Systemic Lupus Erythematosus
Conditions
Keywords
T regulatory cells (Tregs), Interleukin 2, Interleukin-2
Brief summary
The reason for this study is to see if the study drug LY3471851 (NKTR-358) is safe and effective in adults with systemic lupus erythematosus (SLE).
Detailed 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.
Interventions
DRUGLY3471851
Administered SC
DRUGPlacebo
Administered SC
Sponsors
Eli Lilly and Company
Nektar Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Have a clinical diagnosis of SLE at least 24 weeks prior to screening. * Have documentation of having met at least 4 of 11 Revised Criteria for Classification of Systemic Lupus Erythematosus according to the 1997 Update of the 1982 American College of Rheumatology (ACR) criteria for classification of SLE prior to randomization. * Have a positive antinuclear antibody (ANA) (titer ≥1:80) and/or a positive anti-double-stranded deoxyribonucleic acid (dsDNA), and/or a positive anti-Smith (anti-Sm) as assessed by a central laboratory during screening. * Have a total Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≥6 during screening. * Have a clinical SLEDAI-2K score ≥4 at randomization. * Have active arthritis and/or active rash.
Exclusion criteria
* Have severe active lupus nephritis. * Have active central nervous system (CNS) lupus. * Have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute an unacceptable risk when taking investigational product or interfere with the interpretation of data. * Have a current or recent clinically serious viral, bacterial, fungal, or parasitic infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a ≥4 Point Reduction in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 (2K) Score at Week 24 | Week 24 | Percentage of Participants who Achieved a ≥4 Point Reduction in SLEDAI-2K Score at Week 24. A SLEDAI-4 response is defined as a ≥4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score from baseline. The SLEDAI-2K score range is from a minimum of 0 to a maximum of 105 (higher scores represent higher disease activity). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved British Isles Lupus Assessment Group (BILAG) Based Composite Lupus Assessment (BICLA) Response at Week 24. | Week 24 | Percentage of Participants who Achieve BICLA Response at Week 24. The BILAG-based Composite Lupus Assessment (BICLA) is a composite index used to assess disease activity in SLE. A BICLA response is defined as: * Reduction of all baseline BILAG-2004 A to B or C or D; and baseline BILAG-2004 B to C or D; and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B. * No worsening from baseline in SLEDAI-2K, where worsening is defined as any increase from baseline in SLEDAI-2K. * No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point PGA visual analogue scale (VAS). |
| Percentage of Participants Who Achieved Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response at Week 24 | Week 24 | Percentage of Participants who Achieved a SRI-4 Response at Week 24. A SRI-4 response is defined as a decrease in SLEDAI-2K \>= 4 from baseline. No new BILAG A and no more than 1 new BILAG B disease activity score / organ domain (both compared with baseline), and no worsening in PGA (defined as an increase of 0.3 points \[10 mm\] from baseline. |
| Percentage of Participants Who Achieved Lupus Low Disease Activity State (LLDAS) at Week 24 | Week 24 | Percentage of Participants who Achieved LLDAS at Week 24. A LLDAS response is defined as a low level of disease activity attained without use of low-dose steroids and/or standard-of-care immunosuppressant medications. |
| Pharmacokinetics (PK): Trough Concentrations (Ctrough) of LY3471851 | Week 24 | LY3471851 plasma trough concentrations are the concentrations of drug in plasma immediately before the next dose is administered. |
Countries
Argentina, Australia, Canada, Czechia, Germany, Hungary, India, Israel, Japan, Mexico, Poland, Puerto Rico, Romania, Russia, South Korea, Spain, Taiwan, Ukraine, United States
Participant flow
Recruitment details
The study consisted of a 24-week treatment period: participants randomly received either high dose LY3471851 or mid dose LY3471851 or low dose LY3471851 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| LY3471851 High Dose Participants received a subcutaneous injection of high dose LY3471851 every 2 weeks from weeks 0 to 24. | 73 |
| LY3471851 Mid Dose Participants received a subcutaneous injection of mid dose LY3471851 every 2 weeks from weeks 0 to 24. | 70 |
| LY3471851 Low Dose Participants received a subcutaneous injection of low dose LY3471851 every 2 weeks from weeks 0 to 24. | 74 |
| Placebo Participants received a subcutaneous injection of placebo dose every 2 weeks from weeks 0 to 24. | 74 |
| Total | 291 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 4 | 1 | 0 |
| Overall Study | Death | 0 | 1 | 0 | 0 |
| Overall Study | Due to the conflict in Ukraine | 2 | 1 | 1 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 15 | 3 | 15 | 6 |
Baseline characteristics
