Lupus Nephritis
Conditions
Brief summary
Phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of daxdilimab in patients with active, proliferative lupus nephritis (LN).
Detailed description
Approximately 210 participants will be randomized to receive daxdilimab or placebo administered subcutaneously through Week 52 in addition to their standard of care background therapy (mycophenolate mofetil (MMF) and corticosteroids). At Week 64, all participants will be assigned to a quarterly dosing maintenance regimen of either daxdilimab or placebo based upon pre-defined renal response observed by Week 52. The maximum trial duration per participant is approximately 116 weeks including a 4-week screening period, the 104 weeks for the treatment period where participants will receive daxdilimab or placebo, and approximately 8 weeks for the follow-up period. Safety evaluations will be performed regularly throughout the course of the study. Acquired from Horizon in 2024.
Interventions
DRUGDaxdilimab
Daxdilimab will be administered subcutaneously as two injections for each dose. Other Names: HZN-7734
DRUGPlacebo (Normal Saline)
Placebo will be administered subcutaneously as two injections for each dose.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Willing and able to understand and provide written informed consent * Adult men or women 18 to 80 years of age * Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial * Fulfill the 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus (SLE) * Have at least one of the following at Screening per central lab: * Antinuclear antibodies (ANA) ≥ 1:80 * Anti-dsDNA antibodies elevated to above normal range as established by the central laboratory (ie, positive results) * Anti-Smith antibodies elevated to above normal (ie, positive results). * Diagnosis of proliferative LN based on a renal biopsy obtained within 6 months prior to signing the informed consent form (ICF) or during the Screening Period: * Class III (± class V) or class IV (± class V) LN according to the World Health Organization (WHO) or 2003 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) classification (based on local evaluation of renal biopsy). * Urine protein to creatinine ratio ≥113.17 mg/mmol, obtained via a 24-hour urine collection at Screening. * Estimated glomerular filtration rate ≥35 mL/min/1.73 m2 * Negative serum beta-human chorionic gonadotropin test at Screening (females of childbearing potential only). Key
Exclusion criteria
* History of allergy, hypersensitivity reaction, or anaphylaxis to any component of the investigational product or to a previous monoclonal antibody or human immunoglobulin therapy. * Known intolerance to ≤1.0 gm/day of MMF or equivalent dose of mycophenolic acid (MPA). * A diagnosis of pure Class V membranous LN based on a renal biopsy obtained within 6 months prior to signing ICF or during the Screening Period. * History of dialysis within 12 months prior to signing the ICF or expected need for renal replacement therapy (dialysis or renal transplant) within a 12-month period after enrollment. * History of, or current renal diseases (other than LN) that in the opinion of the Investigator could interfere with the LN assessment and confound the disease activity assessment (eg, diabetic nephropathy). * Known history of a primary immunodeficiency or an underlying condition such as known human immunodeficiency virus (HIV) infection, a positive result for HIV infection per central laboratory, splenectomy, or any underlying condition that in the opinion of the Investigator significantly predisposes the participant to infection. * Hepatitis B, Hepatitis C, active tuberculosis (TB), any severe herpes infection, clinically active infection, or opportunistic infection. * Clinically significant cardiac disease including unstable angina, myocardial infarction, congestive heart failure within 6 months prior to Randomization. * History of cancer within the past 5 years, except in situ carcinoma of the cervix, cutaneous basal cell or squamous cell carcinoma with curative therapy. * Receipt of a live vaccine within 4 weeks prior to Day 1. * The use of immunosuppressants, biologics, and DMARDS within the protocol defined washout periods.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved CRR at Week 48 Through Week 52 | Week 48 to Week 52 | CRR was defined as meeting all of the following: * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m\^2 or no worse than 15% below Baseline * 24-hour urine protein to creatinine ratio (UPCR) ≤ 0.5 mg/mg * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in eGFR at Week 52 | Baseline and Week 52 | Change over time in the levels of eGRF present in the blood. |
