Efficacy and Safety of LNP023 Compared With Rituximab in Subjects With Idiopathic Membranous Nephropathy

A Randomized, Open-label, Two Arm, Parallel Group, Proof-of-concept Clinical Trial to Investigate the Efficacy and Safety of LNP023 Compared With Rituximab in the Treatment of Subjects With Idiopathic Membranous Nephropathy

This was a randomized, open-label, two arm, parallel group, proof-of-concept, nonconfirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with Idiopathic (primary) membranous nephropathy (iMN) who are at high risk of disease progression defined on the basis of anti- Phospholipase A2 Receptor (PLA2R) antibody titer ≥ 60 RU/mL and proteinuria with urine protein (UP) ≥ 3.5 g/24h.

Study Overview

• Status: Terminated
• Conditions: Idiopathic Membranous Nephropathy
• Intervention / Treatment: Drug: Rituximab; Drug: LNP023

Detailed Description

The overall study was planned for a total of 65 weeks and included:

• A screening phase of up to 12 weeks
• A treatment phase of up to 24 weeks
• A post-treatment follow-up period of 29 weeks

As per protocol amendment V01, subjects were randomized 1:1 to LNP023 (investigational drug) or Rituximab (comparator) and followed the below dosing schedule:

• LNP023 50mg orally b.i.d. for 4 weeks followed by 200mg orally b.i.d. for 20 weeks
• Rituximab 1g i.v. infusions on Day 1 and Day 15

Initially, per protocol V00, subjects were planned to be randomized in a 1:1:1 ratio to 3 treatment arms:

• Low dose LNP023: LNP023 10mg orally b.i.d. for 4 weeks followed by 50mg orally b.i.d. for 20 weeks
• High dose LNP023: 25mg orally b.i.d. for 4 weeks followed by 200mg orally b.i.d. for 20 weeks
• Rituximab 1g i.v. infusions on Day 1 and Day 15

Following protocol amendment 1 implementation, ongoing subjects were switched to 200mg b.i.d. dose after their initial 4 weeks of treatment.

3 subjects completed treatment under protocol V00. PK/PD data from the 3 completing subjects under protocol V00 are not included in the study results.

The main reason for protocol amendment V01 was to align with the clinical study results obtained from the interim analysis of ongoing phase 2 trials with LNP023 which had shown a dose dependent inhibition of the complement alternative pathway and support best efficacy results with LNP023 at a dose level of 200mg.

The study was early terminated as LNP023 after interim analysis of 12 LNP023 and 14 rituximab subjects because it could already be predicted at that point that the primary goal of superiority of LNP023 vs rituximab in the reduction of UPCR at 24 weeks was not possible to achieve if the study continued to completion.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5016KEH
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1280AEB
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1181ACH
      • Novartis Investigative Site
• China
  • Beijing, China, 100034
    • Novartis Investigative Site
• Czechia
  • Praha, Czechia, 12808
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
• India
  • New Delhi, India, 110029
    • Novartis Investigative Site
  • Uttarakhand
    • DehraDun, Uttarakhand, India, 248001
      • Novartis Investigative Site
• Netherlands
  • Netherland
    • Nijmegen, Netherland, Netherlands, 6525 GA
      • Novartis Investigative Site
• Spain
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46017
      • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United Kingdom
  • Leicester, United Kingdom, LE5 4PW
    • Novartis Investigative Site
  • London, United Kingdom, NW3 2QG
    • Novartis Investigative Site
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female or male adult (≥18 years) subjects at screening visit with a diagnosis of idiopathic (primary) MN confirmed by renal biopsy within 36 months prior to screening. A renal biopsy may be taken at any time during the run-in period to confirm the diagnosis of MN and facilitate subject eligibility, if the most recent biopsy was performed greater than 36 months prior to the screening visit.
• Anti-PLA2R antibody titer of ≥ 60 RU/mL at screening visit. If sites opt to use a local laboratory, with prior agreement with sponsor, an anti-PLA2R titer performed within 4 weeks prior to screening visit can be used.
• Urine protein ≥ 3.5 g/24h at screening and baseline visits
• ≤50% reduction in both anti-PLA2R level and 24h urine protein between screening and baseline
• Estimated GFR (using the CKD-EPI formula) ≥ 30 mL/min per 1.73 m2 at screening
• Receiving stable dose at the maximum recommended dose according to local guidelines or maximum tolerated dose of ACEi and/or ARB and/or statins and/or diuretics for at least 8 weeks prior to Day 1
• Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae (in accordance with local guidelines) at least 28 days prior to Day 1 and no longer than 5 years prior to Day 1.

