A Study to Assess the Efficacy and Safety of XP23829 in Subjects With Moderate-to-Severe Chronic Plaque-Type Psoriasis

Study Design : This is a , multi-center, double blind, placebo-controlled, phase 2 (dose-finding) efficacy and safety study in which subjects with moderate-to- severe chronic plaque-type psoriasis will be randomized in a 1:1:1:1 allocation ratio to 1 of 3 active doses of XP23829 or placebo. Approximately 50 subjects will be enrolled into each treatment group.

Study Periods: The study includes a 4-week screening phase, a 12-week treatment phase (with 9 weeks of XP23829 or placebo at the maintenance dose), and a 4-week observational post-treatment follow-up phase. A treatment-free follow-up period is designed to evaluate safety and disease relapse and rebound.

Specifically, the study periods are as follows:

1. Screening Phase: Weeks -4 through 0
2. Treatment phase included:

1. Titration Phase: Weeks 1 through 3
2. Double-Blind Maintenance Phase: Weeks 4 through 12
3. Post-treatment follow-up: Weeks 13 through 16

Efficacy assessments will be performed in the clinic at Baseline (Visit 2) and at the end of Weeks 2, 4, 8, 12, 14, and 16.

Patient-reported outcome measures will be assessed in the clinic at Baseline and at Week 12.

Blood samples for pharmacodynamic (PD) assessments will be collected at Baseline and at Weeks 4, 8, 12 and 16. PD assessments will be conducted in all subjects, with the intent of evaluating psoriasis-associated inflammatory markers.

• XP23829 400 mg QD (Drug), also known as Tepilamide fumarate 400 mg QD, PPC-06 400 mg QD: active dose 1
• XP 23829 800 mg QD (Drug), also known as Tepilamide fumarate 800 mg QD, PPC-06 800 mg QD: active dose 2
• XP23829 400 mg BID (Drug), also known as Tepilamide fumarate 400 mg BID, PPC-06 400 mg BID: active dose 3
• Placebo (Drug): control

Primary outcomes

• • The Percent Change in PASI (Psoriasis Area and Severity Index) Score From Baseline [12 Weeks]: The PASI is a measure of the average redness, thickness, and scaliness of the lesions (each graded on a 0-4 scale) and is weighted by the area of involvement. The minimum possible score on this scale is '0', while the maximum score on this scale is 72. A lower score on this scale at the end of the study indicates an improvement in the condition of subject.

Secondary outcomes

• • Proportion of Subjects Who Achieve a Reduction of 75% or Greater From Baseline in PASI (PASI-75) [Weeks 2, 4, 8, 12, 14 and 16]: The percentage of subjects who achieve a reduction of 75% or greater from Baseline in the Psoriasis Area and Severity Index score (PASI-75) at efficacy assessments conducted at Weeks 2, 4, 8, 12, 14 and 16. The PASI is a measure of the average redness, thickness, and scaliness of the lesions (each graded on a 0-4 scale) and is weighted by the area of involvement. The minimum possible score on this scale is '0', while the maximum score on this scale is 72. A lower score on this scale at the end of the study indicates an improvement in the condition of subject.
• • Proportion of Subjects Who Achieve a sPGA (Static Physician's Global Assessment) Score of Clear or Almost Clear [Weeks 2, 4, 8, 12, 14 and 16]: The Percentage of subjects who achieve the static Physician's Global Assessment (sPGA) score of 'clear' or 'almost clear' (sPGA score 0 or 1) at efficacy assessments conducted at Weeks 2, 4, 8, 12, 14 and 16. Score Grade : Definition - 0 Clear: No signs of psoriasis 1. Almost clear: No thickening to minimal plaque elevation; Normal to slight pink coloration/faint erythema; Focal to minimal scaling 2. Mild: Slight elevation/thickening; Pink to light red coloration; Predominantly fine scaling partially or mostly covering lesions 3. Moderate: Clearly distinguishable/distinct thickening; Definite red coloration; Coarse scaling covering most plaques 4. Severe: Marked thickening with hard/sharp edges; Bright to deep dark red coloration; Thick/coarse scaling covering almost all or all lesions A lower score on this scale at the end of the study indicates an improvement in the disease condition.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male and female subjects, age ≥ 18.
2. Stable, moderate-to-severe plaque-type psoriasis diagnosed for at least 6 months prior to randomization (no morphology changes or significant flares of disease activity in the last 6 months in the opinion of the investigator).
3. Severity of disease meeting all of the following three criteria prior to randomization:

