Iptacopan for Complement 3 Glomerulopathy

(APPEAR-C3G Trial)

Recruiting at 60 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called iptacopan for complement 3 glomerulopathy (C3G), a kidney disorder where the immune system damages the kidneys. The goal is to determine if iptacopan can safely and effectively treat C3G compared to a placebo (a pill with no active medicine). Suitable participants have a confirmed diagnosis of C3G from a recent kidney biopsy and have been on specific kidney medications for at least 90 days. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

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.

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

Research shows that iptacopan is generally safe and well-tolerated. Previous studies found that most people did not experience serious side effects. Some participants reported mild to moderate effects, but these were not severe enough to discontinue treatment.

Long-term studies indicate that iptacopan helps reduce protein in urine, benefiting kidney health. This suggests the treatment remains effective and safe over time. For those considering joining a trial, these findings suggest iptacopan has been safe for others in the past. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for Complement 3 Glomerulopathy (C3G) focus on managing symptoms and controlling the immune system's response. However, iptacopan is unique because it specifically targets a protein called factor B, which is part of the body's complement system that contributes to kidney damage in C3G. This new mechanism of action could potentially reduce kidney damage more effectively than current treatments. Researchers are excited about iptacopan because it offers a more targeted approach, which might lead to better outcomes for patients with C3G.

What evidence suggests that iptacopan could be an effective treatment for complement 3 glomerulopathy?

Research has shown that iptacopan, which participants in this trial may receive, may help treat Complement 3 Glomerulopathy (C3G), a kidney condition. In one study, patients taking iptacopan experienced a significant decrease in protein in their urine, a sign of kidney damage, after six months. These patients were also seven times more likely to reach a key kidney health goal compared to those taking a placebo. Participants in this trial may receive a placebo as part of the control arm. Specifically, patients taking iptacopan demonstrated better kidney function after twelve months. This suggests that iptacopan could effectively manage C3G by improving how the kidneys filter waste. ^{2 5 6 7 8}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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]

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]

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, 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]

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S2468024924023222

12-MONTH RESULTS FROM THE PHASE 3 APPEAR-C3G ... Iptacopan demonstrated a significant and clinically meaningful proteinuria reduction on top of supportive care at 6 months in the APPEAR-C3G study; sustained up ...

2. fabhalta-hcp.com fabhalta-hcp.com/c3g/efficacy

C3G Efficacy | FABHALTA® (iptacopan) HCP FABHALTA-treated patients had 7-fold higher odds (P=.0166) of achieving a composite renal end point vs placebo-treated patients at Month 6.

3. novartis.com novartis.com/news/media-releases/novartis-oral-fabhalta-iptacopan-sustained-clinically-meaningful-results-one-year-phase-iii-c3-glomerulopathy-c3g-trial

Novartis oral Fabhalta® (iptacopan) sustained clinically ... New APPEAR-C3G data show Fabhalta sustained proteinuria reduction at 12 months1; Upon Fabhalta initiation, improvement observed in estimated ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04817618

NCT04817618 | Study of Efficacy and Safety of Iptacopan ... The purpose of this study is to evaluate the efficacy and safety of iptacopan compared to placebo and standard of care in patients with native C3G.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10719607/

Efficacy and Safety of Iptacopan in Patients With C3 ... Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway.

6. novartis.com novartis.com/news/media-releases/novartis-presents-latest-phase-iii-fabhalta-iptacopan-data-c3-glomerulopathy-c3g-showing-clinically-meaningful-and-statistically-significant-351-proteinuria-reduction-vs-placebo

Novartis presents latest Phase III Fabhalta® (iptacopan ... Efficacy and Safety of Iptacopan in Patients with C3 Glomerulopathy: Results from the Phase 3 APPEAR-C3G Trial. Presented at European Renal ...

7. kireports.org kireports.org/article/S2468-0249(24)03121-8/fulltext

WCN25-1242 UPDATE TO THE LONG-TERM SAFETY ... Long-term treatment with iptacopan was associated with sustained reduction in proteinuria in patients with native C3G (Cohort A), and stabilization of eGFR.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03955445

Study Details | NCT03955445 | Long-term Efficacy, Safety ... The primary (at 9 months) and longer-term (>9 months) efficacy and safety data of iptacopan collected from CLNP023X2202 participants will be used to support ...