| Characteristic | LY3471851 Mid Dose | Total | Placebo | LY3471851 Low Dose | LY3471851 High Dose |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 4 Participants | 2 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 69 Participants | 287 Participants | 72 Participants | 74 Participants | 72 Participants |
| Age, Continuous | 41.3 years STANDARD_DEVIATION 13 | 40.7 years STANDARD_DEVIATION 12.1 | 41.6 years STANDARD_DEVIATION 12 | 39.9 years STANDARD_DEVIATION 12 | 40.0 years STANDARD_DEVIATION 11.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 35 Participants | 11 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 24 Participants | 5 Participants | 11 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 56 Participants | 232 Participants | 58 Participants | 59 Participants | 59 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 23 Participants | 7 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 65 Participants | 16 Participants | 20 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 18 Participants | 5 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 45 Participants | 184 Participants | 46 Participants | 44 Participants | 49 Participants |
| Region of Enrollment Argentina | 11 participants | 44 participants | 8 participants | 12 participants | 13 participants |
| Region of Enrollment Australia | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants |
| Region of Enrollment Canada | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Czechia | 0 participants | 5 participants | 3 participants | 1 participants | 1 participants |
| Region of Enrollment Germany | 1 participants | 4 participants | 0 participants | 0 participants | 3 participants |
| Region of Enrollment Hungary | 1 participants | 2 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment India | 8 participants | 38 participants | 10 participants | 12 participants | 8 participants |
| Region of Enrollment Israel | 0 participants | 2 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Japan | 3 participants | 19 participants | 4 participants | 6 participants | 6 participants |
| Region of Enrollment Mexico | 9 participants | 36 participants | 12 participants | 8 participants | 7 participants |
| Region of Enrollment Poland | 7 participants | 16 participants | 0 participants | 5 participants | 4 participants |
| Region of Enrollment Romania | 2 participants | 14 participants | 6 participants | 4 participants | 2 participants |
| Region of Enrollment Russia | 3 participants | 5 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment South Korea | 1 participants | 3 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Spain | 1 participants | 2 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Taiwan | 2 participants | 5 participants | 1 participants | 1 participants | 1 participants |
| Region of Enrollment Ukraine | 7 participants | 35 participants | 10 participants | 8 participants | 10 participants |
| Region of Enrollment United States | 14 participants | 59 participants | 16 participants | 15 participants | 14 participants |
| Sex: Female, Male Female | 64 Participants | 268 Participants | 67 Participants | 69 Participants | 68 Participants |
| Sex: Female, Male Male | 6 Participants | 23 Participants | 7 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 73 | 1 / 70 | 0 / 74 | 0 / 74 |
| other Total, other adverse events | 54 / 73 | 48 / 70 | 42 / 74 | 40 / 74 |
| serious Total, serious adverse events | 3 / 73 | 7 / 70 | 1 / 74 | 5 / 74 |
Outcome results
Primary
Percentage of Participants Who Achieved a ≥4 Point Reduction in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 (2K) Score at Week 24
Percentage of Participants who Achieved a ≥4 Point Reduction in SLEDAI-2K Score at Week 24. A SLEDAI-4 response is defined as a ≥4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score from baseline. The SLEDAI-2K score range is from a minimum of 0 to a maximum of 105 (higher scores represent higher disease activity).
Time frame: Week 24
Population: Modified Intent to Treat (mITT) patient population: All randomized patients with at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY3471851 High Dose | Percentage of Participants Who Achieved a ≥4 Point Reduction in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 (2K) Score at Week 24 | 20 Participants |
| LY3471851 Mid Dose | Percentage of Participants Who Achieved a ≥4 Point Reduction in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 (2K) Score at Week 24 | 27 Participants |
| LY3471851 Low Dose | Percentage of Participants Who Achieved a ≥4 Point Reduction in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 (2K) Score at Week 24 | 22 Participants |
| Placebo | Percentage of Participants Who Achieved a ≥4 Point Reduction in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 (2K) Score at Week 24 | 22 Participants |
p-value: 0.30995% CI: [0.7, 3.04]Regression, Logistic
p-value: 0.94495% CI: [0.47, 2.03]Regression, Logistic
p-value: 0.64995% CI: [0.4, 1.78]Regression, Logistic
Secondary
Percentage of Participants Who Achieved British Isles Lupus Assessment Group (BILAG) Based Composite Lupus Assessment (BICLA) Response at Week 24.
