at least 4 days before the emrusolmin is administered.

[0179] Aspect 54. The method of any one of Aspects 27, 28, 29, 31, 35, 36, 37, 38, or 39 or the emrusolmin for use according to any one of Aspects 40-42, wherein the one or more moderate CYP1 A2 inhibitors is avoided for at least 4 days before the emrusolmin is administered.

[0180] Aspect 55. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is selected from the list including pipemidic acid, mexiletine, fexinidazole, methoxsalen (8- methoxypsoralen), capmatinib, metamizole (dipyrone), vemurafenib, rucaparib, osilodrostat, ritlecitinib, etintidine, phenylpropanolamine, hormonal contraceptives, vemurafenib, genistein, propranolol, troleandomycin, ciprofloxacin, rofecoxib, fluvoxamine, ciprofloxacin, clinafloxacin, idrocilamide, enoxacin, clinafloxacin, viloxazine - high / supratherapeutic dose, oltipraz, or a combination thereof.

[0181] Aspect 56. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is pipemidic acid, mexiletine, fexinidazole, methoxsalen (8-methoxypsoralen), capmatinib, metamizole (dipyrone), vemurafenib, rucaparib, osilodrostat, ritlecitinib, etintidine, phenylpropanolamine, hormonal contraceptives, vemurafenib, genistein, propranolol, troleandomycin, or a combination thereof.

[0182] Aspect 57. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1 A2 inhibitor is fluvoxamine.

[0183] Aspect 58. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1 A2 inhibitor is ciprofloxacin.

[0184] Aspect 59. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is mexiletine.

[0185] Aspect 60. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is pipemidic acid.

[0186] Aspect 61. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is fexinidazole.

[0187] Aspect 62. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is methoxsalen (8-methoxypsoralen).

[0188] Aspect 63. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is capmatinib.

[0189] Aspect 64. The method of any one of Aspects 25-39 or 43-54 or use according to Aspects any one of Aspects 40-54, wherein the CYP1A2 inhibitor is metamizole (dipyrone).

[0190] Aspect 65. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is vemurafenib.

[0191] Aspect 66. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is rucaparib.

[0192] Aspect 67. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is osilodrostat.

[0193] Aspect 68. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is ritlecitinib.

[0194] Aspect 69. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is etintidine.

[0195] Aspect 70. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is phenylpropanolamine.

[0196] Aspect 71. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is hormonal contraceptives.

[0197] Aspect 72. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is vemurafenib.

[0198] Aspect 73. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is genistein.

[0199] Aspect 74. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is propranolol.

[0200] Aspect 75. The method of any one of Aspects 25-39 or 43-54 or the emrusolmin for use according to Aspects any one of Aspects 40-54, wherein the CYP1 A2 inhibitor is troleandomycin.

[0201] Aspect 76. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1 A2 inhibitor is rofecoxib.

[0202] Aspect 77. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1 A2 inhibitor is clinafloxacin.

[0203] Aspect 78. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1A2 inhibitor is idrocilamide.

[0204] Aspect 79. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1 A2 inhibitor is enoxacin.

[0205] Aspect 80. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1A2 inhibitor is viloxazine - high / supratherapeutic dose.

[0206] Aspect 81. The method of any one of Aspects 25, 27, 29, 30, 31, 33, 35, 37, or 39 or the emrusolmin for use according to any one of Aspects 40, 42, 43, 45, 47, 49, 51, or 53, wherein the CYP1 A2 inhibitor is oltipraz.

[0207] The following examples are representative of the invention and the scope of the invention should not be limited by these examples.

[0208] Example 1 - phase 2 trial in MSA patients

[0209] A. Study Objectives, Endpoints, and Estimands

[0210] (i) Primary and Secondary Study Objectives and Endpoints

[0211] (ii) Primary Estimand

[0212] For the primary efficacy endpoint, the following estimand attributes will be employed:• Treatment: emrusolmin 300 mg QD or matching placebo for approximately 48 weeks• Population: All randomized adult patients with clinically possible or probable MSA• Endpoint: Change from baseline to week 48 in modified UMS ARS part I score• Population-level summary: Difference between treatment groups in mean change from baseline to 48 weeks in modified UMSARS part I score

[0213] The treatment policy strategy will be applied for the intercurrent events of early study discontinuation and concomitant medication / treatment noncompliance, meaning that the patient’s data will be used in the analysis regardless of these intercurrent events.

[0214] (iii) Exploratory Study Objectives and Endpoints

[0215] B. Study Design

[0216] (i) General Study Design and Study Schematic Diagram

[0217] This is a Phase 2, 56- week, multi-centered, randomized, double-blind, 2-arm, placebo-controlled study to evaluate the safety and efficacy of emrusolmin, also known as ANLE138b (anlel38b) or TEV-56286, in adult patients with MSA.

[0218] The study will consist of a screening period (up to 4 weeks), a 48-week double-blind treatment period, and a follow-up visit (approximately 4 weeks after the end of the double-blind treatment period). Patients who qualify for the study based on the inclusion / exclusion criteria will be randomized in a 1:1 ratio (stratified by region and by type of MSA [parkinsonism-predominant versus cerebellar-ataxia-predominant]) to receive either 300 mg test Investigational Medical Product (IMP) or placebo.

[0219] Throughout the study, patients will interact regularly with investigational center personnel, during in-clinic visits and by telephone for the evaluation of safety and tolerability.

[0220] The study schematic diagram is shown in FIG. 1.

[0221] The total duration of patient participation in the study is planned to be approximately 56 weeks, of which approximately 48 weeks are double-blind treatment with IMP.

[0222] At the baseline visit, patients will be randomly assigned to 1 of 2 treatment groups with emrusolmin or placebo in a 1: 1 ratio. There is no reference IMP in this study. For each group, 10 x 30 mg capsules or placebo capsules will be administered QD.

[0223] Patients who complete all scheduled visits will have procedures and assessments performed at week 52 end of study (EOS). Patients who withdraw from the study before completing the 52-week period will have visit 9 [EOT] early termination procedures andassessments performed at their final visit. Patients who complete this study may be eligible to enroll in an open-label extension study to assess the continued effectiveness and long-term safety of emrusolmin, if and when such an option becomes available. This potential open-label extension study is beyond the scope of this protocol. A separate protocol will be issued for the open-label extension study as applicable.

[0224] The end of study is defined as the last follow-up visit of the final patient.

[0225] The study duration will be approximately 27 months.

[0226] (ii) Planned Number of Patients and Countries

[0227] Approximately 190 patients will be screened to achieve approximately 160 enrolled patients.

[0228] Per the primary estimand, all enrolled patients will be evaluable for safety and efficacy analysis in this study following randomization.

[0229] C. Selection and Withdrawal of Patients

[0230] (ii) Patient Inclusion Criteria

[0231] Patients may be randomized / enrolled in this study only if they meet all of the following criteria: a. is a male or female >30 years old at screening b. is considered to be “clinically possible” or “clinically probable” MSA as determined by the Gilman criteria (See, Gilman, Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71(9):670-6) c. is able to ambulate at least 10 meters without the assistance of another person at screening; the use of assistive devices (e.g., walker or cane) is allowed d. If patient is receiving treatment for symptomatic MSA prior to randomization, therapy regimen must have been stable for a period of >28 days with no foreseeable changes predicted during the study including but not limited to: drugs acting against parkinsonism (e.g., levodopa, dopamine-agonists, amantadine, and monoamine oxidase-B inhibitors) drugs acting against autonomic dysfunction (e.g., ephedrine, midodrine, fludrocortisone, octreotide, desmopressin, and oxybutynine)antidepressant drugs (e.g., selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors). e. is able to swallow the IMP, as determined by a dysphagia evaluation during the screening period and in follow-up evaluations during the course of the study; and is willing to swallow the IMP capsules whole, and as scheduled, throughout the duration of the study f. is medically and psychiatrically stable, as indicated by medical and psychiatric history, as well as physical and neurological examination g. In the investigator’s opinion, the patient and / or patient’s caregiver(s) has (have) the ability to understand the nature of the study and its procedures, and is (are) able and willing to comply with the requirements of the study. h. If patient is personally unable to provide written informed consent, caregiver(s) is (are) able and willing to provide written informed consent after being assigned the role by the patient. i. Females of child bearing potential (CBP) may be included only if they have a negative pregnancy test at the screening and baseline visits. j. Females of CBP whose male partners are potentially fertile (i.e., no vasectomy) must use highly effective birth control methods beginning 28 days before the first administration of IMP, the duration of the study, and 28 days after the last dose of IMP. k. Males who are potentially fertile / reproductively competent (not surgically [e.g., vasectomy] or congenitally sterile) and their female partners who are of CBP must use, together with their female partners, highly effective birth control methods for the duration of the study and for 28 days after the last dose of IMP.

[0232] (ii) Patient Exclusion Criteria

[0233] Patients will not be randomized / enrolled in this study if they meet any of the following criteria: a. has any clinically significant uncontrolled medical or psychiatric condition (treated or untreated), other than MSA that could jeopardize or would compromise the patient’s ability to participate in any study assessments b. is severely affected with a UMSARS part IV score of 5c. is suspected of having a neurodegenerative disease other than MSA d. has 2 or more relatives with history of MSA, suggestive of an alternative diagnosis other than MSA e. has participated in another clinical study involving administration of an IMP within 3 months or 5 half-lives (whichever is longer) of this IMP prior to screening, or has previously participated in other studies of neuroprotective therapies (e.g., deferiprone, exenatide, or alpha-synuclein antibodies or vaccinations, anti-sense oligonucleotides); f. has a history of an intracranial or intraspinal space occupying lesion, increased intracranial pressure, or any other known condition in the medical history that may preclude the patient from the procedure of cerebrospinal fluid (CSF) sampling g. has a history of, or acknowledges, alcohol or other substance abuse in the 12 months before screening h. is a female patient who is pregnant or breastfeeding, or plans to become pregnant during the study i. is diagnosed with concurrent severe depression defined by a score >30 on the Beck Depression Inventory-II and / or has a significant risk of committing suicide based on the patient’s medical history / or the C-SSRS (lifetime); patients with a C-SSRS (current) positive response to suicidal ideation items 3, 4, or 5 are not eligible j. has a known hypersensitivity to any components of the IMP k. has moderate to severe renal impairment as assessed by estimated glomerular filtration rate <60 mL / min l. has moderate to severe hepatic impairment as assessed by Child-Pugh Score of 7 or above m. has any disorder that may interfere with absorption, distribution, metabolism, or excretion of IMPs (including relevant gastrointestinal surgery) n. is of a vulnerable population (e.g., people kept in detention) o. patient is using or consuming any prohibited concomitant medications within the specified exclusionary windows of this study

[0234] D. Treatments

[0235] (i) Investigational Medicinal Products Used in the Study

[0236] The IMP in this study is emrusolmin. There is a matching placebo composed of excipients only. Neither the IMP nor placebo are authorized and marketed products.

[0237] (a) Dosing

[0238] emrusolmin or matching placebo will be administered orally at a dose of 300 mg QD (10 x 30 mg) capsules with a sufficient amount of water. Patients will be instructed to self-administer at approximately the same time each day, irrespective of food intake, when inclinic administration is not already scheduled. Administration will be performed during the treatment period of 48 weeks.

[0239] (b) Placebo Investigational Medicinal Product

[0240] The placebo IMP consists of excipient ingredients only which shall be administered identically at a dose of 300 mg QD (10 x 30 mg) capsules. Administration will be performed over a 48-week period.

[0241] (c) Other Components

[0242] A descriptive table of emrusolmin and the placebo is included below:Table 3

[0243] (ii) Prior Prohibited and Concomitant Medication and Therapies

[0244] Any prior or concomitant medication a patient has had before IMP administration and up to the end of study, including follow-up, will be recorded.

[0245] Use of any over-the-counter (OTC) medications, herbal medications, diet aids, or nutritional supplements is prohibited during the study and follow-up period, with the exception of:1. approved forms of contraception2. vitamins within expected ranges of dosing3. approved doses of acetaminophen or ibuprofen4. medications required to treat pre-existing medical conditions

[0246] Medications prescribed for treatment of acute or chronic medical conditions, other than excluded conditions, may be permitted. The prescribed medications may be inclusive of medical marijuana, cannabidiol, OTC, vitamins and nutritional supplements as long as the medicine is maintained under the supervision of a prescribing health care provider. Medications required for the treatment of adverse events shall be permitted under supervision.

