FDA Approves Genentech's Gazyva for Lupus Nephritis Treatment
The FDA has approved Genentech's Gazyva (obinutuzumab) for treating adult patients with active lupus nephritis (LN) receiving standard therapy. The ap...
Breakthrough Clinical Results
The FDA has approved Genentech's Gazyva (obinutuzumab) for treating adult patients with active lupus nephritis (LN) receiving standard therapy. The approval is based on Phase II NOBILITY and Phase III REGENCY studies, demonstrating Gazyva's superiority over standard therapy alone in achieving complete renal response. Gazyva, an anti-CD20 monoclonal antibody, offers a potentially more convenient treatment option with twice-yearly administration after initial doses. The REGENCY study showed that nearly half of the participants on Gazyva with standard therapy achieved a complete renal response compared to 33.1% on standard therapy alone.
Key Highlights
- FDA approves Gazyva (obinutuzumab) for adult patients with active lupus nephritis.
- Approval based on Phase II NOBILITY and Phase III REGENCY data showing superiority over standard therapy.
- Gazyva is the only anti-CD20 monoclonal antibody to demonstrate a complete renal response benefit in lupus nephritis in a randomized Phase III study.
- Gazyva offers a potentially more convenient treatment option with twice-yearly administration after initial doses.
Incidence and Prevalence
Latest Estimates of Incidence and Prevalence of Lupus Nephritis Globally
Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE) and significantly impacts morbidity and mortality. It affects up to 60% of adult patients with SLE and can progress to end-stage kidney failure in 10%-30% of patients.
Global Prevalence
The first comprehensive estimate of biopsy-proven lupus nephritis showed an overall prevalence of 4.4 per 100,000 population (95% CI 3.8-5.0) based on a 2006 study from northwest England. There are dramatic differences according to ethnicity:
- 110.3 per 100,000 (95% CI 55.0-197.3) in Chinese patients
- 99.2 per 100,000 (95% CI 55.5-163.6) in Afro-Caribbean populations
- 21.4 per 100,000 (95% CI 12.0-35.2) in Indo-Asian populations
- 5.6 per 100,000 (95% CI 4.7-6.7) in white patients
Gender Differences
The prevalence is significantly higher among women at 7.1 per 100,000 (95% CI 6.1-8.2) compared to 1.4 per 100,000 (95% CI 1.0-2.0) in men. The male-to-female ratio is approximately 1:5 in lupus nephritis patients.
Incidence Rates
The overall annual incidence rate was reported as 0.40 per 100,000 population per year (95% CI 0.24-0.63), with rates of 0.68 (95% CI 0.40-1.10) in women and 0.09 (95% CI 0.01-0.32) in men.
In Australia, a 2023 study found the estimated incidence of LN in Aboriginal and Torres Strait Islander Australians was 5.08 per 100,000 patient-years compared to 0.47 per 100,000 patient-years in non-Indigenous Australians.
Ethnic and Geographic Variations
The cumulative incidence of LN was 54.3% in all SLE patients, with significant ethnic variations: - 43.1% of Hispanics - 50.5% of African-Americans - 14.3% of Caucasians
Hispanic (OR = 2.71) and African-American ethnicities (OR = 3.13) were significant predictors of LN occurrence.
Evidence suggests higher rates of lupus renal involvement in Asian populations, with possibly more severe nephritis compared to other racial or ethnic groups. In China, the proportion of biopsy-proven lupus nephritis significantly increased with decreasing latitude from north to south.
In Saudi Arabia, lupus nephritis accounted for 48.5% of secondary glomerular diseases, with WHO classes III and IV (aggressive types) accounting for 56% of all patients.
Recent Findings
Recent studies (2021-2024) continue to support that lupus nephritis presents with different characteristics across ethnic groups, with some populations showing a "distinct phenotype" compared to others.
Aboriginal and Torres Strait Islander Australians showed a distinct phenotype with higher rates of neurological manifestations (23.08% vs 0%), hematological manifestations (46.50% vs 16.67%), and pulmonary arterial hypertension (23.08% vs 0%) compared to non-Indigenous Australians.
Racial/ethnic minority patients with lupus have worse long-term outcomes, including progression to end-stage renal disease and overall mortality.
In children, the incidence of systemic lupus erythematosus ranges from 3.3 to 8.8/100,000 with a higher Asian preponderance, though specific global rates for pediatric lupus nephritis are not provided in recent studies.
Study Design Parameters
Study Design Parameters and Endpoints in Key Lupus Nephritis Trials
Trial Designs and Challenges
Randomized controlled trials (RCTs) have been the standard approach for evaluating treatments in lupus nephritis (LN). Despite the significant morbidity and mortality associated with LN, trials have been plagued by repeated failures to meet clinical endpoints. Recent years have seen improvements in trial design and development of targeted approaches, yielding more promising results. Since 2020, these improvements have led to two new FDA-approved LN treatments.
