A Study of NKTR-358 (LY3471851) in Participants With Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus Clinical Trial

Official title:

A Phase 1, Double-blind, Randomized, Placebo-controlled, Ascending Multiple-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous NKTR-358 in Patients With Systemic Lupus Erythematosus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03556007
• Other study ID #: 17238
• Secondary ID: J1P-MC-KFAB17-35
• Status: Completed
• Phase: Phase 1
• Start date: April 18, 2018
• Est. completion date: August 29, 2019

Study information

• Verified date: November 2023
• Source: Nektar Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main purpose of this study is to evaluate the safety and tolerability of a study drug known as LY3471851 in participants with SLE. The study will last about 79 days for each participant.

Description:

LY3471851 is a potential first-in-class therapeutic that may address an underlying immune system imbalance in people with many autoimmune conditions. It targets the interleukin (IL-2) receptor complex in the body in order to stimulate proliferation of inhibitory immune cells known as regulatory T cells. By activating these cells, LY3471851 may act to bring the immune system back into balance.

This study will evaluate the safety, tolerability, pharmacokinetics (PK), and immunologic effects of multiple doses of LY3471851 in participants with minimal to moderate SLE. The effects on SLE disease activity will also be evaluated. SLE participants will be randomized to receive multiple subcutaneous (SC) doses of LY3471851 or receive placebo. After receiving the last dose of LY3471851 or placebo, participants will be followed for an additional 50 days to evaluate safety, PK, pharmacodynamics (PD), and preliminary efficacy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: August 29, 2019
• Est. primary completion date: August 29, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Willing and able to give written informed consent and comply with study procedures and requirements.

• Body mass index (BMI) between 18.0 and 32.0 kilograms per square meter (kg/m²).

• Systolic blood pressure between 90 to 140 millimeters of mercury (mm Hg), diastolic blood pressure between 50 to 90 mm Hg, and resting heart rate between 40 to 100 beats per minute.

• Diagnosis of adult SLE according to the 1997 ACR classification criteria for at least 6 months prior to signing the informed consent form (ICF).

• Minimal to moderate SLE disease activity (active SLE clinical disease is not required for enrollment into the study and participants with severe SLE clinical disease activity, based on the evaluation of the investigator, should be excluded).

• If a participant is taking oral prednisone (or prednisone equivalent) for their SLE, the dose must be less than or equal to (=) 10 milligrams per day (mg/day) for a minimum of 8 weeks prior to screening. In addition, the dose of oral prednisone or prednisone equivalent the participant is taking must be stable for a minimum of 2 weeks prior to screening.

• If a participant is taking any of the medications below for their SLE, the medication must have been administered for a minimum of 12 weeks prior to signing the ICF, and at a stable dose for a minimum of 8 weeks prior to signing the ICF:

• Azathioprine = 200 mg/day

• Antimalarial (e.g., chloroquine, hydroxychloroquine, quinacrine)

• Mycophenolate mofetil = 2 grams per day (g/day) or mycophenolic acid = 1.44 g/day

• Oral, SC, or intramuscular methotrexate = 15 milligrams per week (mg/week).

• Willing and able to participate in the study for a duration of up to 4 months.

• Willing and able to abstain from participating in another clinical study for a duration of up to 4 months.

• Female participants will be non-pregnant, non-lactating, and either postmenopausal for at least 2 years, or surgically sterile for at least 3 months, or will agree to use double barrier contraception from period prior to study enrollment until 5 months following the last dose received; women of child-bearing potential must have a negative serum beta-human chorionic gonadotropin (ß-hCG) test at screening and randomization prior to administration of investigational product.

• Male participants with female partners of childbearing potential must agree to use double barrier contraception during the study (until 5 months following the last dose received). Sperm donation is also restricted during the time-frame that males must be using double barrier contraception. This criterion may be waived for male participants who have had a vasectomy greater than (>) 6 months prior to enrollment.

Exclusion Criteria:

Medical Conditions:

• Current active bacterial, viral, or fungal infection.

• Evidence of significant hematologic dysfunction.

• Evidence of significant liver or kidney dysfunction.

• History of, or current diagnosis of, a clinically significant non SLE-related vasculitis syndrome.

• Active severe or unstable neuropsychiatric SLE.

• Active severe SLE-driven renal disease or history of severe active lupus nephritis with persisting proteinuria levels greater than 0.5 grams/24 hours.

• Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any history of overlap syndromes of SLE.

• History of, or current, inflammatory joint or skin disease other than SLE.

• History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than 2 weeks within the last 24 weeks prior to signing the ICF.

• Active tuberculosis (TB) on the basis of positive medical history or chest radiograph (OR) evidence of latent TB or by positive (or persistently indeterminate) Quantiferon-TB Gold or T-Spot test.

• Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection.

• Confirmed positive serology for hepatitis B, hepatitis C (Viral Hepatitis C Antibody Screen [anti-HCV]), or a positive result for human immunodeficiency virus (HIV) antibody screen.

• Any severe herpes infection at any time prior to screening per judgement of the investigator.

• History of opportunistic infection requiring hospitalization or intravenous antimicrobial treatment within 3 years prior to randomization.

• History of major surgery within 12 weeks of screening or will require major surgery during the study.

• Clinically significant electrocardiographic abnormalities.

• History of any significant cardiovascular disease (e.g., myocardial infarction, congestive heart failure, uncontrolled hypertension, cerebrovascular accident), thrombotic episode, or any severe non-SLE medical illness within the previous 1 year.

