Vafidemstat for use in the treatment of autism spectrum disorder

Abstract

Provided herein is vafidemstat for use in a method for treating an autism spectrum disorder.

Description

[Technical field]

[0001] The present invention relates to methods of treating autism spectrum disorders. [Background technology]

[0002] Autism spectrum disorder (ASD) is a developmental disorder that affects communication and behavior. Although autism can be diagnosed at any age, symptoms generally appear in the first two years of life, hence the term "developmental disorder." People with ASD have difficulties communicating and interacting with other people, restricted interests and repetitive behaviors, and symptoms that impair people's ability to function appropriately in school, work, and other areas of life.

[0003] There are no FDA-approved treatments that address the core features of ASD. Currently approved therapies for use in ASD patients are indicated for the treatment of irritability associated with ASD and exhibit side effects, including sedation and weight gain.

[0004] Thus, there is a strong and unmet medical need for new and / or improved drugs to treat ASD, particularly drugs that act via novel mechanisms of action and treat core features of ASD and / or have a more favorable side effect profile than current therapies. The present invention addresses these and other needs. Summary of the Invention

[0005] The present invention provides a novel method of treating autism spectrum disorder by using vafidemstat (or a pharma- ceutically acceptable salt or solvate thereof).

[0006] Thus, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of an autism spectrum disorder.

[0007] The present invention further provides a method of treating an autism spectrum disorder in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0008] The present invention further provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of an autism spectrum disorder.

[0009] The present invention further provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of an autism spectrum disorder. [Brief description of the drawings]

[0010] [Figure 1] Figure 1 shows the effect of treatment with bufidemstat (as defined herein and in Example 1) to treat aggression in patients with ASD, as shown by a statistically significant reduction in the Neuropsychiatric Inventory (NPI) 4-item Irritability / Aggression (NPI A / A) subscale from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with bufidemstat), as described in more detail in Example 2. Data are presented as mean ± standard error of the mean (SEM); p=0.0098. [Diagram 2] 2 shows the effect of treatment with bufidemstat (as defined herein and in Example 1) for treating aggression in patients with ASD, as shown by a statistically significant reduction in Clinical Global Impression of Improvement (CGI-I) scores from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with bufidemstat), as described in more detail in Example 2. Data are presented as mean ± standard error of the mean (SEM); p=0.0019. [Diagram 3]3 shows the effect of treatment with bufidemstat (as defined herein and in Example 1) for treating aggression in patients with ASD, as shown by reduction in Clinical Global Impression of Severity (CGI-S) scores from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with bufidemstat), as described in more detail in Example 2. Data are presented as mean ± standard error of the mean (SEM). [Figure 4] Figure 4 shows the efficacy of bufidemstat for treating ASD as indicated by the reduction in total NPI (12-item) score from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with bufidemstat), as described in more detail in Example 2. Data are presented as mean ± SEM; p = 0.0019. [Diagram 5] Figure 5 shows the efficacy of bufidemstat to treat ASD as indicated by the reduction in NPI non-aggression-related items (8 items) combined score from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with bufidemstat), as described in more detail in Example 2. Data are presented as mean ± SEM; p = 0.0142. [Figure 6] Figure 6 shows the effect of treatment with bufidemstat on Clinical Global Impression of Severity (CGI-S) scores from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with bufidemstat) for a cohort of ASD patients, including one additional patient, described in more detail in Example 2.4. Data are presented as mean ± standard error of the mean (SEM). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention is based on the unexpected discovery that bafidemstat is useful for treating ASD and is particularly well suited as a therapeutic agent for this purpose. It has been reported that bafidemstat is useful for reducing aggression, such as disease-associated aggression, without sedative effects. Bafidemstat is currently undergoing a Phase IIa clinical trial (REIMAGINE trial) to evaluate its effectiveness in treating aggression in patients with ASD, attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD). The results of this clinical trial unexpectedly demonstrated that bafidemstat is not only effective for treating aggression in ASD patients, but also exhibits additional therapeutic effects on ASD, as detailed below and in the examples. Bafidemstat is useful as a treatment for ASD, including adult ASD.

[0012] Thus, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD.

[0013] The present invention further provides a method of treating ASD in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0014] The present invention further provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD.

[0015] The present invention further provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of ASD.

[0016] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD.

[0017] In some embodiments, the invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or ameliorating) one or more core features of ASD, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0018] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD.

[0019] In some embodiments, the present invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD.

[0020] According to the present invention, "core features of ASD" refers to the essential features of ASD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association, including impairments in social communication and social interaction and restricted and repetitive patterns of behavior or interests.

[0021] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD.

[0022] In some embodiments, the invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0023] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD.

[0024] In some embodiments, the present invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD.

