WO2014151628A1

WO2014151628A1 - Treatment of autism spectrum disorders using helminthic parasite preparations

Info

Publication number: WO2014151628A1
Application number: PCT/US2014/026129
Authority: WO
Inventors: Karin Margareta HEHENBERGER
Original assignee: Coronado Biosciences, Inc.
Priority date: 2013-03-14
Filing date: 2014-03-13
Publication date: 2014-09-25

Abstract

Methods are provided for treating Autism Spectrum Disorder (ASD) using helminthic parasite preparations.

Description

TREATMENT OF AUTISM SPECTRUM DISOR DERS USING HELMINTHIC PA ASITE

PREPARATIONS

FIELD OF THE INVENTION

[0001] The present invention relates generally to methods of treatment of autism spectrum disorder. More particularly, the present invention relates to the use of helminthic parasite ova in pharmaceutical formulations to prevent onset and ameliorate symptoms of autism spectrum disorders. This application claims priority to U.S. Provisional Application No. 61 /783,818, filed March 14. 20 S 3, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] As many as 6 of every 1 ,000 children suffer from a condition characterized as Autism Spectrum Disorder (ASD), and recent studies indicate that the prevalence is on the rise. ASD encompasses a range of developmental disorders that may include symptoms such as social deficits, communication difficulties, stereotyped or repetitive behaviors and interests, and in some cases, cognitive delays.

[0003] The association between ASD and immune dysfunction has been widely documented (DelGiudice-Asch et al, 1999; Hollander et al, 1999). This association suggests that immunomodulatory interventions may be a potential experimental therapeutic option for those with ASD. Additionally, the "febrile hypothesis" of ASD, which is based on observations of clinical improvement in ASD patients in response to fever, has been extensively documented. This fever response could conceivably be modulated by either 1) an immune-inflammatory response, or 2) a direct effect of temperature on clinical symptoms of ASD. Current literature supports a link between CNS dysfunction in ASD and neuroinflammation and a dysreguiated immune response. Studies of cerebrospinal fluid (CSF) in patients with ASD have demonstrated increased proinflammatory cytokines, including 1L-6, interferon-gamma, and MCP-1 , a chemoattractant and protein for monocytes and macrophages (Pardo et al, 2005; Vargas et al, 2005; Zimmerman, 2006). In the peripheral immune system, aberrations consistent with dysreguiated immune response include abnormal or skewed T helper cell type 1 (TH I/TH2 cytokine profiles), decreased lymphocyte numbers, decreased T cell mitogen response, and the imbalance of serum immunoglobulin levels, increased levels of proinflammatory cytokines have been also found in individuals with autoimmune diseases (Simopoulos, 2002). Many studies have documented elevated levels of proinflammatory cytokines in patients with ASD, including TNF-alpha/IL- 12 (Jyonouchi et al., 2005a; Jyonouchi et

-I - al, 2005b), IFN-Gamma and lL- ! RA (Croonenbcrghs et al., 2002a) and IgG2 and igG4 (Croonenberghs et al,, 2002b). An additional study conducted by Li et al . (2009), demonstrated that ASD patients had significantly increased levels of proinflammatory cytokines, including (TNF-a, IL- 6 and GM-CSF), Th l cytokine (I FN- γ) and chemokine (IL-8) when compared to controls. The Th l/Th2 ratio was also significantly increased in A SD patients. It was concluded that ASD patients display an increased innate and adaptive immune response through the Th l pathway, suggesting that localized brain inflammation and autoimmune dysfunction may be involved in the pathogenesis of ASD (Li et al. 2009). Similarly, other studies have found that patients with A SD produce lower levels of 1 L- 1 0, an important counter regulatory cytokine. Additionally, serotonin is known to be a potent immunomodulator, and is one of the most consistent biological findings in autism is elevated whole blood serotonin (5HT) levels (Burgess et al. 2006).

[0004] A ltered cytokine levels have been linked to behavioral changes in both animals and humans. For example, direct administration of I L- S , IL-2 and IL-6 in mice results in profound behavioral changes, including digging exploration, rearing and grooming (Zalcrnan et al. 1998), and other increases in stereotypic motor behavior (Zalcrnan et al. 2002). in mice bred for difference in social behavior, nonaggressive mice had significantly lower gamma interferon and IL-2 production when compared to aggressive mice (Petirto et al. 2004).

