Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the invention relates to compositions and methods of treating autism. Specifically, the invention relates to treating the core symptoms of autism by administering a-methyl-DL-tyrosine. BACKGROUND OF THE INVENTION
• Autism spectrum disorder or autism is defined in the Diagnostic and Statistics Manual of Mental Disorders V (DSM-5) by“difficulties in social communication and social interaction, and restricted and repetitive behavior, interests or activities”. Childhood autism is more prevalent than childhood cancer, juvenile diabetes, and pediatric acquired immunodeficiency syndrome (AIDS) combined, with an estimated prevalence of 1.5 million in the United States (US), 3 million children in Europe and tens of millions throughout the rest of the world. Autism also represents a substantial economic burden in both children and adults. More disturbing is that, for no explicable reason, childhood autism appears to be increasing at a rate of 10-17% per year. Lastly, there are currently no approved medications that address the core symptoms of autism. Autism is a serious disease that represents an area of significant economic burden and unmet medical need.
• DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition (DSM-5) (2013) by“difficulties in social communication and social interaction, and restricted and repetitive behavior, interests or activities.”
• the diagnostic criteria in DSM-5 for the features“difficulties in social communication and social interaction” of ASD include (1) deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions; (2) Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication; and (3) deficits in developing, maintaining, and understanding relationships, ranging, for example
• autism Typically displayed in early childhood, autism is associated with many co-morbidities that include epilepsy, Fragile-X syndrome, Retts syndrome, attention deficit/hyperactivity disorder (ADHD), abnormal sensory or motor responses, disturbed sleep, reduced cognitive functionality, anxiety and aggression.
• epilepsy Fragile-X syndrome, Retts syndrome, attention deficit/hyperactivity disorder (ADHD), abnormal sensory or motor responses, disturbed sleep, reduced cognitive functionality, anxiety and aggression.
• ADHD attention deficit/hyperactivity disorder
• autism is not typically considered to be a fatal disease
• a matched case cohort study based upon the Swedish National Patient Registry and the Cause of Death Registry looked at deaths between 1987 and 2009, and found a 256% greater death rate in autistic patients compared to the general population.
• the mean age at the time of death was 70.2 years for the general population and 58.39 for patients with autism, with suicide associated with better performing patients.
• a review of 1,706 children and adolescents reported an 18% increased risk of suicidal ideation or attempts in autism. 35% of patients with Asperger’s syndrome were reported in a Canadian study to have attempted suicide. Similarly, in Japan, Australia, England, and Belgium. In a French review of the PubMed literature, it was found that overall 21.3% of autism patients reported suicidal ideation or had attempted suicide, with the noteworthy observation that“... the methods used are often violent”.
• Enormous resources are being spent on research into the causes of autism. Genetic, dietary, developmental, pharmacologic, environmental, and behavioral elements have all been implicated as potential causes of this syndrome.
• This first step in catecholamine synthesis is highly stereospecific for L-tyrosine.
• L-AMPT a methylated L-tyrosine, acts as a competitive inhibitor for tyrosine hydroxylase (Demser® Prescribing Information, 2015; FDA Summary Basis of Approval [SBA] for Demser®, 1979).
• Demser® was initially approved by the FDA in 1979 and is indicated for use in the treatment of patients with pheochromocytoma for (1) the preoperative preparation of patients for surgery, (2) management of patients when surgery is contraindicated, and (3) chronic treatment of patients with malignant pheochromocytoma.
• the recommended initial dosage of Demser® for adults and children 12 years of age and older is 250 mg orally four times daily. This dosage may be increased by 250 mg to 500 mg every day to a maximum of 4.0 g/day in 4 divided doses.
• Demser® is commercially available, those ordinarily skilled in the art have not developed methods for treating autism or its core symptoms by administering a racemic mixture of a-methyl-DL-tyrosine, i.e., DL-AMPT.
• autism represents a public health emergency. Accordingly, there exists a vital need for therapeutically effective methods for treating autism, in particular, the core symptoms of this disorder.
• the invention provides a method for treating an autism in a subject in need thereof, the method comprising administering to said subject a composition comprising a therapeutically effective amount of a-methyl-DL-tyrosine and a pharmaceutically acceptable carrier.
• the composition comprises a-methyl-DL-tyrosine in an amount ranging from about 50 mg (w/w) to about 500 mg (w/w).
• the invention provides a method for providing a plasma concentration of a therapeutic drug for a long term for treating an autism in a subject in need thereof, the method comprising administering to said subject said therapeutic drug at a concentration ranging from about 50 mg (w/w) to about 500 mg (w/w) three times a day, wherein said therapeutic drug is a- methyl-DL-tyrosine, wherein said plasma concentration ranges from about 500 ng/ml to 5000 ng/ml, and wherein said term is at least 1 week.
• the invention provides a method for treating an autism associated clinical trait in a subject in need thereof, the method comprising administering to said subject a composition comprising a therapeutically effective amount of a-methyl-DL-tyrosine, thereby treating said autism associated clinical trait in said subject.
• the clinical trait is a deficit in social communication, a deficit in social interaction, a deficit in social motivation, lethargy and social withdrawal, inappropriate speech, hyperactivity, stereotypic behavior, irritability and agitation, restrictive behavior, repetitive behavior, ritualistic behavior, sameness behavior, compulsive behavior, self-injurious behavior or a combination thereof.
• Figure 1 depicts Conners Parent Rating Scale Data results.
• Figure 2 illustrates patient enrollment and disposition.
• Figure 3 shows an example of largest change from baseline in vital signs noted in a patient in Study HT 02-121 (Example 6) and demonstrates that these changes were transient, falling far short of orthostatic criteria.
• Figure 4 shows random L1-79 plasma concentrations (except Day 1 * ) by week, overall mean and by patient from open-label 100 mg and 200 mg TID in Study HT 02-121. * 1 On Day 1, L-79 plasma concentrations were evaluated at 1-hour post-dose.
• Figure 5 shows random L1-79 plasma concentrations by week (excluding Day 1), overall mean and by patient from open-label 100 mg TID group in Study HT 02-121.
• Figure 6 shows random L1-79 plasma concentrations by week (excluding Day 1), overall Mean and by patient from open-label 200 mg TID group in Study HT 02-121.
• FIG. 7 graphically displays shows the CGI– Overall Severity (CGI-S) for L1-79 compared to placebo over time.
• Figure 8 graphically displays the CGI– Overall Improvement (CGI-I) for L1-79 compared to placebo over time.
• Figure 9 shows the change from baseline in CGI-S at week 4 (ITT Population, Draft).
• Figure 10 shows the change in CGI-S from Baseline to Week 4 by Patient (ITT Population, Draft).
• Figure 11 shows the responder analysis for CGI-S at Week 4/LOCF (ITT Population, Draft).
• Figure 12 shows the change from Baseline in VABS II Standardized Socialization Score, Week 0– Week 8 (ITT Population, Draft).