[0025] According to the present invention, "non-aggression" (non-aggressive), for example when used in the context of ASD symptoms, means that said symptoms of ASD are not directly related to or associated with aggression or aggressive behavior. "Aggression", "aggressive" and related terms, as used herein, refer to any type of abnormal, pathological or inappropriate aggressive or violent behavior, hostility or agitation, e.g., physical or verbal, including interpersonal aggression (i.e., directed at other objects) and / or intrapersonal aggression (i.e., self-aggression).

[0026] Examples of non-aggressive symptoms of ASD include deficits in social-emotional reciprocity (e.g., abnormal social approaches and failure to engage in normal conversational exchanges, reduced sharing of interests, feelings, or emotions, and failure to initiate or respond to social interactions); deficits in nonverbal communication behaviors used for social interaction (e.g., poor integration of verbal and nonverbal communication, abnormalities in eye contact and body language, deficits in understanding and using gestures, or lack of facial expression and nonverbal communication); deficits in developing, maintaining, and understanding relationships (e.g., difficulty adjusting behavior to suit various social situations, difficulty sharing imaginative play or making friends, or absence of interest in peers); stereotyped or repetitive dynamic movements, use of objects, or speech (e.g., simple motor stereotypes, lining up toys or waving objects, echolalia, or idiosyncratic speech). phrases); insistence on sameness, inflexible attachment to routine, or ritualized patterns of verbal or nonverbal behavior (e.g. extreme distress at small changes, difficulty with transitions, rigid thought patterns, greeting rituals, need to take the same route or eat the same foods every day); strongly restricted, fixed interests of abnormal intensity or concentration (e.g. intense preoccupation with or preoccupation with unusual objects, extremely focal or perseverative interest); and hyper- or hypo-responsiveness to sensory input or unusual interest in sensory aspects of the environment (e.g. apparent indifference to pain / temperature, noxious responses to distinctive sounds or materials, excessive smelling or touching objects, visual fascination with light or movement).

[0027] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression.

[0028] In some embodiments, the invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0029] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression.

[0030] In some embodiments, the present invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression.

[0031] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) aggression.

[0032] In some embodiments, the invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0033] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) aggression.

[0034] In some embodiments, the present invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) aggression.

[0035] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability.

[0036] In some embodiments, the invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0037] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability.

[0038] In some embodiments, the present invention provides the use of bufidemstat or a pharmaceutically acceptable salt or solvate thereof for the treatment of ASD by treating (e.g., alleviating or improving) one or more core features of ASD and treating (e.g., reducing) excitability.

[0039] In some embodiments, the present invention provides bufidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of ASD by treating (e.g., alleviating or improving) one or more non - aggressive symptoms of ASD and treating (e.g., reducing) excitability.

[0040] In some embodiments, the present invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more non - aggressive symptoms of ASD and treating (e.g., reducing) excitability, the method comprising administering to the patient a therapeutically effective amount of bufidemstat or a pharmaceutically acceptable salt or solvate thereof.

[0041] In some embodiments, the present invention provides the use of bufidemstat or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or improving) one or more non - aggressive symptoms of ASD and treating (e.g., reducing) excitability.

[0042] In some embodiments, the present invention provides the use of bufidemstat or a pharmaceutically acceptable salt or solvate thereof for the treatment of ASD by treating (e.g., alleviating or improving) one or more non - aggressive symptoms of ASD and treating (e.g., reducing) excitability.

[0043] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression.

[0044] In some embodiments, the invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0045] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression.

[0046] In some embodiments, the present invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression.

[0047] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression.

[0048] In some embodiments, the invention provides a method of treating ASD in a patient (preferably a human) by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0049] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression.

[0050] In some embodiments, the present invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression.

[0051] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating patients with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD.

[0052] In some embodiments, the present invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0053] In some embodiments, the invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD.

[0054] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD.

[0055] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD.

[0056] In some embodiments, the invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0057] In some embodiments, the invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD.

[0058] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD.

[0059] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating patients with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression.

[0060] In some embodiments, the invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0061] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression.

[0062] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of patients with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) aggression.

[0063] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating patients with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) aggression.

[0064] In some embodiments, the invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggression symptoms of ASD and treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0065] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) aggression.

[0066] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) aggression.

[0067] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating patients with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability.

[0068] In some embodiments, the invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0069] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability.

[0070] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability.

[0071] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating patients with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability.

[0072] In some embodiments, the invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability, comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0073] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability.

[0074] In some embodiments, the present invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability.

[0075] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating patients with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression.

[0076] In some embodiments, the invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat or a pharmaceutically acceptable salt or solvate thereof.

[0077] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression.

[0078] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of patients with ASD by treating (e.g., alleviating or ameliorating) one or more core features of ASD and treating (e.g., reducing) irritability and aggression.

[0079] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating patients with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression.