[ΘΘΘ5] Despite recent increases in understanding of the pathophysiology of ASD, no current pharmacological approaches to ASD can cure ASD or treat the core symptoms. Further, the pharmacological treatments that do exist have a myriad of side effects, and may not be conducive to oral dosing.

[0006] There remains, therefore, a need for alternative treatments for pediatric, neonatal, and adult ASD patients.

SUMMARY OF THE INVENTION

[0007J The present invention relates to novel therapeutic methods for the treaiment of autism spectrum disorder based on an improved understanding of the autoimmune causes of ASD.

[0008] In particular, one aspect of the present invention provides a method of treating ASD in a human patient comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutically acceptable carrier, wherein the helminthic parasite or

"A" portion thereof is selected from the group consisting of T. suis, S. mansoni, H. polygyrus, T. spiralis, T. irichiura and N. americanus,

[0009] In some embodiments, the biologically active portion of the helminthic parasite may be selected from the group consisting of parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract, parasite cercariae and parasite cercariae extract, in further embodiments, the pharmaceutical formulation comprises embryonated parasite eggs or embyronated parasite egg extract of T. suis. In further embodiments, the autism spectrum disorder may be selected from the group consisting of autism, Asperger's syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett's syndrome. In still further embodiments, the human patient may be a pediatric or neonatal patient,

[0010] In some embodiments, the treatment may act to decrease the frequency or severity of acute and recurrent symptoms of autism. Such acute and recurrent symptoms of autism may, in further embodiments, be selected from the group consisting of aggressive behavior, repetitive movements, language disability, seizure disorder, sensory processing problems, hyperactivity, anxiety, tantrums, and immune dysfunction. In still further embodiments the treatment is a maintenance treatment.

[001 1] The effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, between about 2,000 and about 1 0,000 eggs, be about 2,500 eggs, or be about 7,500 eggs. In further embodiments, the effective amount may be ad inistered between about 1 and about 4 times per month for a duration of three months or greater, six months or greater, or one year or greater. The pharmaceutical formulation may be administered enterally, preferably, orally. In further embodiments, the frequency of administration of the pharmaceutical formulation may be greater for a first period of time taking place at the outset of treatment, than the frequency of administration during a second period of time taking place after the first period of time. In yet further embodiments, the frequency of administration of the pharmaceutical formulation may be increased for a period of time when acute symptoms of ASD appear or are expected to appear, followed by a return to the frequency of administration after the acute symptoms have subsided.

[0012] As used herein, ''about" will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term. [0013] As used herein, the term ''active agent'^* is used to refer to a chemical material or compound that induces a desired beneficial effect when administered topically or orally, and includes agents that are therapeutically and/or prophylactically effective as pharmaceuticals ("pharmacologically active agents"). By an "effective" amount of an active agent is meant a nontoxic but sufficient amount of an active agent to provide the desired beneficial effect.

[0014] As used herein, the term '"egg" refers to either embryonated or nonembryonated, viable helminth ova.

[0015] Additional features, advantages, and embodiments of the present disclosure may be set forth from consideration of the following detailed description, drawings, and claims. Moreover, it is to be understood that both the foregoing summary of the present disclosure and the following detailed description are exemplary and intended to provide further explanation without further limiting the scope of the present disclosure claimed.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The progression of ASD is usually clinically measured by the ABC subscale scores, with secondary assessments via any of the following four scores: CY-BOCS, CGI-i. SRS, and SCQ. Further, secondary objectives include assessment of the effects on quality of life and/or safety outcomes.

[0017] The ABC score stands for Aberrant Behavior Checklist scores, which measure five categories: irritability, hyperactivity, inappropriate speech, lethargy, and stereotypy. The ABC consists of 58 questions and the five subscales as described above. Each question on the ABC is rated on a 4-point scale: 0 == 'not a problem,' 1 -'the behavior is a problem but slight in degree,' 2 == 'the problem is moderately serious,' and 3 = 'the problem is severe in degree.' The subscale score is the sum of the responses to the questions that make up the subscale.