[0247] Concomitant medication and treatment will be queried and recorded until the completion of study activities or the time of patient withdrawal.

[0248] (a) Prohibited Medications and Therapies

[0249] Strong or moderate inhibitors of CYP1A2: Moderate and strong inhibitors of CYP1 A2 are disallowed from the study 14 days or 5 half-lives (whichever is longer) prior to first dose of emrusolmin and until 4 days after last dose of emrusolmin.

[0250] (iii) Assessments of Efficacy

[0251] (a) Unified Multiple System Atrophy Rating Scale (UMSARS)

[0252] The UMSARS is a multidimensional, validated scale for semi-quantitative clinical assessments of MSA patients (Wenning, Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov. Disord. 2004;19(12): 1391-402). It is comprised of 4 parts: part i, historical review of disease-related impairments, 12 items; part II, motor examination, 14 items; part III, autonomic examination; and part IV, global disability scale. As UMSARS is a unified scale, each item in parts I and II achieves a single score using a range of 0 (no impairment) to 4 (severe impairment). To obtain the UMSARS part I score and UMSARS part II score, respectively, the values for the individual items are summed up with higher scores corresponding to a more pronounced clinical disease severity.

[0253] In the derivation of the modified UMSARS part I score, item 11 (sexual function) will be omitted and the item scoring rescaled 0 to 0, 1 to 0, 2 to 1, 3 to 2, and 4 to 3.

[0254] (b) Unified Multiple System Atrophy Rating Scale - Modified Score (UMSARS-MS)

[0255] The UMSARS-MS uses all data collected within part I and part II of the UMSARS. To obtain the classical total UMSARS score, values of 0, 1, 2, 3, or 4 (depending on the level of impairment) are assigned to each item of the UMSARS part I and part II and summed up. For the UMSARS-MS, those values are transformed to reweighted and rescaled values before they are summed up. As the UMSARS-MS is a modified evaluation using different values assigned to the different levels of impairment within the items assessed, the source data for calculation of the score is identical to the data used for the calculation of the classical total UMSARS score. The range of scores (minimum to maximum) is preserved in UMSARS-MS compared to the classical UMSARS.

[0256] In trial simulations based on data from previous MSA cohorts (Dodel, “Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial),” Mov. Disord. 2010; 25(l):97-107; Levin, “Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial. Lancet Neurol,” 2019; 18(8):724-35), the UMSARS-MS had slightly higher statistical power to detect a slowing in disease progression.

[0257] (c) Multiple System Atrophy - Quality of Life (MSA-QoL)

[0258] The MSA-QoL is a patient-reported validated measure correlated with quality of life in a MSA population. The MSA-QoL shows internal consistency and construct validity (Schrag 2007 above). It was shown that MSA-QoL correlates negatively with disease progression in MSA (Schrag 2006 above; Schrag 2007 above). The 40-item MSA-QoL questionnaire is self-administered and each item is rated on a Likert type scale (0: No problem) to (4: Extreme problem). It is comprised of 3 subscales relevant to MSA: motor (14 items), nonmotor (12 items), and emotional / social (14 items). The MSA-QoL total score is the sum of all the items and lower scores indicate better QoL.

[0259] (d) Clinical Global Impression Scale - Severity (CGI-S)

[0260] The CGI-S scale permits a global evaluation of the patient’s current severity of illness on a Likert type scale ranging from 1 to 7, where l=normal / not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=among the most extremely ill patients (Guy, Clinical Global Impressions Scale (CGI). APA PsycTests 1976).

[0261] (e) Clinical Global Impression Scale - Improvement (CGLI)

[0262] The CGLI scale permits a global evaluation of the patient’s overall improvement in symptoms. The CGLI scale rates the patient’s improvement relative to their symptoms at baseline on a 7-point Likert type scale ranging from 1 (very much improved) to 7 (very much worse) (Guy 1976 above).

[0263] (f) Digital Biomarker Assessments

[0264] Patient digital biomarker assessment will be assessed during in-clinic visits by wearing a digital gait monitor for the duration of the gait assessment. This procedure may be combined with the timed 10-meter walk assessment. Patient's activity and sleep will be passively monitored out of clinic by actigraphy watch worn for 2 weeks following each in-clinic visit. Analysis of both in-clinic gait and actigraphy will be reported separately.

[0265] (g) Neurofilament Light Chain (NfL)

[0266] Level of NfL has been identified as a reliable biomarker for neuroaxonal damage in CSF and blood samples of neurodegenerative diseases (Hu, Cerebrospinal fluid levels of neurofilament light chain in multiple system atrophy relative to Parkinson’s disease: a metaanalysis. Neurol Sci 2017;38:407-14; Singer, Alpha-synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from Lewy body synucleinopathies. Ann Neurol 2020;88:503-12). NfL assessment is significantly elevated in MSA in many studies by more than the factor of 2 compared to healthy controls (Hansson, Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017 Mar 7;88(10): 930-937; Zhang, Neurofilament light chain predicts disease severity and progression in multiple system atrophy. Mov. Disord. 2022; 37(2):42L6) and has been shown to be a suitable parameter for detecting neuroprotective treatment effects in other neurodegenerative diseases such as spinal muscular atrophy, a condition in which response to treatment is predicted by adecrease in NfL (Wurster, Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen. J. Neurol. 2020; 267(l):36-44).

[0267] (h) MRI Regional Volumetric Changes in the Brain

[0268] In order to further investigate the correlation between brain volume change and the progression of MSA in emrusolmin and placebo-treated patients, magnetic resonance imaging (MRI) regional volumetric changes will be assessed.

[0269] E. Assessment of Pharmacokinetics, Pharmacodynamics, Biomarkers and Pharmacogenetics

[0270] (i) Pharmacokinetics Assessment

[0271] Blood of sparse pharmacokinetics samples will be collected throughout the study for measurement of sample concentration of emrusolmin (and potential emrusolmin metabolites).

[0272] When the pharmacokinetics blood sample collection coincides with safety assessments or related unscheduled study visits, pharmacokinetics blood samples should be collected as close to the scheduled timepoint as possible. Assessment of vital signs and ECG should precede pharmacokinetics blood sampling.

[0273] The dates and times of IMP administration and the date and timepoint (24-hour clock time) of each sample collection will be recorded both on the source documentation and the patient diary.

[0274] Samples will be analyzed for concentration of emrusolmin using an appropriate validated method. Incurred sample reanalysis may be performed. Samples collected from patients who receive placebo will not be analyzed.

[0275] (ii) Pharmacokinetics / Pharmacodynamics Assessment

[0276] Pharmacodynamic parameters evaluated in this study include selected safety and efficacy endpoints. If data permits, the relationship between the plasma IMP concentration and pharmacodynamics endpoints will be investigated. The results of the pharmacokinetics / pharmacodynamics analysis may be presented in a separate report.

[0277] (iii) Biomarker Assessment

[0278] Biomarkers are defined as biological substances that monitor physiological effects, assessing activity of the medicinal product, predicting clinical outcome, safety, and treatment response.

[0279] Collection of blood samples for biomarker analysis will be a part of this study. This may include misfolded alpha synuclein, NfL in plasma and CSF, glial fibrillary acidic protein concentrations, and disease / pathway implicative proteins. Additional biomarkers may be selected at a later stage before the analysis so as to allow updating with new scientific information.

[0280] Samples may be stored for a maximum of 15 years after the last patient’s last visit.

[0281] Biomarker blood samples will be collected via venipuncture.

[0282] (iv) Pharmacogenomics Assessment

[0283] Blood samples will be stored and analyzed for biomarker / genetic variants thought to play a role in MSA.

[0284] Collection of blood samples for pharmacogenomics analysis will be a part of this study. This shall include genetic polymorphisms (e.g., CYP1A2 genetic variation) to evaluate their association with observed clinical responses to emrusolmin (including emrusolmin pharmacokinetics). Additional pharmacogenomics outcomes may be selected at a later stage before the analysis so as to allow updating with new scientific information.

[0285] Samples may be stored for a maximum of 15 years after the last patient’s last visit.

[0286] The pharmacogenomics blood samples will be collected via venipuncture.

[0287] (v) Efficacy Analysis

[0288] (a) Primary Endpoint

[0289] The primary efficacy endpoint will be change from baseline to week 48 (EOT) as measured by modified UMSARS part I score (excluding item 11, item scoring rescaled 0-3).

[0290] (b) Supplementary Endpoints

[0291] As a supplementary analysis of the primary endpoint of modified UMSARS part I score change from baseline, linear slope of progression in modified UMSARS part I scorefrom baseline to week 48, as well as from week 48 to week 52, will be estimated and compared between treatment groups.

[0292] (c) Planned Method of Analysis

[0293] The ITT / mITT / PP Analysis Sets will be used for all efficacy analyses. Summaries will be presented by treatment group.

[0294] (d) Primary Efficacy Analysis

[0295] The mITT Analysis Set will be used for the primary efficacy endpoint analysis.

[0296] The primary analysis will be a mixed model for repeated measures (MMRM) with modified UMSARS part I score change from baseline as the dependent variable; fixed effects for treatment group, week as a categorical variable, and treatment-by-week interaction; and baseline modified UMS ARS part I score, and the same baseline stratification factors used for randomization as covariates. The unstructured covariance model will be used for repeated observations within patients. If the model does not converge, then simpler covariance structures with fewer parameters will be used, according to the following order: heterogeneous autoregressive (1), heterogeneous compound symmetry, autoregressive (1), and compound symmetry.

[0297] The primary comparison will be treatment contrast at week 48. The difference in least squares (US) mean of the change in modified UMS ARS part I score from baseline to week 48 (active versus placebo) will be compared using a 1 -sided test for superiority at a nominal significance level of a=0.05.

[0298] The US mean and standard error for the treatment groups, the US mean difference, the 2-sided 95% confidence interval, and the p-value for the comparison (active versus placebo) at week 48 will be presented.

[0299] (e) Secondary Efficacy Analysis

[0300] Treatment difference in total UMSARS score (part I and part II combined) change from baseline to week 48 will be analyzed using MMRM with total UMSARS score change from baseline as the dependent variable; fixed effects for treatment group, week as a categorical variable, and treatment-by-week interaction; and baseline total UMSARS score, and the same baseline stratification factors used for randomization as covariates. The unstructured covariance model will be used for repeated observations within patients. If the model does notconverge, then simpler covariance structures with fewer parameters will be used as specified for the primary efficacy endpoint analysis.

[0301] Treatment difference in MSA-QoL scale score change from baseline to week 48 will be analyzed using MMRM with MSA-QoL scale score change from baseline as the dependent variable; fixed effects for treatment group, week as a categorical variable, and treatment-by-week interaction; and baseline MSA-QoL scale score, and the same baseline stratification factors used for randomization as covariates. The unstructured covariance model will be used for repeated observations within patients. If the model does not converge, then simpler covariance structures with fewer parameters will be used as specified for the primary efficacy endpoint analysis.

[0302] Treatment difference in the CGLS scale score change from baseline to week 48 will be analyzed using MMRM with CGLS scale score change from baseline as the dependent variable; fixed effects for treatment group, week as a categorical variable, and treatment-by-week interaction; and baseline CGLS scale score and the same baseline stratification factors used for randomization as covariates. The unstructured covariance model will be used for repeated observations within patients. If the model does not converge, then simpler covariance structures with fewer parameters will be used as specified for the primary efficacy endpoint analysis.

[0303] In addition, since the CGLS may not be normally distributed, the Wilcoxon rank sum test will be performed on the change from baseline to week 48 of the CGLS scale score.

[0304] (f) Supplementary Analysis

[0305] For the supplementary analysis of the primary efficacy endpoint of modified UMS ARS part I score change from baseline, linear slope as a function of continuous time will be estimated and compared between treatment groups. The statistical model will be a repeated measures mixed linear model with modified UMS ARS part I score change from baseline as dependent variable; fixed effects for week as a continuous variable and treatment-by-week interaction; and interaction between week and each of: baseline modified UMSARS part I score and the same baseline stratification factors used for randomization as covariates. The individualpatient linear slope over time will also be included in the model as a random effect. The model will fix the y-intercept (change from baseline at week 0) to be 0.