• Figure 13 shows the change from Baseline in VABS II Standardized Communication Score, Week 0– Week 8 (ITT Population, Draft).
• Figure 14 shows the change from Screening in ADOS-2 Total score, Week 0– Week 4 (ITT Population, Draft).
• Figure 15 shows the change from Screening in ADOS-2 Restrictive and Repetitive Behavior Total score, Week 0– Week 4 (ITT Population, Draft).
• Figure 16 shows the change from Screening in ADOS-2 Social Affect Total Score, Week 0– Week 4 (ITT Population, Draft).
• Figure 17 shows the change in ADOS-2 Total Score from Screening to Week 4 by Patient (ITT Population, Draft).
• Figure 18 shows the change from Baseline in SRS-2 Total T-score, Week 0– Week 8 (ITT Population, Draft).
• Figure 19 shows the change from Baseline in SRS-2 DSM-5 Social Communication and Interaction T-score, Week 0– Week 8 (ITT Population, Draft).
• Figure 20 shows the change from Baseline in SRS-2 Social Communication T-score, Week 0– Week 8 (ITT Population, Draft).
• Figure 21 shows the change from Baseline in SRS-2 Social Motivation T-score, Week 0– Week 8 (ITT Population, Draft).
• Figure 22 shows the change from Baseline in SRS-2 DSM-5 Restrictive and Repetitive Behavior, Week 0– Week 8 (ITT Population, Draft).
• Figure 23 shows the change in SRS-2 Total T-score from Baseline to Week 4 by Patient (ITT Population, Draft).
• Figure 24 shows the change in SRS-2 DSM-5 Social Communication and Interaction T- score from Baseline to Week 4 by Patient (ITT Population, Draft).
• Figure 25 shows the change in SRS-2 Social Communication T-score from Baseline to Week 4 by Patient (ITT Population, Draft).
• Figure 26 shows the change in SRS-2 Social Motivation T-score from Baseline to Week 4 by Patient (ITT Population, Draft).
• Figure 27 shows the responder analysis for SRS-2 Total T-score at Week 4/LOCF (ITT Population, Draft).
• Figure 28 shows the responder analysis for SRS-2 DSM-5 Social Communication and Interaction T-score at Week 4/LOCF (ITT Population, Draft).
• Figure 29 shows the responder analysis for SRS-2 Social Communication T-score at Week 4/LOCF (ITT Population, Draft).
• Figure 30 shows the responder analysis for SRS-2 Social Motivation T-score at Week 4/LOCF (ITT Population, Draft).
• Figure 31 shows the change from Baseline in ABC-C Lethargy and Social Withdrawal Domain, Week 0– Week 8 (ITT Population, Draft).
• Figure 32 shows the change from Baseline in ABC-C Inappropriate Speech Domain, Week 0 - Week 8 (ITT Population, Draft).
• Figure 33 shows the change from Baseline in ABC-C Hyperactivity and Noncompliance Domain, Week 0 - Week 8 (ITT Population, Draft).
• Figure 34 shows the change from Baseline in ABC-C Stereotypic Behavior Domain, Week 0– Week 8 (ITT Population, Draft).
• Figure 35 shows the change from Baseline in ABC-C Irritability and Agitation Domain, Week 0– Week 8 (ITT Population, Draft).
• Figure 36 shows the change in ABC-C Lethargy and Social Withdrawal Domain from Baseline to Week 4 by Patient (ITT Population, Draft).
• Figure 37 shows the change in ABC-C Inappropriate Speech Domain from Baseline to Week 4 by Patient (ITT Population, Draft).
• Figure 38 shows the responder analysis for ABC-C Lethargy and Social Withdrawal Domain at Week 4/LOCF (ITT Population, Draft).
• Figure 39 shows the responder Analysis for ABC-C Inappropriate Speech Domain at Week 4/LOCF (ITT Population, Draft).
• Figure 40 shows the change from Baseline in RBS-R Total Score, Week 0– Week 8 (ITT Population, Draft).
• Figure 41 shows the change from Baseline in RBS-R Restrictive Behavior, Week 0– Week 8 (ITT Population, Draft). There were mean improvements in RBS-R Total Score as noted by a decrease in score for L1-79200 mg compared to placebo.
• Figure 42 shows the change from Baseline in RBS-R Ritualistic Behavior, Week 0–Week 8 (ITT Population, Draft).
• Figure 43 shows the change from Baseline in RBS-R Sameness Behavior, Week 0– Week 8 (ITT Population, Draft).
• Figure 44 shows the change from Baseline in RBS-R Compulsive Behavior, Week 0– Week 8 (ITT Population, Draft).
• Figure 45 shows the change from Baseline in RBS-R Stereotypic Behavior, Week 0– Week 8 (ITT Population, Draft).
• Figure 46 shows the change from Baseline in RBS-R Self-injurious Behavior, Week 0– Week 8 (ITT Population, Draft).
• Figure 47 shows the change in RBS-R Total Score from Baseline to Week 4 by Patient (ITT Population, Draft)
• Figure 48 shows the responder analyses (defined as an improvement or no worsening) for RBS-R Total Score at Week 4 or LOCF.
• composition As used herein, the terms “component,” “composition,” “composition of compounds,” “compound,” “drug,” “pharmacologically active agent,” “active agent,” “therapeutic,” “therapy,” “treatment,” or “medicament” are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
• AUC 0-8 Area under the concentration time curve from 0 to 8 hours
• AUC0- ⁇ Area under the concentration time curve from 0 to infinity
• the negative effect or symptoms can include any of those that are the subject of the diagnostic criteria specified for autism spectrum disorder in the American Psychiatric Association's Diagnostic and Statistical Manual, Fifth Edition (DSM-5, DSM-V), the contents of which are incorporated by reference herein, e.g., deficits in social- emotional reciprocity (ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions) deficits in nonverbal communicative behaviors used for social interaction (ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication); deficits in developing, maintaining, and understanding relationships (ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends;
• Some subpopulations of patients on the autism spectrum include those patients diagnosed with Asperger's Disorder (i.e., Asperger Syndrome) or Social Communication Disorder, exhibit symptoms of Attention Deficit Hyperactivity Disorder (ADHD) (e.g., inattention, hyperactivity, and impulsivity) and/or tics (motor tics or vocal tics). See, e.g., DSM-5.
• ADHD Attention Deficit Hyperactivity Disorder
• Autism symptoms can be performed using methods known in the art.
• CGI Clinical Global Impressions
• ABS Aberrant Behavior Checklist-Community
• ADOS Conners Parent Rating Scale
• Autism symptoms can also be assessed from the clinician's personal, clinical observations, from videographic information taken at regularly scheduled clinic visits, and from information provided by the subject's caregivers over time.
• Compositions and methods of the disclosure result in a reduction of at least 1 point in at least one dimension of the Conners Parent Rating Scale assessment score.
