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 is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with membranous nephropathy (MN) who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria.

Study Overview

• Status: Terminated
• Conditions: Glomerulonephritis, Membranous
• Intervention / Treatment: Drug: Rituximab; Drug: LNP023

Detailed Description

This is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with membranous nephropathy (MN) who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria. The screening period will last up to 12 weeks and the whole study will last up to 65 weeks. Approximately 52 subjects will be randomized to one of the two arms. Treatment with LNP023 or rituximab is open label. LNP023 arm have a 4-week period of initial dose treatment, followed by a 20-week period of full dose treatment to evaluate the effect of the different LNP023 doses on complement biomarkers. Efficacy will be evaluated at the end of the 24-week treatment period. The randomization ratio is 1:1; LNP023 : rituximab.

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

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: andrea.biondani@novartis.com

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
    • L 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
• Genders Eligible for Study: All

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
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: LNP023	Drug: LNP023; Investigation of LNP023
ACTIVE_COMPARATOR: Rituximab	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 and Urine Protein Creatinine Ratio at 24 weeks of treatment (from 24h urine collection)	To assess the efficacy of LNP023 compared with rituximab	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Meausrement of Plasma levels of Bb and sC5b-9	Measurement of LNP023 systemic drug exposure and pharmacodynamics, mode-of-action markers and clinical efficacy	Week 24
Proportion of subjects with a complete remission	LNP023 compared with rituximab on proteinuria remission and renal function, defined as level of proteinuria at 24 weeks, derived from 24 hour urine	Week 24
Proportion of subjects with a partial remission	LNP023 compared with rituximab on proteinuria remission and renal function defined as reduction of proteinuria from baseline at 24 weeks of treatment, derived from 24 hour urine collection	Week 24
Change in (eGFR) estimated Glomerular Filtration Rate from baseline to 24 weeks of treatment	LNP023 compared with rituximab on proteinuria remission and renal function by applying the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation from baseline to 24 weeks of treatment	Baseline, Week 24
Pharmacokinetic parameter Tmax in plasma	Pharmacokinetics of LNP023 : Plasma concentration measured for time to maximum total concentration (Tmax)	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)
Pharmakinetic parameter Cmax in plasma	Pharmacokinetics of LNP023: Plasma concentration measured for (Cmax) maximum or peak concentration of the drug observed after its administration	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: Plasma concentration measured for (AUClast) Area under the curve concentration calculation of AUC from time 0 to the last point	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 : Plasma concentration for (AUCtau) Area Under the Curve (plasma concentration-time curve for a dosing interval)	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: Urine: renal plasma clearance derived from 24 hour urine sample	Week 16
Urine Protein Creatinine Ratio measured in first morning void	Urine Protein Creatinine Ratio (UPCR) measured in first morning void	Week 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

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 (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 8, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Idiopathic membranous nephropathy; MN
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Kidney Diseases; Glomerulonephritis; Glomerulonephritis, Membranous; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: CLNP023D12201

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