Efficacy and Safety of AMG 570 in Subjects With Active Systemic Lupus Erythematosus (SLE)

Study Overview
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Brief Summary
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The purpose of this study is to determine if Rozibafusp Alfa could be a useful therapeutic agent in the current treatment landscape where subjects with SLE have ongoing disease activity despite treatment with standard of care therapies.

Detailed Description
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This is a Bayesian adaptive phase 2b, multi-center, double-blind, randomized, placebo-controlled, 52-week, dose-ranging study in subjects with active SLE and inadequate response to SOC therapies including oral corticosteroids (OCS), immunosuppressants and immunomodulators. Previous biologic use is allowed with an adequate washout period.

Official Title
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A Phase 2b Dose Ranging Study to Evaluate the Efficacy and Safety of Rozibafusp Alfa (AMG 570) in Subjects With Active Systemic Lupus Erythematosus (SLE) With Inadequate Response to Standard of Care (SOC) Therapy

Conditions
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Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
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* Drug: Rozibafusp Alfa
* Drug: Placebo for Rozibafusp Alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Screening Visit: Subject has provided informed consent prior to initiation of any study-specific activities/procedures. Age ≥ 18 years to ≤ 75 years at screening visit. Fulfills classification criteria for SLE according to the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE (Aringer et al, 2019), with antinuclear antibody ≥ 1:80 by immunofluorescence on Hep-2 cells being present at screening. Hybrid SLEDAI score ≥ 6 points with a Clinical hSLEDAI score ≥ 4 points. The Clinical hSLEDAI is the hSLEDAI assessment score without the inclusion of points attributable to laboratory results, including urine or immunologic parameters. Additional protocol-specific rules are applied at screening and throughout the study, as follows: Arthritis: Arthritis (at least 3 tender and swollen joints) must involve joints in the hands or wrists for the hSLEDAI scoring. Alopecia: Subjects should have hair loss without scarring; should neither have alopecia areata nor androgenic alopecia; and should have a CLASI activity score for alopecia ≥ 2. Oral ulcers: Ulcers location and appearance must be documented by the investigator. Scleritis and Episcleritis: the presence of stable SLE-related scleritis and episcleritis must be documented by an ophthalmologist and other causes excluded. Renal: subjects with urine protein/creatinine ratio < 3000 mg/g (or equivalent method) in a clear catch spot urine sample can enroll and be scored in the hSLEDAI, provided the subject has a clinical hSLEDAI ≥ 4 and did not receive induction treatment for nephritis within the last year. Pleurisy and Pericarditis: symptoms of pleurisy and pericarditis must be accompanied by objective findings to be scored in the hSLEDAI. Unless there is a documented intolerance, subjects must be taking: Only 1 of the following SLE treatments: anti-malarial (hydroxychloroquine, chloroquine, or quinacrine), azathioprine, methotrexate, leflunomide, mycophenolate mofetil/acid mycophenolic, or dapsone. OR • 2 of the above-mentioned SLE treatments in which 1 must be anti-malarial (hydroxychloroquine, chloroquine, or quinacrine). Treatment should be taken for ≥ 12 weeks prior to screening and must be a stable dose for ≥ 8 weeks prior to screening. For subjects taking OCS, dose must be ≤ 20 mg/day of prednisone or OCS equivalent, and the dose must be stable at baseline visit for ≥ 2 weeks prior to screening visit. Exclusion Criteria Screening Visit Subjects are excluded from the study if any of the following criteria apply: Disease Related Urine protein creatinine ratio ≥ 3000 mg/g (or equivalent) at screening or induction therapy for lupus nephritis within 1 year prior to screening visit. Active CNS lupus within 1 year prior to screening including, but not limited to, aseptic meningitis, ataxia, CNS vasculitis, cranial neuropathy, demyelinating syndrome, optic neuritis, psychosis, seizures, or transverse myelitis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: This is a Bayesian adaptive phase 2b, multi-center, double-blind, randomized, placebo-controlled, 52-week, dose-ranging study in subjects with active SLE and inadequate response to SOC therapies including OCS, immunosuppressants, and immunomodulators. Subjects will be randomized to receive placebo or 1 of 3 doses of Rozibafusp Alfa with the last dose at week 50. Treatment will be administered every 2 weeks (Q2W). All subjects will be required to complete a 16-week follow-up period after the 52-week treatment period. The first interim analysis (IA) will be executed after the first 40 enrolled subjects have had the opportunity to complete the week 24 assessment. Additional IAs may be executed after approximately every 32 newly enrolled subjects have had the opportunity to complete the week 24 assessment. The last IA will occur when all subjects have had the opportunity to complete the week 24 assessment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rozibafusp Alfa, Dose A<br>Investigational product solution in vial | Drug: Rozibafusp Alfa<br>* Rozibafusp Alfa will be presented in 5 mL glass vial<br>|
| Experimental: Rozibafusp Alfa, Dose B<br>Investigational product solution in vial | Drug: Rozibafusp Alfa<br>* Rozibafusp Alfa will be presented in 5 mL glass vial<br>|
| Experimental: Rozibafusp Alfa, Dose C<br>Investigational product solution in vial | Drug: Rozibafusp Alfa<br>* Rozibafusp Alfa will be presented in 5 mL glass vial<br>|
