Iptacopan for IgA Nephropathy
Recruiting in Palo Alto (17 mi)
+113 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Novartis Pharmaceuticals
Must be taking: ACEi, ARB
Must not be taking: Immunosuppressants, Corticosteroids
Disqualifiers: Severe urinary obstruction, AKI, RPGN, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?The purpose of this study is to evaluate the long-term safety and tolerability, of open label iptacopan in primary IgA nephropathy participants who have completed either the CLNP023X2203 or CLNP023A2301 clinical trials. The open-label design of the current study is appropriate to provide study participants the opportunity to receive treatment with iptacopan until marketing authorizations are received and the drug product becomes commercially available while enabling collection of long-term safety and tolerability data for the investigational drug. Furthermore efficacy assessments conducted every 6 months will afford the opportunity to evaluate the clinical effects of iptacopan on long-term disease progression.
Will I have to stop taking my current medications?
Participants must continue taking ACE inhibitors or ARBs as part of their supportive care. However, if you are on immunosuppressive drugs or certain other medications, you may need to stop them before starting the trial, with specific washout periods required for some drugs.
Is iptacopan safe for human use?
Iptacopan has been well-tolerated in studies for IgA nephropathy and paroxysmal nocturnal hemoglobinuria, with no reports of deaths, serious adverse events, or severe side effects. It was also well-tolerated in healthy volunteers, with its metabolism and elimination pathways well understood, suggesting a low risk associated with its use.
12345How is the drug Iptacopan different from other treatments for IgA nephropathy?
Iptacopan is unique because it is an oral drug that specifically targets and inhibits the alternative complement pathway, which plays a role in the development of IgA nephropathy. This mechanism of action is different from traditional treatments like corticosteroids or tonsillectomy, which do not specifically target this pathway.
12356Eligibility Criteria
This trial is for people with a kidney condition called primary IgA nephropathy who finished earlier trials (CLNP023X2203 or CLNP023A2301). They should be up-to-date on certain vaccinations and judged by their doctor to benefit from the drug iptacopan. Participants must also follow specific guidelines for kidney care and have a minimum eGFR of 20 ml/min/1.73m2.Inclusion Criteria
I am taking ACE inhibitors or ARBs as part of my treatment plan.
For LNP023X2203, participants must have completed part 1 or part 2 of the trial
I can't take certain blood pressure medicines due to allergies or intolerance.
+4 more
Exclusion Criteria
I have severe problems urinating or other urinary tract issues not related to IgAN.
I haven't taken strong immune system affecting drugs recently.
I am not using any experimental drugs or haven't used any in the last 30 days or 5 half-lives, whichever is longer.
+4 more
Trial 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 safety and tolerability
Up to 3 years
Visits every 6 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
7 days after last administration
Open-label extension
Participants may continue treatment with iptacopan until marketing authorizations are received or other specified conditions are met
Long-term
Participant Groups
The study tests the long-term safety and effects of iptacopan, an investigational drug, in patients with IgA nephropathy. It's open-label, meaning everyone knows they're getting iptacopan, and it continues until the drug is commercially available.
1Treatment groups
Experimental Treatment
Group I: LNP023Experimental Treatment1 Intervention
All participants are receiving 200 mg b.i.d
Iptacopan/LNP023 is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Fabhalta for:
- Paroxysmal Nocturnal Hemoglobinuria
- Primary Immunoglobulin A Nephropathy
🇪🇺 Approved in European Union as Fabhalta for:
- Paroxysmal Nocturnal Hemoglobinuria
- Primary Immunoglobulin A Nephropathy
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Brigham and Womens Hosp Harvard Med School .Boston, MA
AZ Kidney Dise and Hypertension CtrGlendale, AZ
University of Colorado AnschutzAurora, CO
DaVita Clinical ResearchLas Vegas, NV
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Novartis PharmaceuticalsLead Sponsor
References
Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. [2023]Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m2 and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Patients were randomized to four iptacopan doses (10, 50, 100, or 200 mg bid) or placebo for either a three-month (Part 1; 46 patients) or a six-month (Part 2; 66 patients) treatment period. The primary analysis evaluated the dose-response relationship of iptacopan versus placebo on 24-hour urine protein-to-creatinine ratio (UPCR) at three months. Other efficacy, safety and biomarker parameters were assessed. Baseline characteristics were generally well-balanced across treatment arms. There was a statistically significant dose-response effect, with 23% reduction in UPCR achieved with iptacopan 200 mg bid (80% confidence interval 8-34%) at three months. UPCR decreased further through six months in iptacopan 100 and 200 mg arms (from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm). A sustained reduction in complement biomarker levels including plasma Bb, serum Wieslab, and urinary C5b-9 was observed. Iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events or bacterial infections, and led to strong inhibition of alternative complement pathway activity and persistent proteinuria reduction in patients with IgAN. Thus, our findings support further evaluation of iptacopan in the ongoing Phase 3 trial (APPLAUSE-IgAN; NCT04578834).
Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. [2022]Iptacopan (LNP023) is a novel, oral selective inhibitor of complement factor B under clinical development for paroxysmal nocturnal hemoglobinuria (PNH). In this ongoing open-label phase 2 study, PNH patients with active hemolysis were randomized to receive single-agent iptacopan twice daily at a dose of either 25 mg for 4 weeks followed by 100 mg for up to 2 years (cohort 1) or 50 mg for 4 weeks followed by 200 mg for up to 2 years (cohort 2). At the time of interim analysis, of 13 PNH patients enrolled, all 12 evaluable for efficacy achieved the primary endpoint of reduction in serum lactate dehydrogenase (LDH) levels by ≥60% by week 12 compared with baseline; mean LDH levels dropped rapidly and durably, namely by 77% and 85% at week 2 and by 86% and 86% at week 12 in cohorts 1 and 2, respectively. Most patients achieved a clinically meaningful improvement in hemoglobin (Hb) levels, and all but 1 patient remained transfusion-free up to week 12. Other markers of hemolysis, including bilirubin, reticulocytes, and haptoglobin, showed consistent improvements. No thromboembolic events were reported, and iptacopan was well tolerated, with no severe or serious adverse events reported until the data cutoff. In addition to the previously reported beneficial effect of iptacopan add-on therapy to eculizumab, this study showed that iptacopan monotherapy in treatment-naïve PNH patients resulted in normalization of hemolytic markers and rapid transfusion-free improvement of Hb levels in most patients. This trial was registered at www.clinicaltrials.gov as #NCT03896152.
Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. [2023]Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy because of its role in immunoglobulin A nephropathy (IgAN) pathophysiology. Iptacopan (LNP023), a proximal complement inhibitor that specifically binds to factor B and inhibits the AP, reduced proteinuria and attenuated AP activation in a Phase 2 study of patients with IgAN, thereby supporting the rationale for its evaluation in a Phase 3 study.
Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. [2023]Iptacopan (LNP023) is an oral, small-molecule, first-in-class, highly potent proximal complement inhibitor that specifically binds factor B and inhibits the alternative complement pathway. Iptacopan is currently in development as a targeted treatment of paroxysmal nocturnal hemoglobinuria and multiple other complement-mediated diseases. In this study, the absorption, distribution, metabolism, and excretion (ADME) of iptacopan was characterized in six healthy volunteers after a single 100 mg oral dose of [14C]iptacopan. This was supplemented with an in vivo rat ADME study and metabolite exposure comparisons between human, rat, and dog, in addition to in vitro assays, to better understand the clearance pathways and enzymes involved in the metabolism of iptacopan. The fraction of [14C]iptacopan absorbed was estimated to be about 71%, with a time to maximum concentration of 1.5 hours and elimination half-life from plasma of 12.3 hours. Following a single dose of [14C]iptacopan, 71.5% of the radioactivity was recovered in feces and 24.8% in urine. [14C]iptacopan was primarily eliminated by hepatic metabolism. The main biotransformation pathways were oxidative metabolism via CYP2C8, with M2 being the major oxidative metabolite, and acyl glucuronidation via UGT1A1. The two acyl glucuronide metabolites in human plasma, M8 and M9, each accounted for ≤ 10% of the total circulating drug-related material; systemic exposure was also observed in toxicology studies in rat and dog, suggesting a low risk associated with these metabolites. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan. SIGNIFICANCE STATEMENT: We characterized the pharmacokinetics, excretion, metabolism and elimination of [14C]iptacopan (an oral, selective small-molecule inhibitor of factor B) in healthy human subjects. [14C]iptacopan was primarily eliminated by metabolism. The primary biotransformation pathways were oxidative metabolism via CYP2C8 and acyl glucuronidation via UGT1A1. Direct secretion of iptacopan into urine and potentially bile represented additional elimination mechanisms. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan.
Comparison of oral steroids with tonsillectomy plus steroid pulse therapy in patients with IgA nephropathy. [2018]Treatment of IgA nephropathy (IgAN) in Japan has recently changed, from oral prednisolone (oPSL) to tonsillectomy plus steroid pulse (TSP) therapy. However, a few studies have compared their efficacy and safety.
Advances in treatment: immunoglobulin A nephropathy. [2007]In this article, we consider a number of treatment options for patients with IgA nephropathy. Major emphasis will be placed on the use of corticosteroids and fish oil capsules because these have shown the most promise in recent publications. We also consider the specific management of two patients with severe manifestations of this disease and describe their responses. Finally, we consider future avenues of research into the treatment of IgA nephropathy. This includes a brief description of a three-arm multicenter, placebo-controlled study evaluating alternate-day prednisone and highly purified fish oil concentrate (Omacor) in children and young adults with moderately severe forms of IgA nephropathy.