[0080] In some embodiments, the invention provides a method of treating a patient (preferably a human) with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression, comprising administering to the patient a therapeutically effective amount of bafidemstat or a pharmaceutically acceptable salt or solvate thereof.

[0081] In some embodiments, the invention provides use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression.

[0082] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of a patient with ASD by treating (e.g., alleviating or ameliorating) one or more non-aggressive symptoms of ASD and treating (e.g., reducing) irritability and aggression.

[0083] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of one or more core features of ASD.

[0084] In some embodiments, the present invention provides a method of treating one or more core features of ASD in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0085] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of one or more core features of ASD.

[0086] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of one or more core features of ASD.

[0087] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of one or more non-aggressive symptoms of ASD.

[0088] In some embodiments, the present invention provides a method of treating one or more non-aggressive symptoms of ASD in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0089] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of one or more non-aggressive symptoms of ASD.

[0090] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of one or more non-aggressive symptoms of ASD.

[0091] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of one or more core features of ASD as well as irritability and / or aggression.

[0092] In some embodiments, the present invention provides a method of treating one or more core features of ASD as well as irritability and / or aggression in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0093] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of one or more core features of ASD as well as irritability and / or aggression.

[0094] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of one or more core features of ASD as well as irritability and / or aggression.

[0095] In some embodiments, the present invention provides bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of one or more non-aggressive symptoms as well as irritability and / or aggression of ASD.

[0096] In some embodiments, the present invention provides a method of treating one or more non-aggressive symptoms of ASD as well as irritability and / or aggression in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof.

[0097] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of one or more non-aggressive symptoms as well as irritability and / or aggression of ASD.

[0098] In some embodiments, the present invention provides the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment of one or more non-aggressive symptoms as well as irritability and / or aggression of ASD.

[0099] Also provided herein is bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for use in treating (e.g., reducing) irritability in ASD. Similarly, provided herein is bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for use in treating (e.g., reducing) irritability in ASD patients. Further provided herein is bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for use in treating ASD patients by treating (e.g., reducing) irritability. Further provided herein is a method of treating (e.g., reducing) irritability in ASD patients (preferably humans), comprising administering to the patient a therapeutically effective amount of bafidemstat or a pharma- ceutically acceptable salt or solvate thereof. Similarly, provided herein is the use of bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating (e.g., reducing) irritability in ASD. Further provided herein is the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment (eg, reduction) of irritability in ASD.

[0100] Also provided herein is bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for use in treating (e.g., reducing) aggression in ASD. Similarly, provided herein is bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for use in treating (e.g., reducing) aggression in ASD patients. Further provided herein is bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for use in treating (e.g., reducing) aggression in ASD patients. Further provided herein is a method of treating (e.g., reducing) aggression in ASD patients (preferably humans), comprising administering to the patient a therapeutically effective amount of bafidemstat or a pharma- ceutically acceptable salt or solvate thereof. Similarly, provided herein is the use of bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating (e.g., reducing) aggression in ASD. Further provided herein is the use of bafidemstat, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment (eg, reduction) of aggression in ASD.

[0101] Bafidemstat is the compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, also known as (41R,42S)-6-oxa-3-aza-1(2)-[1,3,4]oxadiazola-5(1,4),8(1)-dibenzena-4(1,2)-cyclopropanaoctaphan-15-amine, or ORY-2001. The names "bafidemstat", "5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine", "(41R,42S)-6-oxa-3-aza-1(2)-[1,3,4]oxadiazola-5(1,4),8(1)-dibenzena-4(1,2)-cyclopropanaoctaphan-15-amine" or "ORY-2001" are used interchangeably herein.

[0102] In some embodiments, the ASD is adult ASD.

[0103] Preferably, bafidemstat (or a pharma- ceutically acceptable salt or solvate thereof) is administered orally. Exemplary formulations that may be administered via oral ingestion are described in more detail further below.

[0104] As explained above, the present invention provides the compound bafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of ASD.Thus, the present invention relates to the compound bafidemstat as a free base (non-salt form) for use in the treatment of ASD, and further, the present invention also relates to a pharmaceutically acceptable salt or solvate of bafidemstat for use in the treatment of ASD.However, it is preferred that the compound is bafidemstat (non-salt form).

[0105] In some embodiments, bufidemstat is administered orally at a dose of 1.2 mg / day on a 5 days on / 2 days off schedule.

