ADI-001 for Lupus Nephritis

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Adicet Bio, Inc

Disqualifiers: Severe liver disease, Gene therapy, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

ADI-202300103 is a phase 1 multicenter, open label, dose finding and dose expansion, safety/efficacy study in patients with autoimmune disease. The study will consist of different periods including screening, lymphodepletion, treatment, and follow-up

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should have an inadequate response to current treatments, which might imply that some medications could be continued. Please consult with the trial team for specific guidance.

What data supports the effectiveness of the drug ADI-001 for treating lupus nephritis?

Research shows that cyclophosphamide, a component of the treatment, is effective in preserving kidney function in lupus nephritis. Additionally, combining fludarabine with cyclophosphamide has been studied for safety and efficacy in lupus nephritis, suggesting potential benefits. ^{1 2 3 4 5}

Is ADI-001 safe for humans?

The safety of ADI-001 specifically isn't detailed, but related treatments like fludarabine and cyclophosphamide have been studied for lupus nephritis. Cyclophosphamide has been used in various forms and doses, showing some risks of non-remission in certain genetic profiles, while fludarabine's safety was evaluated in different administration methods. ^{4 5 6 7 8}

How is the drug ADI-001 for lupus nephritis different from other treatments?

ADI-001 is unique because it involves a novel approach using CAR-T cells (a type of immune cell modified to better fight disease), which is different from traditional treatments like cyclophosphamide that suppress the immune system. This innovative method targets specific cells involved in lupus nephritis, potentially offering a more targeted and effective treatment. ^{1 4 9 10 11}

Research Team

Eligibility Criteria

This trial is for people with lupus nephritis, a type of kidney inflammation due to systemic lupus erythematosus. Participants must have an active disease confirmed by a biopsy within the last 6 months and significant protein in their urine. They should be able to perform daily activities with some limitations (ECOG ≤ 2).

Inclusion Criteria

I am able to care for myself and perform daily activities.

Proteinuria (or urine protein creatinine ratio (UPCR)) > 1g / 24 hours

I have been diagnosed with systemic lupus erythematosus according to the 2019 criteria.

Exclusion Criteria

I have not had gene or cell therapy treatments before.

LN pure class V, per 2018 ISN/RPS criteria (Bajema 2018)

My liver disease is severe.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants undergo lymphodepletion to prepare for the infusion of ADI-001

1 week

Treatment

Participants receive ADI-001 infusion with dose escalation to determine MTD/MAD

4 weeks

Weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• ADI-001 (Other)
• Cyclophosphamide (Alkylating agents)
• Fludarabine (Anti-metabolites)

Trial Overview The study tests ADI-001, alongside Cyclophosphamide and Fludarabine, for safety and effectiveness in treating lupus nephritis. It's an early-stage trial that includes screening, lymphodepletion (reducing certain white blood cells), treatment administration, and follow-up.

Participant Groups

Group I: ADI-001 Dose Extension Experimental Treatment 3 Interventions

After dose level has been declared safe, additional patients can be enrolled at the declared safe dose to further investigate the safety profile of ADI-001.

Group II: ADI-001 Dose Expansion Experimental Treatment 3 Interventions

Dose Expansion ADI-001 is administered via infusion at the MTD/MAD to confirm recommended phase 2 dose (Part 2).

Group III: ADI-001 Dose Escalation Experimental Treatment 3 Interventions

ADI-001 is administered via infusion with ascending dose levels as a single dose to determine the maximum tolerated dose (MTD) or maximum assessed dose (MAD) of ADI-001.

Who Is Running the Clinical Trial?

Adicet Bio, Inc

Lead Sponsor

Trials

3

Recruited

310+

Adicet Therapeutics

Lead Sponsor

Trials

4

Recruited

370+

Findings from Research

Cyclophosphamide (CYC) is still the first-choice treatment for severe proliferative lupus nephritis, despite the availability of newer treatment options.

There is ongoing debate regarding the optimal route, dosage, and duration of CYC therapy, highlighting the need for further research to refine treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lupus nephritis: current issues. Mavragani, CP., Moutsopoulos, HM.[2019]

High-dose corticosteroids are the standard initial treatment for severe inflammation in lupus nephritis, but long-term management often requires additional therapies to address underlying immune system issues.

New treatment options for lupus nephritis include novel immunosuppressive agents and combination therapies, which may improve efficacy and reduce toxicity compared to traditional treatments like cyclophosphamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress in the treatment of proliferative lupus nephritis. Balow, JE., Austin, HA.[2019]

In a study comparing two treatment methods for diffuse proliferative lupus nephritis, sequential oral cyclophosphamide (CYC) followed by azathioprine (AZA) showed a trend towards better efficacy, with 90% of patients achieving complete or partial remission compared to 73% in the intravenous (IV) CYC group.