[0306] (vi) Tolerability Analysis

[0307] Tolerability analysis will be based on the number (%) of patients who failed to complete the study and the number (%) of patients who failed to complete the study due to adverse events. Time to study withdrawal will be presented by Kaplan-Meier curves for each treatment group.

[0308] (vii) Pharmacokinetics Analysis

[0309] Observed plasma and CSF concentrations will be summarized using descriptive statistics (n, mean, SD, median, minimum, geometric mean, and coefficient of variation). Correlation of observed CSF to plasma concentrations of emrusolmin (and metabolites, if applicable) may be conducted, as data permits.

[0310] The following observed pharmacokinetics parameters for emrusolmin (and potential metabolites) will be determined:• Concentrations of IMP reported by dose, visit, and time.• Minimum concentration (Cmin) prior to dose administration for emrusolmin 6 reported by visit.

[0311] Pharmacokinetics parameters will be summarized using descriptive statistics, including the geometric mean and coefficient of variation, as appropriate. If available, a separate summary may also include pharmacokinetics parameters from the concentration data of patients who discontinue or are withdrawn from the study. Additional pharmacokinetics parameters may be determined if data permits.

[0312] Another potential summary may include stratification by smoking status.

[0313] If data permits, pharmacokinetics of emrusolmin will also be evaluated using a population pharmacokinetics approach, emrusolmin concentration data from this study will be combined with data from previous studies to characterize the following population pharmacokinetics parameters and derived estimates:

[0314] Steady state:• Apparent clearance (CL / F) and volume (V / F),Area under the plasma concentration-time curve (AUC) over the dosing interval (AUCtau),• Maximum concentration at steady state (Cmax,ss),• Minimum concentration at steady state (Cmin,ss) prior to dosing,• Average plasma concentration (Cavg) over a dosing interval,• Time to maximum concentration (tmax).

[0315] Single-dose:• AUC from time 0 to infinity (AUCo-00),• Cmax,• tmax,• Terminal elimination half-life (t / 2),• Additional pharmacokinetics parameters may be calculated if data permits.

[0316] The results of the population pharmacokinetics analysis may be presented in a separate pharmacometrics report.

[0317] (viii) Pharmacokinetics / Pharmacodynamics Analysis

[0318] Population pharmacokinetics / pharmacodynamics analysis of relevant pharmacodynamics variables and / or exposure-response analysis of relevant efficacy or safety endpoints may be performed.

[0319] If relevant data permits, the relationship between the plasma and / or CSF concentration of emrusolmin and pharmacodynamics endpoints may be investigated.

[0320] The pharmacodynamics endpoints for analysis may include modified UMSARS part I, total UMSARS score (part I and part II combined), CGI-S, patient survival, adverse events of interest, NfL in plasma, and MRI brain regional volumetric changes. Additional relevant pharmacodynamics endpoints may be included.

[0321] The results of the pharmacokinetics / pharmacodynamics analysis may be presented in a separate report.

[0322] (ix) Biomarker Analysis

[0323] Change from baseline analysis of selected biomarkers (which may include misfolded alpha-synuclein, NfL in plasma and CSF, glial fibrillary acidic protein concentrations, and disease / pathway-implicative proteins) may be assessed in the relevant matrix.

[0324] Biomarker analysis plans and results, with the exception of NfL concentrations in the plasma, may be reported separately from the main study results.

[0325] Additional relevant biomarker endpoints may be included. The final list of biomarkers to be evaluated will be determined at the time of analysis to be able to account for the most current research.

[0326] (x) Pharmacogenomics Analysis

[0327] Genetic variation assessed from blood such as in CYP1A2 and corresponding metabolizer status may be assessed using descriptive statistics for an association with study endpoints, including safety endpoints, IMP concentration, and pharmacokinetics parameters.

[0328] Pharmacogenetics analysis plans and results may be reported separately from the main study results.

[0329] Additional relevant pharmacogenomics endpoints may be included. The final list of biomarkers to be evaluated will be determined at the time of analysis to be able to account for the most current research.

[0330] (xi) Digital Biomarker Analysis

[0331] Change from baseline in selected digital biomarkers (which may include parameters of gait, general activity and sleep) may be assessed across various timepoints.

[0332] Digital biomarker analysis plans and results may be reported separately from the main study results.

[0333] Raw study data may be used to develop new algorithms to detect disease related and / or general health related features yet to be identified in the study population. Development of novel algorithms may require splitting the data into testing and validation data sets. Details would be outlined in the digital biomarker analysis plan. The final list of digital biomarkers to be evaluated will be determined at the time of analysis to be able to account for the most current research.

[0334] G. Prohibited Medications and Interactions

[0335] The following describes the restricted medications for the study due to potential interactions with emrusolmin.

[0336] The following drugs and compounds are excluded per the study inclusion criteria:• deferiprone• byetta• alpha-synuclein antibodies or vaccinations• anti-sense oligonucleotides• GLP-1 agonists not used for the sole purpose of treating type 2 diabetes mellitus

[0337] Moderate and strong Cytochrome P450 1 A2 inhibitors are prohibited from 2 weeks or 5 half-lives (whichever is of longer duration) prior to first dose of emrusolmin and until 4 days after last dose of emrusolmin. Below is a partial list of moderate and strong CYP450 1A2 inhibitors prohibited:• fluvoxamine• ciprofloxacin• enoxacin• viloxazine• clinafloxacin• idrocilamide• etintidine• genistein• methoxsalen (8-methoxypsoralen)• mexiletine• vemurafenib• osilodrostat• phenylpropanolamine• pipemidic acid• estrogen-containing medications

[0338] Example 2: anle!38b Formulation Studies

[0339] Anlel38b (emrusolmin) is a lipophilic compound. Studies were performed to assess approaches to increase solubility of anlel38b (emrusolmin) for formulation development.

[0340] The formulations were prepared as gelatin capsules and were tested for drug loading, in vitro dissolution in bio-relevant dissolution media 0.1N HCI, simulated gastric fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF) and in vivo (PK in rats).

[0341] In an initial excipient screen, three formulations in which anlel38b (emrusolmin) exhibited solubility were prepared. The composition of the formulations and dissolution data from a 0. IN HCI solution are provided in Table 2.Table 2: anlel38b test formulations* Percent release of anlel38b (emrusolmin)from formulation in 0. IN HCI dissolution solution, h= hour(s) Caprylol® 90 = propylene glycol monocaprylate (type II); Kolliphor® RH40 = PEG- 40 Hydrogenated Castor Oil; Solutol = Polyethylene glycol (15)-hydroxystearate; TPGS = vitamin E, D-a-tocopheryl polyethylene glycol succinate; Transcutol = Diethylene glycol monoethyl ether.

[0342] Vehicles 1, 2, and 3 were selected as having good solubility and were further tested for dissolution in 0. IN HCI medium. Dissolution data show that Vehicle 1 exhibited slow dissolution at a 25 mg dose and too fast a dissolution at the 50 mg dose. Vehicle 2 exhibited slowdissolution at the 25 mg dose and too fast a dissolution at the 50 mg dose. Vehicle 3 exhibited a good dissolution profile for the 50 mg dose and was further tested in simulated gastric fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF). In both media, the sample started to exhibit large flakes which increased over time and may account for the observed rapid release profile after 60 minutes.

[0343] Tables 3A and 3B, provide the dissolution rates of formulation with vehicle 3 as the mean of three samples in SGF and FaSSIF, respectively.Table 3A: Dissolution of anle!38b vehicle 3 formulation in SGFTable 3B: Dissolution of anle!38b vehicle 3 formulation in FaSSIF

[0344] Visual observations in both media (SGF and FaSSIF): the sample started to changed appearance from a fine suspension to large flake / lumps which increased overtime after 45- 60 minutes of the dissolution run. This is in line with the drop in % claim seen after this time point.

[0345] In a second approach, increasing solubility by nanomilling the API was tested. The vehicle was prepared by dissolving 1% w / v of HPMC Pharmacoat 603 (Shin-Etsu) and 0.25% w / v Sodium lauryl Sulphate (SIS) in pure water; anlel38b (emrusolmin) was added and the suspension underwent 3 consecutive cycles (99 minutes each) of milling performed with Retsch Mill MM200 using 0.6 mm diameter Yttrium Zirconium beads, after which time the resultant suspension was recovered and maintained under constant magnetic stirring until dose administrations. Average particle size distribution (PSD) of nanomilled sample is as follows:D(10) 0.07 urn, D(50) 0.156 urn, and D(90) 1.57 urn.FIG. 2 shows the particle size distribution graph of two batches of nanomilled formulation.

[0346] Tables 4A and 4B, provide the dissolution rates of the nanomilled formulation as the mean of three samples in SGF and FaSSIF, respectively.Table 4A: Dissolution of anle!38b nanomilled formulation in SGFTable 4B: Dissolution of anle!38b nanomilled formulation in FaSSIF

[0347] The nanomilled formulation exhibits a slow and steady release profile that releases less than 10% API after 2 h. This was considered to be an unacceptable release profile. Drug product appears as a fine suspension throughout the dissolution run.

[0348] In a third approach, anlel38b (emrusolmin) was formulated in a single solubilizer, lauroyl polyoxyl-32 glycerides, also known by its tradename Gelucire® 44 / 14, a mixture of one monoester and / or diester of a fatty acid, mono-, di- and tri-glycerides of a fatty acid and free PEG.

[0349] Tables 5 A and 5B provide the dissolution rates of the anlel38b (emrusolmin) lauroyl polyoxyl-32 glycerides formulation in capsules as the mean of three samples in SGF and FaSSIF, respectively.Table 5A: Dissolution of anle!38b lauroyl polyoxyl-32 glycerides in SGFTable 5B: Dissolution of anle!38b lauroyl polyoxyl-32 glycerides in FaSSIF

[0350] Tables 5 A and 5B show that the capsules dissolve after around 15 to 30 minutes of the dissolution runs and provide a steady release profile in biologically relevant simulated fluids (simulated gastric fluid (SGF) and fasted state intestinal fluid (FaSSIF)) and was considered to be suitable for clinical use.

[0351] The formulation comprising lauroyl polyoxyl-32 glycerides (“Gelucire® 44 / 14”) was selected for further pre-clinical and clinical development. The studies resulted in the identification of a formulation consisting of a semisolid in capsule formulation in size 00 capsule shells (2 dose strengths, 10 mg and 30 mg anlel38b (emrusolmin) per capsule, respectively, and 1 placebo) with lauroyl polyoxyl-32 glycerides (Gelucire® 44 / 14) as the excipient.

[0352] Example 3 Pharmacokinetic Study in Rat

[0353] A rat study was undertaken to assess the pharmacokinetics of anlel38b in male Sprague Dawley rats (n=3 / arm) following single oral administration of different formulations of anlel38b, as follows, in Table 6.Table 6: anle!38b formulation used in rat studyCapryol® 90 = propylene glycol monocaprylate (type II);Kolliphor® RH40 = PEG-40 Hydrogenated Castor Oil.

[0354] Preparation of Formulation A: The vehicle was prepared by weighing Kolliphor® RH40 (Sigma Aldrich; 45% of final volume); PEG400 (Sigma Aldrich; 35% of final volume) and Caprylol 90 (Gattefosse; 20% of final volume). The mixture was stirred and warmed to approximately 50°C (using a thermostatically controlled bath) for ca. 15 minutes until a clear liquid was obtained. The anlel38b was added to vehicle maintained under continuous agitation at 50°C. The mixture was stirred for a further 15 minutes and sonicated for 10 minutes until a visually clear solution was obtained.

[0355] Preparation of Dose Formulation B: The vehicle was prepared by dissolving 1% w / v of HPMC Pharmacoat 603 (Shin-Etsu) and 0.25% w / v Sodium Lauryl Sulphate (SLS) in pure water; anlel38b was added and the suspension underwent 3 consecutive cycles (each of 99 minutes) milling performed with Retsch Mill MM200 using 0.6 mm diameter Yttrium Zirconium beads, after which time the resultant suspension was recovered and maintained under constant magnetic stirring until dose administrations. Average particle size distribution (PSD) of nanomilled sample is as follows: D(10) 0.07 pm, D(50) 0.156 pm, and D(90) 1.57 pm.

[0356] Preparation of Dose Formulation C: The anlel38b was added to PEG400 (Sigma Aldrich) under constant magnetic stirring until complete dissolution of the test material was obtained.