[0106] As shown in the examples, it has been unexpectedly found in the context of the present invention that bafidemstat is useful for treating ASD, such as adult ASD. As part of a Phase IIa clinical trial evaluating bafidemstat as a treatment for aggression in human patients with a wide range of CNS disorders, bafidemstat has been shown to produce significant improvements in aggressive behavior in ASD patients. As shown in Example 2 and Figures 1, 2 and 3, treatment with bafidemstat causes improvements in several commonly used scales for assessing aggression, particularly NPI A / A (Figure 1), CGI-I (Figure 2) and CGI-S (Figure 3), in ASD patients after 8 weeks of treatment. The Neuropsychiatric Rating Scale Irritability / Aggression (NPI A / A) subscale is based on the NPI scale and consists of four items in the NPI related to aggression / irritability, namely Irritability / Aggression, Disinhibition, Irritability and Dyskinetic Movement Disorder. The Clinical Global Impression of Improvement (CGI-I) and Clinical Global Impression of Severity (CGI-S) values ​​reflect the physician's assessment of the patient's improvement in aggression (CGI-I) and the severity of the patient's aggression (CGI-S). As described in more detail in Example 2 and shown in Figures 4 and 5, it has surprisingly been found that treatment with bafidemstat also produces a therapeutic effect on ASD independent of or beyond its effect on aggression. Bafidemstat produced a statistically significant improvement in the total NPI score, as shown in Figure 4, comparing the total NPI score after 8 weeks of treatment with bafidemstat (score at visit 7) with the score at baseline before starting treatment with bafidemstat (score at visit 1). The total NPI scale consists of 12 items related to various neuropsychiatric domains and can be used to measure the patient's overall functionality. In addition to the reduction in the total NPI score, bufidemstat also produced a statistically significant improvement in the NPI non-aggression related comorbidity score after 8 weeks of treatment with bufidemstat (score at visit 7) compared to the score at baseline before starting treatment with bufidemstat (score at visit 1). See Figure 5.NPI non-aggression-related comorbidity score is the NPI comorbidity score for all other items (8 items) in the NPI that are not related to aggression or irritability. The results obtained in ASD patients using the total NPI scale and the non-aggression-related NPI subscale show that bafidemstat has a broad therapeutic effect in ASD and has a therapeutic effect for treating ASD beyond treating aggression. It has been found that bafidemstat is particularly well suited for treating ASD, including treating the core features of ASD as defined herein.

[0107] Importantly, the therapeutic effect of bafidemstat (or a pharma- ceutically acceptable salt or solvate thereof) in treating ASD can be achieved without causing sedation or weight gain.

[0108] Pharmaceutical preparations While it is possible that bafidemstat may be administered for use in therapy directly as such, it is typically administered in the form of a pharmaceutical composition comprising the compound as the active pharmaceutical ingredient together with one or more pharma- ceutically acceptable excipients or carriers.

[0109] Any reference to bafidemstat throughout this specification includes a reference to the compound as such, i.e. in a non-salt form (e.g., as a free base) or in the form of any pharma- ceutically acceptable salt or solvate thereof, as well as a reference to a pharmaceutical composition comprising said compound and one or more pharma- ceutically acceptable excipients or carriers.

[0110] Bufidemstat may be administered by any means that achieves its intended purpose, including oral, parenteral (including, for example, intravenous, subcutaneous or intracerebral), or topical routes of administration.

[0111] For oral delivery, the compound can be incorporated into a formulation that includes a pharma- ceutically acceptable carrier, such as a binder (e.g., gelatin, cellulose, tragacanth gum), an excipient (e.g., starch, lactose), a lubricant (e.g., magnesium stearate, silicon dioxide), a disintegrant (e.g., alginate, primogel, and corn starch), and a sweetener or flavoring agent (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulation can be delivered orally, for example, in the form of a surrounded gelatin capsule or compressed tablet. The capsules and tablets can be prepared by any conventional technique. The capsules and tablets can also be coated with various coatings known in the art to modify the flavor, taste, color, and shape of the capsules and tablets. Additionally, liquid carriers, such as fatty oils, can also be included in the capsule.

[0112] Suitable oral preparations can also be in the form of suspension, syrup, chewing gum, wafer, elixir and the like.If desired, can also contain conventional agents for modifying flavor, taste, color and shape of special form.In addition, for easy administration by enteral feeding tube in patients who cannot swallow, active compound can be dissolved in acceptable lipophilic vegetable oil medium, such as olive oil, corn oil and safflower oil.

[0113] The compound can also be administered parenterally in the form of a solution or suspension, or in a lyophilized form that can be converted into a solution or suspension before use.In such preparations, diluents or pharma- ceutically acceptable carriers, such as sterile water and physiological saline buffer, can be used.Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants, and antioxidants can all be included.For example, useful components include sodium chloride, acetic acid, citric acid or phosphate buffer, glycerin, dextrose, fixed oils, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.Parenteral preparations can be stored in any conventional container, such as vials and ampoules.

[0114] For external administration, the compound can be formulated into lotion, cream, ointment, gel, powder, paste, spray, suspension, droplets and aerosol.Therefore, one or more thickeners, wetting agents and stabilizers can be included in the formulation.Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like.A special form of external administration is delivery by transdermal patch.The method of preparing transdermal patch is disclosed, for example, in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 (incorporated herein by reference).