| Placebo Comparator: Placebo for Rozibafusp Alfa<br>Placebo Investigational product solution in vial | Drug: Placebo for Rozibafusp Alfa<br>* Placebo for Rozibafusp Alfa will be presented in 5 mL glass vial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of patients achieving Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response at week 52 | SRI-4 response at Week 52 is defined as a greater than or equal to 4-point decrease in the hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) score, and no new British Isles Lupus Assessment Group (BILAG) 2004 A score, no greater than 1 new BILAG B domain scores compared with baseline, and a less than 0.3-point deterioration from baseline in Physician Global Assessment (PGA) (scale 0 to 3), and no use of more than protocol allowed therapies. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of patients achieving a SRI-4 response at week 24 | SRI-4 response at Week 24 is defined as a greater than or equal to 4-point decrease in the hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) score, and no new British Isles Lupus Assessment Group (BILAG) 2004 A score, no greater than 1 new BILAG B domain scores compared with baseline, and a less than 0.3-point deterioration from baseline in Physician Global Assessment (PGA) (scale 0 to 3), and no use of more than protocol allowed therapies. | Week 24 | 
| Percent of patients achieving Lupus Low Disease Activity State (LLDAS) at week 52 | LLDAS response at week 52 is defined as a hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) score ≤ 4 with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, and fever) and no haemolytic anaemia or gastrointestinal activity; no new findings of lupus disease activity compared with the previous assessment; ≤ 1-point in Physician Global Assessment (PGA) (scale 0 to 3) current prednisolone-equivalent dosage ≤ 7.5 mg/day; and standard maintenance dosages of immunosuppressive drugs and approved biologics. | Week 52 | 
| Percent of patients achieving The British Isles Lupus Assessment Group (BILAG) based Combined Lupus Assessment (BICLA) index responses | BICLA response is defined as at least 1 gradation of improvement in baseline BILAG domain scores in all body systems with moderate or severe disease activity at entry (eg, all A [severe disease] domain scores falling to B [moderate], C [mild], or D [no activity], and all B domain scores falling to C or D); no new BILAG 2004 A domain score and no > than 1 new BILAG 2004 B domain scores compared with baseline; no worsening of the hSLEDAI score from baseline; no ≥ 0.3-point deterioration from baseline in Physician Global Assessment (PGA) (scale 0 to 3); and no use of more than protocol-allowed therapies; and no initiation of non-protocol treatment for SLE. | Week 24 and Week 52 | 
| SRI-4 at week 52 with reduction of OCS to less than or equal to 7.5 mg/day by week 44 and sustained through week 52 in subjects with a baseline OCS dose ≥ 10 mg/day | To evaluate the efficacy of Rozibafusp Alfa with oral corticosteroid (OCS)-tapering in subjects with SLE with inadequate response to SOC therapy. | Week 52 | 
| Annualized moderate and severe flare rate | Measured by SELENA-SLEDAI Flare Index. | 52 weeks | 
| Annualized severe flare rate | Measured by SELENA-SLEDAI Flare Index. | 52 weeks | 
| Annualized flare rate | Measured by BILAG score designation of worse or new resulting in a B score in ≥ 2 organs or an A score in ≥ 1 organ) over 52 weeks. | 52 weeks | 
| Total tender and swollen joint count (limited to hands and wrists): ≥ 50% improvement from baseline at week 12, 24, 36, and 52 in subjects with ≥ 6 tender and swollen joints in the hands and wrists at baseline | A joint count will be used to evaluate the effect of Rozibafusp Alfa on additional SLE efficacy endpoints. | Baseline, Week 12, 24, 36, and 52 | 
| Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) activity score ≥ 50% improvement from baseline at week 12, 24, 36, and 52 in subjects with a CLASI activity score ≥ 8 at baseline | To evaluate the effect of Rozibafusp Alfa on additional SLE efficacy endpoints | Baseline, Week 12, 24, 36, and 52 | 
| Patient-Reported Outcome Measurement Information System Fatigue Short Form 7a Instrument (PROMIS-Fatigue SF7A) score change from baseline | To describe the effect of treatment with Rozibafusp Alfa using patient reported outcomes | Baseline, Week 12, 24, 36, 44 and 52 | 
| Medical Outcomes Short Form 36 version 2 Questionnaire (SF-36v2) physical component score change from baseline | To describe the effect of treatment with Rozibafusp Alfa using patient reported outcomes | Baseline, Week 12, 24, 36, 44 and 52 | 
| Medical Outcomes Short Form 36 version 2 Questionnaire (SF-36v2) mental component score individual domains change from baseline | To describe the effect of treatment with Rozibafusp Alfa using patient reported outcomes | Baseline, Week 12, 24, 36, 44 and 52 | 
| Lupus Quality of Life (QoL) score and change from baseline | To describe the effect of treatment with Rozibafusp Alfa using patient reported outcomes | Baseline, Week 12, 24, 36, 44 and 52 | 
| Patient Global Assessment (PtGA) score change from baseline | This is an 11-point NRS with 0 indicating lowest disease and 10 highest disease activity. | Baseline, Week 12, 24, 36, 44 and 52 | 
| Patient incidence of Treatment-Emergent Adverse Events | To characterize the safety of Rozibafusp Alfa. | 52 weeks | 
| Patient incidence of Serious adverse events | To characterize the safety of Rozibafusp Alfa. | 52 weeks | 
| Number of patients with significant changes in laboratory values | To characterize the safety of Rozibafusp Alfa. | 52 weeks | 
| Number of patients with significant changes in vital signs | To characterize the safety of Rozibafusp Alfa. | 52 weeks | 
| Serum Rozibafusp Alfa trough concentrations | To characterize the pharmacokinetics (PK) of Rozibafusp Alfa | 52 Weeks | 
| Rozibafusp Alfa terminal elimination half-life, if possible | To characterize the pharmacokinetics (PK) of Rozibafusp Alfa | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Standard of Care therapies, Oral Corticosteroids, Inmunosuppressants, Immunomodulators, Systemic Lupus Erythematosus, B cell Activating Factor (BAFF), Inducible T cell costimulator ligand (ICOSL)