Ravulizumab for Lupus Nephritis and IgA Nephropathy

(SANCTUARY Trial)

Recruiting at 128 trial locations

Overseen By Alexion Pharmaceuticals, Inc. (Sponsor)

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Alexion Pharmaceuticals

Must be taking: Renin-angiotensin inhibitors

Must not be taking: Complement inhibitors

Disqualifiers: Renal disease, Transplant history, others

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

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

Compensation: Varies

Number of Visits: Unknown

123 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you are in the IgAN cohort, you must have been on a stable dose of renin-angiotensin system inhibitors for at least 3 months. Also, you cannot have taken prednisone over 20 mg per day for more than 14 days or any other immunosuppressants within 6 months.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, if you are in the IgAN cohort, you must have been on a stable dose of renin-angiotensin system inhibitors for at least 3 months.

What data supports the idea that Ravulizumab for Lupus Nephritis and IgA Nephropathy is an effective treatment?

The available research does not provide specific data on Ravulizumab for Lupus Nephritis and IgA Nephropathy. Instead, it focuses on another drug, Belimumab, which has shown some effectiveness in treating Lupus Nephritis. Belimumab was found to reduce the risk of kidney-related events and improve kidney function in some patients. However, there is no direct comparison or data available for Ravulizumab in the provided information. ^{1 2 3 4 5}

What safety data exists for Ravulizumab in treating Lupus Nephritis and IgA Nephropathy?

The provided research does not contain specific safety data for Ravulizumab (also known as Ultomiris, ravulizumab-cwvz, ALXN1210) in the treatment of Lupus Nephritis and IgA Nephropathy. The studies mentioned focus on other treatments such as Belimumab, Tacrolimus, and Rituximab for Lupus Nephritis. Further research or clinical trial data specific to Ravulizumab would be needed to answer this question. ^{1 2 6 7 8}

Is the drug Ravulizumab a promising treatment for Lupus Nephritis and IgA Nephropathy?

Ravulizumab, similar to eculizumab, is a promising drug because it targets the complement system, which plays a key role in diseases like IgA nephropathy. Eculizumab has shown positive results in some cases, suggesting that Ravulizumab might also be effective. ^{1 9 10 11 12}

How is the drug Ravulizumab unique for treating lupus nephritis and IgA nephropathy?

Ravulizumab is unique because it is a long-acting complement inhibitor that targets the C5 protein, similar to eculizumab, which has shown promise in treating conditions like IgA nephropathy by reducing complement activation, a key factor in the disease's progression. This mechanism of action distinguishes it from other treatments that do not specifically target the complement system. ^{1 9 10 11 12}

What is the purpose of this trial?

This trial is testing the safety and effectiveness of a drug called ravulizumab, given through a vein, in patients with specific kidney diseases. The drug aims to reduce kidney damage by blocking part of the immune system.

Eligibility Criteria

This trial is for people with severe kidney inflammation due to Lupus Nephritis (LN) or IgA Nephropathy (IgAN). Participants must have protein in their urine and be vaccinated against certain infections. Those with LN need active disease treatment, while those with IgAN should be on stable blood pressure medication. People can't join if they have very low kidney function, used complement inhibitors before, have other major kidney diseases, uncontrolled high blood pressure, or recent heavy use of steroids/immunosuppressants.

Inclusion Criteria

I have been diagnosed with primary IgA nephropathy.

I have been vaccinated against meningitis.

I am vaccinated for Hib and pneumonia as required.

Exclusion Criteria

I have been diagnosed with a quickly worsening kidney condition.

I do not have significant kidney disease other than lupus nephritis or IgA nephropathy.

My kidney function is low, with an eGFR under 30.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

Initial Evaluation

Participants receive either ravulizumab or placebo IV infusion in combination with background therapy

26 weeks

Extension

Participants continue treatment with either ravulizumab or switch from placebo to ravulizumab, in combination with background therapy

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, receiving background therapy according to the standard of care

36 weeks

Treatment Details

Interventions

• Background Therapy
• Ravulizumab

Trial Overview The study tests Ravulizumab's safety and effectiveness compared to a placebo in patients with LN or IgAN. All participants will continue their usual treatments too. Ravulizumab is given through an IV infusion to see if it can help by blocking part of the immune system that damages the kidneys.

Participant Groups

Group I: Ravulizumab: LN Cohort Experimental Treatment 2 Interventions

Eligible participants will receive ravulizumab IV infusion in combination with background therapy during both the Initial Evaluation Period (26 weeks) and Extension Period (24 weeks). During the Follow-up Period (36 weeks) participants will receive background therapy according to the standard of care.

Group II: Ravulizumab: IgAN Cohort Experimental Treatment 2 Interventions

Eligible participants will receive ravulizumab IV infusion in combination with background therapy during both the Initial Evaluation Period (26 weeks) and Extension Period (24 weeks). During the Follow-up Period (36 weeks) participants will receive background therapy according to the standard of care.