[0018] Another measure of ASD is the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (or, for pediatric patients, CY-BOCS). The scale is a clinician-rated, I Q-item scale, each item rated from 0 (no symptoms) to 4 (extreme symptoms), yielding a total possible score range from 0 to 40. The scale includes questions about the amount of time the patient spends on obsessions, how much impairment or distress they experience, and how much resistance and control they have over these thoughts. The same types of questions are asked about compulsions (e.g., time spent, interference, etc. ) as well. The results can be interpreted based on the total score: 0-7 is sub-clinical; 8-15 is mild; 16-23 is moderate; 24- 1 is severe: and 32-40 is extreme.

[0019] The Clinical Global Impression (CGI) rating scales are also commonly used measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders. CG1-I, the scale measuring "improvement" is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention, and rated as: 1 , very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.

[0020] ASD severity may be also be subjectively quantified in pediatric patients by the Social Responsiveness Scale ("SRS"), a 65-item questionnaire most often filled out by parents or teachers, whose ratings classify children according to 'severity of autistic symptomology.^* Higher scores, above an established threshold, indicate greater autism "severity," and are therefore considered worse.

[0021] A Social Communication Questionnaire (SCQ) may also be used to quantify severity or improvement of pediatric ASD patients. SCQ comprises a 35 -question, true/false questionnaire usually filled out by a third party.

[0022} Other tests may be conducted throughout the course of treatment to determine safety or efficacy of the treatment. As used herein, "clinical chemistry"^* comprises one or more of the tests selected from the group consisting of total protein, albumin, serum creatinine, biood urea nitrogen (BUN), uric acid, bilirubin (total & direct), alkaline phosphatase, alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT), creatine phosphokinase (CPK), glucose, calcium, phosphorus, sodium, potassium, chloride, and bicarbonate.

[0023 | As used herein, "hematology" refers to the following tests: white blood cell (WBC) count, differential white cell count (lymphocytes, monocytes, basophils, eosinophils, neutrophils), red blood cell (RBC) count, hematocrit, hemoglobin and platelet count. As used herein, '^"urinalysis^*' refers to a group of tests comprising color, specific gravity, pH, glucose, ketones, blood, protein, nitrates, leukocyte esterase, RBC, WBC.

Helminthic P parations

[0024] Embryonated eggs of certain helminths, such as, for example, porcine whipworm Trichuris suis {Trichuris suis ova, TSO), have been shown to colonize the human intestine without invading or infecting. Safety of TSO has been demonstrated in clinical studies with patients suffering from iBD, Multiple Sclerosis, allergies and other autoimmune diseases, as shown in Table 1 .

Table S : N umber (%) of Patients Experiencing Treatment-Emergent Adverse Events by

MedDRA Preferred Term - Sorted b Descending Incidence in the Total TSO Column (Study CNDO 201 -002)

Source: Interim Study Report for Study CNDO 201 -002

TEAEs were defined where dose date was on or before the onset data of the event. Events with missing onset dates are considered treatment-emergent events.

[0025] Any immunomodulatory non-infective helminth species may be used in the methods described herein, such as, for example. T. suis, S. mansoni, H. polygyrus, T. spiralis. T. trichiura and

N. amvricanus. The entire adult helminth may be used, or any therapeutically effective portion thereof, such as, for example, parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract parasite cercariae and parasite cereariae extract, in a preferred embodiment, parasite ova are used. |0026| Therapeutically effective amounts of the helminth or biologically active portion thereof can be empirically determined and will vary with the pathology being treated, the severity of the symptoms, and the subject being treated. The effective amount may be determined during preclinical trials and clinical trials by methods familiar to physicians and clinicians. An effective amount of a helminthic parasite preparation useful in the methods may be administered to a mammal in need thereof by any of a number of well-known methods for administering pharmaceutical compounds. The peptide may be administered system ically or locally or. in the case of a neonatal patient, may be administered to the mother. In a preferred embodiment, the administration is oral.