While the oral treatment had a higher rate of herpes zoster infections and menstrual disturbances, these side effects were not statistically significant, indicating that although oral CYC and AZA may be more effective, they could also lead to increased toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of diffuse proliferative lupus glomerulonephritis: a comparison of two cyclophosphamide-containing regimens. Mok, CC., Ho, CT., Siu, YP., et al.[2022]

In a study involving 5 patients with lupus nephritis, both subcutaneous and intravenous administration of fludarabine showed similar pharmacokinetics, indicating that the method of delivery does not significantly affect the drug's absorption and effectiveness.

Subcutaneous administration of fludarabine demonstrated approximately 105% bioavailability compared to intravenous delivery, and no injection site reactions were reported, suggesting it could be a more convenient and equally effective alternative for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis. Kuo, GM., Boumpas, DT., Illei, GG., et al.[2019]

A short course of low-dose fludarabine combined with cyclophosphamide can lead to significant improvements in patients with active proliferative lupus nephritis, with 10 out of 11 evaluated patients showing marked improvement and 7 achieving complete remission.

However, the treatment was associated with severe bone marrow toxicity, including profound lymphocytopenia and serious adverse events, which limits its safety and widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis. Illei, GG., Yarboro, CH., Kuroiwa, T., et al.[2013]

In a study of 77 lupus nephritis patients, those with the GSTA1*A heterozygous mutation had a higher risk of not achieving remission from cyclophosphamide therapy (44% vs. 20%).

Pharmacokinetic analysis showed that patients with the GSTA1*A variant had lower levels of the active metabolite 4-hydroxycyclophosphamide, which was linked to poorer treatment outcomes, indicating that genetic factors can influence the effectiveness of cyclophosphamide in lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients. Wang, HN., Zhu, XY., Zhu, Y., et al.[2015]

This study involves a prospective randomized trial with 12 patients suffering from systemic lupus erythematosus (SLE) and nephritis, focusing on the effects of monthly intravenous cyclophosphamide administration.

Preliminary data suggests that cyclophosphamide may be a potential treatment option for managing SLE-related nephritis, although further results are needed to assess its efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cyclophosphamide pulse therapy of systemic lupus erythematosus with renal involvement]. Hein, R., Neumann, KH., Koch, KM., et al.[2014]

A 6-month outpatient treatment with high-dose oral cyclophosphamide showed improvements in disease activity for most patients with systemic lupus erythematosus (SLE), particularly those with nephritis, as indicated by better SLAM scores and reduced proteinuria.

While the treatment was generally feasible, some patients experienced mild nausea and infections, and three patients did not complete the therapy due to various reasons, suggesting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient monthly oral bolus cyclophosphamide therapy in systemic lupus erythematosus. Dawisha, SM., Yarboro, CH., Vaughan, EM., et al.[2021]

In a study of 17 patients with refractory lupus nephritis, rituximab treatment led to complete or partial renal remission in 53% of cases after 12 months, indicating its potential efficacy as an alternative treatment.

Rituximab also significantly improved proteinuria levels and allowed for a reduction in steroid dosages, suggesting it may help manage the side effects associated with standard treatments like corticosteroids and cyclophosphamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the effectiveness and safety of rituximab in patients with refractory lupus nephritis: a chart review. Contis, A., Vanquaethem, H., Truchetet, ME., et al.[2022]

In a study of 46 patients with systemic lupus erythematosus nephritis treated with oral cyclophosphamide (POCY), 70% achieved durable remission of proteinuria, indicating its effectiveness as a treatment option.

POCY was well tolerated, with adverse effects occurring in less than 10% of patients, suggesting it is a safe alternative to intravenous cyclophosphamide (IVCY) for managing lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cyclophosphamide for lupus glomerulonephritis: an underused therapeutic option. McKinley, A., Park, E., Spetie, D., et al.[2022]

Tacrolimus (TAC) demonstrated significant efficacy in treating lupus nephritis (LN), with 75% of patients achieving complete remission after 12 months, compared to only 40% in the cyclophosphamide (CYC) group.

TAC was associated with fewer severe adverse effects, as the CYC group had cases of end-stage renal disease and serious pneumonia, highlighting TAC's safety profile in patients with severe renal disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis: a non-randomized prospective cohort study. Wang, S., Li, X., Qu, L., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Lupus nephritis: current issues. [2019]

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

Progress in the treatment of proliferative lupus nephritis. [2019]

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

Treatment of diffuse proliferative lupus glomerulonephritis: a comparison of two cyclophosphamide-containing regimens. [2022]

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

Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis. [2019]

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

Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis. [2013]

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

The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients. [2015]

7. Germany pubmed.ncbi.nlm.nih.gov

[Cyclophosphamide pulse therapy of systemic lupus erythematosus with renal involvement]. [2014]

8. Canada pubmed.ncbi.nlm.nih.gov

Outpatient monthly oral bolus cyclophosphamide therapy in systemic lupus erythematosus. [2021]

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

Analysis of the effectiveness and safety of rituximab in patients with refractory lupus nephritis: a chart review. [2022]

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

Oral cyclophosphamide for lupus glomerulonephritis: an underused therapeutic option. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis: a non-randomized prospective cohort study. [2022]