Group III: Placebo: LN Cohort Placebo Group 2 Interventions

Eligible participants will receive placebo IV infusion in combination with background therapy during both the Initial Evaluation Period (26 weeks) and Extension Period (24 weeks). During the Follow-up Period (36 weeks) participants will receive background therapy according to the standard of care.

Group IV: Placebo: IgAN Cohort Placebo Group 3 Interventions

Eligible participants will receive placebo IV infusion in combination with background therapy during the Initial Evaluation Period (26 weeks) and will switch to ravulizumab for the Extension Period (24 weeks). During the Follow-up Period (36 weeks) participants will receive background therapy according to the standard of care.

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

Approved in United States as Ultomiris for:

• Paroxysmal nocturnal hemoglobinuria (PNH)
• Atypical hemolytic uremic syndrome (aHUS)

Approved in European Union as Ultomiris for:

• Paroxysmal nocturnal haemoglobinuria (PNH)

Who Is Running the Clinical Trial?

Alexion Pharmaceuticals

Lead Sponsor

Trials

231

Recruited

36,700+

Marc Dunoyer

Alexion Pharmaceuticals

Chief Executive Officer since 2021

B.A. in Psychology from the University of New Hampshire

Christophe Hotermans

Alexion Pharmaceuticals

Chief Medical Officer since 2023

MD

Alexion

Lead Sponsor

Trials

247

Recruited

38,600+

Marc Dunoyer

Alexion

Chief Executive Officer since 2021

PhD in Molecular Biology, University of Brussels

Christophe Hotermans

Alexion

Chief Medical Officer since 2021

MD, University of Leuven

Alexion Pharmaceuticals, Inc.

Lead Sponsor

Trials

267

Recruited

141,000+

Dr. Alberto R. Martinez

Alexion Pharmaceuticals, Inc.

Chief Medical Officer since 2010

MD from University of Sao Paulo

Marc Dunoyer

Alexion Pharmaceuticals, Inc.

Chief Executive Officer since 2021

PhD in Molecular Biology

Findings from Research

In a study of 1844 nephritis-naïve patients with systemic lupus erythematosus (SLE), low-dose intravenous belimumab (1 mg/kg monthly) significantly reduced the risk of de novo renal flares by nearly 3-fold compared to placebo.

Subcutaneous belimumab (200 mg weekly) also showed a protective effect against renal flares, while the standard approved dose of intravenous belimumab (10 mg/kg monthly) did not demonstrate clear protective benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Belimumab on Preventing de novo Renal Lupus Flares. Parodis, I., Lindblom, J., Cetrez, N., et al.[2023]

In the phase 3 BLISS-LN study involving 448 patients with lupus nephritis, belimumab significantly improved kidney-related outcomes compared to placebo, with a higher percentage of patients achieving primary and complete renal responses, especially in relapsed patients.

The efficacy of belimumab was consistent regardless of whether patients received glucocorticoid pulses during induction therapy, indicating its potential as a reliable treatment option for both newly diagnosed and relapsed lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of belimumab on kidney-related outcomes in patients with lupus nephritis: post hoc subgroup analyses of the phase 3 BLISS-LN trial. Anders, HJ., Furie, R., Malvar, A., et al.[2023]

In a 104-week Phase 3 trial involving 448 patients with lupus nephritis, adding belimumab to standard therapy significantly improved kidney responses, especially in patients with lower baseline urine protein/creatinine ratios.

Belimumab also reduced the risk of kidney-related events, death, and lupus nephritis flare, while slowing the decline in kidney function (eGFR) compared to standard treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Rovin, BH., Furie, R., Teng, YKO., et al.[2022]

In a study of 45 Chinese patients with refractory lupus nephritis, belimumab treatment resulted in a 55.6% overall renal response rate, with 13.3% achieving complete renal response and 42.2% achieving partial renal response after 24 weeks.

Belimumab was found to be safe, with only 3 reported adverse events (2 infections and 1 allergy) and no serious events, while also allowing 20% of patients to reduce their prednisone dosage significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to belimumab among patients with refractory lupus nephritis: a real-world observational retrospective multicenter study. Zhang, S., Qiu, Q., Zeng, S., et al.[2023]

In a pooled analysis of 1684 patients from the BLISS trials, belimumab showed potential renal benefits in patients with systemic lupus erythematosus (SLE) who had renal involvement, particularly when combined with mycophenolate mofetil.

While belimumab favored improvements in renal outcomes such as renal flare rates and proteinuria reduction, most differences compared to placebo were not statistically significant, indicating the need for further research, especially in patients with severe lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Dooley, MA., Houssiau, F., Aranow, C., et al.[2016]

In a study of 1355 patients with lupus nephritis treated with tacrolimus for 5 years, the treatment was found to be well tolerated, with serious adverse drug reactions occurring mainly in the first 28 weeks and no significant increase in risk over time.