[0357] Preparation of Dose Formulation D: The vehicle (Gattefosse; lauroyl polyoxyl- 32 glycerides) was warmed to at least 20°C above its melting point and anlel38b was added under constant magnetic stirring. The formulation was maintained at 40°C in a thermostaticallycontrolled water bath and syringes and cannula in the treatment room were also pre- assembled and warmed prior to dosing.

[0358] Anlel38b was formulated on the day of dosing, except for formula C, which was prepared one day in advance.

[0359] Male Sprague Dawley (SD) rats (n=3 / formulation) sourced from Charles River Italia were kept for 5 days acclimatization. Feeding regimen was ad libitum except on the day of dosing when the food was supplied 4 hours post dosing, having been removed the evening beforehand. Animals were orally dosed with anlel38b (10 mg / kg) formulated as above. An individual serial plasma profile was drawn from each animal over a period of 24 hours after dosing.

[0360] Actual body weights were recorded on the day of dose administration. Dose volumes were adjusted taking into account the weight of the animal at the time of dose administration.

[0361] The dose formulations were administered orally via gastric gavage (2 ml / kg); any remaining formulation after dosing was discarded.

[0362] After oral administration, blood samples were collected from the tail vein of each rat at the time-points detailed: Pre dose, 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing

[0363] Approximately 150 pL blood was collected into tubes containing anticoagulant (K3 EDTA), placed on crushed wet-ice and then centrifuged (2000 g at +4 °C for 10 minutes) as soon as practicable and in any case within 1 hour. The resultant plasma was separated from the erythrocyte pellet and then transferred to uniquely labeled clear polypropylene tubes and frozen immediately over solid carbon dioxide or in a freezer at nominally -20°C.

[0364] PK profiling was performed by non-compartmental analysis using Phoenix™ WinNonlin. All computations utilized the nominal sampling times. Where feasible, the systemic exposure to anlel38b was determined by calculating the area under the plasma concentration time curve (AUC) from the start of dosing to the last quantifiable time-point (AUCo-t, t=8h) using the linear- logarithmic trapezoidal rule. The maximum observed peak plasma concentration (Cmax) and the time at which it was observed (Tmax) were determined by inspection of the observed data.

[0365] The relative bioavailability (Free%) of anlel38b between dose formulations was calculated by comparing systemic exposure (AUCo-t), and are reported rounded to at least 2 significant figures. All dose levels, plasma concentrations and pharmacokinetic parameters are given in terms of parent compound anlel38b.

[0366] Results: Following a single oral administration of anlel38b 10 mg / kg to male rats, anlel38b was quantifiable in the plasma of all animals up to 8 hours after dosing. Tmax occurred between 2 and 8 hours post dosing. Notable differences in systemic exposure to anlel38b, as mean Cmax and AUCo-t, were observed between the four formulations evaluated. PK values (mean and ranges) are provided in Table 7.Table 7: PK date from rat formulation studyAUCo-t = area under the plasma concentration-time curve (AUC) from the start of dosing (0) to the last quantifiable time point (t) which was 8 hours.

[0367] Differences in systemic exposure to anlel38b, as mean Cmax and AUCo-sh, were observed between the four formulations. Formulations A and D performed the best in terms of AUC and Cmax, with administration of formulation D, resulting in an anlel38 mean AUCo-sh approximately 5.6, 3 and 1.4- fold higher than the values obtained after dosing of formulations B, C and A, respectively.

[0368] Using formulation A as a reference point, the relative bioavailability (Frei%) of anlel38b formulated as B vs A (ref) was approximately 25%, C vs A (ref) was approximately 49% and D vs A (ref) was approximately 140%. The PK rat data shows that following a singleadministration, the formulae A and D exhibited better AUC and higher Cmax than a suspension of nanomilled anlel38b or anlel38b in PEG400. Formula D (Gelucire 44 / 14) exhibited the more favorable AUC and Tmax overall and was selected for further development and testing.

[0369] FIGs. 3A-3D are graphs showing PK Cmax profiles of each of the 3 animals in each group. FIG. 3A represents PK results with formulation A, FIG. 3B represents PK results with formulation B, FIG. 3C represents PK results with formulation C, FIG. 3D represents PK results with formulation D.

[0370] Example 4 Phase 1 Drug Product (DP)

[0371] Table 8 provides the anle!38b phase 1 DP ingredientsTable 8: 10 mg and 30 mg drug product ingredients.* water evaporates during capsule band drying

[0372] The DP was filled into white high-density polyethylene (HDPE) bottles closed with tamper evident caps.

[0373] Evaluation of Solubility in Lauroyl Polyoxyl-32 Glycerides: The visual solubility of API in molten lauroyl polyoxyl-32 glycerides was assessed at 55 °C. Six solutions at different concentrations (up to saturation) were prepared and then cooled down to room temperature.

[0374] The concentration of 50 mg (API) / g of lauroyl polyoxyl-32-glycerides was considered as a reference start.

[0375] Preparation of Capsules and Stressed Stability Study: Two API doses were selected (10 mg and 30 mg) and corresponding solutions of API in molten lauroyl polyoxyl-32glycerides were prepared to be filled into capsules. These capsule prototypes were banded and then stored at 40 °C / 75 % RH and 50 °C / ambient RH condition and tested for assay and impurities after 15 days and 30 days to check for any incompatibility (RH: relative humidity).

[0376] Scale-up with Technical Batch Manufacture: The manufacture of semisolid in capsule formulations (two dose strengths) was scaled up to a batch size representative of clinical manufacture (1000-3000 units). A placebo batch was also prepared.

[0377] Preparation of solution: The vehicle was prepared by melting the lauroyl polyoxyl-32 glycerides at 55 °C. API was then added and mixed until complete solubilization.

[0378] Preparation of capsules: The solution (pure molten vehicle for placebo) was filled into capsules by a HIBAR-P0450 machine at an appropriate fill weight and then capsules were banded using the BONAPACE-BD3000 banding machine using an appropriate solution of gelatin in water. After banding, visually damaged and / or unsuitably sealed capsules were discarded.

[0379] Capsules were left to dry for at least 24 h and then checked for integrity of shell and banding and for possible leaking under vacuum (T= 55 °C and P < 100 mbar; Heraeus VT6130M).

[0380] Capsules showing material leaks were discarded.

[0381] Formal Stability Study on Technical Batch: Stability testing of two active batches and one placebo batch, packaged in typical primary packaging (i.e., HOPE bottle packs with desiccant) was conducted as detailed within the schedule shown below, in Table 9.Table 9: Stability test of DPKey: T = Tested for appearance, and drug-related impurities (by single HPLC method), dissolution, and water content by KF titration. (T) = Optional testing (i.e., storage only). T* = Assumes QC release testing results are used for initials (i.e., stability study is set down within 30 days of QC release testing).

[0382] The anlel38b capsules (DP test and placebo) were studied in a 36 month long ICH compliant stability study under long-term conditions (at 25°C / 60% RH) and 6 months under accelerated conditions (at 40°C / 75% RH). Drug product stability is tested using standard assays including content uniformity, impurities, appearance, water content, dissolution.

[0383] The anlel38b DP as described herein is stable for at least 18 months at 25°C / 60% RH, preferably for at least 24 months and more preferably for at least 36 months.

[0384] For subsequent clinical trials, a drug product using hydroxypropyl methylcellulose (HPMC) capsules was manufactured as described above substituting the HPMC capsules for the gelatin capsules.

[0385] Example 5: Phase 1 first in human study in healthy subjects

[0386] Safety, tolerability, and pharmacokinetics of anlel38b: a first-in- human (FIH) randomized, double-blind, placebo-controlled phase 1 trial.

[0387] Anlel38b was studied in a single-centre, double-blind, randomised, placebo- controlled single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy subjects.

[0388] Eligible participants were randomly assigned (1: 1 for sentinel subjects and 1 : 5 for main group) to placebo or anlel38b (dose ranging from 50 mg to 300 mg per day), respectively. In addition, the effect of food on the pharmacokinetics (PK) of anlel38b in healthy subjects was examined at doses of 150 mg per day (FES, food effect study). Participants were randomized to treatment sequence (fed fasted) or (fasted fed). Treatment for the SAD, MAD and FES arms of the study was administered orally in hard gelatin capsules containing either 10 mg or 30 mg of anlel38b with excipient (i.e., lauroyl polyoxyl-32 glycerides) or excipient only. The primary endpoints were safety and tolerability, the secondary endpoint was pharmacokinetics. Data from all randomized individuals were evaluated. [Clinicaltrials. gov-identifier: NCT04208152. EudraCT-number: 2019-004218-33]

[0389] Findings: 196 healthy volunteers were screened and 68 participants were enrolled. Of these, all completed the study per protocol. Adverse events in this healthy volunteertrial were mostly mild and all fully recovered or resolved. No abnormal trend was seen in any system organ class. The study drug was safe and well tolerated at all dose levels and reached significantly higher plasma levels in humans than those required for full therapeutic efficacy in M12 mice, a recently established a-synucleinopathy rodent model (Wegrzynowicz, 2019, “Depopulation of dense a-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model,” Acta Neuropathol., 138(4):575-95; Levin, “Safety, tolerability and pharmacokinetics of the oligomer modulator anlel38b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase la trial,” EBioMedicine. 2022; 80: 104021; doi: 10.1016 / j.ebiom.2022.104021).

[0390] Methods

[0391] Study design: A single-centre, double-blind, randomised, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) study of anlel38b in doses of up to 300 mg per day in healthy subjects. The effect of food (FES) on the PK of anlel38b in healthy subjects was examined using doses of 150 mg. Participants were recruited from Quotient Sciences (the “CRO,” Nottingham, UK) volunteer database. Approvals from the ethical review board and from the Medicines and Healthcare products Regulatory Agency (UK) were obtained. This study was conducted in accordance with the protocol and with the following legislation: The updated version of the international Council for Harmonisation Good Clinical Practice (GCP) including the integrated Addendum E6, the Medicines for Human Use (Clinical Trials) Regulations including amendments No. 1928, 2984 and 941. In addition, the study was performed according to the ethical principles outlined in the World Medical Association Declaration of Helsinki and its amendments. The study data was monitored. An independent study monitor was appointed to verify that the study was conducted in accordance with current GCP, regulatory requirements, the protocol and that the data were authentic, accurate and complete.

[0392] Participants were healthy volunteers aged 18 to 55 and able to understand the nature of the study and any risks involved in participation. They needed to be willing to cooperate and comply with the protocol restrictions and requirements and be capable and willing to give written informed consent. The study included healthy male volunteers and healthy femalevolunteers with no childbearing potential. Eligible participants needed to have a body mass index of (BMI) of 18.5 to 30.0 kg / m2at screening. For participation in the food effect study, subjects had to be able to eat 90% of the US Food and Drug Administration (FDA)-approved high-fat breakfast, including bacon.

[0393] Randomization and masking: Eight participants were enrolled per dosing cohort in the SAD and MAD parts of the study. Participants were randomly assigned to placebo (N=2) or to anlel38b (N=6). Sentinel subjects were randomized 1 : 1 and the main group 1 :5 for placebo or anlel38b, respectively. A computer-generated randomization schedule was used. All participants and study personnel directly interacting with participants were blinded to treatment assignment. The medication kits were numbered in a consecutive manner.

[0394] In FES, participants (N=12) were unblinded to treatment as this cohort did not include placebo, but were randomized in a 1: 1 ratio to the sequences of treatment in a 2-way crossover design. Hence, 6 volunteers were randomized to the treatment sequence with prandial state first fed and then fasted, the remaining 6 volunteers to the fasted state first and then fed.

[0395] Safe starting dose & exposure limit justification:

[0396] This trial followed the recommendations of the EMA (European Medicines Agency) (EMEA / CHMP / SWP / 28367 / 07 Rev. 1; 20 July 2017) and the FDA (Food and Drug Administration) (Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2005) for dose finding in a first-in-human study. The safe starting dose was set based on toxicity studies in animals. In a 28-day toxicity study in rats, the no-observed-adverse- effect-level (NOAEL) was determined to be 50 mg / kg / day (human equivalent dose of 8.1 mg / kg). The dose range of the current trial was designed to start at 50 mg. Escalation between doses was planned to be flexible depending on emerging results but not to exceed an increment of 2-fold.

[0397] Procedures: The trial medication was produced by Aptuit, Italy. Anlel38b in a capsule was prepared as described in Example 2.3, supra.

