Iptacopan for Complement 3 Glomerulopathy

(APPEAR-C3G Trial)

Recruiting at 54 trial locations

Overseen By Novartis Pharmaceuticals

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: ACEI, ARB

Must not be taking: Complement inhibitors, Immunosuppressants

Disqualifiers: Transplantation, Rapidly progressive glomerulonephritis, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

98 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing iptacopan, a medication, in patients with a rare kidney disease called C3G. The drug aims to reduce kidney damage by calming an overactive part of the immune system. Researchers are evaluating its effects to see if it can improve kidney function and reduce protein levels in urine.

Will I have to stop taking my current medications?

The trial requires that participants have been on a stable dose of certain medications like ACE inhibitors or ARBs for at least 90 days before joining. Other medications, like mycophenolic acid and corticosteroids, should also be stable for 90 days. If you're taking specific immune system drugs or high-dose corticosteroids, you may need to stop them before joining.

What data supports the effectiveness of the drug Iptacopan for treating Complement 3 Glomerulopathy?

In a Phase II study, Iptacopan showed promise for treating C3 Glomerulopathy by reducing proteinuria (excess protein in urine) and C3 deposit scores in patients. Additionally, in a study for another kidney condition, IgA nephropathy, Iptacopan significantly reduced protein levels in urine, suggesting its potential effectiveness in similar kidney diseases. ^{1 2 3 4 5}

What makes the drug Iptacopan unique for treating C3 glomerulopathy?

Iptacopan is unique because it is an oral drug that specifically inhibits factor B, a key component of the alternative pathway of the complement system, which is dysregulated in C3 glomerulopathy. Unlike other treatments, it is the first of its kind and has shown promise in reducing proteinuria and C3 deposits in patients with this rare kidney disease. ^{2 3 6 7 8}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for people aged 12-60 with C3 Glomerulopathy confirmed by a kidney biopsy. They must have low serum C3 levels, been on certain blood pressure medications for at least 90 days, and show specific urine protein levels. Participants need functioning kidneys and vaccinations against certain infections.

Inclusion Criteria

I have been on the highest dose possible of ACEI or ARB for at least 90 days.

My kidney disease (C3G) was confirmed by a biopsy recently.

I am between 12 and 60 years old.

Exclusion Criteria

I have not had a serious infection in the last 14 days.

I haven't taken any complement factor inhibitors in the last 6 months.

My kidney biopsy shows more than 50% scarring.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive iptacopan or placebo for 12 months to evaluate efficacy and safety in C3 glomerulopathy

12 months

Monthly visits (in-person)

Open-label extension

Participants may continue to receive iptacopan in an open-label setting to further assess long-term effects

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Treatment Details

Interventions

• Iptacopan
• Placebo

Trial Overview The study tests the effectiveness and safety of iptacopan compared to a placebo in treating Complement 3 Glomerulopathy. It's randomized, meaning participants are put into the iptacopan or placebo group by chance, double-blind so neither researchers nor participants know who gets what treatment.

Participant Groups

Group I: iptacopan 200mg Experimental Treatment 1 Intervention

iptacopan 200 mg b.i.d.

Group II: Placebo to iptacopan 200mg Placebo Group 1 Intervention

Placebo to iptacopan 200mg b.i.d.

Iptacopan is already approved in United States for the following indications:

Approved in United States as Fabhalta for:

• Paroxysmal nocturnal hemoglobinuria (PNH)
• Primary immunoglobulin A nephropathy (IgAN)

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

Iptacopan, an oral complement inhibitor, showed a significant dose-response effect in reducing proteinuria in patients with immunoglobulin A nephropathy (IgAN), with a 23% reduction in urine protein-to-creatinine ratio at the highest dose after three months.

The treatment was well-tolerated with no serious adverse events reported, indicating a favorable safety profile, and it demonstrated sustained reductions in complement biomarkers, supporting its potential for further evaluation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. Zhang, H., Rizk, DV., Perkovic, V., et al.[2023]

Danicopan, an orally active factor D inhibitor, was tested in two phase 2 studies for its efficacy in treating C3 glomerulopathy (C3G) and showed a favorable safety profile, but did not achieve the necessary levels of complement inhibition for effective treatment.