• the term "effective amount” refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to the treatment of the relevant disorder, condition, or side effect. It will be appreciated that the effective amount of components of the present invention will vary from patient to patient not only with respect to the particular compound, component or composition selected, the route of administration, and the ability of the components to elicit a desired result in the individual, but also with respect to factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage being at the discretion of the attending physician.
• the invention also provides a pharmaceutical composition comprising compounds of the invention and one or more pharmaceutically acceptable carriers.
• “Pharmaceutically acceptable carriers” include any excipient which is nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.
• the pharmaceutical composition may include one or additional therapeutic agents.
• “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 and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
• Examples of a pharmaceutically acceptable carrier include, for example, but not limited to, solvents, dispersion media, buffers, coatings, antibacterial and antifungal agents, wetting agents, preservatives, buggers, chelating agents, antioxidants, isotonic agents and absorption delaying agents.
• Examples of a pharmaceutically acceptable carrier also include, for example, but not limited to, water; saline; phosphate buffered saline; dextrose; glycerol; alcohols such as ethanol and isopropanol; phosphate, citrate and other organic acids; ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; EDTA; salt forming counterions such as sodium; and/or nonionic surfactants such as TWEEN, polyethylene glycol (PEG), and PLURONICS; isotonic agents such as sugars, polyalcohols such as mannitol and
• the disclosed compounds may be prepared in the form of pharmaceutically acceptable salts.
• “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
• physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
• Compounds described herein can be prepared in alternate forms. For example, many amino-containing compounds can be used or prepared as an acid addition salt. Often such salts improve isolation and handling properties of the compound. For example, depending on the reagents, reaction conditions and the like, compounds as described herein can be used or prepared, for example, as their hydrochloride or tosylate salts. Isomorphic crystalline forms, all chiral and racemic forms, N-oxide, hydrates, solvates, and acid salt hydrates, are also contemplated to be within the scope of the present invention.
• Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxy groups often exist in equilibrium with their zwitterionic forms. Thus, any of the compounds described herein that contain, for example, both amino and carboxy groups, also include reference to their corresponding zwitterions.
• stereoisomers refers to compounds that have identical chemical constitution, but differ as regards the arrangement of the atoms or groups in space.
• enantiomers refers to stereoisomers that are mirror images of each other that are non-superimposable.
• administering means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
• inhibitor includes compounds that inhibit the expression or activity of a protein, polypeptide or enzyme and does not necessarily mean complete inhibition of expression and/or activity. Rather, the inhibition includes inhibition of the expression and/or activity of a protein, polypeptide or enzyme to an extent, and for a time, sufficient to produce the desired effect.
• tyrosine hydroxylase inhibitors function by decreasing the amount of adrenaline secreted into the bloodstream.
• tyrosine hydroxylase inhibitor is well known in the art and fully described in, for example, U.S. Patent Application Publications US 2015/0290279, US 2015/0216827, US 2015/0111937, US 2015/0111878, US 2013/0184214, and US 20130183263; U.S. Patents US 8,481,498, US 9,308,188, and US 9,326,962; and PCT Patent Application Publication WO2015061328, which are incorporated by reference herein in their entirety. Any suitable tyrosine hydroxylase inhibitor, known to one of skilled in the art, can be used.
• the tyrosine hydroxylase inhibitor is a tyrosine derivative.
• the tyrosine derivative can be capable of existing in different isomeric forms, including stereoisomers and enantiomers.
• the tyrosine derivative can, for example, exist in both L-form or D-form.
• the tyrosine derivative can, for example, also exist in a racemic form.
• Representative tyrosine derivatives include, for example, one or more of methyl (2R)-2- amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-tyrosine(tBu)-allyl ester hydrochloride, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)- 2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2- chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4- dimeth
• the tyrosine derivative is a-methyl-D-tyrosine. In other embodiments, the tyrosine derivative is a-methyl-DL-tyrosine in a racemic form as shown below:
• the tyrosine derivative is a structural variant of a-methyl-L- tyrosine or a-methyl-DL-tyrosine.
• the structural variants of a-methyl-L-tyrosine or a-methyl- DL-tyrosine are well known in the art and fully described in, for example, U.S. Patent 4, 160,835, which is incorporated by reference herein in its entirety.
• the tyrosine derivative of the invention is an arylalanine compound having the formula:
• R1 is hydrogen, methyl or ethyl ester group, or alkyl of from 1 to 4 carbon atoms
• R 2 is hydrogen, lower alkyl, lower alkene, succinimide, or alkyl of from 1 to 4 carbon atoms
• R 3 is a substituted benzene ring of the following general formula
• Y1 is located at the para position and is hydrogen, hydroxy, methyl ether, dimethyl ether, trimethyl ether, or an unsubstituted or halogen-substituted benzyl
• Y 2 , and Y 3 are the same or different and wherein one or both Y2, and Y3 located at either meta position or ortho position, and wherein Y2, and Y3 are hydrogen, hydroxy, halogen, methyl ether, or nitro
• R4 is hydrogen, acetyl, tert-butyloxycarbonyl or fluorenylmethyloxycarbonyl.
• Y1 and Y2 are the same or different and are selected from hydrogen, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminomethyl, guanidino, hydroxy, methanesulfonamido, nitro, amino, methanesulfonyloxy, carboxymethoxy, formyl, methoxy and a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing carbon and one or more nitrogen, sulfur or oxygen atoms, specific examples of such heterocyclic rings being pyrrol- 1-yl, 2-carboxypyrrol-1-yl, imidazol-2-ylamino, indol-1-yl, carbazol-9-yl, 4,5-dihydro-4- hydroxy-4-trifluoromethylthiazol-3-yl, 4-trifluoromethylthiazol-2-yl, imidazol-2-yl and 4,5- dihydroimi
• R 3 is a substituted or unsubstituted benzoheterocyclic ring having the formula:
• the benzoheterocyclic ring is selected from the group consisting of indolin-5-yl, 1-(N-benzoylcarbamimidoyl)-indolin-5-yl, 1-carbamimidoylindolin-5-yl, 1 H-2-oxindol-5-yl, indol-5-yl, 2-mercaptobenzimidazol-5(6)-yl, 2-aminobenzimidazol-5(6)-yl, 2- methanesulfonamido-benzimidazol-5(6)-yl, 1 H-benzoxazol-2-on-6-yl, 2-aminobenzothiazol-6- yl, 2-amino-4-mercaptobenzothiazol-6-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-2,2-dioxo- 2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-1,3-dimethyl-2,2-di
• R3 is a substituted or unsubstituted heterocyclic ring having the formula: in which the heterocyclic ring is selected from the group consisting of 5-hydroxy-4 H- pyran-4-on-2-yl, 2-hydroxypyrid-4-yl, 2-aminopyrid-4-yl, 2-carboxypyrid-4-yl, or tetrazolo[1,5- a]pyrid-7-yl.