[0027] Oral compositions may also include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipienis and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as .magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetenin agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0028] Additionally, the helminthic parasite preparation may also comprise a second active agent for the treatment of ASD. Such an active agent may be selected from the group consisting of risperidone, pentoxifylline, lithium, and pioglitazone.

[0029] The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compositions described herein can include a single treatment or a series of treatments.

[0030} In preferred embodiments, each dose may comprise from about 500 to about 20,000 eggs, or from about 2,000 eggs to about 10,000 eggs. In further embodiments, each dose may comprise about 1 ,000 eggs, about 1 ,500 eggs, about 2,000 eggs, about 2,500 eggs, about 3,000 eggs, about 3,500 eggs, about 4,000 eggs, about 4,500 eggs, about 5,000 eggs, about 5,500 eggs, about 6,000 eggs, about 6,500 egg, about 7,000 eggs, about 7,500 eggs, about 8.000 eggs, about 8,500 eggs, about 9,000 eggs, about 9,500 eggs, about 10,000 eggs, about 10,500 eggs, about 1 1 ,000 eggs, about 1 1 ,500 eggs, about 12,000 eggs, about 12,500 eggs, about 13,000 eggs, about 13,500 eggs, about 14,000 eggs, about 14.500 eggs, about 15,000 eggs, about ! 5,500 eggs, about 16,000 eggs, about 16,500 eggs, about 1 7,000 eggs, about 17,500 eggs, about 18,000 eggs, about 18,500 eggs, about 1 9,000 eggs, or about 19,500 eggs.

}θθ3ί] Administration may take place as often or as rarely as necessary to be therapeutically effective. The amount administered may be between about 1 and about 4 times per month for a duration of six months or greater, depending on the pathology of the patient and the presence of acute symptoms. In preferred embodiments, the frequency of administration of the pharmaceutical formulation may be greater for a first period of time taking place at the outset of treatment, than the frequency of administration during a second period of time taking place after the first period of time. Alternatively or additionally, the frequency of administration of the pharmaceutical formulation may be increased for a period of time when acute symptoms of ASD appear or are expected to appear, followed by a return to the frequency of administration after the acute symptoms have subsided.

[0032] The present invention is further illustrated by the following examples, which should not be construed as limiting in any way.

Examples

Example 1 : Treatment of ASD in Pediatric Patients Using Helminthic Parasite Preparations

[0033] In order to demonstrate the efficacy of helminthic preparations in treatment of ASD, sixty subjects with a confirmed Autism diagnosis are recruited, having the following inclusion criteria: males or females, 6-17 years old (inclusive), with a diagnosis via the Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM-1V) and confirmed via Autism Diagnostic Observation Schedule (ADOSl), CGI severity score of greater than or equal to 4, with an ABC irritability score of greater than or equal to 18. The subjects must have a mental age of greater than 1 8 months, and be currently psychotropic medication free or on stable dose o psychotropic medication for at least three months prior to the study. They must be willing to comply with the schedule of study visits and protocol requirements, and the patient and/or guardian must have the ability to provide informed consent. [0034] in addition, subjects may not have the following exclusion criteria: previous diagnosis of Rett's Disorder, Aspergers Disorder, Childhood Disintegrative Disorder, Fragile X Syndrome, or other disorders on the autism spectrum; a history of Bipolar Disorder, Psychotic Disorders, or major Depression; Seizure within the previous 6 months; antibiotic, anti fungal or antiparasitic medication in the last 2 weeks prior to Screening and/or would potentially require this during the study treatment period; a history of drug or alcohol abuse within 6 months prior to Screening; patients with evidence of poor compliance with medical advice and instruction including diet or medication: patients who are unable or unwilling to swallow study medication suspension; patients with a significant medical condition which puts the patient at risk for study participation and/or for any reason is considered by the investigator to be an unsuitable candidate to receive TSO or is potentially put at risk by study procedures: patients who have participated in another clinical trial within 30 days of Screening for this trial and/or any experimental treatment for this population; females of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period; females who are pregnant or breastfeeding at the time of enrollment; patients with a white blood cell count < 3,000/mm3 (< 3.0 x 109/L) or > 14,0QQ/mm3 (> 14 x 109/L); platelet count < 100,000/μί ( 100 x 109/L); serum creatinine >2 x upper limit of normal (ULN); AST (SCOT) or ALT (SGPT) > 2 x ULN; total bilirubin >2 mg/dL (34 μιτιοΙ/L); hemoglobin < 9 g/dL.

