Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects With Moderate to Severe Plaque-Type Psoriasis

Study Overview
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Brief Summary
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This double-blind, placebo-controlled study will be conducted at 5 study centers in the United States. Approximately 30 subjects with moderate to severe plaque-type psoriasis will take part. The study will consist of a screening period of up to 21 days, a 12-week treatment period with 7 on-treatment clinic visits (approximately one every 2 weeks) and a post-dosing follow-up clinic visit approximately 30 days after the last dose of study drug is taken. Subjects will be randomized to receive either 250mg, 500mg or 1000mg of study drug or placebo. Study drug will be taken by mouth on a full stomach, every day for 84 days. Vital signs, clinical laboratory results (hematology, chemistry, and urinalysis), ECGs and physical examinations will be assessed at periodic intervals from Day 1 through Day 84. A skin biopsy will be taken at the beginning and the end of the dosing period to evaluate any effects of the study drug on psoriasis. Investigators will perform other psoriasis evaluations (including the Psoriasis Area and Severity Index [PASI] and the Physician's Global Assessment [PGA] at 5 different times throughout the study to quantify the effects of SRT2104 on psoriasis activity. Subjects will complete questionnaires throughout the study, to document their sense of well-being and mood at 4 different times during the study. Five blood samples will be obtained at different timepoints during the study, to measure the amount of SRT2104 in the body.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects With Moderate to Severe Plaque-Type Psoriasis

Conditions
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Psoriasis

Intervention / Treatment
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* Drug: Placebo
* Drug: SRT2104


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent to participate in the study Be male or female aged 18 to 80 years (inclusive) Have a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving ≥10% of body surface area Have a baseline PASI of ≥10 Be a candidate for systemic psoriasis therapy, in the opinion of the investigator If a female subject of child-bearing potential, be willing to use reliable contraception for the duration of the study, through the 30 day safety follow up telephone call Be willing and able to comply with the protocol for the duration of the study Exclusion Criteria: Has received systemic non-biologic psoriasis therapy or PUVA phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or UVB phototherapy within 2 weeks prior to the Screening Visit Has received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life is unknown) prior to the first dose of SRT2104 Has received a live vaccination within 4 weeks prior to the Screening Visit or intends to have a live vaccination during the course of the study Use of any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however, the administration of proton pump inhibitors during the study dosing period is prohibited Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit Has received any investigational drug or experimental procedure within 30 days prior to the first dose of SRT2104 Has an active infection (e.g., sepsis, pneumonia, abscess, etc.) or be at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104 Has a history of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that cannot be attributed to a prior BCG inoculation Has a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit Has a positive test for HIV antibody Has an abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, would preclude entry into the trial Has a 12-lead electrocardiogram (ECG) with changes considered to be clinically significant on medical review including prolonged QTc intervals as defined below: QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period) QTcB ≥480 msec in subjects with Bundle Branch Block Has renal or liver impairment, defined as: Serum creatinine level of ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males AST and ALT ≥ 2xULN or Alkaline phosphatase and bilirubin > 1.5xULN (an isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%) Has active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which have been definitively treated with standard of care approaches) Is pregnant or breast-feeding. Confirmation that a female subject is not pregnant must be established by negative pregnancy tests at Screening and Day 1 Has a significant history of alcoholism or drug/chemical abuse, or consumes more than 3 standard units/day of alcohol. A standard unit of alcohol is defined as 250 mL of beer, 25 mL of spirit, or 125 mL of wine History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation Has an acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 2 - 500mg SRT2104/placebo dose group<br>10 subjects will be randomized 4:1 (SRT2104: placebo) in each of 3 treatment arms (250mg, 500mg, or 1000mg). Cohort 2 will commence after Cohort 1 has completed 28 consecutive days of dosing, followed by the completion of a safety review by an Independent Safety Review Committee. Cohort 2 will be administered at approximately the same time every day, approximately 15 minutes following the consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories. Dietary recommendations for the meal that precedes dosing will be provided to the study subjects by the clinical site staff. | Drug: Placebo<br>* For the placebo product, the SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product.<br>Drug: SRT2104<br>* SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged in dosing bottles containing a single daily dose.<br>|