• the tyrosine hydroxylase inhibitor is aquayamycin.
• aquayamycin is a compound of the formula set forth below.
• the tyrosine hydroxylase inhibitor is oudenone.
• oudenone is a compound of the formula set forth below.
• tyrosine hydroxylase inhibitor known to one of skilled in the art, can also be used.
• tyrosine hydroxylase inhibitor include, for example, but not limited to, cycloheximide, anisomycin, 3-iodo-L-tyrosine, pyratrione, phenyl carbonyl derivatives having catechol or triphenolic ring systems, for example, phenethylamine and gallic acid derivatives, 4- isopropyltropolone, 2-(4 -thiazolyl)benzimidazole, 8-hydroxyquinoline, o-phenantroline, 5-iodo- 8-hydroxyquinoline, bilirubin, 2,9-dimethyl-1, 10- phenantroline, a-a’-dipyridil, dibenzo [f,h]quinoxaline, 2,4,6-tripyridil-s-triazine, ethyl 3-amino4H-pyrrolo-isoxazo
• the tyrosine hydroxylase inhibitor is L1:79, which refers to a- methyl-DL-tyrosine in a racemic form or D,L a-methyl-para-tyrosine (abbreviated as DL-AMPT).
• a-methyl-DL-tyrosine inhibits the activity of tyrosine hydroxylase (TH), which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA), which is the rate limiting step in catecholamine synthesis.
• TH tyrosine hydroxylase
• DOPA dihydroxyphenylalanine
• a- methyl-DL-tyrosine is a tyrosine analog that competes competitively for TH and is excreted mostly unchanged in the urine.
• Demser i.e., a-methyl-L-tyrosine
• the racemic mixture i.e., a-methyl-DL-tyrosine
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount or dose of a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL- tyrosine) and a pharmaceutically acceptable carrier.
• a tyrosine hydroxylase inhibitor e.g., a-methyl-DL- tyrosine
• compositions of the present invention for treatment of autism as described herein vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is an adult or a child, other medications administered, and whether treatment is prophylactic or therapeutic.
• the patient is a human but non-human mammals including transgenic mammals can also be treated. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
• the pharmaceutical compositions of the invention may include a“therapeutically effective amount.”
• A“therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
• a therapeutically effective amount of a molecule may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the molecule to elicit a desired response in the individual.
• a therapeutically effective amount is also one in which any toxic or detrimental effects of the molecule are outweighed by the therapeutically beneficial effects.
• the terms“treat” and“treatment” refer to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition.
• Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable.
• Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
• Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response).
• a single bolus may be administered.
• several divided doses may be administered over time.
• a dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
• Dosage unit form refers to physically discrete units suited as unitary dosages for treating mammalian subjects. Each unit may contain a predetermined quantity of active compound calculated to produce a desired therapeutic effect. In some embodiments, the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved.
• composition of the invention may be administered only once, or it may be administered multiple times.
• the composition may be, for example, administered three times a day, twice a day, once a day, once every two days, twice a week, weekly, once every two weeks, or monthly.
• dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
• administering to a subject is not limited to any particular delivery system and may include, without limitation, oral (for example, in capsules, suspensions or tablets), parenteral (including subcutaneous, intravenous, intramedullary, intraarticular, intramuscular, or intraperitoneal injection), topical, or transdermal.
• Administration to a host may occur in a single dose or in repeat administrations, and in any of a variety of physiologically acceptable salt forms, and/or with an acceptable pharmaceutical carrier and/or additive as part of a pharmaceutical composition (described earlier).
• physiologically acceptable salt forms and standard pharmaceutical formulation techniques are well known to persons skilled in the art (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co.).
• the dosage of tyrosine hydroxylase inhibitor may range from about 1 mg to about 4g. In a particular embodiment, the dosage of tyrosine hydroxylase inhibitor may range from about 10 mg to about 1500 mg.
• the composition comprises a tyrosine hydroxylase inhibitor (i.e., a-methyl-DL-tyrosine) in an amount ranging from about 50 mg (w/w) to about 1500 mg (w/w); from about 50 mg (w/w) to about 500 mg (w/w); from about 75 mg (w/w) to about 350 mg (w/w); from about 90 mg (w/w) to about 350 mg (w/w); from about 100 mg (w/w) to about 300 mg (w/w); or from about 100 mg (w/w) to about 200 mg (w/w).
• a tyrosine hydroxylase inhibitor i.e., a-methyl-DL-tyrosine
• the composition comprises a tyrosine hydroxylase inhibitor (i.e., a-methyl-DL-tyrosine) in an amount of about 90, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 750, 1000, or 1500 mg (w/w/).
• a "composition” refers to any composition that contains a pharmaceutically effective amount of one or more active ingredients (e.g., a tyrosine hydroxylase inhibitor, another acne treating agent, or a combination thereof).
• a plurality of compositions having different dosages are administered concurrently or sequentially.
• a first composition comprising a-methyl-DL-tyrosine in an amount of about 200 mg (w/w) and a second composition comprising a-methyl-DL-tyrosine in an amount of about 100 mg (w/w) are administered concurrently.
• a first composition comprising a-methyl-DL-tyrosine in an amount of about 200 mg (w/w) and a second composition comprising a-methyl-DL-tyrosine in an amount of about 100 mg (w/w) are administered sequentially.
• the composition is administered for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In another aspect, the composition is administered for a duration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 week dosing period. In yet another aspect, the composition is administered for a duration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 month dosing period.
• the invention provides a method for obtaining a plasma concentration of a therapeutic tyrosine hydroxylase inhibitor drug (e.g., a-methyl-DL-tyrosine) for a long term for treating an autism in a subject in need thereof, the method comprising administering to said subject said therapeutic drug at a concentration ranging from about 50 mg (w/w) to about 500 mg (w/w) three times a day, wherein said plasma concentration ranges from about 500 ng/ml to 5000 ng/ml, and wherein said term is at least 1 week.
• a therapeutic tyrosine hydroxylase inhibitor drug e.g., a-methyl-DL-tyrosine
• the drug is administered for at least 1 day, 2 day, 3 day, 4 day, 5 day, 6 day, 1 week, 2 week, 3 week, or 4 week.
• the drug is administered for a duration ranging from about 1 day to about 4 weeks; from about 2 days to about 4 weeks; or from about 1 week to about 4 weeks.
• the drug is administered for a duration of therapeutic regimens in excess of 6 months.
• composition of the invention may result in a plasma concentration ranging from about 500 ng/ml to 5000 ng/ml; from about 800 ng/ml to 2500 ng/ml, or from about 1400 ng/ml to 1800 ng/ml.
• compositions of the invention may be formulated in a variety of ways, including for example, solid, semi-solid, and liquid dosage forms, such as capsules, tablets, pills, powders, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories.
• the compositions are in the form of injectable or infusible solutions.
