Obinutuzumab for Lupus Nephritis

(POSTERITY Trial)

Recruiting at 63 trial locations

Overseen By Reference Study ID Number: WA42985 http://www.roche.com/about_roche/roche_worldwide.htm

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Hoffmann-La Roche

Must be taking: IV methylprednisolone

Disqualifiers: CNS SLE, Cancer, Immunodeficiency, others

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 52 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II, randomized, double-blind, placebo-controlled study is designed to evaluate the safety, efficacy and pharmacokinetics (PK) of obinutuzumab in adolescent participants (AP) aged 12 to less than 18 with biopsy-confirmed proliferative lupus nephritis (LN). It will also evaluate open label safety and PK of obinutuzumab in pediatric participants (PP), aged 5 to \<12 with LN.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug Obinutuzumab for treating lupus nephritis?

Research shows that Obinutuzumab, when added to standard lupus nephritis therapy, can help preserve kidney function and achieve better kidney remission compared to placebo. It is also effective in treating chronic lymphocytic leukemia, suggesting its potential in managing other conditions involving the immune system. ^{1 2 3 4 5}

Is Obinutuzumab generally safe for humans?

Obinutuzumab has been studied for safety in humans, primarily for blood cancers like chronic lymphocytic leukemia. Common side effects include neutropenia (low white blood cell count) and infusion-related reactions, which are usually mild to moderate and can be managed by adjusting the infusion rate. Hypersensitivity reactions are rare in humans, although they were observed in animal studies. ^{3 4 6 7 8}

How is the drug obinutuzumab unique for treating lupus nephritis?

Obinutuzumab is unique because it is a type II anti-CD20 monoclonal antibody that induces strong B-cell depletion, which is different from other treatments like rituximab that have not shown benefits for lupus nephritis. It is also used in combination with standard therapies to potentially improve kidney function preservation with less reliance on glucocorticoids. ^{1 2 3 4 8}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

Adolescents aged 12-17 with active Class III or IV Lupus Nephritis (LN) and children aged 5-11 for safety assessment can join this trial. They must have a biopsy confirming LN, meet specific criteria for protein in urine, and have received certain treatments for LN within the last year. Those with isolated Class V disease, severe other diseases, recent cancers, uncontrolled CNS SLE symptoms, drug abuse history or current infections cannot participate.

Inclusion Criteria

My kidney biopsy shows I have Class III or IV lupus nephritis.

I am between 12 and 17 years old.

I am between 5 and 11 years old.

Exclusion Criteria

I do not have severe brain-related lupus symptoms like vision loss, uncontrolled seizures, confusion, or difficulty moving.

I have not had a serious infection or been treated with IV or oral anti-infectives recently.

You have a history of weak immune system or severe blood disorders.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive obinutuzumab or placebo infusions on Days 1, 14, Week 24, Week 26, and Week 52

52 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Open-label extension

Evaluation of open label safety and pharmacokinetics in pediatric participants aged 5 to <12

Long-term

Treatment Details

Interventions

• Obinutuzumab

Trial Overview The study is testing Obinutuzumab's effectiveness and safety in treating Lupus Nephritis in adolescents compared to a placebo. It includes medications like Prednisone and Mycophenolate Mofetil as part of treatment regimens. The trial also assesses how the body processes Obinutuzumab in younger children.

Participant Groups

Group I: Open-Label Obinutuzumab Experimental Treatment 6 Interventions

Younger participants aged 5 to \<12 will receive obinutuzumab 1000 mg IV infusions on Days 1, 14, Week 24, Week 26 and Week 52.

Group II: Blinded Obinutuzumab Experimental Treatment 6 Interventions

Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusions on Day 1, Day 14, Week 24, Week 26 and Week 52. Participants with a body weight of 45 kg or more will receive the 1000 mg dose. Participants with a body weight below 45 kg will receive a weight adjusted dose of 20 mg/kilogram (kg).

Group III: Placebo Placebo Group 6 Interventions

Placebo participants will receive obinutuzumab matched placebo on Day 1, Day 14, Week 24, Week 26 and Week 52.

Obinutuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Adding obinutuzumab to standard lupus nephritis therapy significantly reduced the risk of unfavorable kidney outcomes by 60% and LN flares by 57%, based on post hoc analyses of the phase II NOBILITY trial involving 125 patients.