[0115] Subcutaneous implantation for sustained release of the compound may also be a suitable route of administration. This involves a surgical procedure to implant the active compound in any suitable formulation into the subcutaneous space, e.g., under the anterior abdominal wall. See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as carriers for sustained release of the active compound. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network that swells in water to form a gel-like material. Preferably, the hydrogel is biodegradable or bioabsorbable. For purposes of the present invention, hydrogels made from polyethylene glycol, collagen, or poly(glycol-co-L-lactic acid) may be useful. See, e.g., Phillips et al. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

[0116] Compounds can also be conjugated to water-soluble, non-immunogenic, non-peptidic, high molecular weight polymers to form polymer conjugates. For example, compounds can be covalently linked to polyethylene glycol to form conjugates. Typically, such conjugates exhibit improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, the compound in the conjugate can have a longer half-life in the body and exhibit better efficacy. See generally Burnham (1994) Am. J. Hosp. Pharm. 15:210-218. PEGylated proteins are currently used for protein replacement therapy and other therapeutic uses. For example, PEGylated interferon (PEG-INTRON A®) is used clinically to treat hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is used to treat severe combined immunodeficiency syndrome (SCIDS). PEGylated L-asparaginase (ONCAPSPAR®) has been used to treat acute lymphoblastic leukemia (ALL). The covalent linkage between the polymer and the active compound and / or the polymer itself is preferably hydrolytically degradable under physiological conditions. Such conjugates, known as “prodrugs”, can readily release the active compound in the body. Controlled release of the active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels, as is generally known in the art. Other pharma- ceutically acceptable prodrugs of the compounds include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, and sulfonate esters.

[0117] Liposomes can also be used as carriers for active compounds. Liposomes are micelles made from various lipids, such as cholesterol, phospholipids, fatty acids, and their derivatives. Various modified lipids can also be used. Liposomes can reduce the toxicity of active compounds and increase their stability. Methods for preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, for example, U.S. Pat. No. 4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976).

[0118] Pharmaceutical compositions such as oral and parenteral compositions can be formulated in unit dosage form for ease of administration and uniformity of dosage.As used herein, "unit dosage form" refers to a physically separate unit suitable for administration to subject as a unit dosage, each unit containing a predetermined amount of active ingredient calculated to produce desired therapeutic effect, together with one or more suitable pharmaceutical carriers.

[0119] In therapeutic applications, the pharmaceutical composition is administered in a manner appropriate for the disease to be treated, as determined by those skilled in the medical art. The appropriate dose and the suitable duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the disease, the specific form of the active ingredient, and the method of administration, among others. In general, an appropriate dose and administration regimen provides a sufficient amount of the pharmaceutical composition to provide a therapeutic benefit, such as an improved clinical outcome, such as more frequent complete or partial relief, or longer disease-free and / or overall survival, or a reduction in the severity of symptoms, or any other objectively identifiable improvement as recognized by the clinician. Effective doses may generally be estimated or extrapolated using experimental models, such as in vitro or animal model test systems, or dose-response curves derived from clinical trials.

[0120] The pharmaceutical compositions of the present invention can be included in a container, pack, or dispenser together with instructions for administration.

[0121] As shown in Example 2, bafidemstat has been found to be orally active and effective in treating ASD when administered orally, and thus, bafidemstat is preferably administered by the oral route for the treatment of ASD.

[0122] The present invention also encompasses the use of vafidemstat in which one or more atoms have been replaced by a unique isotope of the corresponding atom. For example, the present invention encompasses the use of vafidemstat in which one or more hydrogen atoms (or, for example, all hydrogen atoms) have been replaced by a deuterium atom (i.e., 2 The present invention also includes the use of vafidemstat in which deuterium has been replaced by hydrogen (H; also referred to as "D"). Thus, the present invention also includes deuterium-enriched vafidemstat. Naturally occurring hydrogen is approximately 99.98 mol-% hydrogen-1 ( 1 H) and approximately 0.0156 mol-% deuterium ( 2 The deuterium content at one or more hydrogen positions in bafidemstat can be increased using deuteration techniques known in the art. For example, bafidemstat or reactants or precursors used in the synthesis of bafidemstat can be deuterized with, for example, deuterium oxide (D 2O) can be subjected to a H / D exchange reaction. Further suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise indicated, it is preferred that the bafidemstat used according to the present invention is not enriched with deuterium. Thus, the naturally occurring hydrogen atoms or 1 The presence of H hydrogen atoms is preferred. Generally, it is preferred that none of the atoms in the vafidemstat used according to the present invention are replaced by a unique isotope.

[0123] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0124] Unless otherwise stated, the following definitions apply throughout the present specification and claims.

[0125] A "patient" or "subject" for the purposes of the present invention includes humans and other animals, particularly mammals. Thus, the methods and uses of the present invention are applicable to both human therapy and veterinary applications. In a preferred embodiment, the subject or patient is a mammal, and in a most preferred embodiment, the subject or patient is a human (e.g., a male or female human).