10035] The active drug product, Trichuris sitis ova 2500 or 7500 is a non-steriie, aqueous suspension of the viable, embryonated eggs of the whipworm Trichuris suis for oral use. Active TSO is administered in 15 mL of the suspension medium supplied in either one or two 30 raL glass containers. The suspension medium is an aqueous solution containing phosphate buffer, pH 5 and 0.05% potassium sorbate as antimicrobial preservative. Each unit dose is supplied in a 30 mL amber glass container with black outer lacquer and is sealed with a white polypropylene screw cap and a blue tamper evident ring.

[0036] The TSO is prepared in two strengths as delineated in Table 2. Both formulations are stored at a temperature between 2°C (36 °F) and 8°C (46 °F) and are protected from any risk of freezing (i.e., not be placed directly on freezer packs or in ice that could be below 0°C or 32 °F) or temperature greater than 25° C (77 °F). TSO is agitated gently before use to disperse the ova. Following dosing, tap water is to be added to the glass container, agitated, and ingested to ensure administration of the full d ose of TSO. Table 2: TSO Product

10037] Following informed consent, the sixty subjects are screened on the basis of clinical laboratories and ASD severity. ABC, CGI-S, vital signs, clinical laboratories, medical history and a physical examination will be conducted. Treatment then proceeds according to the Schedule of Events shown in Table 3.

11 [0038] Eligible subjects are randomized to treatment with TSO 2500, TSO 7500, or placebo (in a ratio of 1 : 1 : 1 ). During the treatment phase, study drug will be provided in a liquid form and wit! be administered every 2 weeks, starting with the Baseline visit, through Week 1 6. Subjects will return to the clinic every 2 weeks through Week 14. Efficacy endpoints will be assessed at Weeks 4. 8. and 12. Week 34 is the last treatment administration of the study, while Week 16 is the primary time point for assessment of efficacy. Efficacy and safety indices will be assessed as per the Schedule of Events.

[0039] At the screening assessments, the following evaluations are performed: informed consent, inclusion and exclusion criteria, medical history, physical examination, clinical laboratories (including hematology, serum chemistry, C-rcactive protein, l .FTs), urinalysis, pregnancy laboratory (serum test for female subjects of child-bearing age only), vital signs, 12- Lead ECG, prior and on-going medications. Aberrant Behavio Checklist and CG1- Sevei'ity.

100401 Subjects who satisfy eligibility requirements from screening will return to the clinic for their baseline (pre-treatment) assessments. If subjects are still, deemed to be eligible, the subject will be randomized and treated with their first dose of study medication. Baseline assessments will include: inclusion and exclusion criteria to ensure subject still meets requirements, medical history to assess any changes since screening, physical examination to assess any changes since screening, vital signs, prior medications and on-going medications, ABC checklist, CY-BOCS assessment, SRS assessment, SCQ assessment. For patients who still meet eligibility criteria, the subject will be randomized and receive their first dose of medication.

[0041] At weeks 2, 6, 10, and 14, subjects return to the clinic for the following assessments: adverse events, concomitant medications, symptom-driven physical examination, vital signs, and dosing with study medication,

[0042] At weeks 4. 8, and 12, subjects return to the clinic for the following assessments: adverse events, concomitant medications, physical examination, vital signs, ABC, CY- BOCS, SRS, SCQ, CGI- Improvement, and dosing with study medication.

100431 At week 1 6, the end of the treatment phase, subjects return to the clinic for the following end-of-treatment phase assessments: adverse events, concomitant medications, vital signs, clinical laboratories (including hematology, serum chemistry, C-reactive protein, LFTs), urinalysis, stool culture, pregnancy laboratory (female subjects only), 12-lead ECG, ABC, CY-BOCS, SRS, SCQ, and CGI-lraprovement.