• the composition is in a form suitable for oral, topical, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, or transdermal administration.
• the composition is in the form of a capsule.
• the composition is in the form of a tablet.
• Administration of the pharmaceutical composition can be through various routes, including orally, nasally, subcutaneously, intravenously, intramuscularly, transdermally, vaginally, rectally or in any combination thereof.
• Transdermal administration can be effected using, for example, oleic acid, 1-methyl-2-pyrrolidone, dodecylnonaoxyethylene.
• the invention provides administering to a subject a therapeutically effective amount of a first tyrosine hydroxylase inhibitor, for example, a-methyl-DL-tyrosine in combination with a therapeutically effective amount of a second tyrosine hydroxylase inhibitor, for example, a-methyl-L-tyrosine.
• a therapeutically effective amount of one or more tyrosine hydroxylase inhibitors for example, a-methyl-DL-tyrosine and/or a-methyl-L-tyrosine in combination with a therapeutically effective amount of another agent useful in the treatment of autism.
• ⁇ -aminobutyric acid can be administered with the tyrosine hydroxylase inhibitor (e.g., a-methyl-DL-tyrosine).
• the GABA can be administered simultaneously with the tyrosine hydroxylase inhibitor.
• the GABA can be administered separately from the tyrosine hydroxylase inhibitor, e.g., at another time during the day.
• the GABA is administered at bedtime.
• dosages of the GABA are from about 5 mg to about 30 mg, for example, 5, 10, 15, 20, 25, or about 30 mg of GABA., with 15 mg of GABA being particularly preferred.
• a p4503A4 promoter is administered in addition to the tyrosine hydroxylase inhibitor (e.g., a-methyl-DL-tyrosine) and the optional GABA.
• Preferred p450 3A4 promoters include 5,5-diphenylhydantoin, valproic acid, and carbamazepine.
• tyrosine hydroxylase inhibitor can be any of the tyrosine hydroxylase inhibitors described herein, with a-methyl-DL-tyrosine being particularly preferred.
• Beta adrenergic agonists are known in the art and include, for example, albuterol, levalbuterol, fenoterol, formoterol, isoproterenol, metaproterenol, salmeterol, terbutaline, clenbuterol, isoetarine, pirbuterol, procaterol, ritodrine, epinephrine, and combinations thereof.
• Albuterol is a particularly preferred beta adrenergic agonist.
• the tyrosine hydroxylase inhibitor and the beta adrenergic inhibitor are administered simultaneously.
• the beta adrenergic inhibitor is administered separately from the a-methyl-DL-tyrosine, e.g., at another time during the day.
• the described methods for treating a disease or disorder can be used in combination with treatment methods that are also known to be effective in treating the same disease or disorder.
• autism behaviors and symptoms can be treated with compounds that affect autonomic neurotransmission (e.g. amphetamine, methylphenidate, and the like), psychotopic drugs (e.g., risperidone), neutotransmitter reuptake inhibitors (e.g., fluoxetine), compounds that stimulate glutaminergic transmission (e.g., LY2140023), and/or compounds that affect cholinergic neurotransmission (e.g., galantamine).
• autonomic neurotransmission e.g. amphetamine, methylphenidate, and the like
• psychotopic drugs e.g., risperidone
• neutotransmitter reuptake inhibitors e.g., fluoxetine
• compounds that stimulate glutaminergic transmission e.g., LY2140023
• compounds that affect cholinergic neurotransmission e.g., gal
• the disclosure is also directed to methods of treating autism in a patient by administering an effective amount of a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL-tyrosine) and an effective amount of a compound that affects autonomic neurotransmission, a psychotopic drug, a neutotransmitter reuptake inhibitor, a compound that stimulates glutaminergic transmission, and/or a compound that affects cholinergic neurotransmission.
• the invention provides methods of treating autism in a patient by administering a therapeutically effective amount of a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL-tyrosine) and a therapeutically effective amount of a central nervous system (CNS) agent.
• a tyrosine hydroxylase inhibitor e.g., a-methyl-DL-tyrosine
• CNS central nervous system
• the diseases or disorders treated by the composition of the invention include, for example, autism or its associated disease or disorder.
• the autonomic nervous system has been implicated in symptoms that resemble those seen in autism.
• Autism spectrum disorder (ASD) has been associated with abnormal findings in autonomic related structures including the insula and the amygdala.
• Autonomic related changes such as increases in basal heart rate and diminished heart rate due to psychosocial challenges are seen in autism.
• the autism-autonomic linkage is exemplified by the consequences of respiratory sinus arrhythmia (RSA) that includes difficulties with socialization, language difficulties, and delays in cognitive development.
• RSA respiratory sinus arrhythmia
• the present invention also relates to the treatment of the core symptoms of ASD by administration of a-methyl-DL-tyrosine to subjects in need thereof.
• the tyrosine hydroxylase inhibitor e.g., a-methyl-DL-tyrosine administered according to the present invention modulates the catecholaminergic pathways implicated in autism, more specifically such pathways involved in the core symptoms of ASD, including the catecholaminergic functions in the CNS and in the gastrointestinal tract.
• the known effects of catecholamines on the endocrine and neuroendocrine systems are regulated by administration of the tyrosine hydroxylase inhibitor (e.g., a-methyl-DL-tyrosine), including but not limited to decreasing the amount of adrenaline secreted into the bloodstream, which may lessen the intensity of irritability and agitation, and other core symptoms of ASD.
• the tyrosine hydroxylase inhibitor e.g., a-methyl-DL-tyrosine
• the invention provides a method for treating core symptoms of Autism Spectrum Disorder (ASD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a racemic mixture of a-methyl-DL-tyrosine.
• ASD Autism Spectrum Disorder
• the invention provides a method for treating an autism associated clinical trait in a subject in need thereof, the method comprising administering to said subject a composition comprising a therapeutically effective amount of a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL-tyrosine), thereby treating said autism associated clinical trait in said subject.
• a tyrosine hydroxylase inhibitor e.g., a-methyl-DL-tyrosine
• Examples of an autism associated clinical trait include, for example, but not limited to, a lack of social communication, a lack of social interaction, a lack of social motivation, lethargy and social withdrawal, inappropriate speech, hyperactivity, stereotypic behavior, irritability and agitation, restrictive behavior, repetitive behavior, ritualistic behavior, sameness behavior, compulsive behavior, self-injurious behavior or a combination thereof.
• the clinical trait is assessed based upon a change from a baseline in one or more psychometric tests.
• a psychometric test include, for example, but not limited to, clinical global impression (CGI) rating scale, Vineland adoptive behavior scale (VABS), autism diagnostic observation schedule (ADOS), social responsiveness scale (SRS), aberrant behavior checklist– community (ABC-C), repetitive behavior scale (RBS), Conners parent rating scale (CPRS), or a combination thereof.