| Proportion of Participants Achieving a Decrease in Daily Oral Corticosteroid (OCS) Dose of ≤ 2.5 mg Prednisone-Equivalent by Week 24 Maintained Through Week 52 | Week 24 to Week 52 | Sustained reduction of OCS dose: * Prednisone-equivalent dose ≤ 2.5 mg/day by Week 24 and not exceeding this dose through Week 52 and * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment |
| Percentage of Participants Who Achieved Overall Renal Response (ORR) at Week 48 Through Week 52 | Week 48 to Week 52 | CRR was defined as meeting all of the following: * EGFR ≥ 60 mL/min/1.73 m\^2 or no worse than 15% below Baseline * 24-hour UPCR ≤ 0.5 mg/mg * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment Partial renal response (PRR) was defined as meeting all of the following: * EGFR ≥ 60 mL/min/1.73 m\^2 or no worse than 15% below Baseline * Improvement in 24-hour UPCR: * For participants with a Baseline UPCR ≤ 3.0 mg/mg: \< 1.0 mg/mg * For participants with a Baseline UPCR \> 3.0 mg/mg: \> 50% improvement from baseline and ≤ 3.0 mg/mg * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment |
| Number of Participants With Detectable Anti-Drug Antibodies (ADA) Against Daxdilimab | Up to approximately 36 weeks | Assessed via blood test at multiple time points throughout the duration of the study. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Up to approximately 36 weeks | An AE was any untoward medical occurrence in a participant or clinical subject who was administered a pharmaceutical product, which may or may not have been causally related to the treatment. A serious AE (SAE) was any AE resulting in death, life-threatening situations, inpatient hospitalization or its prolongation, persistent/significant disability/incapacity, congenital abnormality/birth defect, or other significant medical events that may have jeopardized the participant or required medical/surgical intervention to prevent the outcomes listed above. Treatment-emergent AEs of special interest (AESI) included hypersensitivity reactions (e.g., anaphylaxis), severe viral infections/reactivations (Common Terminology for Adverse Events \[CTCAE\] Grade 3+), herpes zoster, opportunistic infections, and malignancies. |
| Serum Concentration of Daxdilimab | Week 0 pre-dose, and 6 hours post-dose; Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 36 | Levels of daxdilimab present in the blood serum at different time points. |
Countries
Argentina, Brazil, Croatia, Israel, Malaysia, Philippines, Poland, Serbia, Spain, Taiwan, Thailand, United States
Participant flow
Recruitment details
Participants with active proliferative lupus nephritis were recruited from centers in Argentina, Brazil, Malaysia, the Philippines, Poland, Serbia, and Thailand between April 2023 and January 2024, when the study was terminated.
Pre-assignment details
Participants were randomized in a 1:1:1 ratio to receive either daxdilimab 300 mg or 100 mg subcutaneously (SC) or placebo SC in addition to standard of care (SOC) background therapy for a Treatment Period of about 104 weeks. Participants were followed up for 12 weeks following last dose of investigational product (IP).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive placebo SC in addition to SOC background therapy at Day 1, Week 2, and Week 4. Thereafter, placebo was administered every 4 weeks (Q4W) through Week 52. At Week 64, dosing would have been adjusted based on renal response criteria: participants who achieved either partial renal response (PRR) or complete renal response (CRR) at both Weeks 48 and 52 would have continued to receive placebo at Week 64 and every 12 weeks (Q12W) through Week 104 (last dose at Week 100), in addition to SOC therapy. Participants who didn't achieve PRR or CRR at either Week 48 or 52 would have received daxdilimab 300 mg at Week 64 and then Q12W through Week 104 (last dose at Week 100), in addition to SOC therapy. However, the study was terminated prior to any participants reaching Week 64. | 6 |
| Daxdilimab 100 mg Participants were randomized to receive daxdilimab 100 mg SC in addition to SOC background therapy at Day 1, Week 2, and Week 4. From Week 8 through Week 52, daxdilimab was administered Q4W. At Week 64, dosing would have been adjusted based on renal response criteria: participants who achieved PRR or CRR at both Weeks 48 and 52 would have continued to receive daxdilimab 100 mg at Week 64 and Q12W through Week 104 (last dose at Week 100), in addition to SOC therapy. Participants who didn't achieve PRR or CRR at Week 48 or 52 would have received daxdilimab 300 mg at Week 64 and Q12W through Week 104 (last dose at Week 100), in addition to SOC therapy. However, the study was terminated prior to any participants reaching Week 64. | 6 |