[0126] The terms "treatment", "treat" and the like are used herein to generally mean obtaining a desired pharmacological and / or physiological effect. The effect may be preventative in that it completely or partially prevents a disease (herein, ASD) or its symptoms, and / or may be therapeutic in that it partially or completely cures or ameliorates a disease (i.e., ASD) and / or symptoms or adverse effects attributable to the disease, or partially or completely stops the progression of a disease and / or symptoms or adverse effects attributable to the disease. The term "treatment" as used herein covers any treatment of a disease (i.e., ASD) in a patient, including, but not limited to, any one or more of the following: (a) preventing ASD in a patient who may be predisposed / at risk of developing ASD; (b) delaying the onset of ASD; (c) inhibiting ASD, i.e., halting, delaying or slowing its onset / progression; or (d) alleviating ASD, i.e., causing (complete or partial) regression, correction or remission of ASD. The present invention relates particularly and separately to each of these forms of treatment.

[0127] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired biological effect (e.g., a therapeutic effect) in a subject. Thus, a therapeutically effective amount of a compound may be an amount sufficient to treat a disease (i.e., ASD) and / or delay the onset or progression of the disease and / or alleviate one or more symptoms of the disease when administered to a subject suffering from or susceptible to the disease.

[0128] As used herein, the abbreviation "ASD" refers to autism spectrum disorder.

[0129] As used herein, "pharmaceutically acceptable salts" is intended to mean salts that retain the biological effectiveness of the free acids and / or bases of the specified compound and which are not biologically or otherwise undesirable. The compounds may have functional groups that are sufficiently acidic, sufficiently basic, or both, and thus may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. Exemplary pharma- ceutically acceptable salts of a compound according to the invention, e.g., bafidemstat, include salts of mineral or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, pyrosulfuric acid, bisulfate, sulfurous acid, bisulfite, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, metaphosphoric acid, pyrophosphoric acid, chloride, bromide, iodide, nitric acid, acetic acid, propionic acid, decanoic acid, caprylic acid, acrylic acid, formic acid, isobutyric acid, caproic acid, heptanoic acid, propiolic acid, oxalic acid, malonic acid, succinic acid, suberic acid, sebacic acid, fumaric acid, maleic acid, butyne-1,4-dioic acid, hexyne-1,6-dioic acid, benzoic acid, chlorobenzoic acid, Examples of suitable pharmaceutically acceptable salts include salts prepared by reaction with methylbenzoic acid, dinitrobenzoic acid, hydroxybenzoic acid, methoxybenzoic acid, phthalic acid, sulfonic acid, xylenesulfonic acid, phenylacetic acid, phenylpropionic acid, phenylbutyric acid, citric acid, lactic acid, gamma-hydroxybutyric acid, glycolic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, mandelic acid, pyruvic acid, stearic acid, ascorbic acid, or salicylic acid. When the compound has an acidic moiety, suitable pharmaceutically acceptable salts thereof include salts formed with alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and suitable organic ligands, such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, and the like. Pharmaceutically acceptable salts are well known in the art.

[0130] As used herein, "pharmaceutically acceptable solvates" refers to complexes of variable stoichiometry formed by a solute and a pharmaceutically acceptable solvent, such as water, ethanol, and the like. Complexes with water are known as hydrates. It should be understood that the present invention encompasses pharmaceutically acceptable solvates of bafidemstat in both the non-salt form and in the form of its pharmaceutically acceptable salts.

[0131] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" refer to non-API (API refers to active pharmaceutical ingredient) materials used in the formulation of pharmaceutical products, such as disintegrants, binders, fillers, and lubricants. They are generally safe for human administration according to established government standards, including those published by the United States Food and Drug Administration and / or the European Medicines Agency. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.

[0132] As used herein, the term "comprising" (or "comprise", "comprises", "contain", "contains" or "containing") has the meaning "particularly containing", i.e. "containing, among other optional elements", unless expressly indicated otherwise or contradicted by context. In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprising B and C" has the meaning "A containing in particular B and C", and A may contain further optional elements (e.g., "A containing B, C and D" is also included), but the term also includes the meanings "A consisting essentially of B and C" as well as "A consisting of B and C" (i.e., A does not include any components other than B and C).

[0133] As used herein, unless expressly indicated otherwise or contradicted by context, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one." EXAMPLES

[0134] The following examples illustrate various aspects of the present invention. It should be understood that the examples are, of course, merely illustrative of certain embodiments of the present invention and do not constitute limitations on the scope of the present invention. Results are also presented and described in the figures and figure legends.

