Zanubrutinib for Primary Membranous Nephropathy

(ALMOND Trial)

Recruiting at 90 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: BeiGene

Must be taking: ACE inhibitors, ARBs

Disqualifiers: Diabetes, Severe renal disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: Unknown

282 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must have been on a stable dose of an ACE inhibitor or ARB for at least 24 weeks before joining the study.

What data supports the effectiveness of the drug Zanubrutinib for primary membranous nephropathy?

While there is no direct evidence for Zanubrutinib in primary membranous nephropathy, studies have shown that targeting autoantibody-producing cells with biological agents can be effective in controlling the disease. Tacrolimus, another drug mentioned, has been studied for its efficacy and safety in primary membranous nephropathy, suggesting potential benefits in managing the condition. ^{1 2 3 4 5}

How is the drug Zanubrutinib different from other treatments for primary membranous nephropathy?

Zanubrutinib is unique because it is a Bruton tyrosine kinase (BTK) inhibitor, which targets specific pathways in the immune system that are involved in the production of harmful antibodies, potentially offering a new approach compared to traditional immunosuppressive treatments like rituximab or steroids. ^{1 2 3 5 6}

What is the purpose of this trial?

This trial tests zanubrutinib, a medication aimed at reducing kidney damage, in patients with a specific kidney disease. It measures how well it lowers protein in the urine and compares its effectiveness to another drug, tacrolimus. Zanubrutinib is an oral medication approved in Europe for certain conditions and is being reviewed for approval in the United States.

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

This trial is for people with primary membranous nephropathy, confirmed by biopsy. They must have been treated with specific blood pressure medications (ACEI or ARB) for at least 24 weeks and have certain levels of protein in their urine. It's not open to those with secondary causes of the disease, active hepatitis B or C, severe liver issues, significant heart diseases, very low kidney function, a history of immune deficiency conditions like HIV or past spleen removals.

Inclusion Criteria

The amount of protein in your urine is too high.

I've been on the highest dose possible of ACEI or ARB for my condition for at least 24 weeks, with controlled blood pressure.

My kidney disease was confirmed by a biopsy.

Exclusion Criteria

My liver is not working well (severe issues).

I have a condition like HIV or have had my spleen removed, making me more prone to infections.

You have tuberculosis when tested before the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive zanubrutinib to evaluate efficacy as measured by proteinuria reduction

24 weeks

Treatment Part 2

Participants receive zanubrutinib or tacrolimus to evaluate efficacy as measured by complete remission rate

64 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

40 weeks

Treatment Details

Interventions

• Tacrolimus
• Zanubrutinib

Trial Overview The study tests Zanubrutinib's ability to reduce protein in urine and compares its effectiveness against Tacrolimus in achieving complete remission. Participants are already on optimal supportive care and will be divided into two parts: one focusing on Zanubrutinib alone and the other comparing it directly with Tacrolimus.

Participant Groups

Group I: Part 2: Zanubrutinib Low Dose Experimental Treatment 1 Intervention

Participants will receive zanubrutinib once daily.

Group II: Part 2: Zanubrutinib High Dose Experimental Treatment 1 Intervention

Participants will receive zanubrutinib twice daily.

Group III: Part 1: Zanubrutinib High Dose Experimental Treatment 1 Intervention

Participants will receive zanubrutinib twice daily.

Group IV: Part 2: Tacrolimus Active Control 1 Intervention

Participants will receive tacrolimus capsules twice daily for 64 weeks.

Zanubrutinib is already approved in United States, China for the following indications:

Approved in United States as Brukinsa for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)

Approved in China as Brukinsa for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a pilot study involving 13 high-risk patients with severe membranous nephropathy, a novel treatment combining rituximab and cyclosporine led to a significant reduction in proteinuria, with a 65% decrease at 3 months and 80% at 6 months.

The treatment resulted in a high remission rate, with 92% of patients achieving complete or partial remission by 9 months, and 54% achieving complete remission by 12 months, while maintaining stable renal function and showing good tolerance to the regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and Rituximab. Waldman, M., Beck, LH., Braun, M., et al.[2020]

Primary membranous nephropathy, primarily caused by anti-PLA2R antibodies, is the leading cause of nephrotic syndrome in adults, and recent studies indicate that biological agents targeting autoantibody-producing cells can effectively manage the disease with a good safety profile.

The review proposes a diagnostic and therapeutic algorithm for managing primary membranous nephropathy, comparing the efficacy and safety of treatments like rituximab and highlighting the need for further advancements in clinical care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary membranous nephropathy in the era of autoantibodies and biological therapies. Rojas-Rivera, JE., Ortiz Arduán, A.[2021]

Recent advancements in understanding membranous nephropathy have led to improved molecular diagnoses through the identification of target antigens, which helps in monitoring disease progression and guiding treatment decisions.

Rituximab, a B-cell-depleting agent, has emerged as a leading treatment option for primary membranous nephropathy, showing promise in randomized controlled trials compared to traditional immunosuppressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Membranous Nephropathy: Core Curriculum 2021. Alsharhan, L., Beck, LH.[2021]

In a study of 3 patients with primary membranous nephropathy who were resistant to or could not tolerate steroids, treatment with tacrolimus for 6 months resulted in significant reductions in proteinuria, with one patient experiencing almost complete disappearance of proteinuria.

Although proteinuria increased again in 2 patients after stopping tacrolimus, it did not return to pretreatment levels, suggesting that tacrolimus may provide a modest and lasting benefit in managing resistant membranous nephropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases. Szeto, CC., Leung, CB., Lai, FM., et al.[2019]

In a small phase II trial involving 9 patients with lupus membranous nephropathy, filgotinib showed a significant median reduction of 50.7% in 24-hour urine protein after 16 weeks, suggesting potential efficacy in treating this condition.

Filgotinib was well tolerated by patients, while the results for lanraplenib were inconclusive due to the limited number of participants, indicating that further research on JAK inhibitors like filgotinib is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II, randomised, double-blind, multicentre study evaluating the safety and efficacy of filgotinib and lanraplenib in patients with lupus membranous nephropathy. Baker, M., Chaichian, Y., Genovese, M., et al.[2022]

In a 2-year study involving patients with idiopathic membranous nephropathy and steroid-resistant nephrotic syndrome, the combination of mizoribine (MZR) and prednisolone (PSL) led to a complete remission rate of 52.6% in the once-a-day MZR group compared to 38.9% in the three-times-a-day group, indicating that once-daily dosing may be more effective.

The study found that achieving a peak serum concentration (C max) of MZR greater than 1.1 µg/mL was necessary for complete remission, highlighting the importance of monitoring drug levels to optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome. Saito, T., Iwano, M., Matsumoto, K., et al.[2022]

References

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

Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and Rituximab. [2020]

2. Spain pubmed.ncbi.nlm.nih.gov

Primary membranous nephropathy in the era of autoantibodies and biological therapies. [2021]

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

Membranous Nephropathy: Core Curriculum 2021. [2021]

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

Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases. [2019]

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

Phase II, randomised, double-blind, multicentre study evaluating the safety and efficacy of filgotinib and lanraplenib in patients with lupus membranous nephropathy. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome. [2022]