Patients receiving obinutuzumab experienced a slower decline in kidney function, with a notable 4.1 ml/min/1.73 m²/year advantage in eGFR slope, and 38% achieved complete renal response with lower glucocorticoid use compared to 16% in the placebo group at week 76.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kidney Outcomes and Preservation of Kidney Function With Obinutuzumab in Patients With Lupus Nephritis: A Post Hoc Analysis of the NOBILITY Trial. Rovin, BH., Furie, RA., Ross Terres, JA., et al.[2023]

In a study involving 125 patients with proliferative lupus nephritis, obinutuzumab showed a significant improvement in complete renal response at week 104 compared to placebo, with 41% of patients achieving this response versus 23% for the placebo group.

Obinutuzumab was well tolerated, with no increase in serious adverse events or deaths, although non-serious infusion-related reactions were more common, indicating it is a safe option for enhancing renal responses in lupus nephritis treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Furie, RA., Aroca, G., Cascino, MD., et al.[2022]

Obinutuzumab is an effective treatment for B-cell malignancies, specifically approved in the US for chronic lymphocytic leukaemia (CLL) in combination with chlorambucil, showcasing its efficacy in targeting cancer cells.

Utilizing GlycoMAb® technology, obinutuzumab enhances immune-mediated cell death through increased antibody-dependent cellular cytotoxicity, making it a promising option in ongoing phase III trials for various B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: first global approval. Cameron, F., McCormack, PL.[2021]

In a multinational phase III study, obinutuzumab combined with chlorambucil significantly improved progression-free survival and event-free survival in adults with previously untreated chronic lymphocytic leukaemia (CLL) compared to chlorambucil alone and rituximab plus chlorambucil.

Obinutuzumab plus chlorambucil had a manageable safety profile, with neutropenia and infusion-related reactions being the most common serious side effects, primarily occurring during the first infusion and generally manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. Hoy, SM.[2018]

In a meta-analysis of 10 clinical trials involving 2148 subjects, belimumab and obinutuzumab were found to be the most effective biologics for achieving complete remission in lupus nephritis, significantly outperforming placebo and other treatments.

The safety profile of these new biologics is generally good, with belimumab and obinutuzumab showing fewer serious adverse events compared to other treatments, indicating they are safe options for patients when combined with standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of novel biologics in the treatment of lupus nephritis based on registered clinical trials: a systematic review and network meta-analysis. Li, F., Cui, W., Huang, G., et al.[2023]

In a study of 9 systemic lupus erythematosus (SLE) patients who did not respond to rituximab, obinutuzumab treatment led to significant reductions in disease activity scores after 6 months, indicating its efficacy in this challenging patient population.

Obinutuzumab also allowed for a reduction in steroid use for many patients, suggesting it may be a safer, steroid-sparing option for managing SLE in those with secondary non-response to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab. Arnold, J., Dass, S., Twigg, S., et al.[2023]

In preclinical studies involving cynomolgus monkeys, obinutuzumab caused expected B-cell depletion but also led to hypersensitivity reactions, indicating potential safety concerns that were observed at all doses.

Despite these reactions in monkeys, clinical evidence suggests that hypersensitivity to obinutuzumab is rare in humans, highlighting that animal studies may not always predict human responses to immunogenicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypersensitivity Reactions to Obinutuzumab in Cynomolgus Monkeys and Relevance to Humans. Husar, E., Solonets, M., Kuhlmann, O., et al.[2018]

Obinutuzumab (OBZ) was used to treat a patient with refractory cryoglobulinaemic vasculitis (CV) who was immunized against rituximab (RTX), and no cross-reactivity between anti-RTX antibodies and OBZ was found, suggesting OBZ can be a viable alternative.

The patient experienced a flare of CV after OBZ infusion, which may be linked to the release of immune complexes due to B cell lysis, indicating that the use of OBZ in patients with mixed CV should be approached with caution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flare of a mixed cryoglobulinaemic vasculitis after obinutuzumab infusion. Martin de Fremont, G., Chiron, A., Krzysiek, R., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Kidney Outcomes and Preservation of Kidney Function With Obinutuzumab in Patients With Lupus Nephritis: A Post Hoc Analysis of the NOBILITY Trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Obinutuzumab: first global approval. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. [2018]

5. Italy pubmed.ncbi.nlm.nih.gov

Efficacy and safety of novel biologics in the treatment of lupus nephritis based on registered clinical trials: a systematic review and network meta-analysis. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Hypersensitivity Reactions to Obinutuzumab in Cynomolgus Monkeys and Relevance to Humans. [2018]

8. Italy pubmed.ncbi.nlm.nih.gov

Flare of a mixed cryoglobulinaemic vasculitis after obinutuzumab infusion. [2022]