[0135] Example 1: Vafidemstat Bafidemstat (recommended international nonproprietary name) is the compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, also known as (-)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, (41R,42S)-6-oxa-3-aza-1(2)-[1,3,4]oxadiazola-5(1,4),8(1)-dibenzena-4(1,2)-cyclopropanaoctaphan-15-amine or ORY-2001, the chemical structure of which is shown below. [ka]

[0136] This compound may be obtained as disclosed in WO 2012 / 013728.

[0137] Bafidemstat is a KDM1A inhibitor with an average IC of 101±40 nM obtained in the KDM1A assay described below. 50 It has a value.

[0138] In vitro KDM1A inhibition assay: Human recombinant KDM1A protein (GenBank accession no. NM_015013, amino acids 158-terminal with an N-terminal GST tag, MW: 103 kDa) was used. Serial 3-fold dilutions of test compounds ranging from 30 μM to 1 nM were pre-incubated with human recombinant KDM1A enzyme (BPS Bioscience, Ref. 50100) for 15 min on ice in assay buffer (50 mM sodium phosphate, pH 7.4). Each concentration of inhibitor was tested in duplicate. The approximate K of KDM1A was M The enzymatic reaction was started by the addition of dimethyl H3K4 peptide substrate (Anaspec, Ref. 63677) at 37 °C. After 30 min of incubation at 37 °C, Amplex Red reagent and horseradish peroxidase (HRP) solution were added to inhibit the H formed in the enzymatic reaction, according to the recommendations provided by the supplier (Invitrogen). 2 O 2 was detected. The mix was incubated for 5 min at room temperature in the dark and the conversion of Amplex Red reagent to highly fluorescent resofurin was analyzed using an Infinite F200 Tecan fluorescence microplate reader (lambda excitation = 540 nm, lambda emission = 590 nm). The maximum demethylase activity of KDM1A was obtained in the absence of inhibitors and corrected for background fluorescence in the absence of KDM1A. The IC of test compounds was 50 Values ​​were calculated using GraphPad Prism5 Software from a minimum of two independent experiments.

[0139] Example 2: Evaluating the efficacy of vafidemstat to treat ASD in humans As part of a Phase IIa clinical trial (REIMAGINE study, EudraCT number 2018-002140-88) to evaluate the safety, tolerability and efficacy of vafidemstat for treating aggression in an adult population of patients with different CNS disorders, a cohort of patients with ASD was recruited and treated with vafidemstat for 8 weeks. The protocol of this clinical trial and a summary of the results obtained in the ASD cohort are provided below.

[0140] 2.1 Clinical Trial Design Reimagine is a single-center, open-label, one-arm, eight-week clinical study to evaluate the efficacy, safety and tolerability of vafidemstat in aggression in an adult population with ASD, ADHD and BPD.

[0141] Primary objective of the study: To evaluate the safety and tolerability of vafidemstat in the adult population with ASD, ADHD, and BPD.

[0142] Secondary objective of the study: To examine the efficacy of vafidemstat on aggression in adult populations with ASD, ADHD and BPD.

[0143] Main inclusion criteria: Ages 18-85 -Diagnosed with ASD, ADHD or BPD according to DSM-5 criteria Significant or persistent irritability or aggression that interferes with the patient's daily life or is harmful to the patient for at least 3 days per week for at least 4 weeks prior to the screening visit

[0144] Treatment: All patients received bafidemstat (as free base) at a dose of 1.2 mg / day administered orally as a single capsule on a 5 days on / 2 days off schedule for 8 weeks.

[0145] 2.2 ASD cohort Six ASD patients were recruited, one dropped out, and therefore the results described herein correspond to the five ASD subjects eligible for analysis. A summary of patients recruited into this ASD cohort (baseline demographic data) can be seen in Table 1. [Table 1]

[0146] 2.3 Evaluating efficacy in the ASD cohort The evaluation of the effect of treatment on buffering dementia status against aggressiveness was performed using the CGI-I and CGI-S scales in addition to the NPI A / A. The NPI A / A subscale is based on the NPI and consists of four items in the NPI regarding aggressiveness / excitability, namely, excitability / aggressiveness, disinhibition, irritability, and abnormal movement disorder. The severity of each of the four items in the NPI A / A scale is scored from 1 to 3 (1 = mild, 2 = moderate, 3 = severe), and the NPI A / A score is calculated as the sum of the scores of all four items. The CGI value reflects the clinician's scoring of the severity of the patient's aggressiveness (CGI-S scale) and the improvement in aggressiveness from the start of treatment (baseline) (CGI-I scale). In the CGI-I scale, the change from the start of treatment is scored using a 7-point scale, where 1 = very large improvement from the start of treatment, 7 = very large worsening from the start of treatment, and 4 = no change from baseline. In the CGI-S scale, the severity of the illness / condition is scored using a 7-point scale, and the higher the score, the more severe the illness / condition, with 1 = normal, not ill at all, and 7 = patient with the most severe illness.