| Daxdilimab 300 mg Participants were randomized to receive daxdilimab 300 mg SC in addition to SOC background therapy at Day 1, Week 2, and Week 4. From Week 8 through Week 52, daxdilimab was administered Q4W. At Week 64, dosing would have been adjusted based on renal response criteria: participants who achieved PRR or CRR at both Weeks 48 and 52 would have continued to receive daxdilimab 300 mg at Week 64 and Q12W through Week 104 (last dose at Week 100), in addition to SOC therapy. Participants who didn't achieve PRR or CRR at Week 48 or 52 would have received daxdilimab 300 mg at Week 64 and Q12W through Week 104 (last dose at Week 100), in addition to SOC therapy. However, the study was terminated prior to any participants reaching Week 64. | 7 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Study terminated by sponsor | 6 | 6 | 7 |
Baseline characteristics
| Characteristic | Placebo | Daxdilimab 100 mg | Daxdilimab 300 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 37.2 years STANDARD_DEVIATION 5.91 | 31.5 years STANDARD_DEVIATION 10.97 | 30.3 years STANDARD_DEVIATION 6.47 | 32.8 years STANDARD_DEVIATION 8.15 |
| Race/Ethnicity, Customized Asian | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 3 Participants | 6 Participants | 4 Participants | 13 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 2 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 5 Participants | 17 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 13 | 0 / 19 |
| other Total, other adverse events | 2 / 6 | 2 / 6 | 5 / 7 | 7 / 13 | 9 / 19 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 1 / 7 | 1 / 13 | 1 / 19 |
Outcome results
Primary
Percentage of Participants Who Achieved CRR at Week 48 Through Week 52
CRR was defined as meeting all of the following: * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m\^2 or no worse than 15% below Baseline * 24-hour urine protein to creatinine ratio (UPCR) ≤ 0.5 mg/mg * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment
Time frame: Week 48 to Week 52
Population: Due to early termination data were not collected.
Secondary
Change From Baseline in eGFR at Week 52
Change over time in the levels of eGRF present in the blood.
Time frame: Baseline and Week 52
Population: Due to early termination data were not collected.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Change From Baseline in eGFR at Week 52 | Baseline | — |
| Unknown | Change From Baseline in eGFR at Week 52 | Week 52 | — |
Secondary
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
An AE was any untoward medical occurrence in a participant or clinical subject who was administered a pharmaceutical product, which may or may not have been causally related to the treatment. A serious AE (SAE) was any AE resulting in death, life-threatening situations, inpatient hospitalization or its prolongation, persistent/significant disability/incapacity, congenital abnormality/birth defect, or other significant medical events that may have jeopardized the participant or required medical/surgical intervention to prevent the outcomes listed above. Treatment-emergent AEs of special interest (AESI) included hypersensitivity reactions (e.g., anaphylaxis), severe viral infections/reactivations (Common Terminology for Adverse Events \[CTCAE\] Grade 3+), herpes zoster, opportunistic infections, and malignancies.
Time frame: Up to approximately 36 weeks
Population: Safety Analysis Set: All participants who received any dose of IP in the trial.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 2 Participants |
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 0 Participants |
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All ≥ Grade 3 AESI | 0 Participants |
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Fatal AEs | 0 Participants |
| Daxdilimab 100 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Fatal AEs | 0 Participants |
| Daxdilimab 100 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 2 Participants |
| Daxdilimab 100 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All ≥ Grade 3 AESI | 0 Participants |
| Daxdilimab 100 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 0 Participants |
| Daxdilimab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Fatal AEs | 0 Participants |
| Daxdilimab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 1 Participants |
| Daxdilimab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All ≥ Grade 3 AESI | 0 Participants |
| Daxdilimab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 5 Participants |
Secondary
Number of Participants With Detectable Anti-Drug Antibodies (ADA) Against Daxdilimab
Assessed via blood test at multiple time points throughout the duration of the study.