A 2024 scoping review evaluated 124 intervention arms within 61 RCTs, involving 7,058 participants. Only 14.8% of these RCTs had follow-up periods ≥24 months, and 16.4% exclusively included participants with severe or refractory LN. Notably, Black and other race participants were under-represented, as were participants from Middle East, North Africa, and sub-Saharan African regions.
Key Medications Studied
Major medications evaluated in LN trials include: - Belimumab: A monoclonal antibody targeting the B cell survival cytokine BAFF - Voclosporin: A cyclosporin analog with improved pharmacokinetic characteristics - Rituximab: A monoclonal antibody inducing B-cell depletion (failed in EXPLORER and LUNAR trials) - Cyclophosphamide: Commonly prescribed as induction therapy - Mycophenolate mofetil (MMF): Commonly used as maintenance therapy
Primary Endpoints
The primary outcome in clinical trials for lupus nephritis is typically overall response rate (ORR). More specific primary endpoints include:
- Primary efficacy renal response (PERR): Defined as proteinuria ≤0.7 g/24h, eGFR≥60 ml/min/1.73m² without rescue therapy
- Complete renal response (CRR): Defined as proteinuria <0.5 g/24h, eGFR≥90 ml/min/1.73m²
- Renal improvement rate: Higher proportion in treatment group versus control
- Remission of kidney disease: Can be categorized as complete or partial remission
Recent studies indicate that proteinuria of less than 0.7-0.8 g at 12 months is most predictive of good long-term renal outcome, and that including urine red blood cells worsens the predictive value of proteinuria alone.
Secondary Endpoints
Secondary endpoints commonly assessed include:
- Change from baseline in SLE-DAI score (Systemic Lupus Erythematosus Disease Activity Index)
- Negative conversion ratio of anti-double-stranded DNA (anti-dsDNA)
- Proteinuria improvement at various timepoints
- Normalization of biomarkers including anti-double-stranded DNA, C3 and C4 levels
- Glucocorticoid dosage reduction
- Adverse events
- Mortality
- Long-term renal outcomes
Real-World Evidence
The BeRLiSS study, a multicenter Italian lupus cohort, provided real-world evidence for belimumab treatment. Among 91 LN patients, 70.3% achieved PERR, of whom 38.4% reached CRR. Importantly, 86.7% of patients achieving PERR at 6 months maintained response throughout follow-up.
Safety Outcomes
Treatment-related adverse events are critical endpoints, with gastrointestinal intolerances (31.2%) being most common with MMF. Only 47.5% of RCTs reported serious adverse events, and few described patient-reported outcomes. Despite good response with immunosuppressive regimens, relapse and treatment-related complications remain major problems in LN management.
Drug used in other indications
Obinutuzumab Clinical Trials Beyond Lupus Nephritis
Indications Under Investigation
Obinutuzumab is being investigated for several indications beyond Lupus Nephritis:
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Chronic Lymphocytic Leukemia (CLL)
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Mentioned in a 2017 publication as part of treatment algorithms defined by international practice guidelines
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Chlorambucil with obinutuzumab is established as a treatment for older CLL patients with comorbidities
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A cost-effectiveness study evaluated obinutuzumab plus chlorambucil (chemoimmunotherapy) as a treatment alternative
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Diffuse Large B-cell Lymphoma (DLBCL)
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Investigated in a randomized phase II trial for relapsed/refractory DLBCL
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The trial enrolled 25 DLBCL patients across two dosing regimens
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Demonstrated end-of-treatment response rate of 28%
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Showed efficacy in rituximab-refractory patients with 20% exhibiting treatment response
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Mantle-cell Lymphoma (MCL)
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Also part of the same randomized phase II trial for relapsed/refractory disease
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The trial included 15 MCL patients across two dosing arms
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IgG4-related Ophthalmic Disease (IgG4-ROD)
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Evaluated in a 2019 study with eight patients
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Resulted in 75% complete remission and 25% partial remission
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Described as a "safe and promising therapeutic option for IgG4-ROD"
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Advanced CEA-positive Solid Tumors
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Used as pretreatment to mitigate anti-drug antibodies in patients receiving cibisatamab
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Evaluated with cibisatamab in a Phase 1 study (NCT02324257)
Intervention Models
The clinical trials employed various intervention models:
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For DLBCL and MCL (randomized phase II trial):
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Two different dosing regimens were tested:
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Flat dose arm: 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8)
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Escalating dose arm: 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8
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Treatment consisted of eight cycles in total
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Randomized assignment of patients between the two dosing arms
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For IgG4-ROD:
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Fixed dose model: 1000 mg obinutuzumab administered intravenously at baseline
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Response-adaptive dosing: The number of treatment sessions was based on treatment response
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Retrospective enrollment of eight patients
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For Advanced CEA-positive Solid Tumors:
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Used as pretreatment in combination with cibisatamab
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Part of a Phase 1 study (NCT02324257)
The most common adverse events across trials were infusion-related reactions (IRRs), which were generally manageable. In the DLBCL/MCL trial, only three patients experienced grade 3/4 IRRs, and grade 3/4 neutropenia was observed in only one patient.