Tacrolimus significantly improved key health markers related to lupus nephritis, such as urine protein levels and anti-dsDNA antibody levels, while maintaining a low cumulative rate of progression to renal failure (6.6% at Year 5) and manageable relapse rates (30.6% at Year 5).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis: 5-year Interim Postmarketing Surveillance Study in Japan (TRUST). Takeuchi, T., Wakasugi, N., Uno, S., et al.[2021]

The combination of rituximab and belimumab was found to be safe for patients with refractory lupus nephritis, showing no increase in adverse events compared to those receiving rituximab alone.

While the addition of belimumab did not improve clinical efficacy compared to rituximab and cyclophosphamide alone, it did lead to a greater reduction in certain B cell populations, suggesting a mechanism that enhances the negative selection of autoreactive B cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Atisha-Fregoso, Y., Malkiel, S., Harris, KM., et al.[2022]

In a real-life study of 91 lupus patients treated with belimumab, 70.3% achieved a primary efficacy renal response (PERR) after treatment, indicating that belimumab is effective in improving kidney function in lupus glomerulonephritis.

Factors such as hypertension and high baseline proteinuria negatively predicted the likelihood of achieving PERR, while positive predictors included the presence of anti-Sm antibodies and achieving PERR at 6 months, suggesting that early response is crucial for long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable renal response and safety with add-on belimumab in patients with lupus nephritis in real-life setting (BeRLiSS-LN). Results from a large, nationwide, multicentric cohort. Gatto, M., Saccon, F., Andreoli, L., et al.[2022]

Eculizumab, an anti-C5 antibody, was successfully used to achieve clinical remission of atypical hemolytic uremic syndrome (aHUS) in a patient with both aHUS and crescentic IgA nephropathy, highlighting its potential efficacy in treating complex kidney conditions.

Despite the remission of aHUS, the patient's renal function did not recover, indicating that while eculizumab can be effective in managing aHUS, it may not restore kidney function in cases of severe or refractory kidney injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coexistence of atypical hemolytic uremic syndrome and crescentic IgA nephropathy treated with eculizumab: a case report. Matsumura, D., Tanaka, A., Nakamura, T., et al.[2020]

A 16-year-old male with the vasculitic form of IgA nephropathy (IgAN) showed a rapid response to treatment with the complement inhibitor eculizumab after failing conventional therapies, maintaining stable kidney function for over 6 months.

Despite the initial success in stabilizing kidney function, the patient continued to experience high levels of proteinuria and showed severe chronic changes in a follow-up renal biopsy, suggesting that chronic kidney damage may occur independently of complement activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of eculizumab in crescentic IgA nephropathy: proof of principle and conundrum? Ring, T., Pedersen, BB., Salkus, G., et al.[2022]

Rituximab, originally approved for non-Hodgkin's B-cell lymphoma, has been shown to be an effective immunosuppressant for various immune-mediated diseases, including ANCA-associated vasculitis, based on recent large clinical trials.

Its favorable efficacy and safety profile make rituximab a promising treatment option for glomerular diseases such as membranous nephropathy and lupus nephritis, positioning it as a critical therapy in nephrology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. Kattah, AG., Fervenza, FC., Roccatello, D.[2018]

Rituximab (RTX) significantly improves total renal remission rates and complete renal remission rates in lupus nephritis patients, showing better efficacy compared to standard treatments like mycophenolate mofetil and cyclophosphamide, based on a meta-analysis of six studies involving 588 patients.

RTX treatment does not increase the risk of adverse events compared to control groups, indicating it is a safe option for patients with lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of an anti-CD20 monoclonal antibody, rituximab, for lupus nephritis: A meta-analysis. Teng, S., Tian, Y., Luo, N., et al.[2022]

References

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

Effect of Belimumab on Preventing de novo Renal Lupus Flares. [2023]

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

Effect of belimumab on kidney-related outcomes in patients with lupus nephritis: post hoc subgroup analyses of the phase 3 BLISS-LN trial. [2023]

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

A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Response to belimumab among patients with refractory lupus nephritis: a real-world observational retrospective multicenter study. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. [2016]

6. Canada pubmed.ncbi.nlm.nih.gov

Long-term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis: 5-year Interim Postmarketing Surveillance Study in Japan (TRUST). [2021]

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

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Durable renal response and safety with add-on belimumab in patients with lupus nephritis in real-life setting (BeRLiSS-LN). Results from a large, nationwide, multicentric cohort. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Coexistence of atypical hemolytic uremic syndrome and crescentic IgA nephropathy treated with eculizumab: a case report. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Use of eculizumab in crescentic IgA nephropathy: proof of principle and conundrum? [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of an anti-CD20 monoclonal antibody, rituximab, for lupus nephritis: A meta-analysis. [2022]