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Efficacy and Safety of Obinutuzumab in Patients with Active System Lupus Erythematosus

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ALLEGORY Study Design

Baseline Patient Demographics

Primary Endpoint

Secondary Endpoints

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Disclaimer: This publication concerns information not contained within the approved product labeling for Genentech products and therefore may contain information for which the safety and effectiveness have not yet been established. Individual treatment decisions should be based on the prescribing physician’s determination of the benefits and risk.

Phase 3 ALLEGORY Study Overview

This page highlights findings from the Phase 3 ALLEGORY study, published in the New England Journal of Medicine (NEJM) on March 6, 2026, which evaluated the efficacy and safety of obinutuzumab in adults with active systemic lupus erythematosus (SLE). Despite available therapies, many patients continue to experience persistent disease activity, progressive organ damage, treatment-limiting side effects, or premature death, underscoring the need for additional therapeutic options. Included are the study design, key eligibility criteria, baseline patient characteristics, efficacy outcomes, exploratory analyses, and safety findings from the ALLEGORY clinical program. The findings are discussed within the context of SLE disease management and ongoing efforts to improve patient outcomes.

Clinical data current as of September 2026. This page has been reviewed by Genentech Medical Affairs.

Clinical Measures

ANA — antinuclear antibody
anti-dsDNA — anti–double-stranded DNA
BICLA — BILAG-Based Combined Lupus Assessment
BILAG — British Isles Lupus Assessment Group
C3 — complement component 3
C4 — complement component 4
CD19+ — cluster of differentiation 19–positive
CD20 — cluster of differentiation 20
DORIS — Definition of Remission in SLE
eGFR — estimated glomerular filtration rate
LLDAS — Lupus Low Disease Activity State
PGA-VAS — Physician Global Assessment - Visual Analogue Scale
SLEDAI-2K — Systemic Lupus Erythematosus Disease Activity Index 2000
SRI-4 — SLE Responder Index-4
SRI-6 — SLE Responder Index-6

Other Abbreviations

ACR — American College of Rheumatology
AU — Arbitrary unit
BTK — Bruton’s tyrosine kinase
CI — confidence interval
EULAR - European Alliance of Associations for Reuhamology
FDA — Food and Drug Administration
GC — glucocorticoid
HBV — hepatitis B virus
HR — hazard ratio
ITT — intent-to-treat
IU/mL — international units per milliliter
JAK — Janus kinase
mg/day — milligrams per day
MSL — Medical Science Liaison
NEJM — New England Journal of Medicine
Obi — obinutuzumab
OLT — open-label treatment
PML — progressive multifocal leukoencephalopathy
R — randomized
SLE — systemic lupus erythematosus
ST — standard therapy
TEAE — treatment emergent adverse event
TYK2— tyrosine kinase 2

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ALLEGORY Study Design

ALLEGORY is a Phase 3, multicenter, double-blind, placebo-controlled trial involving adults with active SLE but without proliferative or membranous lupus nephritis who were receiving standard therapy.^1,2

Randomization was stratified according to SLEDAI-2K score at screening (<12 or ≥12) and baseline prednisone or equivalent dose (<10 mg/day or ≥10 mg/day)

Schematic of the randomized, double-blind study design. Patients with SLE were randomized 1:1 to receive obinutuzumab (n=151) or placebo (n=152) in addition to standard SLE therapy. All patients at baseline received stable background SLE therapy, including prednisone ≤30 mg/day (or equivalent), an antimalarial, and or one immunosuppressant.

Obinutuzumab or placebo infusions were administered at weeks 0, 2, 24, and 26. Prednisone was tapered to ≤5 mg/day by week 24, with no dose changes after week 40.

The primary endpoint, SRI-4 response, was assessed at week 52. Following the week 52 assessment, patients in the obinutuzumab and placebo arm could receive open-label treatment at weeks 54, 56, 78, and 104.

SLE therapies after week 52 were managed at the investigator's discretion, and study follow-up continued after week 104.

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Select Baseline Patient Demographics

ALLEGORY studied a diverse population of patients diagnosed with SLE

Demographics Disease Activity Baseline Treatment

Participant Demographics^a
	Obinutuzumab + ST (n=151)	Placebo + ST (n=152)
Age (years)	41.1±12.3	41.4±12.6
Female sex, n (%)	139 (92.1)	135 (88.8)
Hispanic/Latino ethnic group, n (%)^b	75 (49.7)	86 (56.6)

Race or Ethnic Group

Ethnicity was generally balanced between treatment arms. In the obinutuzumab group (n=151), participants identified as White (42.4%), American Indian or Alaska Native (29.1%), Black (14.6%), Asian (2.6%), unknown or not reported race or ethnicity (6.6%), or multiple races or ethnicities (4.6%); no participants identified as Native Hawaiian or Other Pacific Islander. In the placebo group (n=152), participants identified as White (40.8%), American Indian or Alaska Native (27.6%), Black (16.4%), Asian (1.3%), Native Hawaiian or Other Pacific Islander (0.7%), unknown or not reported race or ethnicity (5.9%), or multiple races or ethnicities (7.2%).

