A Study to Characterize the Pharmacokinetics, Pharmacodynamics, and Safety of Anifrolumab in Adult Type I Interferon Test High Systemic Lupus Erythematosus Subject With Active Skin Manifestations

Study Overview
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Brief Summary
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This study will be conducted to characterize pharmacokinetics, pharmacodynamics, safety, and tolerability of anifrolumab given via the subcutaneous (SC) route of administration in adult Systemic Lupus Erythematosus (SLE) subjects with a type I Interferon (IFN) test high result and active skin manifestations while receiving Standard of Care (SOC) treatment. In addition, the efficacy of anifrolumab on SLE skin manifestations will be characterized.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study Characterizing the Pharmacokinetics, Pharmacodynamics, and Safety of Anifrolumab Following Subcutaneous Administration in Adult Systemic Lupus Erythematosus Subjects With Type I Interferon Test High Result and Active Skin Manifestations.

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Anifrolumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 through 70 years Diagnosis of paediatric or adult SLE for > 24 weeks and fulfilling ≥4 of the 11 American College of Rheumatology (ACR) classification criteria with at least one being: Positive antinuclear antibody (ANA) or Elevated anti-dsDNA antibodies or anti-Smith (anti-Sm) antibodies Interferon high test result Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score ≥ 10 Currently receiving at least 1 of the following for treatment of SLE: • Oral prednisone or equivalent of ≤40 mg/day for a minimum of 2 weeks prior to signing the Informed Consent Form (ICF) and with stable dose for at least 2 weeks prior to randomization • Any of the following medications for at least 12 weeks prior to signing the ICF, and at a stable doses for at least 8 weeks prior to randomization: (i) Azathioprine ≤200 mg/day (ii) Antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine) (iii) Mycophenolate mofetil ≤2 g/day or mycophenolic acid ≤1.44 g/day (iv) Oral, subcutaneous (SC), or intramuscular methotrexate ≤25 mg/week (v) Mizoribine ≤150 mg/day Must not have signs of active or latent tuberculosis (TB). Must not be pregnant or breastfeeding. Exclusion Criteria: Active severe or unstable neuropsychiatric SLE Active severe SLE-driven renal disease Any severe herpes infection at any time Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV infection. Known history of a primary immunodeficiency (splenectomy, or any underlying condition predisposing for infection Receipt of any investigation product within 4 weeks or 5 half -lives prior to signing of the ICF History of cancer, apart from: Squamous or basal cell carcinoma of the skin if successfully treated. Cervical cancer in situ if successfully treated

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Experimental: Anifrolumab - Lower dose<br>1ml, once every second week, one subcutaneous injection as added to stand of care, from week 0 to week 50 | Drug: Anifrolumab<br>* subcutaneous administration every 2 weeks from week 0 to week 50<br>|
| Placebo Comparator: Placebo matching for lower dose of Anifrolumab<br>1ml, once every second week, one subcutaneous injection added to stand of care, from week 0 to week 50 | Drug: Placebo<br>* subcutaneous administration every two weeks from week 0 to week 50<br>|
| Experimental: Anifrolumab - Higher dose<br>2×1ml, once every second week, two subcutaneous injections as added to stand of care, from week 0 to week 50 | Drug: Anifrolumab<br>* subcutaneous administration every 2 weeks from week 0 to week 50<br>|
| Placebo Comparator: Placebo matching for higher dose of Anifrolumab<br>2×1ml , once every second week, two subcutaneous injections as added to stand of care, from week 0 to week 50 | Drug: Placebo<br>* subcutaneous administration every two weeks from week 0 to week 50<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration of Anifrolumab in Serum After First Dose | Maximum concentration (Cmax) of anifrolumab is based on sample collected 5 to 8 days after the first dose of strudy treatment. | Week 0 | 
| Steady-state Serum Trough (Predose) Concentration (Ctrough) of Anifrolumab | Steady-state serum through concentration (Ctrough) is based on sample collected at Week 12 prior to dosing of study treatment (predose). | Week 12 | 
| 21-gene Type 1 IFN Signature Score (Fold-change) | 21-gene type I IFN signature score (fold change) is based on samples collected both at baseline and Week 12 prior to dosing of study treatment. Levels of 21-gene type I IFN pharmacodynamics signature is derived as relative to a pooled normal control. | Week 12 | 
| 21-gene Type 1 IFN Neutralization Ratio (Percent Suppression of Fold Change) | 21-gene type I IFN signature score (fold change) is based on samples collected both at baseline and Week 12 prior to dosing of study treatment. For each individual participant and assessment, the level of 21-gene type I IFN pharmacodynamics signature is derived as relative to a pooled normal control, as the median of 100-(((baseline-Week 12)/baseline)*100) for the 21 genes. At a population level, the results are presented as mean the above. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Antidrug Antibody (ADA) | Post-baseline ADA incidence based on the number of participants with Antidrug antibody (ADA) | Baseline to Week 52 | 
| Number of Participants With Neutralizing Antibodies (nAb) | Incidence of detectable nAb in post-baseline ADA positive participants. | Baseline to Week 52 | 
| Number AEs (Adverse Events) and SAEs (Serious Adverse Events), Including Adverse Events of Special Interest (AESI) | Number of participants with any AEs (Adverse events), any SAEs (serious adverse events), and any adverse events of special interest (AESI) are summarized. More details are reported in the Adverse Events section. | Baseline to Week 52 | 
| Change From Baseline for Vital Signs | Change from baseline for vital signs. | Baseline to Week 60 | 
| Change From Baseline for Physical Examination | Physical examination is reported as change from baseline in body weight. | Baseline to Week 60 | 
| Change From Baseline for 12-lead ECG | The 12-lead ECG measurements were assessed by the investigators, and reported as normal, abnormal (not clinically significant [NCS]), abnormal (clinically significant [CS]), or not done. | Baseline to Week 52 | 
| Value of Haemoglobin Blood Test to Detect Change From Baseline | Change from baseline in haemoglobin blood tests are reported. | Baseline to Week 60 | 
| Value of Haematology Blood Tests to Detect Change From Baseline | Change from baseline in haematology blood tests (leucocytes [particle concentration], platelets [particle concentration]) are reported. | Baseline to Week 60 | 
| Value of Protein-creatinine Urinalysis Test to Detect Change From Baseline | Change from baseline in protein-creatinine ratio urinalysis tests are reported. | Baseline to Week 60 | 
| Value of Total Protein Urinalysis Test to Detect Change From Baseline | Change from baseline in total protein urinalysis tests are reported. | Baseline to Week 60 | 
| Value of Clinical Chemistry Blood Tests to Detect Change From Baseline (Serum) | Change from baseline in clinical chemistry blood tests (Alanine Aminotransferase, Aspartate Aminotransferase) are reported. | Baseline to Week 60 | 
| Value of Creatinine Clinical Chemistry Blood Tests to Detect Change From Baseline (Serum) | Change from baseline in clinical creatinine chemistry blood tests (serum) are reported. | Baseline to Week 60 | 
| Value of Inflammatory Marker Panel Blood Tests to Detect Change From Baseline | Change from baseline in the Erythrocyte Sedimentation Rate (ESR) inflammatory marker is reported. | Baseline to Week 60 | 
| Value of Autoantibody Blood Panel Blood Tests to Detect Change From Baseline | Change from baseline in Anti-Double Stranded DNA IgG (anti-dsDNA) is reported. | Baseline to Week 60 | 
| Number of Participants With Positive Hepatitis B Core Antibody Post-baseline. | Change from screening in Hepatitis B core antibody was monitored during the study for participants tested positive at screening. | Baseline to Week 60 |