• CGI clinical global impression
• VABS Vineland adoptive behavior scale
• ADOS autism diagnostic observation schedule
• SRS social responsiveness scale
• ABS aberrant behavior checklist— community
• RBS repetitive behavior scale
• CPRS Conners parent rating scale
• the clinical trait meets the requirements of Diagnostic and Statistical Manual of Mental Disorders– V (DSM-V) criteria.
• subject refers to an animal, for example a human, to whom treatment, including prophylactic treatment, with the pharmaceutical composition according to the present invention, is provided.
• subject refers to human and non-human animals.
• non-human animals and “non- human mammals” are used interchangeably herein and include all vertebrates, e.g., mammals, such as non-human primates, (particularly higher primates), sheep, dog, rodent, (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses and non-mammals such as reptiles, amphibians, chickens, and turkeys.
• the subject is a human patient between 3 years of age and 21 years of age; 5 years of age and 21 years of age; or 6 years of age and 17 years of age. In another embodiment, the subject is an adult human patient.
• kits comprising one or more molecules or compositions described herein.
• the following examples are provided to supplement the prior disclosure and to provide a better understanding of the subject matter described herein. These examples should not be considered to limit the described subject matter. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be apparent to persons skilled in the art and are to be included within, and can be made without departing from, the true scope of the invention.
• a high blood glucose level (hyperglycemia) is defined as a fasting plasma blood glucose level of 126 mg/dl or greater on two separate occasions.
• the average patient age was sixty- two years old and the median patient age was sixty years old.
• Six of the patients were female and three of the patients were male.
• Five of the patients were fifty to sixty years old and four of the patients were over the age of sixty.
• the patients in the study were administered a treatment regimen that included a tyrosine hydroxylase inhibitor (i.e., a-methyl-DL tyrosine), a melanin promoter (i.e., melanotan II), a p450 3A4 promoter (i.e., 5, 5-diphenylhydantoin), and a leucine aminopeptidase inhibitor (i.e., N- [(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine).
• a tyrosine hydroxylase inhibitor i.e., a-methyl-DL tyrosine
• melanin promoter i.e., melanotan II
• a p450 3A4 promoter i.e., 5, 5-diphenylhydantoin
• a leucine aminopeptidase inhibitor i.e., N- [(2S,3R)-3-amino
• a subgroup of those satisfying the criteria are administered a treatment regimen that includes a tyrosine hydroxylase inhibitor (i.e., a-methyl-DL tyrosine) at dose of 50-100 mg three times daily.
• Another subgroup is administered a treatment regimen that further includes a p450 3A4 promoter (i.e., 5, 5-diphenylhydantoin) in one daily dose of 30 mg.
• Gamma- aminobutyric acid is optionally administered to both subgroups at bedtime at a dose of 15 mg to aid sleeping and to quiet ticks and repetitive behaviors like teeth grinding.
• Vasopressin is administered as needed to assist brain governance. Following each administration of the treatment regimen, changes in the extent to which the subjects satisfy the DSM-5 criteria is again assessed.
• Study Design Blinded, randomized, 2 arm, 8-week treatment period followed by additional follow-up visits off treatment over the next 18 weeks for a total of 26 weeks' study participation. Treatment arms consist of LI -79 alone or placebo.
• Evaluation Schedule Patients will receive 8 weeks of the schedule above with weekly treatment evaluations for weeks 1-8 then post-treatment follow up visits at weeks 10, 13 & 26.
• Safety Measures Regularly scheduled complete history and physical examination, vital signs, CBC, differential, platelet counts, urine analysis, serum enzymes including: total protein, albumin, glucose, BUN, creatinine, direct and total bilirubin, alkaline phosphatase, phosphorous, calcium, aspartate aminotransferase (“AST”), alanine aminotransferase (“ALT”), sodium, potassium, chloride, bicarbonate, T4, TSH, and adverse events assessments. An independent DMC will oversee the conduct of this trial to assure patient safety.
• Study Duration A maximum of 50 weeks (12 weeks' enrollment, 38 weeks' treatment and follow-up).
• Study Endpoints The primary end point will be the assessment of the attending physician as reflected in the Clinical Global Impressions (CGI) scale based upon changes from baseline in various psychometric tests, including the Aberrant Behavior Checklist-Community (ABC-C), Conners Parent Rating Scale and the Autism Diagnostic Observation Schedule (ADOS), as well as from their personal observations in the clinic, and from videographic information taken at regularly scheduled clinic visits (per this protocol) and provided by caregivers over the course of this study.
• CGI Clinical Global Impressions
• ABS Aberrant Behavior Checklist-Community
• ADOS Autism Diagnostic Observation Schedule
• AMPT a-methyl-DL tyrosine
• ABS-C Aberrant Behavior Checklist - Community
• ADOS Autism Diagnostic Observation Schedule
• CPRS Conners Parent Rating Scale
• L1-79 was used anecdotally in two patients followed by a more structured evaluation in 8 additional patients with autism. All patients were administered a starting dose of L1-79 of 90 mg TID for a minimum of 3 months. During the evaluation doses as high as 400 mg TID were used. A summary of data available on these 10 patients was provided in the Summary of Clinical Efficacy, Use of L1-79 to treat autism, submitted to IND 128673, sequence number 0005. While the sample size was small and involved open-label administration of L1-79, the results were encouraging with consistent improvements in the ABC-C domains and an average reduction in the ADOS-2 of 30%, and one child manifesting an ADOS-2 decrease of 60% which resulted in the loss of his autism diagnosis.
• This clinical study was a randomized double-blind, placebo-controlled two-cohort, 4-week dose-escalation study that incorporated two open-label treatment groups to assess the safety and efficacy of L1-79100 mg and 200 mg TID in male patients between the ages of 12 - 21 years of age diagnosed with autism.
• the first cohort of 20 patients was comprised of three groups of patients: The first group of five patients received open-label L1-79 100 mg TID and underwent PK and EKG assessments. The remaining two groups in this cohort consisted of 15 patients randomized on a 2:1 basis to receive L1-79100 mg TID or placebo.
• the PK and safety data from the open-label L1-79100 mg TID group was submitted to FDA for review and acceptance before the second cohort was enrolled.
• the second cohort was procedurally identical to the first.
• the second cohort of 20 patients was comprised of the same three groups of patients but a dose of 200 mg TID was used instead of 100 mg TID.
• the key inclusion criteria were as follows: (1) males between 13 and 21 years of age, (2) DSM-5 compliant diagnosis of autism spectrum disorder, confirmed by the Autistic Diagnosis Interview Review (ADIR), and by an ADOS-2 score consistent with a diagnosis of autism, (3) must have been stable on no more than one concomitant medication and no planned changes in psychosocial interventions during the study.