Disease Activity
	Obinutuzumab + ST (n=151)	Placebo + ST (n=152)
Mean SLEDAI-2K^c Global Score	13.1±4.4	13.2±4.0
SLEDAI-2K Score of ≥12 – no. (%)^d	98 (64.9)	99 (65.1)

Mean PGA Score^f	1.9±0.4	1.9±0.4

Baseline Treatment
	Obinutuzumab + ST (n=151)	Placebo + ST (n=152)
Antimalarial: hydroxychloroquine, chloroquine, or quinacrine – no. (%)	121 (80.1)	124 (81.6)
Conventional immunosuppressant – no. (%)	107 (70.9)	102 (67.1)
Immunosuppressant use
Azathioprine – no./total no. (%)	40/107 (37.4)	26/102 (25.5)
Methotrexate – no./total no. (%)	32/107 (29.9)	28/102 (27.5)
Mycophenolate mofetil or mycophenolic acid – no./total no. (%)	34/107 (31.8)	44/102 (43.1)
Prednisone (or equivalent) dose of ≥10 mg/day – no. (%)	86 (57.0)	85 (55.9)

Baseline demographics were well balanced across treatment arms.

View Publication for Full Baseline Characteristics.

^aPlus-minus values are means ±SD. The intention-to-treat population included all the patients who had undergone randomization. Percentages may not total 100 owing to rounding. SLE denotes systemic lupus erythematosus. ^bRace and ethnic group were reported by the patients. Patients in North and South America who did not identify themselves as White, Black, or Asian were categorized by the investigators as American Indian according to Food and Drug Administration guidance. ^cThe Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) is a 24-item weighted score of SLE activity that ranges from 0 to 105, with higher scores indicating greater disease activity. ^dRandomization was stratified according to screening SLEDAI-2K score (<12 or ≥12) and baseline prednisone (or equivalent) dose (<10 mg per day or ≥10 mg per day). ^eThe British Isles Lupus Assessment Group (BILAG) 2004 index (BILAG-2004) is an assessment of 97 clinical and laboratory variables across nine organ domains, with scores ranging from A (severe) to E (never involved) for each organ domain. ^fThe Physician's Global Assessment (PGA) of disease activity uses a visual analogue scale, with scores ranging from 0 (no disease activity) to 3 (most severe disease).

BILAG-2004=British Isles Lupus Assessment Group 2004 Index; PGA=Physician's Global Assessment; SD=standard deviation; SLE=systemic lupus erythematosus; SLEDAI-2K=Systemic Lupus Erythematosus Disease Activity Index 2000; ST=standard therapy.

Furie RA, et al. N Engl J Med. Published online Mar 6, 2026. doi:10.1056/NEJMoa2516150

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Primary Endpoint

SRI-4 response at Week 52

Bar chart titled “SRI-4 response at week 52.” The y-axis shows the proportion of patients achieving an SRI-4 response at Week 52 (95% CI), ranging from 0% to 100%. Two treatment groups are compared.

Obinutuzumab + standard therapy (n=151): 76.7% of patients achieved an SRI-4 response (95% CI, 69.8% to 83.5%).
Placebo + standard therapy (n=152): 53.5% of patients achieved an SRI-4 response (95% CI, 45.3% to 61.6%).

A callout box indicates an adjusted treatment difference of 23.1 percentage points in favor of obinutuzumab plus standard therapy (95% CI, 12.5 to 33.6).

ALLEGORY met its primary endpoint: A significantly higher proportion of patients achieved SRI-4 response at week 52 with obinutuzumab

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Secondary Endpoints

Key Secondary Endpoints Additional Secondary Endpoints

Key Secondary Endpoints

Additional Secondary Endpoints

Achievement of DORIS and LLDAS at Week 52 was an additional secondary endpoint and was not included among the hierarchically tested key secondary endpoints. The widths of the confidence intervals were not adjusted for multiplicity; therefore, the intervals should not be interpreted as a substitute for hypothesis testing.

Key Takeaways

More patients achieved DORIS remission at week 52 with obinutuzumab
Higher rates of LLDAS were observed at week 52 with obinutuzumab

Bar charts summarize key secondary endpoints and additional secondary endpoints comparing obinutuzumab plus standard therapy (n=151) with placebo plus standard therapy (n=152).