Time frame: Up to approximately 36 weeks
Population: Safety Analysis Set: All participants who received any dose of IP in the trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Detectable Anti-Drug Antibodies (ADA) Against Daxdilimab | 6 Participants |
| Daxdilimab 100 mg | Number of Participants With Detectable Anti-Drug Antibodies (ADA) Against Daxdilimab | 6 Participants |
| Daxdilimab 300 mg | Number of Participants With Detectable Anti-Drug Antibodies (ADA) Against Daxdilimab | 7 Participants |
Secondary
Percentage of Participants Who Achieved Overall Renal Response (ORR) at Week 48 Through Week 52
CRR was defined as meeting all of the following: * EGFR ≥ 60 mL/min/1.73 m\^2 or no worse than 15% below Baseline * 24-hour UPCR ≤ 0.5 mg/mg * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment Partial renal response (PRR) was defined as meeting all of the following: * EGFR ≥ 60 mL/min/1.73 m\^2 or no worse than 15% below Baseline * Improvement in 24-hour UPCR: * For participants with a Baseline UPCR ≤ 3.0 mg/mg: \< 1.0 mg/mg * For participants with a Baseline UPCR \> 3.0 mg/mg: \> 50% improvement from baseline and ≤ 3.0 mg/mg * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment
Time frame: Week 48 to Week 52
Population: Due to early termination data were not collected.
Secondary
Proportion of Participants Achieving a Decrease in Daily Oral Corticosteroid (OCS) Dose of ≤ 2.5 mg Prednisone-Equivalent by Week 24 Maintained Through Week 52
Sustained reduction of OCS dose: * Prednisone-equivalent dose ≤ 2.5 mg/day by Week 24 and not exceeding this dose through Week 52 and * No discontinuation of trial intervention or use of restricted medication beyond the protocol-allowed threshold before assessment
Time frame: Week 24 to Week 52
Population: Due to early termination data were not collected.
Secondary
Serum Concentration of Daxdilimab
Levels of daxdilimab present in the blood serum at different time points.
Time frame: Week 0 pre-dose, and 6 hours post-dose; Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 36
Population: Pharmacokinetic (PK) Analysis Set: all participants who received any dose of daxdilimab and had at least 1 quantifiable PK observation following the initial dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Concentration of Daxdilimab | Week 12 | 2988.00 ng/mL | Standard Deviation 1223.83 |
| Placebo | Serum Concentration of Daxdilimab | Week 0 post-dose | 689.07 ng/mL | Standard Deviation 498.4 |
| Placebo | Serum Concentration of Daxdilimab | Week 16 | 1080.33 ng/mL | Standard Deviation 1020.32 |
| Placebo | Serum Concentration of Daxdilimab | Week 4 | 8531.67 ng/mL | Standard Deviation 3993.99 |
| Placebo | Serum Concentration of Daxdilimab | Week 20 | 240.83 ng/mL | Standard Deviation 184.66 |
| Placebo | Serum Concentration of Daxdilimab | Week 0 pre-dose | 7.80 ng/mL | Standard Deviation 0 |
| Placebo | Serum Concentration of Daxdilimab | Week 24 | 93.85 ng/mL | Standard Deviation 94.96 |
| Placebo | Serum Concentration of Daxdilimab | Week 8 | 3533.33 ng/mL | Standard Deviation 1727.54 |
| Placebo | Serum Concentration of Daxdilimab | Week 2 | 4996.67 ng/mL | Standard Deviation 1732.21 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 0 pre-dose | 7.80 ng/mL | Standard Deviation 0 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 36 | 1040.00 ng/mL | — |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 0 post-dose | 3854.29 ng/mL | Standard Deviation 3312.12 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 2 | 17610.00 ng/mL | Standard Deviation 10382.53 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 4 | 22171.43 ng/mL | Standard Deviation 9187.26 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 8 | 10330.00 ng/mL | Standard Deviation 4167.07 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 12 | 10201.67 ng/mL | Standard Deviation 4619.64 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 16 | 5051.50 ng/mL | Standard Deviation 6644.68 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 20 | 2003.00 ng/mL | Standard Deviation 3907.13 |
| Daxdilimab 100 mg | Serum Concentration of Daxdilimab | Week 24 | 9660.00 ng/mL | — |