• ADIR Autistic Diagnosis Interview Review
• the key exclusion criteria were as follows: (1) sexually active males, (2) a history of Fragile-X syndrome, Rett syndrome or any other co-morbidity including but not limited to cancer, genetic diseases, or any disease or syndrome that required drug therapy, (3) DSM-5 diagnosis of schizophrenia, schizoaffective disorder, alcohol use disorder or attention deficit hyperactivity disorder (ADHD), (4) had any active medical problem(s), including epilepsy and asthma, (5) uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic cardio-vascular disease, hepatic disease, renal disease, skeleto-muscular disease, human immunodeficiency virus (HIV), hemorrhagic cerebrovascular accident (HCVA), hepatitis B virus (HBV), or psychiatric illness/social situations that would limit compliance with study requirements, (6) any disease that required chronic treatment, (7) any disease that required treatment with an immunosuppressive drug, and/or (8) current or lifetime diagnosis of severe psychiatric disorder.
• the first five patients in each cohort were assigned to receive active medication in an open- label fashion.
• the patients were treated identically to the randomized patients with the following exceptions: (1) blood samples were drawn at baseline and 1 hour after dosing, and at Week 1, 2, 3 and 4 treatment visits 1 hour after dosing to determine the PK of L1-79, (2) EKGs were assessed at baseline and within 3-days prior to the Week 1, 2, 3 and 4 treatment visits as well as the 1-week and 4-week post-dosing follow-up visits, (3) vital signs, physical exams, and ASD assessments were performed at 1-week postdosing visit, (4) blood and urine samples were drawn at baseline and at Week 1, 2, 3 and 4 treatment visits 1 hour after dosing as well as the 1-week and 4-week post-dosing follow-up visits for safety analyses.
• the primary efficacy endpoint was the determination of the clinical improvement by the investigator as documented by the Clinical Global Impression (CGI) rating scales. Additional efficacy endpoints included: (1) changes from baseline in the Socialization and Communication Domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS II) parent/caregiver rating form, (2) changes from baseline in the ADOS-2 Total Score and subscores, (3) changes in the Social Responsiveness Scale, Second Edition (SRS-2) Total Score and subscales, (4) changes in the ABC-C domains, (5) changes in the Repetitive Behavior Scale– Revised (RBS–R) Total Score and subscales. Given the exploratory design of this study only descriptive statistics were planned.
• CGI Clinical Global Impression
• FIG. 1 A small number of subjects demonstrated asymptomatic drop in systolic and/or diastolic blood pressures, along with increase in heart rate at Week 1 or Week 2 of treatment, but these resolved by Week 4 and were mild in nature (e.g., a drop of 10 mm Hg in systolic blood pressure, 5 mm Hg in diastolic pressure and increase of 15– 24 beats per minute in heart rate).
• Figure 3 provides an example of the largest change from baseline that was noted, and demonstrates that these changes were transient, falling far short of orthostatic criteria.
• responder analyses are intended to focus on the number of patients demonstrating any benefit, rather than the overall change in the studied population.
• responders are defined as patients whose target symptoms demonstrate a pre-specified improvement in the efficacy endpoint. This definition is consistent with accepted standards for judging mid and long term outcomes for experimental treatments studied in nearly every disorder, including autism. However, it does not take into account the need for a refined definition in studies of short duration for disorders, like autism, that have oscillations in symptom severity.
• a‘baseline’ measure may in fact be at the apex, midpoint or nadir of one of these oscillations. If they are at an apex or mid-point when the target symptoms under study are measured at baseline, then a short duration study may only have the opportunity to demonstrate initial efficacy by preventing the target symptom from returning back to its oscillatory nadir. To account for this probable occurrence among some study patients, the responder definition includes patients demonstrating either short term stability or improvement in the target symptoms. Thus, for each efficacy endpoint demonstrating a positive trend, responder analyses were conducted as defined herein.
• CGI-S CGI– Overall Severity
• CGI-I CGI– Overall Improvement
• CGI-S responder definitions for CGI-S were defined as improvement only (instead of improvement or no change) since, unlike the other measures which were performed weekly, the CGI-S requires the clinician to give an overall assessment of the patients’ clinical symptom severity based on all of the outcome measures and their movement over the entirety of the study.
• VABS II Vineland Adaptive Behavior Scales, Second Edition
• ADOS-2 Autism Diagnostic Observation Schedule, Second Edition
• the Social Communication and Interaction scale are comprised of the DSM-5 criteria that make up the social communication and social interaction deficits required for the diagnosis of ASD.
• Responder analyses (defined as an improvement or no worsening) are presented for SRS- 2 Total T-score, SRS-2 DSM-5 Social, Communication and Interaction T-score, SRS-2 Social Communication T-score, and SRS-2 Social-Motivation T-score at Week 4 or LOCF in Figure 27, Figure 28, Figure 29, and Figure 30, respectively.
• Figures 27-30 demonstrate that the percent of responders (as defined by improvement or no worsening were greater with L1-79 200 mg, compared to placebo; see Responder Definition (section above).
• Results from Study HT 02-121 provide proof of concept that L1-79 appears to provide benefit in treating the core symptoms of ASD.
• ASD is defined primarily as persistent deficits in social communication and social interaction as well as restricted and repetitive behavior patterns, interests or activities.
• Preliminary evidence from multiple independent assessments specifically used to measure both the social and behavioral intensity of these core symptoms demonstrated consistent trends that were repeatable across multiple instruments. While the limited size and short duration of the study precluded any expectation or ability to demonstrate statistically significant improvements in the outcome measures used, the agreement between the multiple measures utilized in this study is very encouraging.
• the blinded assessment by the clinicians involved in the study demonstrated a nearly one-point change in the CGI-S compared to baseline.
• patients receiving L1-79 improved by nearly one point from baseline in ADOS-2 scores within the same time period.
• the completed Study HT 02-121 was a Phase II safety study of L1-79 for the treatment of autism.
• Study HT 02-121 was a randomized double-blind, placebo-controlled two- cohort, 4-week dose-escalation study that incorporated 2 open-label treatment groups to assess the safety and efficacy of L1-79100 mg and 200 mg TID in male patients between the ages of 13 and 21 years of age with autism.
• Results from Study HT 02-121 provide proof of concept that L1-79 appears to provide benefit in treating the core symptoms of ASD. Preliminary evidence from multiple independent assessments specifically used to measure both the social and behavioral intensity of these core symptoms demonstrated consistent trends that were repeatable across multiple instruments.
• Example 8 also referred to herein as“Study 301”) seeks to quantify the safety and efficacy of L1-79 administered TID at doses of 200 or 300 mg to subjects with a diagnosis of autism based upon their Autism Diagnostic Observation Schedule-2 (ADOS-2) results in a prospectively randomized and double-blind manner.
• ADOS-2 Autism Diagnostic Observation Schedule-2
• the dosage form is a capsule containing 100 mg of DL-a-methyl-para-tyrosine capsules (hereafter referred to as“L1-79”).
• the intended dosing regimen of L1-79 for Phase III clinical studies is 2 or 3 capsules administered orally three times daily (TID).