Key Secondary Endpoints

BICLA response at week 52: 62.0% (95% CI, 54.2 to 69.8) in the obinutuzumab group versus 40.1% (95% CI, 32.1 to 48.1) in the placebo group. The adjusted treatment difference was 21.9% (95% CI, 10.8 to 32.9; p<0.001).
Reduction in glucocorticoid dose to ≤7.5 mg/day sustained from week 40 to week 52: 80.0% (95% CI, 71.5 to 88.5) in the obinutuzumab group versus 54.1% (95% CI, 43.5 to 64.7) in the placebo group. The adjusted treatment difference was 26.1% (95% CI, 12.7 to 39.5; p<0.001).
Sustained SRI-4 response from week 40 to week 52: 72.0% (95% CI, 64.6 to 79.3) in the obinutuzumab group versus 46.4% (95% CI, 38.3 to 54.6) in the placebo group. The adjusted treatment difference was 25.4% (95% CI, 14.6 to 36.2; p<0.001).
SRI-6 response at week 52: 68.9% (95% CI, 61.4 to 76.5) in the obinutuzumab group versus 38.9% (95% CI, 31.0 to 46.9) in the placebo group. The adjusted treatment difference was 30% (95% CI, 19.2 to 40.7; p<0.001).
Patients experiencing BILAG flare through week 52 in the ITT population: 33.8% (95% CI, 26.2 to 41.3) in the obinutuzumab group versus 48.7% (95% CI, 40.7 to 56.6) in the placebo group. The hazard ratio was 0.58 (95% CI, 0.40 to 0.82; p=0.002).

Additional Secondary Endpoints

DORIS remission at week 52: 33.8% of patients in the obinutuzumab group achieved DORIS remission compared with 13.8% in the placebo group. The adjusted treatment difference was 19.9% (95% CI, 10.6 to 29.2).
LLDAS at week 52: 57.6% of patients in the obinutuzumab group achieved LLDAS compared with 25.0% in the placebo group. The adjusted treatment difference was 32.6% (95% CI, 22.3 to 43.0).

Key Takeaways

Significantly more patients achieved BICLA response at week 52 with obinutuzumab
Obinutuzumab demonstrated significantly higher rates of sustained steroid reduction to ≤7.5 mg/day in patients receiving >=10 mg/day (n=85 in each arm) from week 40 to 52
A significantly greater proportion of patients achieved sustained SRI-4 from week 40 to week 52 with obinutuzumab
A significantly greater proportion of patients achieved SRI-6 response at week 52 with obinutuzumab
Significantly fewer BILAG flares with obinutuzumab vs placebo through week 52
Obinutuzumab significantly reduced the risk of a BILAG flare in the first year by 42%.
Separation in time to first BILAG flare was observed as early as 4 weeks

^aThe differences between the two groups and the associated 95% confidence intervals based on Newcombe method were adjusted for the stratification factors (SLEDAI-2K score at screening [<12 vs ≥12], glucocorticoid dose at baseline [<10 mg/day vs ≥10 mg/day of prednisone or equivalent]), except for the glucocorticoid reduction endpoint where the difference was adjusted for SLEDAI-2K score at screening (<12 vs ≥12) only. Between-groups differences were calculated in percentages (the percentage in the obinutuzumab group minus the percentage in the placebo group), except as indicated. ^bThis endpoint was assessed in patients taking ≥10 mg/day of prednisone or equivalent at baseline; n=85 in each arm. ^cData were missing for 5 patients in the obinutuzumab group and 9 patients in the placebo group. ^dAchievement of DORIS and LLDAS at Week 52 was an additional secondary endpoint and was not included in the hierarchically tested key secondary endpoints; the widths of the confidence interval were not adjusted for multiplicity, and the intervals may not be used in place of hypothesis testing.

BICLA=BILAG-Based Composite Lupus Assessment; CI=confidence interval; CNS=central nervous system; GC=glucocorticoid; DORIS=Definition of Remission in SLE; HR=hazard ratio; ITT=intent-to-treat; LLDAS=Lupus Low Disease Activity State; SLE=systemic lupus erythematosus; SRI-4=SLE Responder Index-4; SRI-6=SLE Responder Index-6; ST=standard therapy.

