A 12-week Dose-Ranging Trial in Patients With Moderate to Severe Plaque Psoriasis

A Randomized, Double-Blind, Placebo-Controlled, 12-week Dose-Ranging Trial of IMO-8400 in Patients With Moderate to Sever Plaque Psoriasis

IMO 8400 is a second-generation oligonucleotide antagonist of endosomal Toll-like receptors (TLR) 7, TLR8 and TLR9. These TLR react to complexes of exogenous nucleic acids (as might be encountered during infection) and endogenous nucleic acids (as might be released during tissue damage during autoimmune disease). In vitro and in multiple animal models of autoimmune disease, IMO-8400 blocks immune activation mediated through TLR7, 8 and 9. In Phase 1 studies (Protocol 8400-001) IMO 8400 has been administered to healthy adults by SC injection at single-doses and multiple-doses (4 weeks) up to 0.6 mg/kg. All treatments were well-tolerated, with mild injection site reactions and no pattern of systemic reactions or laboratory changes.

The current study represents the first clinical trial of IMO-8400 in patients with active autoimmune disease. Moderate to severe plaque psoriasis was chosen for this 12-week proof of activity trial based on a prior 4-week study using a first generation TLR7 and 9 antagonist which demonstrated clinical improvement in this patient population.

Eligible subjects will be enrolled and randomized to receive one of the four treatments (three dose levels of IMO-8400 or Saline Placebo). Treatments will be administered once weekly by subcutaneous injections. Subjects will received treatment for 12 weeks and then be followed for an additional 6 weeks to assess the durability of the response.

Inclusion Criteria:

1. Is age 18 to 70 years, inclusive
2. Completes the informed consent procedure (see Section 15.2), including signing and dating the informed consent form
3. Has moderate to severe plaque psoriasis meeting the criteria specified above
4. Is willing and able to comply with the restrictions detailed above
5. Female subjects must have a negative pregnancy test at screening and on Day 1 prior to start of treatment
6. Female subjects of childbearing potential (see Section 8.2) and male subjects who have partners of childbearing potential must agree to use effective birth control (contraception; see Section 8.2) from Screening through the treatment period and for ninety (90) days after the last injection of study drug

Exclusion Criteria:

1. Has known hypersensitivity to any oligodeoxynucleotide

2. Is nursing

3. Has body weight <50 kg

4. Has BMI >34.9 kg/m2

5. Regularly consumes >3 drinks of alcoholic beverages (beer, wine, or distilled spirits) per day

6. Has a positive test for antibody to human immunodeficiency virus (HIV-1 or -2) or hepatitis C virus (HCV)

7. Has a positive test for hepatitis B surface antigen (HBsAg)

8. Has at screening safety laboratory tests meeting one or more of the following criteria:

   • hemoglobin <6.52 mmol/L (<10.5 g/dL)
   • white blood cell count <4x109/L ( <4,000/mm3)
   • absolute neutrophil count (ANC) <1.5x109/L (<1500/mm3)
   • platelet count <100x109/L (<100,000/mm3 )
   • serum creatinine >1.3x ULN;
   • alanine transaminase (ALT; SGPT) >2.5x ULN
   • aspartate transaminase (AST; SGOT) >2.5x ULN
   • serum total bilirubin >1.4x ULN (except if consistent with Gilbert's disease: i.e., total bilirubin <103 μmol/L (6 mg/dL) and conjugated bilirubin <1.2x ULN)

9. Has a history of allogeneic organ transplant (including bone marrow or stem cells)

10. Has, within the past 10 years, had evidence of or required treatment for cancer (except for treated, non-invasive carcinoma of the skin or cured cervical carcinoma-in-situ)

11. Has had within the past three months or is expected to have during the study period any of the following treatments:

    • surgery requiring general anesthesia
    • hematopoietic stimulating agents (e.g., erythropoietin, G-CSF, GM-CSF)
    • another investigational drug;

12. Has other significant medical conditions (chronic or active within the past 6 months), including, but not limited to: cardiac disease (e.g., unstable angina, myocardial infarction, congestive heart failure, ventricular arrhythmia); uncontrolled seizure disorder; liver disease; uncontrolled diabetes

13. Has any other condition that would, in the opinion of the Investigator, potentially compromise the safety or compliance of the patient or may preclude the patient's successful completion of the clinical trial