Despite some patients showing stable disease or improvement, the overall clinical response was limited due to inadequate and inconsistent inhibition of the alternative pathway of complement, highlighting the need for complete and sustained inhibition for effective treatment in C3G.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies. Nester, C., Appel, GB., Bomback, AS., et al.[2023]

Iptacopan, a selective inhibitor of factor B in the alternative complement pathway, is being evaluated in a Phase III study involving 68 adults with complement 3 glomerulopathy (C3G) to assess its efficacy and safety in reducing proteinuria and improving kidney function.

The study aims to show that iptacopan can significantly reduce protein levels in urine (measured by urine protein:creatinine ratio) compared to a placebo, potentially offering a new treatment option for patients with this rare kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial. Bomback, AS., Kavanagh, D., Vivarelli, M., et al.[2022]

Iptacopan, a complement inhibitor, is being evaluated in a Phase 3 study (APPLAUSE-IgAN) involving approximately 450 adults with immunoglobulin A nephropathy (IgAN) to determine its efficacy in reducing proteinuria and slowing kidney function decline over 24 months.

The primary goal of the study is to show that iptacopan is superior to placebo in reducing the urine protein-to-creatinine ratio and in slowing the decline of estimated glomerular filtration rate, with safety and tolerability also being assessed as secondary outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. Rizk, DV., Rovin, BH., Zhang, H., et al.[2023]

Iptacopan, a first-in-class oral complement inhibitor, showed a 71% absorption rate in healthy volunteers, with a peak concentration reached in 1.5 hours and a half-life of 12.3 hours, indicating effective systemic availability for therapeutic use.

The drug is primarily eliminated through hepatic metabolism, with the main pathways involving CYP2C8 and UGT1A1, suggesting a low risk associated with its metabolites based on toxicology studies in rats and dogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. James, AD., Kulmatycki, K., Poller, B., et al.[2023]

In a study of 29 patients with C3 glomerulopathy (C3G), significant systemic activation of the alternative complement pathway was observed, indicated by reduced levels of C3 and C5 and elevated levels of sC5b-9, which are important biomarkers for understanding the disease's progression.

Strong correlations were found between complement biomarkers and kidney function, with lower eGFR associated with higher baseline concentrations of Ba and factor D, suggesting that these biomarkers could help characterize the severity and progression of C3G.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan. Podos, SD., Trachtman, H., Appel, GB., et al.[2023]

C3 glomerulopathy is a complex kidney disease affecting a diverse group of patients, with a mean diagnosis age of 40.4 years, and is characterized by significant proteinuria and hematuria, indicating kidney damage.

The disease shows a variable response to treatment, with most patients receiving corticosteroids and immunosuppressive drugs; however, 9.2% of patients without monoclonal immunoglobulin progressed to end-stage renal disease within a median follow-up of 22.3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic. Ravindran, A., Fervenza, FC., Smith, RJH., et al.[2020]

Avacopan, a C5aR antagonist, was safely administered to a child with C3 glomerulonephritis (C3GN) in a Phase 2 clinical trial, demonstrating good tolerability and safety.

The patient was able to discontinue the use of mycophenolate mofetil (MMF) while maintaining remission from C3GN, suggesting that avacopan may be an effective treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment with avacopan (CCX168) in a pediatric patient with C3 glomerulonephritis. Zotta, F., Diomedi-Camassei, F., Gargiulo, A., et al.[2023]

References

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

Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies. [2023]

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

Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial. [2022]

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

Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. [2023]

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

Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan. [2023]

7. England pubmed.ncbi.nlm.nih.gov

C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic. [2020]

8. Germany pubmed.ncbi.nlm.nih.gov

Successful treatment with avacopan (CCX168) in a pediatric patient with C3 glomerulonephritis. [2023]