Percentage of Participants who Achieve BICLA Response at Week 24. The BILAG-based Composite Lupus Assessment (BICLA) is a composite index used to assess disease activity in SLE. A BICLA response is defined as: * Reduction of all baseline BILAG-2004 A to B or C or D; and baseline BILAG-2004 B to C or D; and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B. * No worsening from baseline in SLEDAI-2K, where worsening is defined as any increase from baseline in SLEDAI-2K. * No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point PGA visual analogue scale (VAS).
Time frame: Week 24
Population: A subset of modified intent-to-treat (mITT) patients with at least 1 BILAG A score or 2 BILAG B scores at Baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY3471851 High Dose | Percentage of Participants Who Achieved British Isles Lupus Assessment Group (BILAG) Based Composite Lupus Assessment (BICLA) Response at Week 24. | 12 Participants |
| LY3471851 Mid Dose | Percentage of Participants Who Achieved British Isles Lupus Assessment Group (BILAG) Based Composite Lupus Assessment (BICLA) Response at Week 24. | 26 Participants |
| LY3471851 Low Dose | Percentage of Participants Who Achieved British Isles Lupus Assessment Group (BILAG) Based Composite Lupus Assessment (BICLA) Response at Week 24. | 18 Participants |
| Placebo | Percentage of Participants Who Achieved British Isles Lupus Assessment Group (BILAG) Based Composite Lupus Assessment (BICLA) Response at Week 24. | 18 Participants |
p-value: 0.13195% CI: [0.83, 4.3]Regression, Logistic
p-value: 0.84495% CI: [0.47, 2.5]Regression, Logistic
p-value: 0.21895% CI: [0.24, 1.39]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Lupus Low Disease Activity State (LLDAS) at Week 24
Percentage of Participants who Achieved LLDAS at Week 24. A LLDAS response is defined as a low level of disease activity attained without use of low-dose steroids and/or standard-of-care immunosuppressant medications.
Time frame: Week 24
Population: Modified Intent to Treat (mITT) patient population: All randomized patients with at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY3471851 High Dose | Percentage of Participants Who Achieved Lupus Low Disease Activity State (LLDAS) at Week 24 | 12 Participants |
| LY3471851 Mid Dose | Percentage of Participants Who Achieved Lupus Low Disease Activity State (LLDAS) at Week 24 | 18 Participants |
| LY3471851 Low Dose | Percentage of Participants Who Achieved Lupus Low Disease Activity State (LLDAS) at Week 24 | 11 Participants |
| Placebo | Percentage of Participants Who Achieved Lupus Low Disease Activity State (LLDAS) at Week 24 | 10 Participants |
p-value: 0.20395% CI: [0.71, 5.2]Regression, Logistic
p-value: 0.86595% CI: [0.38, 3.16]Regression, Logistic
p-value: 0.89695% CI: [0.38, 3.05]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response at Week 24
Percentage of Participants who Achieved a SRI-4 Response at Week 24. A SRI-4 response is defined as a decrease in SLEDAI-2K \>= 4 from baseline. No new BILAG A and no more than 1 new BILAG B disease activity score / organ domain (both compared with baseline), and no worsening in PGA (defined as an increase of 0.3 points \[10 mm\] from baseline.
Time frame: Week 24
Population: Modified Intent to Treat (mITT) patient population: All randomized patients with at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY3471851 High Dose | Percentage of Participants Who Achieved Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response at Week 24 | 20 Participants |
| LY3471851 Mid Dose | Percentage of Participants Who Achieved Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response at Week 24 | 27 Participants |
| LY3471851 Low Dose | Percentage of Participants Who Achieved Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response at Week 24 | 22 Participants |
| Placebo | Percentage of Participants Who Achieved Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response at Week 24 | 22 Participants |
p-value: 0.94495% CI: [0.47, 2.03]Regression, Logistic
p-value: 0.30995% CI: [0.7, 3.04]Regression, Logistic
p-value: 0.64995% CI: [0.4, 1.78]Regression, Logistic
Secondary
Pharmacokinetics (PK): Trough Concentrations (Ctrough) of LY3471851
LY3471851 plasma trough concentrations are the concentrations of drug in plasma immediately before the next dose is administered.
Time frame: Week 24
Population: PK population at Week 24 is a subset of the mITT population with PK samples collected and available at Week 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY3471851 High Dose | Pharmacokinetics (PK): Trough Concentrations (Ctrough) of LY3471851 | 214.4 ng/mL | Standard Deviation 96.7 |
| LY3471851 Mid Dose | Pharmacokinetics (PK): Trough Concentrations (Ctrough) of LY3471851 | 133.3 ng/mL | Standard Deviation 50.6 |
| LY3471851 Low Dose | Pharmacokinetics (PK): Trough Concentrations (Ctrough) of LY3471851 | 55.9 ng/mL | Standard Deviation 30.6 |