[0398] Subjects were screened for enrolment in the study up to 28 days before dosing, were admitted in the morning on the day before dosing (day -1) to the clinical site, and remainedon site until 48 h post last dose. A post study follow-up visit took place 5 to 7 days post last dose for safety & well-being monitoring. Screening of the volunteers included full physical examination, taking medical history and reviewing medical report, checking body weight and height to calculate body mass index (BMI), safety procedures such as safety bloods (hematology, clinical chemistry & virology, serum pregnancy test), 12 lead ECGs, vital signs (blood pressure, heart rate, and oral temperature), carbon monoxide breath tests, drug screen for drug of abuse, alcohol breath tests and urinalysis.

[0399] In SAD, subjects received a single dose of anlel38b or placebo after fasting from all food and drink (except water) for a minimum of 8 h prior to dosing. The dosing in the four SAD- cohorts were 50 mg, 100 mg, 200 mg and 300 mg of free anlel38b equivalent, QD, cohorts A, B, C and D, respectively. In the MAD part, participants received anlel38b or placebo once daily (QD) for 7 days after fasting from all food and drink (except water) for a minimum of 8 h prior to dosing. The dosing in the three MAD-cohorts was 100 mg, 200 mg and 300 mg of free anlel38b equivalent, cohorts AM, BM and CM, respectively. Post dosing mouth and hand checks were conducted to ensure the capsules were swallowed. In-study decisions were made by the safety advisory committee (SAC) comprising the principal investigator, the sponsor's medical monitor and a PK expert. For dose escalation to proceed, data needed to be available from a minimum of 6 subjects per cohort with completed per protocol safety and PK assessments up to 48 h after dosing to ensure at least 4 subjects had received active IMP. The decision to proceed to the next higher dose level was based on safety, tolerability and available PK data to 48 h postadministration. The following data were analyzed: Adverse events, vital signs, safety laboratory, ECG, physical examinations, plasma concentrations of anlel38b with interim PK parameter estimations (Tmax, Cmax, AUCo-24, AUCo-tau, AUCo-iast and T%, where applicable). Data were provided to the SAC in accordance with CRO standard operating procedure (SOP) on interim dose decision-making and dose escalation.

[0400] In the food effect study (FES), the effect of food on the PK of anlel38b was explored using a single dose of 150 mg anlel38b, a dose level that was previously deemed safe and well tolerated in the SAD and MAD cohorts. This dose was administered either i) after a standard FDA-approved high-fat breakfast or ii) in the fasted state, i.e., fasted from all food and drink (except water) for a minimum of 8 h prior to dosing. In total, one cohort of 12 subjects wasrandomised in a 1: 1 ratio to 2 treatment sequences (fed fasted) or (fasted fed). A minimum washout of at least 5 half-lives of anlel38b between each dose was assured.

[0401] Outcome measures: The primary objective was to assess the safety and tolerability of single (SAD) and multiple (MAD) ascending doses of anlel38b to healthy subjects in the fasted state and to assess the safety and tolerability of single doses of anlel38b in both the fasted and fed state (FES). To this end, adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), QT interval corrected for heart rate using Fridericia's formula (QTcF), and physical examination findings were recorded. Participants were instructed to report all potential AEs immediately to the on-site personnel and were assessed by a physician before each dose of study drug. In addition, a physical examination of the relevant body system was performed in the event that a subject reports any new symptoms or AEs. AEs were defined following standard criteria, which are described in the protocol. The detailed PK parameters are provided in Tables 10-12, below. Any clinically significant abnormality in these assessments, including changes from baseline, were needed to be reported as an AE.

[0402] Secondary outcome measures were the oral PK of single (SAD) and multiple (MAD) ascending doses of anlel38b in the fasted state as well as the effect of co-administration with food on the PK of anlel38b. To this end PK blood samples were taken at day 1 (and for MAD day 7) pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 20 h post- administration, at days 2 to 6 pre-dose only (MAD) and 24, 30, 36 and 48 h post final dose. Analysis of anlel38b in plasma was done at Aptuit. Time point of last quantifiable data was seen to increase with an increase in dose as follows: SAD: from the 50 mg dose (subjects ranged between 8-24 h) to the 300 mg dose (subjects ranged between 36-48 h). MAD: from the 100 mg dose (subjects ranged between 8-36 h) to the 300 mg dose (subjects ranged between 20-48 h). In FES, subjects ranged between 24-48 h.

[0403] Data management was performed by the CRO using a validated electronic case report form (eCRF) database system and subjected to data consistency and validation checks. Data queries were raised within the study eCRF database by data management staff and resolved with the assistance of clinical staff.

[0404] AEs and medications were coded using the Medical Dictionary for Regulatory Activities (MedDRA) (v22 - 1). An independent coding review was performed within the DataSciences department. Clinical chemistry and hematology data (and other safety laboratory data) were collected by a central laboratory (The Doctors Laboratory) and transferred electronically to the CRO. All demographic details and sample dates were cross-referenced with the corresponding data on the study database. Data was monitored by an external entity (Wirral Clinical Consultancy Ltd, Heswall, UK). Monitoring included the conduct of a site initiation visit, interim monitoring visits and a close-out visit. The database was closed after all queries had been resolved.

[0405] Statistical analysis: The study was exploratory and no formal sample size calculation was made. Based on experience from previous studies of similar design, eight subjects per cohort were enrolled for parts 1 (SAD) and 2 (MAD) and a total of twelve subjects for part 3 (FES). Populations and analysis sets were determined for safety and PK data after database lock using the criteria defined in the reporting and analysis plan. The safety population and safety analysis set for SAD and MAD were defined after database lock but prior to study unblinding. Statistical analysis and production of summary tables, figures and listings for all safety data (AEs, vital signs, ECGs and safety laboratory assessments) including changes from baseline as required in this study were performed using the statistical package SAS (v9-4). Additional statistics were provided for PK-related data including coefficient of variation (CV%), geometric mean, geometric CV% and geometric n (i.e., the number of subjects with an observation that were included in the natural logarithmic transformation). In SAD and MAD, dose proportionality was assessed. Formal statistical analysis was performed on the log- transformed PK parameters AUCo-iast, AUCo-inf, and Cmax for SAD (day 1), and AUCo-tau and Cmax for MAD (day 1 and day 7) to assess dose proportionality using the following power model: loge (AUC or Cmax) = g + 0x loge (dose)

[0406] The relationship between the PK parameter (y) and dose is defined as follows: y = a * dose where y is AUC or Cmax.

[0407] Dose proportionality requires that =1 for dose dependent parameters. This becomes a linear relationship after logarithmic transformation:Log(y) = p + P * log(dose)

[0408] where p=log (a) is the intercept and is the slope from the linear model. Using this model it is possible to estimate (measure of dose proportionality) and obtain 90% confidence interval (CI) for (Gough, “Assessment of Dose Proportionality: Report from the Statisticians in the Pharmaceutical Industry / Pharmacokinetics UK Joint Working Party, Drug Information Journal, 1995, 29: 1039-1048; Smith, “Confidence Interval Criteria for Assessment of Dose Proportionality,” Pharmaceutical Research, 2000, 17(10): 1278-1283. 2000). The estimate of together with its 90% CI (I, u) was used to quantify the degree of non-proportionality. In MAD, formal statistical analysis was performed on the PK parameters AUCo-tau and Cmax to assess dose accumulation. Log-transformed AUCo-tau and Cmax was subjected to a mixed-effects model with treatment (dose level), day (day 1 or 7) and treatment-by-day interaction as fixed effects and subject as a random effect. The adjusted means obtained from the model, including differences for each comparison of interest and the associated 90% Cis, was back-transformed on the log scale to obtain adjusted geometric means, adjusted geometric mean ratios (GMRs) and 90% Cis of the ratio. The GM Rs and 90% Cis were provided for each treatment and overall, i.e., day 7 / day 1. In the FES, formal statistical analysis was performed on the PK parameters Cmax, AUCo- iast and AUCO-24 to assess the effects of food on anlel38b. The PK parameters underwent a natural logarithmic transformation and were analyzed using a mixed-effect model with terms for treatment (i.e., prandial state), period and sequence as fixed effects and subject nested within sequence as a random effect. Adjusted GMRs and 90% Cis for the adjusted GMRs for the comparison between fed and fasted states were provided where the ratios are defined as fed / fasted.

[0409] Results Of 196 individuals assessed for eligibility, 89 failed screening, 39 served as reserve subjects and 68 were included in the study. Of the included participants, 32 subjects (4 dosing groups of 8) were included in the SAD part, 24 subjects (3 dosing groups of 8) in the MAD part and 12 subjects in the FES. In the SAD part, 8 participants received placebo. In the MAD part, 6 participants received placebo. All participants completed the study as planned per protocol. There were no dropouts or early discontinuations. Demographic characteristics of the study population at baseline were similar for all cohorts and groups. Of 32 participants in the SAD part, 3 (9%) were female, all other participants including those in the MAD part and the FES were male. 100 % of the study medication was taken as scheduled in all groups.

[0410] The primary read-outs of this trial were safety and tolerability. There were no serious adverse events (SAEs) and no AEs leading to study medication withdrawal in any part of the study. Treatment-emergent AEs were reported in comparable numbers in treated and placebo groups. There was no dose dependency with regard to AE reporting. All AEs completely recovered. In summary, daily oral administration of anlel38b was shown to be safe and well tolerated up to the highest, daily dose of 300 mg per subject administered for up to 7 consecutive days. The secondary read-out was PK.

[0411] Study anlel38b-Pl-01 Part 1 (SAD)

[0412] Table 10 shows Geometric Mean (CV%) key pharmacokinetic parameters of anlel38b in healthy volunteers following single dose oral administration of anlel38b DP. For Tmax Median (range) is shown. Abbreviations: Tmax: Time to maximum peak; Cmax: Maximum concentration; AUC: Area under the curve (= exposure); T1 / 2: Plasma half-life; h: hour; ng: nanogram; ml: milliliter; NA: Not applicable. Maximum concentrations were achieved at between 0.5 and 2 hours post-administration (median Tmax of 1 to 1.5 hours post-administration).Table 10: Geometric Mean (CV%) key pharmacokinetic parameters of anlel38b in healthy volunteers, fasted, following single oral administration of anlel38b DP*Median (range)

[0413] Overall, PK data showed drug was systemically available following oral administration with rapid absorption and a bi-phasic elimination. The practical terminal elimination half-time was ~12 h. Potential therapeutic exposure (based upon nonclinical in vivo models) was already achieved after single 100 mg doses of anlel38b. With increased doses of200 or 300 mg, therapeutic exposures were increased correspondingly, without any relevant safety concerns.

[0414] Following oral administration of the DP, plasma concentrations of anlel38b became quantifiable at 0.5 hours post-administration in all subjects and remained quantifiable for up 5 to 24 hours post-administration in the lowest dose group and for up to 48 hours postadministration in the highest dose group. Single Dose Plasma Concentrations of anlel38b (FIG. 4, logarithmic plot).

[0415] Cmax values increased supra-proportionally over the 50 to 200 mg dose range and proportionally from 200 to 300 mg. A 2-fold increase in dose from 50 mg to 100 mg resulted in an approximate 2.9-fold increase in Cmax, and 3.3-fold increase in AUC. Another 2-fold increase in dose from 100 mg to 200 mg resulted in an approximate 2.9-fold increase in Cmax, and 3.0- fold increase in AUC. A 1.5-fold increase in dose from 200 mg to 300 mg resulted in an approximate 1.5-fold increase in Cmax, and 1.5-fold increase in AUC.

[0416] The elimination half-life of anlel38b was variable. Tl;2 was 3.9 hours in the 50 mg cohort and 10.8 hand 12.8 h, respectively, in the 100 mg and 200 mg cohorts. Tl;2 increased to 16.2 h in the 300 mg group. The variability in Tl;2 is suspected to be due to differences in the time of last quantifiable concentrations between subjects, leading to an inaccurate characterization of the true terminal elimination phase especially in the 50 mg cohort. The change with dose may also be attributed to drug's auto-inhibition of its metabolic pathways such as CYP1A2.

[0417] Study anlel38b-Pl-01 Part 2 (MAD)

[0418] Following oral administration of anlel38b in capsule form, plasma concentrations of anlel38b became quantifiable at 0.5 hours post-administration in all subjects and remained quantifiable for up to 24 hours post-administration in all dose groups. This was seen both at Day 1 and at Day 7 (FIG. 5A and 5B, respectively).

