RO7434656 for IgA Nephropathy

(IMAGINATION Trial)

Recruiting at 271 trial locations

Overseen By WA43966 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 3

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) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 1

Duration: 105 weeks

428 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called sefaxersen (RO7434656) for individuals with primary IgA nephropathy, a kidney disease, who remain at risk of worsening despite the best current care. The trial aims to determine if this treatment is safe and effective in slowing the disease's progression. Participants will receive either the treatment or a placebo, with the option to continue the treatment after the main study concludes. Suitable candidates have been diagnosed with primary IgA nephropathy and are on stable doses of specific blood pressure medications. As a Phase 3 trial, this study is the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that sefaxersen (RO7434656) is being tested for safety in treating IgA nephropathy (IgAN), a kidney condition. Earlier patients demonstrated that sefaxersen can lower certain proteins linked to this disease. In previous trials, patients had less protein in their urine, a positive sign for kidney health.

Importantly, the treatment appears well-tolerated. Reports suggest it can reduce specific immune proteins by up to 69% with repeated use. This reduction is beneficial as it may help slow or stop kidney damage.

Although the current study is in an advanced stage, indicating some evidence of safety, participants must report any side effects they experience. This ensures the treatment remains safe for everyone. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for IgA nephropathy?

Researchers are excited about sefaxersen (RO7434656) for IgA nephropathy because it offers a unique approach compared to existing treatments like corticosteroids, immunosuppressants, and ACE inhibitors. Unlike these treatments, which primarily manage symptoms and slow disease progression, sefaxersen works by targeting a specific molecular pathway involved in the disease, potentially addressing the root cause. This targeted mechanism could lead to more effective disease management and better outcomes for patients. Additionally, the subcutaneous administration of sefaxersen allows for more convenient dosing, which could improve patient adherence and quality of life.

What evidence suggests that sefaxersen might be an effective treatment for IgA nephropathy?

Research has shown that sefaxersen (RO7434656), which participants in this trial may receive, may help treat IgA nephropathy (IgAN). In earlier studies, this treatment reduced protein levels in urine by 44% over six months. High protein levels in urine indicate kidney damage, making this reduction significant. The treatment blocks a part of the immune system called the alternative complement pathway, which can harm the kidneys. These early results suggest that sefaxersen could help slow or prevent kidney damage in people with IgAN. ^{1 2 4 6 7}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• RO7434656

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.

How Is the Trial Designed?

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 (Q4W) 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 Q4W 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

Published Research Related to This Trial

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]

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 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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05797610

A Study to Evaluate the Efficacy and Safety of Sefaxersen ... The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of sefaxersen (RO7434656), a novel Antisense Oligonucleotide (ASO) ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2468024924003929

A GLOBAL PHASE 3 TRIAL OF RO7434656, AN ... In a Phase 2 trial (NCT04014335), RO7434656 inhibited alternative complement pathway activation and demonstrated a clinically meaningful reduction in the urine ...

3. ir.ionis.com ir.ionis.com/news-releases/news-release-details/ionis-presents-positive-phase-2-data-patients-iga-nephropathy

Ionis presents positive Phase 2 data in patients with IgA ... IONIS-FB-LRx achieved a 44% mean reduction in proteinuria in patients treated for 6 months. – Roche to advance IONIS-FB-LRx into Phase 3 development in H1 ...

4. genentech-clinicaltrials.com genentech-clinicaltrials.com/en/trials/kidney-disorder/iga-nephropathy/a-study-to-evaluate-the-efficacy-and-safety-of-ro743465-06097.html

Clinical Trial - WA43966 - RO7434656 or placebo - primary... A clinical trial to see how well RO7434656 (also called sefaxersen) works compared with placebo in people with primary IgA nephropathy

5. journals.lww.com journals.lww.com/jasn/fulltext/2023/11001/imagination__a_global_phase_3_trial_of_ro7434656,.3439.aspx

IMAGINATION: A Global Phase 3 Trial of RO7434656, an... In a Phase 2 trial (NCT04014335), RO7434656 inhibited alternative complement pathway activation and demonstrated a clinically meaningful reduction in UPCR ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39893955/

Inhibiting the alternative pathway of complement by ... Mean levels of systemic complement factor B (FB) were reduced up to 38 % after single administration and 69 % after repeated administration.

7. academic.oup.com academic.oup.com/ndt/article-abstract/39/Supplement_1/gfae069-1327-388/7678389

388 IONIS-FB-LRx, an antisense oligonucleotide to ... Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Since overactivity of ...