• TID three times daily
• ASD is a disorder marked by deficits in social interaction and the presence of restricted, repetitive patterns of behavior, interests, or activities during childhood development (Swedo, S. E., Baird, G., Cook, E. H., Happe’, F. G., Harris, J. C., Kaufmann, W. E.,... Wright, Harry, H. (Eds.). (2013). Neurodevelopmental Disorders. In American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). American Psychiatric Association.). Recent literature has implicated peripheral and autonomic nervous system involvement in children and adults with ASD (Baker, 2017; Fenning, 2017). As a result, electrodermal skin testing may serve as an important biomarker for the population of patients more likely to respond to treatments targeting the sympathetic nervous system.
• the primary objectives of the study are to evaluate the efficacy, safety, and tolerability of L1-79 compared to placebo for the treatment of the core deficits in social communication and interaction in adolescents and adults with autism spectrum disorder (ASD).
• ASD autism spectrum disorder
• [216] 3. to evaluate the effect of L1-79 compared to placebo on reducing aberrant behaviors in ASD, including hyperactivity, agitation, and irritability; and [217] 4. to perform additional modeling of pharmacokinetics (PK) and pharmacodynamics (PD) for L1-79 in a subset of subjects through timed intermittent sparse sampling.
• PK pharmacokinetics
• PD pharmacodynamics
• DSM-5 Diagnostic and Statistical Manual of Mental Disorders–5th edition
• CGI-S Clinical Global Impression of Severity
• Subjects will be randomized to placebo, L1-79200 mg, or L1-79300 mg three times daily (TID) groups in a 1:2:2 ratio.
• Subjects in the 200 and 300 mg group will be started on 200 mg TID. Subjects in the 300 mg group will titrate up to 300 mg TID after 7 days.
• Screening assessments will include the ADOS-2, a review of ASD criteria from the DSM- 5 and the CGI-S.
• An adaptive design will be used with a proposed interim analysis being used to make decisions on the following criteria; potential endpoints for the primary outcome, modification of the defined study population, and estimated sample size.
• the data monitoring committee and independent statistical group will implement the interim analysis and make recommendations to the sponsor regarding proposed changes in the study based on predefined criteria.
• the sample size recalculation will depend on the primary outcome and potential study populations that will be determined at the interim analysis. The sample size recalculation will be based on blinded data.
• a schedule of events is provided in Table 30.
• ABC-C Aberrant Behavior Checklist-Community
• ADOS-2 Autism Diagnostic Observation Scale-2
• ASD autism spectrum disorder
• CGI-C Clinical Information
• CGI-S Clinical Global Impression of Severity
• DSM-5 Diagnostic and Statistical Manual of Mental Disorders–5th edition
• PSI Parenting Stress Index
• RBS-R Repetitive Behavior Scale-Revised
• SAS Spence Anxiety Scale
• SSP Spence Anxiety Scale
• SRS-2 Social
• VABS-3 Vineland Adaptive Behavior Scales– 3rd Edition
• WASI-2 Weschler Abbreviated Scales of Intelligence
• ADOS-2 Will be videotaped for potential use as an additional review for Reciprocal Social Interaction by Blinded reviewer
• Subjects must be male or female adolescents or adults up to age 21
• Post menarche females must be on birth control if appropriate.
• Diagnosis of ASD based upon an assessment tool that utilizes the DSM-5 criteria [e.g., Autism Symptom Rating Scale (ASRS), Childhood Autism Rating Scale-2 (CARS2), or Autism Diagnostic Interview-Revised (ADI-R)], and confirmed with the ADOS-2, with a CGI-S score of 4 or greater.
• ASRS Autism Symptom Rating Scale
• CARS2 Childhood Autism Rating Scale-2
• ADI-R Autism Diagnostic Interview-Revised
• Subject must be stable on no more than one concomitant medication, and no planned changes in psychosocial interventions during the trial
• Subjects must have a caregiver who has known the them for over a year, spends at least 10 hours per week with them, and is willing to accompany them to each appointment.
• Subjects must, in the opinion of the Investigator, be sufficiently tolerant and capable of complying with the requirements of this trial. For example, patients who will not tolerate blood draws or ECG are not qualified candidates for this study.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic cardio-vascular disease, hepatic disease, renal disease, skeletomuscular disease, HIV, HCVA, HBV, or psychiatric illness/social situations that would limit compliance with study requirements.
• Fragile-X syndrome e.g., congenital or acquired brain injury, brain malformations, stroke, neurogenetic or metabolic disorder.
• Two dose arms will be tested as 200 mg TID (one 200 mg dose combined with placebo) and 300 mg TID (one 200 mg capsule and one 100 mg capsule) Duration of Treatment:
• Baseline assessments not included in the measurement of efficacy include the Weschler Abbreviated Scales of Intelligence (WASI-2) and the Spence Anxiety Scale (SAS). Electrodermal testing will be performed at baseline to determine if greater autonomic nervous system variability correlates with response to treatment. (See Study Rationale).
• the primary outcome measure will be the change from baseline at Week 12 on a 5-factor composite measure comprising the Socialization (SOC), Communication (COM), and Daily Living Skills (DLS) domains from the Adaptive Behavior Composite (ABC) of the Vineland Adaptive Behavior Scales - 3rd Edition (VABS-3) and the Socialization, Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB) subscales of the Social Responsiveness Scale-2 (SRS-2).
• SOC Socialization
• COM Communication
• DLS Daily Living Skills
• ABS Adaptive Behavior Composite
• VABS-3rd Edition VABS-3rd Edition
• SCI Socialization, Communication and Interaction
• RRB Restricted Interests and Repetitive Behavior
• the primary secondary outcome measure will be based on the change from baseline CGI-S at Week 12.
• SAS Spence Anxiety Scale
• ADOS-2 Total Score* (ADOS-2 will be videotaped at screening and at end of study for potential use in blinded review of reciprocal interaction.)
• Safety assessments include physical examination, orthostatic measurements of blood pressure and pulse, standard hematology and clinical chemistry assessments, concomitant medication use, urinalysis, ECGs, and spontaneously reported adverse events.
• PK Assessments include physical examination, orthostatic measurements of blood pressure and pulse, standard hematology and clinical chemistry assessments, concomitant medication use, urinalysis, ECGs, and spontaneously reported adverse events.
• the adaptive design will assess three components of the study; the outcome variable, a potential modification of the inclusion criteria, and a sample size recalculation based on the decisions made at the time of the interim analysis.
• the modification of the inclusion criteria will be based on an evaluation of potential endophenotypes for ASD of baseline severity of the following characteristics known to directly influence treatment and intervention strategies for people with ASD: 1) Severity of anxiety based on assessment by the Spence Anxiety Scale, IQ as assessed by the Weschler Abbreviated Scale of Intelligence and disruptive behavior symptom severity, based on the ABC-C irritability and hyperactivity subscales.

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