Exclusion Criteria:

• Secondary causes of MN, e.g. systemic autoimmune diseases, solid or haematological malignancies, infections or chronic intake of drugs (e.g. gold salts, NSAIDs, penicillamines)
• Diagnostic renal biopsy showing evidence of crescent formation in glomeruli, suggestive of an alternative or additional diagnosis to primary idiopathic MN.
• Previous treatment with B-cell depleting or B-cell modifying agents such as, but not limited to rituximab, belimumab, daratumomab or bortezomib.
• Previous treatment with immunosuppressive agents such as cyclophosphamide, chlorambucil, mycophenolate mofetil (or equivalent), cyclosporine, tacrolimus or azathioprine within 90 days prior to Day 1. Low dose systemic corticosteroid therapy is permitted, though the subject should have been on stable dose equivalent to ≤10 mg prednisolone for at least 90 days prior to Day 1.
• Previous treatment with gemfibrozil or strong CYP2C8 inhibitors such as clopidogrel within 7 days prior to Day 1
• Presence or suspicion (based on judgment of the investigator) of active infection within 30 days prior to Day 1, or history of severe recurrent bacterial infections
• Known contra-indications for the use of rituximab, including hypersensitivity to the active substance or to murine proteins, or to any of the excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections). Other contra-indications for the use of rituximab, including active, severe infection, patients in a severely immunocompromised state, severe heart failure (NYHA Class IV) or severe, uncontrolled cardiac disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LNP023; As per protocol V00, participants took LNP023 10 mg orally b.i.d. for 4 weeks followed by LNP023 50 mg orally b.i.d. for 20 weeks. As per protocol amendment V01, participants took LNP023 50mg orally b.i.d. for 4 weeks followed by LNP023 200mg for 20 weeks.	Drug: LNP023; Investigation of LNP023
Active Comparator: Rituximab; Rituximab 1 g i.v. at Day 1 and Day 15	Drug: Rituximab; Comparison of rituximab dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection)	The primary endpoint of this study is the ratio between UPCR at 24 weeks of treatment measured in 24h urine and baseline UPCR . To assess the primary objective, the log-transformed ratio to baseline in UPCR was analyzed using a mixed model for repeated measures (MMRM). The results were back transformed and presented on the original scale.	Baseline, Day 113, Day 169

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb)	The drug (LNP023) is expected to block the complement alternative pathway dysregulation and thereby should normalize complement biomarker levels in serum. Bb is a biomarker that accurately reflects the level of complement Alternative Pathway activation. Baseline is defined as the last non-missing measurement prior to randomization. Measurements for LNP023 group were done pre-dose.	Baseline, Day 15, Day 29, Day 57, Day 113 and Day 169
Change From Baseline in Plasma Levels of sC5b-9	Soluble C5b-9 (sC5b-9) is a biomarker of the complement pathway activity that correlate with disease progression. Baseline is defined as the last non-missing measurement prior to randomization. Measurements for LNP023 group were done pre-dose.	Baseline, Day 15, Day 29, Day 57, Day 113, Day 169
Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void	Adjusted geometric mean ratio to baseline of Urine Protein Creatinine Ratio (UPCR) measured in first morning void. First morning void urine sample was collected in the morning of the day before the visit and kept in the fridge.	Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 266 and Day 378
Number of Participants by Treatment Response at 24 Weeks of Treatment	Participants were considered complete responders if at 24 weeks of treatment, they showed complete remission of proteinuria (i.e., Urine Protein (UP) ≤ 0.3 g/24h), partial responders if they showed partial remission (i.e., UP > 0.3g/24h and ≤ 3.5 g/24h and a reduction of UP by >50% from baseline), and non-responders if UP >3.5g/24h and/or reduction of UP from baseline <50%.	Baseline, Day 169
Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time	Changes in renal function were assessed via estimated glomerular filtration rate (eGFR). Change in eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.	Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169
Pharmacokinetic Parameter Tmax in Plasma	Pharmacokinetics of LNP023 : Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration (time). Actual sampling time points were considered for the calculation of PK parameters.	Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose)
Pharmacokinetic Parameter Cmax in Plasma	Pharmacokinetics of LNP023: Cmax is the maximum (peak) observed plasma drug concentration after dose administration (mass x volume-1)	Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose)
Pharmacokinetic Parameter AUClast in Plasma	Pharmacokinetics of LNP023: AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1)	Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose)
Pharmacokinetic Parameter AUCtau in Plasma	Pharmacokinetics of LNP023 : AUCtau is the AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)	Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose)
Pharmacokinetics in Urine: Renal Plasma Clearance Derived From 24 Hour Urine Sample	Pharmacokinetics of LNP023 in urine: Renal plasma clearance derived from 24 hour urine sample	Day 113

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• CLNP023D12201_NovCTR__28_Dec_2023.docx attachment has been refreshed from the Clinical Trials Results Word Form template. Data may be populated from the following (as available) : Study (123.0), Protocol (9.43), Results(1.6)
• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2019
• Primary Completion (Actual): January 20, 2023
• Study Completion (Actual): January 20, 2023

Study Registration Dates

• First Submitted: October 8, 2019
• First Submitted That Met QC Criteria: November 4, 2019
• First Posted (Actual): November 6, 2019

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Idiopathic membranous nephropathy; MN
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Glomerulonephritis, Membranous; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: CLNP023D12201; 2019-001734-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No