• History of cancer, apart from:

• Squamous or basal cell carcinoma of the skin that has been successfully treated.

• Cervical cancer in situ that has been successfully treated.

Medications:

• Receipt of any investigational product (small molecule or biologic agent) within 4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater.

• Receipt of belimumab in 6 months prior to screening.

• History of treatment with rituximab or ocrelizumab (or other B cell depleting agent) within 6 months prior to screening. For participants who received their last treatment with rituximab or ocrelizumab more than 6 months earlier, evidence of significant and persisting low B cell levels in blood.

• History of cytotoxic medications (e.g., cyclophosphamide) within preceding 12 months.

• Receipt of any intra-articular, intramuscular, or intravenous (IV) glucocorticoids within 6 weeks prior to screening.

• Receipt of blood products within 6 months prior to screening.

General:

• Receipt of blood products within 6 months prior to screening and donation of blood or plasma to a blood bank or for a clinical study (except for screening of this study) within 28 days prior to screening.

• Participants who have a history of organ or bone marrow transplant.

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus

Intervention

Drug:
• LY3471851
LY3471851 drug product is a sterile liquid for subcutaneous injection that will be diluted with sterile 0.9% sodium chloride solution for injection (USP) prior to administration.
• Placebo
The placebo dosing solution is 0.9% sodium chloride for injection (USP).

Locations

Country	Name	City	State
United States	Investigator Site - Anniston	Anniston	Alabama
United States	Investigator Site - Austin	Austin	Texas
United States	Investigator Site - Clearwater	Clearwater	Florida
United States	Investigator Site - Dallas	Dallas	Texas
United States	Investigator Site - Duncansville	Duncansville	Pennsylvania
United States	Investigator Site - Great Neck	Great Neck	New York
United States	Investigator Site - Jackson	Jackson	Tennessee
United States	Investigator Site - La Jolla	La Jolla	California
United States	Investigator Site - Memphis	Memphis	Tennessee
United States	Investigator Site - Mesquite	Mesquite	Texas
United States	Investigator Site - Middleburg Heights	Middleburg Heights	Ohio
United States	Investigator Site - Orlando	Orlando	Florida
United States	Investigator Site-Tampa	Tampa	Florida
United States	Investigator Site- Wilmington	Wilmington	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Nektar Therapeutics	Eli Lilly and Company

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability of LY3471851 - Number of Participants Experiencing Adverse Events	Safety and tolerability of LY3471851 as assessed through collection of adverse events, serious adverse events, change in vital signs (body temperature, blood pressure, heart rate, rate of breathing and oxygen in blood); electrocardiograms (ECG); laboratory evaluations (hematology, chemistry, liver function and urine analysis).	Informed consent until last study visit (approximately 79 days after first dose of study drug)
Secondary	Pharmacokinetics (PK): Area Under the Drug Concentration - Time Curve from Zero to the End of Dosing Interval (i.e, 14 days past each dose) (AUC[0-Day 14]) of LY3471851	PK measurement of AUC 0-Day 14	Baseline until 14 days after last dose (approximately 43 days after first dose of study drug)
Secondary	PK: Maximum Observed Drug Concentration (Cmax) of LY3471851 After First and Last Dose	PK: Measurement of Cmax	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	PK: Time to Maximum Plasma Concentration (Tmax) of LY3471851	PK: Measurement of Tmax	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	PK: Time to Decrease in Concentration of LY3471851 by Half (T1/2) Due to Elimination	PK: Measurement of T1/2	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Pharmacodynamics (PD): Measurement of Change in Number of Regulatory T Cells (Tregs) and Subsets of Tregs in Blood	PD: Measurement of Change in Number of Regulatory T Cells (Tregs) and Subsets of Tregs in Blood	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	PD: Measurement Activity of Tregs	PD: Measurement Activity of Tregs	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	PD: Measurement of Change in Number of Subsets of Conventional T Cells (Tcons) in Blood	PD: Measurement of Change in Number of Subsets of Conventional T Cells	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	PD: Measurement of Change in Number of Natural Killer Cells (NK Cells) in Blood	PD: Measurement of Change in Number of Natural Killer Cells (NK Cells) in Blood	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	PD: Measurement of Cytokines in Blood	PD: Measurement of Cytokines in Blood	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (SLEDAI): Urine; Measurement of Hematuria, Pyuria, Urinary Casts, Creatinine, Protein	Change in Disease Activity (SLEDAI): Urine; Measurement of Hematuria, Pyuria, Urinary Casts, Creatinine, Protein	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (SLEDAI): Blood: Measurement of Anti-dsDNA, Complement, White Blood Cells and Platelets	Change in Disease Activity (SLEDAI): Blood: Measurement of Anti-dsDNA, Complement, White Blood Cells and Platelets	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): Physical Examination	Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): Physical Examination	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): Urine Analysis	Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): Urine Analysis	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): Blood Analysis	Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): Blood Analysis	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Skin on the Body	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Skin on the Body	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Mucous Membrane	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Mucous Membrane	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Scalp	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Scalp	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Hair Loss	Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI): Evaluation of Hair Loss	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Joint score): Evaluation of Tender Joints in the Body	Change in Disease Activity (Joint score): Evaluation of Tender Joints in the Body	Baseline until last study visit (approximately 79 days after first dose of study drug)
Secondary	Change in Disease Activity (Joint Score): Evaluation of Swollen Joints in the Body	Change in Disease Activity (Joint Score): Evaluation of Swollen Joints in the Body	Baseline until last study visit (approximately 79 days after first dose of study drug)