[0044] At month 10 (week 40), subjects return to the clinic for the following assessments: adverse events, concomitant medications, vital signs, clinical laboratories (including hematology, serum chemistry, C-reactive protein, LFTs), urinalysis, stool culture, pregnancy laboratory (female subjects only), 12-lead ECG, ABC, CY-BOCS, SRS, SCQ, and CGI-Improvement.

[0045] Data analysis will be presented using both descriptive and inferential statistics. Efficacy outcomes will be evaluated using the Intent-to-Treat population (all patients randomized and treated with at least one dose of study medication). All inferential tests are two -sided and pairwise between each active TSO arm and the placebo arm.

[0046] Generally, categorical endpoints will be assessed using a 2-sided chi-square test. Changes and percent changes from pre-treatment to on-treatment time points will be calculated for continuous efficacy endpoints, Continuous data will be assessed via a mixed model; adjusted (LS eans) estimates and standard errors will be presented for these values with their associated pairwise p-va!ues. The primary comparisons will be pairwise between the individual TSO treatment arms and placebo. Longitudinal assessment of changes over time may be performed for select endpoints, utilizing longitudinal mixed effects model with effects for treatment, center, and time. Graphical displays of changes over time will be presented for select outcomes. All data captured on the case report form (and in the clinical laboratory and other electronic databases) will be presented in by-domain data listirsgs. As this is an exploratory study, no adjustments for multiple testing are planned. Dose-response outcomes will be assessed.

[0047] The foregoing description of illustrative embodiments has been presented for purposes of illustration and of description. It is not intended to be exhaustive or limiting with respect to the precise form disclosed, and modifications and variations are possible in light of the above teachings or may be acquired from practice of the disclosed embodiments. It is intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims

WHAT IS CLAIMED IS:

1 . A method of treating an autism spectrum disorder in a human patient comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a hioiogicaily active portion thereof and a pharmaceutically acceptable carrier, wherein the helminthic parasite or portion thereof is selected from the group consisting of T. suis, S. mansoni, H. poi gyrus, T, spiralis, T. irichvura and N, mericanus.

2. The method of claim 1 , wherein the biologically acti ve portion of the helminthic parasite is selected from the group consisting of parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract, parasite cercariae and parasite cercariae extract.

3. The method of claim 1 , wherein the pharmaceutical formulation comprises embryonated parasite eggs or embyronated parasite egg extract of T. suis,

4. The method of claim 1 , wherein the autism spectrum disorder is selected from the group consisting of autism, Asperger's syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett's syndrome.

5. The method of claim 1 , wherein the autism spectrum disorder is autism.

6. The method of claim I , wherein the human patient is a pediatric or neonatal patient.

7. The method of claim 5, wherein the treatment decreases the frequency or severity of acute and recurrent symptoms of autism.

8. The method of claim 7, wherein the acute and recurrent symptoms of autism are selected from the group consisting of aggressive behavior, repetitive movements, language disability, seizure disorder, sensory processing problems, hyperactivity, anxiety, tantrums, and immune dysfunction.

9. The method of claim 1 , wherein the treatment is a maintenance treatment.

10. The method of claim 3 , wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T. suis.

1 1. The method of claim 10, wherein the iherapeuiscaily effective amouni is between about 500 and about 20.000 eggs.

12. The method of claim 1 1 , wherein the amount is administered between about I and about 4 times per month for a duration of six months or greater.

S 3. The method of claim I , wherein the pharmaceutical tormulauon is administered orally.

14. The method of claim 10, wherein the therapeutically effective amount is between about 2,000 and about 10,000 eggs,

1 5. The method of claim 10, wherein the therapeutically effective amount is about 2,500 eggs.

16- The method of c!airn 10, wherein the therapeutically effective amount is about 7,500 eggs.

17. The method of claim i , wherein the frequency of administration of the pharmaceutical formulation is greater for a first period of time taking place at the outset of treatment, than the frequency of administration during a second period of time taking place after the first period of time.

1 8. The method of claim S , wherein the frequency of administration of the pharmaceutical formulation is increased for a period of time when acute symptoms of ASD appear or are expected to appear, followed by a return to the frequency of administration after the acute symptoms have subsided.

! 9. The method of claim 1 , wherein the pharmaceutical formulation is adm inistered enterally.