| Active Comparator: Cohort 3 - 1000mg SRT2104/placebo dose group<br>10 subjects will be randomized 4:1 (SRT2104: placebo) in each of 3 treatment arms (250mg, 500mg, or 1000mg). Cohort 3 will commence after Cohort 2 has completed 28 consecutive days of dosing, followed by the completion of a safety review by an Independent Safety Review Committee. Cohort 3 will be administered four SRT2104 capsules at approximately the same time every day, approximately 15 minutes following the consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories. Dietary recommendations for the meal that precedes dosing will be provided to the study subjects by the clinical site staff. | Drug: Placebo<br>* For the placebo product, the SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product.<br>Drug: SRT2104<br>* SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged in dosing bottles containing a single daily dose.<br>|
| Active Comparator: Cohort 1 - 250mg SRT2104/placebo dose group<br>10 subjects will be randomized 4:1 (SRT2104: placebo) in each of 3 treatment arms (250mg, 500mg, or 1000mg). Cohort 1 will be administered at approximately the same time every day, approximately 15 minutes following the consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories. Dietary recommendations for the meal that precedes dosing will be provided to the study subjects by the clinical site staff. Dosing for Cohort 2 will not commence until Cohort 1 has completed 28 consecutive days of dosing, followed by the completion of a safety review by an Independent Safety Review Committee. | Drug: Placebo<br>* For the placebo product, the SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product.<br>Drug: SRT2104<br>* SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged in dosing bottles containing a single daily dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Clinical Activity by Improvement Score (Using Krueger Criteria): Number of Participants With Good or Excellent Improvement Score Based on Histological Assessments of Skin Biopsies After 12 Weeks of Exposure | According to the Krueger criteria, improvement score is classified as Good improvement defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but most keratinocytes still express K16. Excellent improvement defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16. No improvement defined as no improvement in epidermal thickness keratinocyte differentiation or K16 expression on keratinocytes. A binomial response was defined for each participant according to whether the participant had an improvement score of good or excellent improvement (response=1) or not (response=0). Number of participants with good or excellent improvement score are presented. | 12 weeks | 
| Number of Participants With Any Adverse Events (AE) and Serious Adverse Events (SAE) | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. The AE category in the data table includes participants who experienced serious or non-serious adverse events or both. | Up to Follow-up (Day 114) | 
| Number of Participants With Hematology and Coagulation Abnormalities of Potential Clinical Concern | Hematology parameters included hemoglobin, hematocrit, red blood cell count, red cell distribution width, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, white blood cell count and complete white blood cell count differential. Coagulation parameters included activated partial thromboplastin time and prothrombin time/international normalized ratio. The potential clinical concern range for hematology parameters were: white blood cell count (low: <0.67x10^9/Liter x lower limit of normal [LLN] and high: >1.82x10^9/L x upper limit of normal [ULN]), neutrophil count: (low: <0.83x10^9/Liter x LLN), hemoglobin (low: <0.85 gram/Liter x LLN and high: >1.03 gram/Liter x ULN for males and >1.13 gram/Liter x ULN for females), hematocrit with units ratio (high: >1.02 x ULN for males and >1.17 x ULN for females), platelet count (low: <0.67x10^9/Liter x LLN and high >1.57x10^9/Liter x ULN) and lymphocytes (low: <0.81x10^9/Liter x LLN). | Up to Follow-up (Day 114) | 
| Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance | The potential clinical concern range for clinical chemistry parameters were: Albumin:(low: <0.86 gram/Liter x LLN), Calcium:(low: <0.91 millimol/Liter [mmol/L] x LLN and high: >1.06 mmol/L x ULN), Creatinine: (high: >1.3 mmol /L x ULN), Glucose: (low: <0.71 mmol/L x LLN, high: >1.41 mmol/L x ULN), Magnesium: (low: <0.63 mmol/L x LLN, high: >1.03 mmol/L x ULN), Phosphorus: (low: <0.8 mmol/L x LLN, high: >1.14 mmol/L x ULN), Sodium: (low: <0.96 mmol/L x LLN, high: >1.03 mmol/L x ULN), Urea: (high: >1.5 mmol/L x ULN), Gamma glutamyl transferase: (high: >2 International units per L x ULN), Total bilirubin (high: 1.5 x ULN), both alanine amino transferase and aspartate amino transferase (high:≥ 2x ULN Units/L) and Bicarbonate: (low: <18 mmol/L and high: >32 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented. | Up to Follow-up (Day 114) | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Values | 12-lead ECG was performed in the rested state with the participant in the supine position with ECG leads on for at least 5 minutes prior to ECG recording. ECGs included PR (PQ), QRS, QT and QT corrected by Bazett's formula (QTcB), QT corrected by Fridericia's formula (QTcF) intervals. Identification of any conduction abnormalities were recorded in the eCRF. If a participant's QTc intervals were prolonged, then the ECG was done in triplicate with results reported as an average of the three ECGs. Number of participants with abnormal electrocardiogram (ECG) values are presented. | Up to Follow-up (Day 114) | 
