A Phase Ib/IIa, Double-Blind, Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of S-777469 in Subjects With Atopic Dermatitis

A Phase Ib/IIa, Multiple-Dose, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of S-777469 in Subjects With Mild to Moderate Atopic Dermatitis

The purpose of this randomized, double-blind, placebo-controlled, sequential-cohort, dose-escalation study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of S-777469, a CB2 cannabinoid receptor agonist, in subjects with mild to moderate atopic dermatitis.

Inclusion Criteria:

• Otherwise healthy males and females between 18 and 65 years of age at the time of obtaining the written informed consent
• Subject understands the study procedures and agrees to participate in the study by giving written informed consent
• Subject satisfies the diagnostic criteria for mild to moderate atopic dermatitis (AD) as judged by the Physician's Global Assessment Score and modified criteria

All of these features must be present:

1. Pruritus

2. Eczema (acute, subacute, chronic) with the following characteristics:current or prior flexural lesions, lesions on the face, neck, and extensor surfaces, sparing of groin and axillary regions (no lesions)

3. History of a chronic and relapsing course of eczema

4. Personal or family history of atopy

   • Subject is judged to be in general good health based on medical history, physical examination, and routine laboratory tests performed at screen and baseline, with the exception of diagnosis of mild to moderate AD
   • Subject has a negative laboratory results for hepatitis B surface antigen, hepatitis C virus (anti-HCV antibodies), and Human Immunodeficiency Virus antibody screens
   • Female subjects have a negative pregnancy test at screen and baseline
   • Serum creatinine in the normal range [0.5 to 1.5 mg/dl]
   • Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma glutamyl transpeptidase [GGT]) within normal range
   • Negative screen for drugs of abuse at screen and baseline
   • Subject agrees to refrain from smoking for the duration of the trial
   • Subject has no clinically significant abnormality on screening or baseline electrocardiogram (ECG). Inclusion of a subject with any ECG abnormality at screening or baseline must be jointly agreed upon by both Study Investigator and Sponsor to be not clinically relevant within the context of the study, prior to enrollment
   • Use of adequate birth control, if of reproductive potential and sexually active Adequate birth control is defined as agreement to consistently practice an effective and accepted method of contraception throughout the duration of the study and for 1 additional month after last administration/dose of study drug.

For females, adequate birth control methods will be defined as: oral contraceptives, intrauterine device or double barrier contraception, i.e., condom + diaphragm, condom or diaphragm + spermicidal gel or foam For males adequate birth control methods will be defined as double barrier contraception, i.e., condom + diaphragm, condom or diaphragm + spermicidal gel or foam

• For female subjects, menopause is defined as one year without menses; if in question, a follicle-stimulating hormone of >40 U/ml must be documented. Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, as applicable
• Subject has not used any topical or systemic treatments for AD for 3 weeks prior to the Day 1 visit (i.e., the washout period), including topical corticosteroids (3 weeks prior to the Day 1 visit), antihistamines (3 weeks prior to the Day 1 visit), herbal preparation, cosmetic or emollient preparations (3 weeks prior to the Day 1 visit), immunosuppressant drugs or corticosteroids (3 weeks prior to the Day 1 visit), any other AD treatments (including light treatment) for 3 weeks prior to the Day 1 visit
• Subject is willing to completely avoid the use of any prescription or nonprescription (including over the counter) drugs or any topical preparations [other than those topical emollient preparations provided by the study site during screening, e.g., Cetaphil® cream] for 3 weeks prior to the first dose of study drug and during the entire study
• If a subject does not discontinue all prior medications within 3 weeks of study start, he/she may be included in the study only if both the Study Investigator and Sponsor's Medical Monitor agree that this is not clinically relevant within the context of the study
• Use of hormone replacement therapy (for postmenopausal females) and/or use of oral, implantable, transdermal, or injectable contraceptive(s) will be allowed
• Subject is willing to avoid strenuous physical activity (i.e., strenuous or unaccustomed weight lifting, running, exercise, etc.) from the screening visit, throughout the study, and until the post-study follow-up visit
• Subject is willing to avoid grapefruit-containing products/medications for 72 hours prior to entry into the clinical research unit and for the duration of the study
• Subject has no history of frequent or recent acetaminophen use and is willing to refrain from use of acetaminophen throughout the trial and for 4 days after the last dose

Exclusion Criteria:

Subjects will not be eligible if they meet any of the following criteria:

• Subject is under the age of legal consent (see inclusion criteria), is mentally or legally incapacitated, has significant emotional problems at the time of study entry, or has a history of psychiatric disorders
• Active dermatologic conditions which may confound the diagnosis of AD, such as scabies, allergic contact dermatitis, seborrheic dermatitis, cutaneous lymphoma, ichthyosis, or psoriasis
• History of malignancy not in remission for >5 years
• Presence of comorbid conditions that would preclude participation in the study, including:

Immune compromised state, including recent chemotherapy, immunotherapy, or organ transplant History or clinical manifestations of significant metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal or urological History or clinical manifestations of significant neurological or psychiatric disorders Subject has an active, intercurrent infection Subject has a history of clinically significant hypersensitivity, anaphylaxis, or allergies to any drug compound In no circumstances should a subject who did not qualify under inclusion criteria regarding liver function tests (ALT, AST, and GGT) be re-screened and/or re-qualified for this study

• Subject has any acute or chronic condition or prior therapy that, in the opinion of the Investigator, would limit the subject's ability to complete and/or participate in this clinical study or otherwise would make the subject unsuitable for this study
• Subject has a history of drug abuse within 1 year prior to Day 1
• Subject consumes excess amounts of alcohol, defined as exceeding an average of 14 drinks/week (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor, or any combination of them) within 2 months prior to Study Entry, or is unwilling to comply with the restricted use of alcohol from screening, throughout the study, and until study completion (post-study visit)
• Subject has used any systemic antibiotics for 3 weeks prior to the Day 1 visit (washout period)
• Subject is pregnant or lactating or intends to become pregnant or, in the case of a male subject, intends to father a child during the study period and for 1 month after the last dose of study medication
• Subject requires use of immunosuppressive drugs such as oral corticosteroids or inhaled corticosteroids
• Subject has donated blood within 6 weeks prior to Day 1 or plasma within 2 weeks prior to screening, or received blood products within 2 months prior to Day 1
• Subject has poor peripheral venous access
• Subject has participated in any other investigational study drug trial in which receipt of an investigational study drug occurred within 30 days prior to Day 1
• Any reason which, in the opinion of the investigator, interferes with the ability of the subject to participate to, or complete, the trial