   1. Psoriasis Area and Severity Index (PASI) score of 12 or greater
   2. Total Body Surface Area (BSA) affected by plaque psoriasis of 10% or greater
   3. Static Physician's Global Assessment (sPGA) score of 3 or greater
4. Must be a candidate for phototherapy and/or systemic therapy for psoriasis.

Exclusion Criteria:

1. Subjects with current inverse, erythrodermic, predominantly guttate, or pustular psoriasis.
2. Subjects with current drug-induced or drug-exacerbated psoriasis.
3. Subjects with moderate-to-severe psoriatic arthritis of any type; and subjects with mild psoriatic arthritis, who require systemic disease-modifying therapy.
4. Subjects with unstable or significant illness, including the presence of laboratory abnormalities at screening that in the opinion of the investigator would place the subject at unacceptable risk if he/she were to participate in the study.
5. Any skin condition (e.g. eczema) which confounds the ability to interpret data from the study.
6. Treatment with a topical anti-psoriatic therapy within 14 days prior to randomization (including topical steroids, topical vitamin A or D analog preparations, tacrolimus, pimecrolimus, or anthralin).
7. Phototherapy or prolonged sun exposure or use of ultraviolet (UV) light sources within 28 days of randomization.
8. Use of investigational or approved biologic treatments that are known to affect psoriasis, such as adalimumab, etanercept, golimumab or infliximab within 12 weeks of randomization and ustekinumab within 24 weeks of randomization.
9. Use of systemic medications (non-biologics) that are known to affect psoriasis (including but not limited to oral corticosteroids, cyclosporine, methotrexate, lithium, and beta-adrenergic blockers) within 4 weeks of randomization, or 5 half-lives, whichever is longer.
10. Prior treatment with Dimethyl Fumarate (Fumaderm® or Tecfidera®) or any other Fumaric Acid Ester (FAE) containing products.
11. Have failed (due to inadequate response) more than 3 approved systemic agents for the treatment of psoriasis.

Participant flow

Outcome results

• • The Percent Change in PASI (Psoriasis Area and Severity Index) Score From Baseline (Primary), Least squares mean, percentage change from baseline: XP23829 400 mg QD (Once Daily) -38.1 +/- 5.07; XP23829 800 mg QD (Once Daily) -48.2 +/- 5.06; XP23829 400 mg BID (Twice Daily) -50.7 +/- 5.50; Placebo -25.0 +/- 5.06 (p 0.066)
• • Proportion of Subjects Who Achieve a Reduction of 75% or Greater From Baseline in PASI (PASI-75) (Secondary), Count of participants, Participants: XP23829 400 mg QD (Once Daily) 1; XP23829 800 mg QD (Once Daily) 0; XP23829 400 mg BID (Twice Daily) 0; Placebo 0 (p 0.501)
• • Proportion of Subjects Who Achieve a sPGA (Static Physician's Global Assessment) Score of Clear or Almost Clear (Secondary), Count of participants, Participants: XP23829 400 mg QD (Once Daily) 0; XP23829 800 mg QD (Once Daily) 0; XP23829 400 mg BID (Twice Daily) 0; Placebo 0 (p 0.229)

Adverse events

Time frame: Baseline to Week 16 or study discontinuation

Serious adverse events by term

Other adverse events by term

• Dmitri Lissin, M.D., Study director, XenoPort, Inc.