| Number of Participants With Vital Signs of Potential Clinical Importance | Vital sign assessments included measurements of resting heart rate and blood pressure. Potential clinical concern range for systolic blood pressure: <85 and >160 millimeter of mercury (mmHg), for diastolic: <45 and >100 mmHg and heart rate: <40 and >110 beats per minute. Number of participants with vital signs of potential clinical importance are presented. | Up to Follow-up (Day 114) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Activity in Psoriasis Area and Severity Index (PASI) Score After 4, 8, and 12 Weeks of Exposure | PASI score was determined by evaluation of body surface area (BSA) covered by plaque psoriasis in 4 areas (head/neck, arms, trunk and legs with area score of 0.1, 0.2, 0.3 and 0.4 respectively). This test included combination of both degree of involvement (assessed as per the % of affected body area using a 7-point scale such that 0=0% involvement, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89% and 6=90-100%) and severity (evaluated individually using a 5-point scale that ranged as 0=No evidence of sign, 1=slight evidence, 2=moderate evidence, 3=marked evidence and 4=very marked, most severe evidence of sign) of erythema, induration and desquamation in each of the same 4 areas. PASI score ranges from 0 (no psoriasis) to 72 (worse psoriasis). Final PASI=(sum of severity score for each area)x(% body affected score x area score). | Weeks 4, 8 and 12 | 
| Summary of Physician's Global Assessment (PGA) Score After 4, 8 and 12 Weeks of Exposure | The severity of psoriatic lesions over the whole body were assessed by the investigator using the PGA scoring system. A 0 to 6 point rating scale was used, as follows: 0 = Clear (no signs of psoriasis), 1 = Almost clear (slight elevation, scale and/or erythema), 2 = Mild (mild plaque elevation, scale and/or erythema), 3 = Mild to moderate (mild plaque elevation with moderate erythema and/or scale), 4 = Moderate (moderate plaque elevation, scale and/or erythema), 5 = Moderate to severe (marked plaque elevation, scale and/or erythema), 6 = Severe (very marked plaque elevation, scale and/or erythema). Higher scores indicated worse psoriasis. Participants in the SRT2104 0.25 g dose group inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available. Participants in the SRT2104 0.25 g dose group inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available. | Weeks 4, 8 and 12 | 
| Area Under Curve (AUC) of 12 Weeks of Dosing With 0.25 g, 0.5 g and 1.0 g SRT2104 in the Fed State in Participants | A total of five blood samples (6 milliliter [mL] each) were obtained from each participant up to Week 12, for determination of SRT2104 plasma concentrations. No two samples were separated by less than an hour. One pre-dose sample was collected prior to taking study medication (30 minutes or less before dosing) at any Visit 4 (Week 4), Visit 6 (Week 8) or Visit 8 (Week 12). A single pharmacokinetic (PK) sample was collected in the time interval of 0.5 to 2 hours post-dose and also 3 to 6 hours post-dose at any Visit 4 (Week 4), Visit 6 (Week 8) or Visit 8 (Week 12). Two PK samples were collected in the time interval of 6 to 22 hours post dose at any Visit 4 (Week 4), Visit 6 (Week 8) or Visit 8 (Week 12). | Pre-dose (30 minutes or less before dosing: 1 sample), 0.5 to 2 hours and 3 to 6 hours post-dose (1 sample), 6 to 22 hours post-dose (2 samples) up to Week 12 | 
| Maximum Plasma Concentration (Cmax) of 12 Weeks of Dosing With 250 Milligrams (mg), 500 mg and 1000 mg SRT2104 in the Fed State in Participants | A total of five blood samples (6 mL each) were obtained from each participant at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12), for determination of SRT2104 plasma concentrations. No two samples were separated by less than an hour. One pre-dose sample was collected prior to taking study medication (30 minutes or less before dosing) at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12). A single pharmacokinetic (PK) sample was collected in the time interval of 0.5 to 2 hours post-dose and also 3 to 6 hours post-dose at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12). Two PK samples were collected in the time interval of 6 to 22 hours post dose at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12). | One sample: Pre-dose (30 minutes or less before dosing), One sample: 0.5 to 2 hours post-dose and 3 to 6 hours post-dose and 2 samples 6 to 22 hours post dose, at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12) | 
| Change From Baseline in Fibroblast Growth Factor 21 (FGF21) as an Indicator of the Pharmacodynamic Effects of SRT2104 | The pharmacodynamic effects of SRT2104 was measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation (hsCRP and FGF21) in blood samples. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values. | Baseline (Day 1) and Days 28, 56 and 84 | 
| Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) as an Indicator of the Pharmacodynamic Effects of SRT2104 | The pharmacodynamic effects of SRT2104 was measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation (hsCRP and FGF21) in blood samples. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values. | Baseline (Day 1) and Days 28, 56 and 84 |