Furie RA, et al. N Engl J Med. Published online Mar 6, 2026. doi:10.1056/NEJMoa2516150

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Safety

Adverse Events through Week 52 (Safety Population)^a
Event	Obinutuzumab + ST (N=151)	Placebo + ST (N=151)
Any adverse event, n (%)	134 (88.7)	123 (81.5)
Total no. of adverse events	568	468
Any serious adverse event, n (%)	24 (15.9)	18 (11.9)
Deaths, n (%)	1 (0.7)	3 (2.0)
Adverse events leading to withdrawal from trial, n (%)	1 (0.7)	2 (1.3)
Adverse event of Grade 3 or higher, n (%)	25 (16.6)	21 (13.9)
Infection, n (%)	103 (68.2)	82 (54.3)
Infection as a serious adverse event, n (%)	13 (8.6)	7 (4.6)
Adverse event with fatal outcome, n (%)^b	1 (0.7)	5 (3.3)
Adverse event leading to discontinuation of obinutuzumab or placebo, n (%)	6 (4.0)	6 (4.0)
Serious adverse event leading to discontinuation of obinutuzumab or placebo, n (%)	3 (2.0)	3 (2.0)
Infusion-related reaction, n (%)	18 (11.9)	5 (3.3)
Infection of Grade 3 or higher, n (%)	11 (7.3)	7 (4.6)
Any hepatitis B reactivation or progressive multifocal leukoencephalopathy, n (%)	0	0
Drug-related neutropenia, n (%)	7 (4.6)	3 (2.0)
Drug-related thrombocytopenia, n (%)	0	0
Gastrointestinal perforation, n (%)	0	1 (0.7)
Worsening of preexisting cardiac conditions, n (%)	0	0
Potential drug-induced liver failure meeting Hy’s law criteria, n (%)	0	1 (0.7)
Suspected transmission of an infectious agent by obinutuzumab or placebo, n (%)	0	0

No new or unexpected safety signals were identified in ALLEGORY

^aOne patient assigned to the placebo group did not receive placebo and was subsequently excluded from the safety analysis. Multiple occurrences of the same adverse event in the same patient were counted only once, except for "total no. of adverse events," in which multiple occurrences of the same adverse event were counted separately. Included are adverse events that occurred until the time of rescue for patients who received rescue therapy. ^bTwo deaths in the placebo group occurred after week 52, but the adverse events started during the 52-week blinded period.

Furie RA, et al. N Engl J Med. Published online Mar 6, 2026. doi:10.1056/NEJMoa2516150.

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Key Takeaways

In the Phase 3 ALLEGORY Study, obinutuzumab plus standard therapy was significantly more effective than placebo plus standard therapy in achieving SRI-4 response at week 52
All key secondary endpoints in ALLEGORY were superior in the obinutuzumab group
Infusion-related reactions, Grade ≥3 infections, and drug-related neutropenia, which are expected risks of obinutuzumab treatment, were more frequent in the obinutuzumab group than in the placebo group

Furie RA, et al. N Engl J Med. Published online Mar 6, 2026. doi:10.1056/NEJMoa2516150.

Full Disclosure:

This reprint concerns information not contained within the approved product labeling for Gazyva^® (obinutuzumab), and therefore may include data for which the safety and effectiveness has not yet been established. Individual treatment decisions should be made based on the prescribing physician's determination of benefits and risks.

Gazyva is not FDA-approved for the treatment of systemic lupus erythematosus.

Gazyva is FDA-approved:

For the treatment of adult patients with active lupus nephritis who are receiving standard therapy
- To reduce the risk of relapse in adult and pediatric patients 2 years of age and older with frequently relapsing or steroid dependent childhood-onset idiopathic nephrotic syndrome who are in complete remission
In combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia
In combination with bendamustine followed by Gazyva monotherapy, for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen
In combination with chemotherapy followed by Gazyva monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma

BOXED WARNINGS: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including Gazyva. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with Gazyva. Discontinue Gazyva and concomitant medications in the event of HBV reactivation
Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving Gazyva

Contraindications

Gazyva is contraindicated in patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use.

Warnings and Precautions

Infusion-Related Reactions, Hypersensitivity Reactions, Including Serum Sickness, Tumor Lysis Syndrome, Serious, Including Fatal Infections, Neutropenia, Thrombocytopenia, Disseminated Intravascular Coagulation, Immunization, and Embryo-Fetal Toxicity.

Please see the full prescribing information for Gazyva for important safety and other information related to the approved use, including potential embryo-fetal toxicity. Gazyva can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

To report suspected adverse reactions, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

You can access Genentech Clinical and Scientific information on our Medical Information Website. You can also contact our Medical Information Team at 1-800-821-8590.

Additional Disclosures

Reimbursement under public and private health care programs may not be available for unapproved product use. It is your responsibility to check applicable reimbursement policies before submitting claims for coverage.
This reprint is being distributed by Genentech, a member of the Roche Group, who markets Gazyva. Please note that the clinical investigation was supported by F. Hoffmann-La Roche and the investigators or authors were present or former employees of the Roche Group or may have received compensation.
The opinions expressed in this reprint do not necessarily reflect those of Genentech. Readers are encouraged to contact the primary authors with questions regarding the content of the reprint.

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