[0147] In addition to assessing its effect on aggression, the effect of treatment with vafidemstat in ASD patients was also evaluated using the Total NPI Scale and the NPI Non-Aggression Related Comorbidity Score. The Total NPI Scale consists of 12 items related to various neuropsychiatric domains (i.e., delusions, hallucinations, agitation / aggression, depression, anxiety, euphoria / hyperactivity, affective blunting / apathy, disinhibition, irritability, abnormal movement disorders, nocturnal behavior, and appetite / eating disorders) and was used to measure global functionality in ASD patients. The severity of each item in the NPI is rated from 1 to 3 (1 = mild, 2 = moderate, 3 = severe), and the Total NPI score is calculated as the sum of the scores of all 12 items. The NPI non-aggression-related comorbidity score is the NPI comorbidity score of all other items in the NPI that are not related to aggression or agitation (8 items; i.e., delusions, hallucinations, depression, anxiety, euphoria / hyperactivity, affective blunting / apathy, nocturnal behavior, and appetite / eating disorders). The severity of each item in the NPI non-aggression-related scale is rated from 1 to 3 (1 = mild, 2 = moderate, 3 = severe), and the NPI non-aggression-related comorbidity score is calculated as the sum of the scores of all 8 items.

[0148] All efficacy assessments were performed by assessing the change in each scale score from baseline (Visit 1) to Week 8 (Visit 7). In the graphs, data are presented as the mean ± standard error of the mean (SEM).

[0149] Statistical analysis was performed using a one-tailed paired t-test analysis comparing Visit 1 values ​​with Visit 7 values. Corresponding p-values ​​are indicated in the graphs and in the Results section below. For CGI-S, paired tests could not be calculated as all data pairs had the same variance.

[0150] 2.4 Results Treatment with vafidemstat in patients with ASD was safe and well tolerated, without any serious adverse events. One patient experienced a transient event of hematological changes, but no clinically relevant alterations of the hematological and biochemical parameters examined were observed. No sedative effects were reported.

[0151] As shown in Figure 1 (NPI A / A, p=0.0098) and Figure 2 (CGI-I, p=0.0019), treatment of ASD patients with vafidemstat for 8 weeks resulted in a significant improvement in aggression, as indicated by a statistically significant reduction in NPI A / A and CGI-I values ​​from Visit 1 to Visit 7. A reduction in CGI-S values ​​from Visit 1 to Visit 7 was also observed (see Figure 3). Additional data was obtained within the REIMAGINE trial for one additional ASD patient enrolled in the study, with the overall CGI-S data (i.e., n=6) shown in Figure 6, which showed a statistically significant reduction in CGI-S scores from Visit 1 to Visit 7 (p=0.0006).

[0152] Unexpectedly, in addition to producing improvements in aggression, the total NPI score and the combined NPI non-aggression-related score also showed a statistically significant reduction after 2 months of treatment with bufidemstat, as shown in Figure 4 (total NPI, p=0.0019) and Figure 5 (non-aggression-related NPI, p=0.0142). These results indicate that bufidemstat exerts therapeutic effects in ASD patients that go beyond therapeutic effects on aggression.

[0153] In summary, the data and results provided in Example 2 support the use of vafidemstat for the treatment of ASD, including the treatment of ASD symptoms unrelated to core features of ASD or aggression.

[0154] All publications, patents, and patent applications referenced herein are hereby incorporated by reference in their entirety.

[0155] The publications, patents, and patent applications mentioned herein are provided solely for their disclosure prior to the filing date of the present application, and nothing herein should be construed as an admission that they are prior art to the present application.

[0156] Although the invention has been described in connection with its particular embodiments, further modifications are possible, and this application is intended to cover any variations, uses, or adaptations of the invention that fall within the known or customary practice within the relevant technical field to which the invention pertains, which are consistent with the principles of the invention, which can be applied to the essential features described above, and which follow the appended claims.

Claims

1. 1. A pharmaceutical composition for use in the treatment of autism spectrum disorder by treating one or more non-aggressive symptoms of autism spectrum disorder, comprising bafidemstat or a pharma- ceutically acceptable salt or solvate thereof and one or more pharma- ceutically acceptable excipients or carriers.

2. The pharmaceutical composition of claim 1, wherein the patient to be treated is a human.

3. The pharmaceutical composition according to claim 1 or 2, which is administered orally.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the autism spectrum disorder is adult autism spectrum disorder.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition comprises bafidemstat.

6. Use of bafidemstat or a pharma- ceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of autism spectrum disorder by treating one or more non-aggressive symptoms of autism spectrum disorder.

7. The use according to claim 6, wherein the medicament is for the treatment of a human patient.

8. 8. The use according to claim 6 or 7, wherein the medicament is for oral administration.

9. The use according to any one of claims 6 to 8, wherein the autism spectrum disorder is adult autism spectrum disorder.

10. The use according to any one of claims 6 to 9, wherein bafidemstat is used for the manufacture of said medicament.

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