LNP023 for Complement 3 Glomerulopathy

Recruiting at 45 trial locations

Overseen By Novartis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Disqualifiers: Advanced cardiac disease, Severe infections, ECG abnormalities, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 66 months

225 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug LNP023 (Iptacopan) for treating Complement 3 Glomerulopathy?

Research shows that Iptacopan, which targets a part of the immune system called the alternative complement pathway, reduced protein levels in urine and improved kidney health in patients with similar kidney conditions like IgA nephropathy. In a study with C3 Glomerulopathy patients, Iptacopan also reduced proteinuria and C3 deposits, suggesting it may help manage this condition. ^{1 2 3 4 5}

Is LNP023 (Iptacopan) safe for human use?

Iptacopan (LNP023) has been tested in several studies for different conditions, including IgA nephropathy, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria. In these studies, it was generally well-tolerated, with no reports of severe or serious side effects, deaths, or treatment-related serious adverse events. ^{1 3 6 7 8}

How is the drug LNP023 (Iptacopan) different from other treatments for C3 glomerulopathy?

LNP023 (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 a first-in-class drug and has shown promise in reducing proteinuria and C3 deposits in patients with C3G, while there are currently no approved treatments for this condition. ^{2 4 5 9 10}

What is the purpose of this trial?

This is an open-label extension study to evaluate the long-term efficacy, safety and tolerability of iptacopan in subjects with C3 glomerulopathy or idiopathic immune-complex-membranoproliferative glomerulonephritis

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for patients who have completed the CLNP023X2202 trial for C3 glomerulopathy. It's not open to those with HIV, severe diseases like advanced heart disease or pulmonary hypertension, active infections close to screening time, fever shortly before screening, or certain ECG abnormalities.

Inclusion Criteria

- Patients must have completed the treatment period of the CLNP023X2202 trial on study drug

Exclusion Criteria

I haven't had a serious infection or fever over 100.4°F in the last 14 days.

History or current diagnosis of ECG abnormalities indicating significant risk of safety for subjects

Severe concurrent co-morbidities, e.g. advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), or any illness or medical condition that in the opinion of the investigator and sponsor is likely to prevent the patient from safely tolerating LNP023 or complying with the requirements of the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive open-label iptacopan to evaluate long-term efficacy, safety, and tolerability

Up to 66 months

Regular visits as per study protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Continued access to iptacopan for participants from Phase 3 programs until the drug becomes commercially available

Up to 66 months

Treatment Details

Interventions

• LNP023

Trial Overview The study tests the long-term effects of a drug called LNP023 on people with C3 glomerulopathy. As an open-label extension study, all participants know they are receiving LNP023 and its impact over a longer period will be observed.

Participant Groups

Group I: Cohort F: participants with IC-MPGN randomized to ipatocan in CLNP023B12302 Experimental Treatment 1 Intervention

IC-MPGN participants (adults and adolescents) from study CLNP023B12302 who were randomized to iptacopan in the core study receiving iptacopan capsules 200mg b.i.d

Group II: Cohort E: participants with IC-MPGN randomized to placebo in CLNP023B12302 Experimental Treatment 1 Intervention

IC-MPGN participants (adults and adolescents) from study CLNP023B12302 who were randomized to placebo in the core study receiving iptacopan capsules 200mg b.i.d

Group III: Cohort D: particpants with native C3G randomised to iptacopan in CLNP023B12301 Experimental Treatment 1 Intervention

Native C3G participants (adults and adolescents) from study CLNP023B12301 who were randomized to iptacopan in the core study. Receiving iptacopan capsules 200mg b.i.d

Group IV: Cohort C: Participants with native C3G randomized to placebo in CLNP023B12301 Experimental Treatment 1 Intervention

Native C3G Participants (adults and adolescents) from CLNP023B12301 study who were randomized to placebo in the core study receiving iptacopan capsules 200mg b.i.d

Group V: Cohort B: participants with transplanted kidneys and recurrent C3G from CLNP023X2202 Experimental Treatment 1 Intervention

C3G participants from study CLNP023X2202 who have undergone kidney transplant and have recurrence of C3G receiving iptacopan capsules 200 mg b.i.d

Group VI: Cohort A: participants with native kidneys from CLNP023X2202 Experimental Treatment 1 Intervention

C3G participants from study CLNP023X2202 with native kidneys receiving iptacopan capsules 200 mg b.i.d

LNP023 is already approved in United States, European Union for the following indications:

Approved in United States as FABHALTA for:

• Paroxysmal nocturnal hemoglobinuria (PNH)

Approved in European Union as FABHALTA for:

• Paroxysmal nocturnal hemoglobinuria (PNH)

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, 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 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]

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]

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 (LNP023) is a promising oral treatment for atypical hemolytic uremic syndrome (aHUS), showing potential for effective complement inhibition and convenience compared to current intravenous therapies.

The ongoing Phase 3 study (APPELHUS) will evaluate the safety and efficacy of iptacopan in 50 patients with aHUS, focusing on achieving a complete response to thrombotic microangiopathy without the need for plasma exchange or anti-C5 therapy over 26 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome. Kavanagh, D., Greenbaum, LA., Bagga, A., et al.[2023]

LNP023 significantly improved lupus nephritis (LN) in MRL/lpr mice by reducing lupus-like symptoms, enhancing renal function, and decreasing harmful immune complex deposition in the kidneys after 2 weeks of treatment.

The mechanism of action for LNP023 involves inhibiting complement factor B (CFB) in the alternative complement pathway, which leads to reduced expression of key complement proteins and regulation of important targets like AKT and TNF-α.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complement factor B inhibitor LNP023 improves lupus nephritis in MRL/lpr mice. Chen, K., Deng, Y., Shang, S., et al.[2022]

In a phase 2 study involving 13 patients with paroxysmal nocturnal hemoglobinuria (PNH), iptacopan demonstrated significant efficacy, with 12 out of 12 evaluable patients achieving a reduction in serum lactate dehydrogenase (LDH) levels by at least 60% by week 12, indicating effective control of hemolysis.

Iptacopan was well tolerated with no severe adverse events reported, and most patients experienced clinically meaningful improvements in hemoglobin levels, remaining transfusion-free for up to 12 weeks, showcasing its potential as a safe and effective monotherapy for treatment-naïve PNH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. Jang, JH., Wong, L., Ko, BS., et al.[2022]

In a study of 21 patients with post-transplant complement 3 glomerulopathy (C3G), early recurrence of the disease was observed in six patients within the first month, indicating a significant risk of graft dysfunction shortly after transplantation.

The long-term clinical outcomes were poor, with only 28% of patients maintaining stable graft function after 140 months, while 34% experienced graft loss and 19% died, highlighting the challenges in managing C3G post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy. Kumar, A., Ramachandran, R., Rawat, A., et al.[2022]

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

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

2. 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]

3. 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]

4. 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]

5. 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]

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

Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome. [2023]

7. France pubmed.ncbi.nlm.nih.gov

Complement factor B inhibitor LNP023 improves lupus nephritis in MRL/lpr mice. [2022]

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

Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

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