RO7434656 for IgA Nephropathy

(IMAGINATION Trial)

Recruiting at204 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Hoffmann-La Roche

Must be taking: Ace inhibitors, Arbs

Must not be taking: Sglt2 inhibitors, Corticosteroids

Disqualifiers: Pregnancy, Diabetes, Hypertension, Substance abuse, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment that uses small genetic pieces to block harmful proteins in people with a specific kidney disease that isn't improving with current treatments. The treatment aims to stop the body from making proteins that make the disease worse.

Will I have to stop taking my current medications?

The trial requires that you continue taking ACE inhibitors or ARBs if you can tolerate them. You may need to stop certain medications like SGLT2 inhibitors, endothelin receptor antagonists, and others listed in the exclusion criteria before joining the trial.

What makes the drug RO7434656 unique for treating IgA Nephropathy?

RO7434656 is unique because it targets complement factor B, which plays a role in the immune system's complement pathway, potentially reducing kidney inflammation and damage in IgA Nephropathy. This approach is different from standard treatments that often focus on controlling blood pressure and reducing protein in the urine. ^{1 2 3 4 5}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

This trial is for adults with primary IgA Nephropathy, a kidney disease, who are at risk of worsening despite current treatments. They must have had a confirming kidney biopsy within the last 7 years and be on stable doses of specific blood pressure medicines. Participants need functioning kidneys (eGFR ≥ 20) and significant protein in their urine. Pregnant women or those planning pregnancy soon after the trial can't join, nor can people with certain diabetes indicators or recent use of strong immune system drugs.

Inclusion Criteria

eGFR ≥ 20 mL/min/1.73 m^2, as calculated by the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (Inker et al. 2021a)

I am using effective birth control methods.

Urine Protein-to-Creatinine Ratio (UPCR) ≥ 1 gram per gram (g/g) or urine protein excretion ≥ 1 gram per day (g/day) (with UPCR ≥ 0.8 g/g), all measured from a 24-hour urine collection during screening obtained no longer than 60 days prior to Day 1

Exclusion Criteria

My kidney disease is rapidly worsening, as shown by tests or doctor's opinion.

I have not had anti-CD20 therapy in the last 9 months.

Histopathologic or other evidence of another autoimmune glomerular disease

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive subcutaneous doses of sefaxersen (RO7434656) or placebo on Days 1, 15, and 29, followed by once every 4 weeks until Week 105

105 weeks

Initial visits on Days 1, 15, 29, then every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term after Week 105 at the investigator's discretion until up to 1 year after the common-close timepoint

Up to 1 year

Treatment Details

Interventions

• RO7434656 (Antisense Oligonucleotide)

Trial Overview The study tests RO7434656, an experimental Antisense Oligonucleotide therapy against a placebo to see if it's effective and safe for slowing down kidney disease progression in high-risk IgA Nephropathy patients. The participants will receive either the new drug or a placebo without knowing which one they're getting.

Participant Groups

Group I: sefaxersen (RO7434656) Experimental Treatment 1 Intervention

Participants will receive subcutaneous (SC) doses of sefaxersen (RO7434656) on Days 1, 15, and 29 followed by once every 4 weeks until Week 105. Participants may be eligible to switch to open-label treatment after Week 105 at the investigator's discretion until up to 1 year after the common-close timepoint, the date when the last participant completes the Week 105 assessment, withdraws, or is discontinued from the study.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive SC doses of sefaxersen (RO7434656) matching placebo on Days 1, 15, and 29 followed by once every 4 weeks until Week 105. Participants may be eligible to switch to open-label treatment after Week 105 at the investigator's discretion until up to 1 year after the common-close timepoint, the date when the last participant completes the Week 105 assessment, withdraws, or is discontinued from the study.

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

Findings from Research

In patients with idiopathic immunoglobulin A (IgA) nephropathy, the antigens HLA-B35 and DR5 were significantly more common, indicating a higher relative risk for developing the disease (1.385 and 1.487, respectively).

Conversely, certain haplotypes, such as HLA-A1, B8, DR3 and HLA-A3, B7, DR2, were found to be protective against IgA nephropathy, with relative risk values ranging from 0.309 to 0.587, suggesting potential genetic factors influencing disease susceptibility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure. Doxiadis, II., De Lange, P., De Vries, E., et al.[2019]

In a study of 1781 Chinese patients with IgA nephropathy, the rs6677604-GG genotype was linked to increased mesangial C3 deposition, which correlated with more severe kidney damage and lower kidney function (eGFR).

The intensity of mesangial C3 deposition was a significant predictor of poor long-term kidney outcomes in IgA nephropathy, indicating that it may be a critical factor in disease progression, rather than the rs6677604 genotype itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy. Kang, Y., Xu, B., Shi, S., et al.[2023]

In a study of 36 Caucasian patients with IgA nephropathy, the HLA-DQw7 allele was found to be significantly associated with the disease, showing a frequency of 71% compared to 27.8% in controls, indicating a strong genetic link to susceptibility.

While HLA-DR4 and DR5 alleles were more common in patients, these increases were not statistically significant, suggesting that the DQw7 allele is a more critical factor in the genetic predisposition to IgA nephropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians. Li, PK., Burns, AP., So, AK., et al.[2022]

Recent advancements in IgA nephropathy research have identified several genetic susceptibility loci that highlight the role of inherited factors and their connection to geographic and ethnic differences in disease prevalence.

The discovery of the 'Intestinal Immune Network for IgA Production' as a potential therapeutic target suggests new avenues for treatment, aligning with the multihit pathogenesis model that explains the disease's complexity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Magistroni, R., D'Agati, VD., Appel, GB., et al.[2022]

In a study of 37 pediatric patients with primary IgA nephropathy, C4B deficiency was found to be significantly more common, with 16% of patients showing homozygous C4B null compared to only 4% in healthy controls, indicating a potential genetic link to the disease.

The presence of C4B deficiency may be one of several factors contributing to the development of IgA nephropathy, as no significant differences were observed in other related alleles, suggesting a specific role for C4B in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

C4 isotype deficiency in IgA nephropathy. Welch, TR., Berry, A., Beischel, LS.[2019]

References

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

Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure. [2019]

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

Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy. [2023]

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

The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians. [2022]

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

New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

C4 isotype deficiency in IgA nephropathy. [2019]