[0419] Tmax appeared to be relatively unaffected by multiple dosing. Maximum concentrations were achieved at between 1.0 and 2.0 hours post-administration (median Tmax of 1 to 1.5 hours post- administration). On Day 1, Cmax values increased supra-proportionally over the 100 to 300 mg dose range. A 2-fold increase in dose from 100 mg to 200 mg resulted in a 3.3- fold increase in Cmax, and 3.5-fold increase in AUC. A 1.5-fold increase in dose from 200 mg to300 mg resulted in a 2.0-fold increase in Cmax, and 2.4-fold increase in AUC (Table 11).Repeated administration of anlel38b capsules in the fasted state resulted in reductions in Cmax and AUC exposures. Thus, compared to Day 1, Cmax and AUC in the 100 mg group were reduced by about 53%, Cmax and AUC in the 200 mg group were reduced by about 70%, and Cmax and AUC in the 300 mg group were reduced by 66% and 71%. The accumulation ratios were therefore below 0.54 per cohort. The individual Cmax and AUC values at Day 7 increased about dose-proportional with increasing doses.

[0420] Multiple dosing also tended to result in a decrease in half-life compared to the single ascending doses in Part 1 of the study, with the exception of the Tl;2 in the 200 mg group that was about 10 hours and, thus, largely similar in MAD and in SAD. This presentation may relate to drug's auto-induction of its metabolic pathways.Table 11: Geometric Mean (CV%) key pharmacokinetic parameters of anlel38b in healthy volunteers, fasted, following multiple oral administration of anlel38b in capsule form*Median (range); NA= not applicable

[0421] Overall, repeated daily dosing resulted in a ~50 to -70% decrease in Cmax and AUC of anlel38b. These decreases with multiple dosing are in line with the results seen in repeat-dosing animal studies. The decreased exposure is likely a result of the induction of metabolizing enzymes, such as CYP1A2 (oxidative metabolism). A reduction of levels ofanlel38b was also observed for trough (i.e., pre-dose) levels. Of note, steady state exposure appeared to be reached by day 5 based on trough levels.

[0422] In summary, the PK data showed that the study drug was safe and well tolerated at all dose levels. The practical elimination half-time was ~12 h. Cmax and AUC following single administrations of anlel38b increased with dose. Potential therapeutic exposure levels (AUCo-24 >300 ng*h / ml) were obtained with the 100 mg dose. Maximum concentrations were achieved between 0.5 and 2 hours post-administration (median Tmax of 1 to 1.5 hours postadministration). The terminal elimination half-time was ~12 h. The MAD part of the study generally confirmed the Tmax-Cmax and AUC values following 7-day daily dosing were decreased by approximately 50% to -70%, likely due to induction of metabolizing CYP enzymes, particularly CYP1A2.

[0423] Overall, potential therapeutic exposure based upon nonclinical in vivo models was achieved after a single 100 mg dose. With increased doses of 200 or 300 mg, exposure levels were increased correspondingly, without any safety concerns.

[0424] Study Part 3: Food Effect

[0425] Following oral administration of anlel38b under both fasted and fed conditions, plasma concentrations of anlel38b became quantifiable between 0.5 and 1.0 hours post- administration and remained quantifiable for up to 24 to 48 hours post-administration (FIG. 6).

[0426] Maximum concentrations were achieved between 1 and 2 hours postadministration (median Tmax of 1.25 hours post-administration) in the fasted state and between 1.5 and 3 hours post-administration (median Tmax of 3.00 hours post-administration) in the fed state (Table 12).

[0427] A change in prandial state from fasted to fed resulted in approximately 74% (90% CI: 61%, 84%) of the dose being bioavailable in the fed state compare to the fasted state. Cmax was decreased by about half with food (mean Cmax fed 196 ng / ml (range 110-479), fasted 442 ng / ml (range 225-1420)), in line with the delay in Tmax-Total exposure was less affected following administration with food (mean AUCo-24 fasted 896 ng*h / ml (range 433-2720), fed 641 ng*h / ml (range 378-1920)). Inter-subject variability with relation to exposure (Cmax andAUC) was moderate across both regimens. Overall, the range of exposure observed was overlapping for fed and fasted dosing.

[0428] The elimination half-life of anlel38b was only slightly higher in the prandial state, with geometric mean values of 11.3 and 15.2 hours, following administration in the fasted and fed regimens, respectively.Table 12: Geometric Mean (CV%) key pharmacokinetic parameters of anlel38b in healthy volunteers following single oral administration of anlel38b in fasted and fed state

[0429] Overall, the PK data showed that the study drug was safe and well tolerated following both fasted and fed conditions. Treatment under fed conditions led to a delay in time to maximum concentration, which can be expected based on the altered kinetics of IMP uptake in a filled compared to an empty stomach. Cmax was decreased by about half with food, in line with the delay in T max.

[0430] Administration of anlel38b with food led to a slight decrease in total exposure, but the decrease is not considered clinically relevant for dosing, as a largely overlapping range of exposure levels was observed for fed and fasted dosing.

[0431] Example 6: Phase 1 Clinical Study in PD patients

[0432] Study Title: A Single Part Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of anlel38b, and to Characterize the Effect of Food on the Pharmacokinetics of anlel38b in Patients with Mild to Moderate Parkinson’s Disease.

[0433] This was a two-center, double-blind, randomized, placebo-controlled study that enrolled twenty two (22) participants in cohorts (i.e., regimens) A-C. All completed the study per protocol. After completion of Cohorts A to C it was decided to add Cohorts D and E of 24subjects. Cohort D expanded sample size of previous dosing regiments 150 mg and 300 mg QD and Cohort E administration of anlel38b 300 mg for 28 days, under non-fasted conditions.

[0434] Drug product used is described supra, placebo was vehicle in capsule. Subjects were between 50 and 80 years of age with a diagnosis of idiopathic PD as defined by the Movement Disorders Society criteria (either fulfilling criteria for “Clinically Established PD” or for “Clinically Probable PD”). They had to present with Hoehn and Yahr stage 1-111 (i.e., able to walk unaided), and stable medication for PD for 1 month prior to inclusion and anticipated over the study period. The subjects were randomly assigned to receive one of three drug regimens, A, B or C, as follows:■ Regimen A -150 mg (5 x 30 mg) anlel38b oral capsules or matching placebo QD, for 7 consecutive days in the fasted state, followed by a single administration of 150 mg anlel38b oral capsule or matching placebo on Day 9 in the fed state,■ Regimen B - 300 mg (10 x 30 mg) anlel38b oral capsules or matching placebo QD, for 7 consecutive days in the fasted state, followed by a single administration of 300 mg anlel38b oral capsule (10 x 30 mg capsules) or matching placebo on Day 9 in the fed state,■ Regimen C -150 mg (5 x 30 mg) anlel38b oral capsules or matching placebo BID (total 300 mg daily), for 7 consecutive days in the fasted state.

[0435] Subjects in Regimen E were randomly assigned to receive QD doses of either 300 mg (10 x 30 mg) anlel38b oral capsules or matching placebo, for 28 consecutive days in the non-fasted state.

[0436] Fed state conditions were considered moderate with standard size breakfast; 570 kcal including 24% fat.

[0437] Primary endpoints provided safety and tolerability information for the test product by assessing: AEs, vital signs, ECGs, physical examinations and laboratory safety tests, and to provide additional safety and tolerability information for the test product taken also in the fed state by assessing: AEs, vital signs, ECGs, physical examinations and laboratory safety tests.

[0438] Secondary endpoints provided PK information for the test product in PD patients by assessing plasma exposure under fast and fed conditions.

[0439] Pharmacodynamic assessments included Movement Disorder Society- sponsored revision of the Unified PD Rating Scale (MDS-UPDRS). An interim data review following each cohort was performed to agree progression and the dose level for the next cohort.

[0440] To allow for an additional safety factor of 2 compared with the highest dose tested in the first in human (FIH) study (i.e., 300 mg), a dose of 150 mg of anlel38b was selected for the first dosing cohort of the study (see example 3.1, above).

[0441] Results: data show that doses up to 300 mg of anlel38b were safe and well tolerated under the tested conditions. Furthermore, PK data were similar to the PK data obtained in the FIH, healthy volunteer study. Table 13 provides the geometric mean (CV%) key pharmacokinetic parameters of anlel38b in patients on Day 1 and Day 7 in the fasted state following multiple oral administration of anlel38b in capsule form.

[0442] The 28 day dosing of 300 mg of anlel38b has comparable PK trends as observed following 7 day dosing. Concentrations are expected to be in similar ranges. Therefore, efficacy response is expected not be jeopardized, with general well tolerated safety profile.Table 13: Geometric mean (CV%) key PK parameters of anlel38b in patients on Day 1 and Day 7 in the fasted state following multiple oral administration of anlel38b in capsule form.*median (range), a: based on a tau of 24h when dosing QD, b: based on tau of 12h when dosing BID, N / A- Not Applicable; c Individual subject values

[0443] Table 14 shows the geometric mean (CV%) key pharmacokinetic parameters of anlel38b in patients following a single oral administration of anlel38b in capsule form on Day 9 in the fed state.Table 14: Geometric mean (CV%) key PK parameters of anlel38b in patients following a single oral administration of anlel38b in capsule form on Day 9 in the fed state*median (range);aFrei: Comparison Day 9 fed vs Day 7 QD fasted. Note: day 9 fed dosing was only investigated in Regimens A and B

[0444] Following single oral administration of anlel 38b in capsule form at 150 mg (Regimens A [QD] and C [BID]) and 300 mg (Regimen B (QD)) on Day 1 in the fasted state, peak plasma concentrations (Cmax) of anlel 38b occurred between 1.00-1.50 hours (h) postadministration, 1.00-4.00 h post-administration and 1.00-2.00 h post-administration, respectively, and median Tmax occurred at 1.25 h, 1.50 h and 1.00 h post-administration, respectively, for Regimens A, B and C.

[0445] Following once daily oral administration of anlel 38b in capsule form at 150 mg (Regimens A [QD] and C [BID]) and 300 mg (Regimen B [QD]) for 7 days, peak plasma concentrations of anlel 38b occurred between 1.00-2.00 h post-administration, 1.00-2.00 h postadministration and between 1.00-1.50 h post-administration, respectively, and median Tmax occurred at 1.00 h, 1.50 h and 1.00 h post-administration, respectively, for Regimens A, B and C.

[0446] Following once and twice daily oral administration for 7 days, systemic exposure appeared to decrease in all three regimens, with geometric mean accumulation ratios on Day 7 of 0.346, 0.428 and 0.333 for Cmax and values of 0.371, 0.351 and 0.299 for AUCo-tau, respectively, for Regimens A, B and C. The geometric mean T% values were 11.8 hand 14.1 h, respectively, for Regimens B and C. The individual terminal half-lives following administration of 150 mg anlel38b QD for 7 days (Regimen A) were 16.25 h and 17.10 h.

[0447] Following single oral administration of DP at 150 mg and 300 mg in the fed state on Day 9, peak plasma concentrations (Cmax) of anlel38b occurred between 1.50-4.00 h post dose and between 3.00 h-4.00 h post-administration, respectively. Median Tmax occurred at3.00 h post-administration following dosing of both regimens. The geometric mean terminal TA were 15.9 h and 13.0 h, respectively, at the 150 mg and 300 mg dose levels.

[0448] The geometric mean relative bioavailability of anlel38b when administered in the presence of food following a single dose on Day 9, relative to when fasted on Day 7 was 104% and 71.4% based on Cmax and 132% and 109% based on AUC0-24, respectively, at the 150 mg and 300 mg dose levels.

[0449] Following single oral administration of anlel38b in capsule form at 150 mg (Regimens A-QD and C-BID) and 300 mg (Regimen B-QD) on Day 1 in the fasted state, the maximum individual Cmax and AUC0-24 values were approximately 24.9% and 6.19%, 75.8% and 8.4% and 26.4% and 4.94% of the exposure limits of anlel38b outlined in the protocol, respectively, for Regimens A, B and C. (Note that for Regimen C, AUCo-tau on this dosing occasion was equivalent to AUC0-12, with exposures limits based on AUC0-24).

[0450] Following multiple QD oral doses of 300 mg anlel38b to male and female patients with mild to moderate PD in the fasted state, the geometric mean (geometric CV%) CSF anlel38b concentration was 0.3186 ng / ml (108.1%) and the geometric mean (geometric CV%) plasma anlel38b concentration was 132.593 ng / ml (58.5%) at 3 h post-dose on Day 5. The geometric mean (geometric CV%) CSF / plasma anlel38b concentration ratio was 0.00240 (45.0%).

[0451] Discussion

[0452] In a phase 1 study (first in human) disclosed in Levin et al. (2022) and WO2023166045 and in PD patients (Levin et. Al. Aug 2023, Anlel38b-Pl-02: A randomised, double-blinded, placebo-controlled, phase lb study to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of the oligomer modulator anlel38b in Parkinson's disease, International Congress of Parkinson ’s Disease and Movement Disorders, Copenhagen, Denmark.), no safety issues were found. Adverse events were mostly mild and all fully recovered or resolved. No abnormal trend was seen in any system organ class. The study drug was safe and well tolerated at all dose levels and reached significantly higher plasma levels in humans than those required for full therapeutic efficacy in MI2 mice, a recently established a- synucleinopathy rodent model. The treatment-emergent AEs were reported in comparablenumbers in treated and placebo groups and that there was no dose dependency with regards to AE reporting.

[0453] As described above and as disclosed in Levin et al. (2022) and WO2023166045, there was a decrease in emrusolmin Cmax and AUC values following 7-day daily dosing. The decrease can be speculated as relating to emrusolmin’ s auto-induction of its metabolic pathways. As such, it was suggested that these decreases might be due to induction of metabolizing CYP enzymes, for example, CYP1A2. Noteworthy, however, the reasoning regarding why there was a decrease in Cmax and AUC was not established following this study.

[0454] Example 7: Toxicology studies

[0455] In a toxicology study in monkeys, up to 50 mg / kg emrusolmin (0, 15, 30 or 50 mg / kg) were administered. Findings observed at the low dose of 15 mg / kg in the 39- week monkey study were restricted to mild liquid feces, minimal decrease in body weight, minor changes in clinical pathology parameters that were not associated with pathological changes, and non-adverse microscopic findings in the digits. Overall, the low dose of 15 mg / kg was the study NOAEL, providing safety margins of 2.8- to 4.1 -fold (based on Cmax for males and females, respectively) and 3.2- to 4.9-fold (based on AUC for males and females, respectively) above the clinical exposure at the clinical intended dose of 300 mg in humans at steady state, and 1.7- to 2.6-fold (based on Cmax for males and females, respectively) and 2.3- to 3.7-fold (based on AUC for males and females, respectively) above the clinical exposure at the clinical intended dose of 300 mg in humans for a single dose administration.

[0456] Example 8: Drug-Drug Interaction Study

[0457] A single center, open-label, drug-drug interaction (DDI) study was performed to assess the effect, if any, of emrusolmin as a victim of drug interactions. The primary objectives of the study were to assess the effect, if any, of fluvoxamine (CYP1 A2 inhibitor) on the PK of emrusolmin following repeat doses at steady state

[0458] The study assessed the effect of fluvoxamine (CYP1A2 inhibitor; perpetrator) on the PK of emrusolmin (victim drug) in healthy males and females of non-childbearing potential. On the mornings of Days 1 to 14, at a consistent time each day and after a minimum 8 h overnight fast, subjects received an oral dose of 150 mg emrusolmin QD. PK blood samples for emrusolmin were collected up to 24 h post-dose and before administration of the nextemrusolmin dose. From Days 15 to 19, subjects received concomitantly oral dosing of QD 150 mg emrusolmin and 100 mg fluvoxamine. PK blood samples for emrusolmin and fluvoxamine were collected up to 48 h post final-dose on Day 19. Subjects were discharged on Day 21 (48 h post final-dose). A follow-up visit took place on Day 27 (± 3 days) to ensure the ongoing wellbeing of the subjects.

[0459] DDI Study Results and Conclusions

[0460] Co-administration of emrusolmin 150 mg QD with fluvoxamine (strong CYP1 A2 inhibitor) 100 mg QD on Day 19 (after emrusolmin QD dosing alone for 14 consecutive days), resulted in an approximately 8.2-fold increase in emrusolmin exposures (expressed by Cmax and AUC(O-tau)). As such, emrusolmin may be referred to as a sensitive CYP1 A2 substrate.. The emrusolmin plasma concentration-time profile was comparable following emrusolmin multiple administrations alone for 14 consecutive days (Day 14) and in combination with fluvoxamine (Day 19), with a consistent median Tmax (1.5 h post-dose) and elimination half-life (arithmetic means of 10.7 h to 10.8 h). Steady state of emrusolmin 150 mg based on the trough concentrations assessment appeared to be reached following approximately 7 days of multiple daily dosing. There were no severe or serious AEs, deaths or AEs leading to subject withdrawal.

[0461] Example 9: Development of a Physiologically Based Pharmacokinetic Model

[0462] A whole-body physiologically based pharmacokinetic (PBPK) model was developed in order to predict the effect of co-administration of emrusolmin with CYP1 A2 inhibitors of different strengths (including strong CYP1A2 inhibitors, moderate CYP1A2inhibitors, and weak CYP1A2 inhibitors) on emrusolmin exposure in patients. This prediction is important in order to understand the predicted effect of co-administration of strong CYP1 A2 inhibitors, moderate CYP1A2 inhibitors, and / or weak CYP1A2 inhibitors on emrusolmin exposure in patients administered emrusolmin which are also in need of one or more CYP1 A2 inhibitors. The model was based on data regarding emrusolmin’ s physicochemical and biopharmaceutical properties, clinical data in healthy subjects, and the drug-released profiles. The drug-specific parameters were determined through a combination of optimized values from in vitro studies and default values for non-sensitive or unavailable parameters. The developed model incorporated CYP1A2 auto induction and auto inhibition effects by the drug.

[0463] For model development and validation, data from a phase 1 study in healthy volunteers as described in Levin et. al, and the DDI study (Example 7) were utilized.

[0464] The developed PBPK model demonstrated good predictive capability, accurately capturing the plasma concentration- time profiles of emrusolmin in healthy subjects and Parkinson’s disease (PD) patients (NCT04685265; EudraCT: 2020-004869-38) for various dose regimens under fasted and fed conditions. The simulations aligned with clinically observed data, with most area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) values falling within a 2-fold error range. The model showcased good performance in predicting DDIs with Fluvoxamine, as evidenced by DDI AUCiast and DDI Cmax ratios that remained within the 2-fold range (predicted vs. observed values), indicating the reasonable contribution of CYP1 A2 to emrusolmin metabolism.

[0465] The validated DDI model was applied to simulate various clinical DDI scenarios involving emrusolmin as the victim drug when co-administered with perpetrators of different strengths (Strong, Moderate, and Weak), affecting the activity of CYP1 A2. According to the model simulation, co-administration of emrusolmin with Fluvoxamine (strong inhibitor) resulted in a strong DDI effect, with DDI AUC ratios ranging from 5.66 to 6.46 and DDI Cmax ratios from 3.5 to 4.5, following single dose simulations and AUC ratios ranging from 3.79 to 5.18 and DDI Cmax ratios from 2.2 to 3.2 following steady state simulations, consistent with the results observed in Example 7. According to the model simulation, co-administration with Mexiletine (moderate inhibitor) exhibited a moderate DDI effect, with DDI AUC ratios ranging from 3.52 to 3.89 and DDI Cmax ratios from 2.86 to 3.30 following single dose simulations andAUC ratios ranging from 2.17 to 2.35 and DDI Cmax ratios from 2.16 to 2.29 following steady state simulations. Co-administration with Cimetidine (weak inhibitor) using the model yielded a weak DDI effect, with DDI AUC ratios ranging from 1.37 to 1.50 and DDI Cmax ratios from 1.20 to 1.28 following single dose simulations and AUC ratios ranging from 1.27 to 1.39 and DDI Cmax ratios from 1.27 to 1.37 following steady state simulations.The table, below, summarizes results obtained from the model. In Scenario 1 (single dose administration of emrusolmin), the inhibitor drugs were first administered to reach steady state and emrusolmin was introduced on day 8 or day 10. Scenario 2 (emrusolmin steady state), emrusolmin was initially administered to reach steady state. Starting from day 15, the inhibitor drugs were introduced and co-administered with emrusolmin until day 19.[]: 90% confident interval

[0466] Based on the PBPK model, as considered in light of the safety margins determined from toxicology studies (see supra), co-administration of emrusolmin with strong CYP1 A2 inhibitors, including but not limited to fluvoxamine, should be contraindicated. In addition, based on the PBPK model, co-administration of emrusolmin with moderate CYP1 A2 inhibitors including but not limited to mexiletine should be contraindicated.

[0467] Discussion

[0468] In some instances, concomitant administration with a metabolic pathway inhibitor may result in increased exposure (Cmax and / or AUC) of a drug. In some cases, the change in exposure does not create any safety concern related to the drug’s administration. In other instances, increased in exposure creates a potential safety concern related to the drug. E.g., a safety concern may be raised when co-administration of the drug with an inhibitor of the metabolic enzyme results in increased exposure that is above the safety margins. In light of such an increase, a concern may be raised for adverse drug-drug interactions. Whether a potential safety concern exists will depend on a number of variables, including the safety margins of the drug, a predicted or actual increase in the drug's exposure upon co-administration with aparticular inhibitor, and the like. In those cases where the change in exposure creates a potential safety concern, e.g., a risk of adverse drug-drug interactions, the drug’s instructions for use (e.g., labeling information) may include comments related to interactions with metabolic pathway inhibitors.

[0469] While the Phase 1 study of emrusolmin in healthy patients as disclosed prior to the current invention indicated that emrusolmin’ s metabolism may be affected by CYP1 A2, none of the published results suggested the extent to which emrusolmin is metabolized through CYP1 A2 pathway and the potential impact of inhibiting this pathway. None of the published results suggested that any safety concerns may be related to long term administration of the drug. The published Phase 1 emrusolmin data suggested that emrusolmin reported no dose effect relating to safety. Additionally, emrusolmin exposures, even at exposures exceeding those predicted for efficacy, were reported to be safe. Therefore, there was no expectation that coadministration of emrusolmin with a CYP1A2 inhibitor (e.g., strong, moderate, moderate to strong, or weak) would be contraindicated.

[0470] Based on the published information regarding emrusolmin, those of ordinary skill in the art would not have concluded that the administration of CYP1 A2 inhibitors (e.g., strong, moderate, moderate to strong, or weak) would be contraindicated for co-administration with emrusolmin. It was not known at the time of the invention that any safety concerns would be found following higher and longer exposures to emrusolmin. It was only after the tox studies in animals, that such a risk concern was found, and safety margins established. Even after the establishment of the safety margins, however, it was not known that co-administration of emrusolmin with a CYP1 A2 inhibitor (e.g., strong, moderate, moderate to strong, or weak) would lead to an increase in the exposure of emrusolmin in the blood of the patients that would potentially exceed the safety margins.

[0471] Prior to this DDI study, there was no public evidence to conclusively establish that emrusolmin was metabolized by CYP1 A2. In addition, it was not known whether co- administration of emrusolmin (e.g., 300 mg / daily or 150 mg / daily) with a strong CYP1A2 inhibitor, e.g., fluvoxamine, would lead to an increase in the exposure of emrusolmin in the blood of the patients that would exceed the safety margins. The results of the DDI study showed that co-administration with a strong CYP1A2 inhibitor, e.g., fluvoxamine, led to an increase inemrusolmin exposure which exceeds the safety margins set for 300mg / day administration. Therefore, the results of the DDI study showed that co-administration of 300 mg emrusolmin on daily basis with a strong CYP1A2 inhibitor, e.g., fluvoxamine should be contraindicated. The results of this study do not, however, provide any information as to whether co-administration of emrusolmin with other CYP1A2 inhibitors would be contraindicated.

[0472] In continuation to the tox studies and the DDI studies, the inventors of the current invention further established a model to predict the increase in emrusolmin exposure resulting from co-administration with weak, moderate and strong CYP1A2 inhibitors. The model was established based on data from a phase 1 study in healthy subjects as well as on nonpublished data from the DDI study that are part of the current invention. The results were then considered against the safety margins established by the inventors of the current invention. It was concluded that strong CYP1A2 inhibitors, e.g., fluvoxamine, as well as moderate CYP1A2 inhibitors, e.g., mexiletine, but not weak CYP1A2 inhibitors, e.g., cimetidine, should be contraindicated with emrusolmin given at a 300mg / daily dose. It was also concluded that strong CYP1 A2 inhibitors, e.g., fluvoxamine, but not moderate CYP1A2 inhibitors, e.g., mexiletine, and not weak CYP1A2 inhibitors, e.g., cimetidine, should be contraindicated with emrusolmin given at a 150mg / daily dose.

[0473] In view of the data summarized herein it has now been determined that co- administration of 300 mg emrusolmin daily with moderate and strong CYP1 A2 inhibitors is contraindicated. Prior to starting 300mg / daily emrusolmin therapy, it must be determined whether the subject is currently taking one or more moderate and / or strong CYP1A2 inhibitors and if so, the subject should discontinue the moderate and / or strong CYP1A2 inhibitor prior to starting emrusolmin therapy. While taking emrusolmin therapy, the subject should also avoid concomitant use of one or more moderate and / or strong CYP1 A2 inhibitors, to avoid potential adverse drug-drug interactions.

[0474] A subject in need of therapy with one or more moderate or strong CYP1 A2 inhibitor, who is also in need of therapy with 300mg emrusolmin daily, should discontinue the moderate or strong CYP1 A2 inhibitor therapy before beginning emrusolmin therapy. While taking emrusolmin therapy, the subject should also avoid moderate and / or strong CYP1A2 inhibitors to avoid co-administration.

[0475] A subject in need of therapy with one or more moderate CYP1A2 inhibitor, who is also in need of therapy with 300mg emrusolmin daily, should discontinue the moderate CYP1 A2 inhibitor therapy before beginning emrusolmin therapy. While taking emrusolmin therapy, the subject should also avoid moderate CYP1A2 inhibitors to avoid co-administration.

[0476] A subject in need of therapy with a strong CYP1 A2 inhibitor, who is also in need of therapy with 300 mg emrusolmin daily, should discontinue the strong CYP1A2 inhibitor therapy before beginning emrusolmin therapy. A subject in need of therapy with a strong CYP1A2 inhibitor, who is also in need of therapy with 150 mg emrusolmin daily, should discontinue the strong CYP1 A2 inhibitor therapy before beginning emrusolmin therapy. While taking emrusolmin therapy, the subject should also avoid strong CYP1A2 inhibitors to avoid coadministration.

[0477] During treatment with 300 mg emrusolmin daily, a subject should avoid coadministration with moderate and / or strong CYP1A2 inhibitors. That is, while administered 300 mg emrusolmin daily, a subject who is or becomes in need of therapy with one or more moderate and / or strong CYP1A2 inhibitors should avoid co-administration of the one or more moderate and / or strong CYP1A2 inhibitors. While on 300 mg / daily therapy with emrusolmin, a subject who is or becomes also in need of therapy with one or more moderate CYP1A2 inhibitors should avoid co-administration of the one or more moderate CYP1A2 inhibitors. While on 300 mg / daily therapy with emrusolmin, a subject who is or who becomes also in need of therapy with one or more strong CYP1A2 inhibitors should avoid co-administration of the one or more strong CYP1A2 inhibitors. While on 150 mg / daily therapy with emrusolmin, a subject who is or who becomes also in need of therapy with one or more strong CYP1A2 inhibitors should avoid co- administration of the one or more strong CYP1A2 inhibitors.

[0478] In addition, it was found that during treatment with 150 mg emrusolmin daily, a subject should avoid co-administration with strong CYP1A2 inhibitors. That is, while administered 150 mg emrusolmin daily, a subject who is or who becomes in need of therapy with one or more strong CYP1A2 inhibitors should avoid co-administration of the one or more strong CYP1A2 inhibitors. While on 150 mg / daily therapy with emrusolmin, a subject who is or becomes also in need of therapy with one or more strong CYP1A2 inhibitors should avoid co- administration of the one or more strong CYP1A2 inhibitors.

[0479] A subject in need of therapy with one or more strong CYP1 A2 inhibitor, who is also in need of therapy with 150 mg emrusolmin daily, should discontinue the strong CYP1A2 inhibitor therapy before beginning emrusolmin therapy. While on 150 mg daily emrusolmin therapy, the subject should also avoid strong CYP1A2 inhibitors to avoid co-administration.

[0480] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the disclosure and that such changes and modifications can be made without departing from the spirit of the disclosure. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the disclosure.

Claims

What is claimed:

1. Emrusolmin for use in:(a) stabilizing one or more symptoms of Multiple System Atrophy (MSA) in a human in need of stabilization thereof, characterized in that 300 mg emrusolmin is orally administered, on a daily basis, and the stabilization is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof; or(b) limiting the clinical progression of MSA in a human in need of limitation thereof, characterized in that 300 mg emrusolmin is orally administered, on a daily basis and the limiting is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof; or(c) slowing the clinical progression of MSA in a human in need of slowing thereof, characterized in that 300 mg emrusolmin is orally administered, on a daily basis, and the slowing is determined as a change from baseline in the human’s Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof; or(d) stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, characterized in that 300 mg emrusolmin is orally administered, on a daily basis, and the clinical progression is determined as a change from baseline in the human’s total UMSARS score of part I and part II combined, or a modification thereof; or(e) stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, characterized in that 300 mg emrusolmin is orally administered, on a daily basis, and the clinical progression is determined as a change from baseline in the human’s CGLS score; or(f) of stabilizing the clinical progression, limiting the clinical progression, and / or slowing the clinical progression of MSA in a human in need thereof, characterized in that 300 mg emrusolmin is orally administered, on a daily basis and the clinical progression is determined as a change from baseline in the human’s MSA-QoL score; or(g) treating a human having Multiple System Atrophy (MSA) and in need of treatment thereof, characterized in that the treatment comprises a treatment period, comprising 300 mg ofemrusolmin is orally administered to the human, once daily, for a period of treatment, the administration results in a reduced rate of progression of the human’s MSA symptoms during the treatment period, the reduced rate of progression is as compared to a placebo treatment, and the rate of progression of MSA symptoms is measured using a (a) Unified Multiple System Atrophy Rating Scale (UMSARS) score, or a modification thereof; (b) total UMSARS score, or a modification thereof; (c) CGI-S; and / or (d) MSA-QoL; or(h) improving overall survival or progress-free survival in a human with MSA characterized in that 300 mg emrusolmin is orally administered, on a daily basis, characterized in that the improvement in overall survival or progress-free is relative to a human with MSA who is not receiving treatment with emrusolmin; or(i) stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, characterized in that the patient is being administered one or more moderate or strong CYP1A2 inhibitors, said one or more moderate or strong CYP1 A2 inhibitors is discontinued, and 300 mg of emrusolmin is administered to the patient, on a daily basis; or(j) stabilizing, limiting and / or slowing the clinical progression of MSA in a patient in need of stabilization, limitation and / or slowing thereof, characterized in that the patient is also in need one or more moderate or strong CYP1A2 inhibitors, 300 mg of emrusolmin is administered, on a daily basis, and concomitant administration of said one or more moderate or strong inhibitors CYP1A2 is avoided; or(k) treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1 A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1A2 inhibitors; or(l) treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate inhibitors of CYP1 A2, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate CYP1A2 inhibitors; or(m) treating a patient in need of emrusolmin therapy, and in need of therapy with one or more moderate or strong inhibitors of CYP1A2, while avoiding an adverse drug-drug interactionin said patient, characterized in that the treating comprises avoiding, contraindicating, or discontinuing concomitant use or co-administration of said one or more moderate or strong CYP1 A2 inhibitors so that an adverse drug-drug interaction is avoided in said patient.

2. The emrusolmin for use of claim 1 , wherein the emrusolmin administration does not result in a serious adverse event in the human.

3. The emrusolmin for use of claim 1 or 2, wherein the stabilizing, limiting, or slowing is relative to a patient population with MSA that is not receiving treatment with emrusolmin.

4. The emrusolmin for use of any one of claims 1-3, wherein emrusolmin reduces the clinical progression by at least about 20%, such as about 40 to about 60%, or about 30 to about 40% relative to a treatment for MSA lacking emrusolmin.

5. The emrusolmin for use of any one of claims 1-4, wherein the clinical progression comprises worsening MSA symptoms.

6. The emrusolmin for use of any one of the preceding claims, characterized in that the human received at least one therapy for the treatment of MSA prior to administration of emrusolmin.

7. The emrusolmin for use of any one of the preceding claims, wherein the human is resistant to treatment with levodopa or has acquired resistance to treatment with levodopa.

8. The emrusolmin for use of any one of the preceding claims, wherein the MSA is multiple system atrophy-parkinsonian type (MSA-P) or multiple system atrophy-cerebellar subtype (MSA-C).

9. The emrusolmin for use of any one of the preceding claims, characterized in that the human is diagnosed with MSA-P or MSA-C.

10. The emrusolmin for use of any one of the preceding claims, characterized in that the patient is being administered one or more moderate or strong CYP1 A2 inhibitors, wherein the treatment comprises (a) first discontinuing administration of said one or more moderate or strongCYP1 A2 inhibitors, and then (b) administering to the patient, on a daily basis, 300 mg of emrusolmin.

11. The emrusolmin for use of any one of the preceding claims, characterized in that the human is in need of one or more moderate or strong CYP1 A2 inhibitors, wherein the treatment comprises (a) administering, on a daily basis, 300 mg of emrusolmin and (b) avoiding concomitant administration of said one or more moderate or strong CYP1 A2 inhibitors.

12. The emrusolmin for use of any one of the preceding claims, characterized in that the patient is administered a weak CYP1 A2 inhibitor, wherein the patient is also in need of said weak CYP1A2 inhibitor.

13. The emrusolmin for use according to any one of the preceding claims, wherein the one or more moderate or strong CYP1A2 inhibitors is avoided or discontinued for at least 4 days, 2 weeks, 4 weeks before the emrusolmin is administered.

14. The emrusolmin for use according to any one of the preceding claims, wherein the CYP1A2 inhibitor is pipemidic acid, mexiletine, fexinidazole, methoxsalen (8- methoxypsoralen), capmatinib, metamizole (dipyrone), vemurafenib, rucaparib, osilodrostat, ritlecitinib, etintidine, phenylpropanolamine, hormonal contraceptives, vemurafenib, genistein, propranolol, troleandomycin, ciprofloxacin, rofecoxib, fluvoxamine, ciprofloxacin, clinafloxacin, idrocilamide, enoxacin, clinafloxacin, viloxazine - high / supratherapeutic dose, oltipraz, or a combination thereof, or the CYP1 A2 inhibitor is pipemidic acid, mexiletine, fexinidazole, methoxsalen (8-methoxypsoralen), capmatinib, metamizole (dipyrone), vemurafenib, rucaparib, osilodrostat, ritlecitinib, etintidine, phenylpropanolamine, hormonal contraceptives, vemurafenib, genistein, propranolol, troleandomycin, or a combination thereof, or the CYP1 A2 inhibitor is fluvoxamine, or the CYP1A2 inhibitor is ciprofloxacin, or the CYP1 A2 inhibitor is mexiletine, or the CYP1 A2 inhibitor is pipemidic acid, or the CYP1A2 inhibitor is fexinidazole, or the CYP1 A2 inhibitor is methoxsalen (8-methoxypsoralen), or the CYP1 A2 inhibitor is capmatinib, or the CYP1A2 inhibitor is metamizole (dipyrone), or the CYP1 A2 inhibitor is vemurafenib, or the CYP1A2 inhibitor is rucaparib, or the CYP1 A2 inhibitor is osilodrostat, the CYP1 A2 inhibitor is ritlecitinib, the CYP1A2 inhibitor is etintidine, the CYP1A2 inhibitor isphenylpropanolamine, the CYP1A2 inhibitor is hormonal contraceptives, the CYP1A2 inhibitor is vemurafenib, the CYP1A2 inhibitor is genistein, the CYP1A2 inhibitor is propranolol, the CYP1 A2 inhibitor is troleandomycin, or the CYP1A2 inhibitor is rofecoxib, the CYP1A2 inhibitor is clinafloxacin, the CYP1A2 inhibitor is idrocilamide, the CYP1A2 inhibitor is enoxacin, the CYP1 A2 inhibitor is viloxazine - high / supratherapeutic dose, or the CYP1A2 inhibitor is oltipraz.

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