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

NCT04154787 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: CLNP023D122012019-001734-34
• Study Type: interventional
• Target: 37
• Locations: 9 countries
• Sites: 18

Brief Summary

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.

Conditions

Idiopathic Membranous Nephropathy

Keywords

Idiopathic membranous nephropathy; MN

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb)

  Baseline, Day 15, Day 29, Day 57, Day 113 and Day 169

• Change From Baseline in Plasma Levels of sC5b-9

  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

  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

  Baseline, Day 169

• Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time

  Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169

Study Arms (2)

LNP023

EXPERIMENTAL

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

Rituximab

ACTIVE COMPARATOR

Rituximab 1 g i.v. at Day 1 and Day 15

Drug: Rituximab

Interventions

LNP023 DRUG

Investigation of LNP023

LNP023

Rituximab DRUG

Comparison of rituximab dose

Rituximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (18)

Novartis Investigative Site

CABA, Buenos Aires, C1181ACH, Argentina

Location

Novartis Investigative Site

Caba, Buenos Aires, C1280AEB, Argentina

Location

Novartis Investigative Site

Córdoba, X5016KEH, Argentina

Location

Novartis Investigative Site

Beijing, 100034, China

Location

Novartis Investigative Site

Prague, 12808, Czechia

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Dresden, 01307, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Jena, 07740, Germany

Location

Novartis Investigative Site

Dehradun, Uttarakhand, 248001, India

Location

Novartis Investigative Site

New Delhi, 110029, India

Location

Novartis Investigative Site

Nijmegen, Netherland, 6525 GA, Netherlands

Location

Novartis Investigative Site

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Novartis Investigative Site

Valencia, Valencia, 46017, Spain

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Leicester, LE5 4PW, United Kingdom

Location

Novartis Investigative Site

London, NW3 2QG, United Kingdom

Location

Novartis Investigative Site

Manchester, M13 9WL, United Kingdom

Location

Related 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

MeSH Terms

Conditions

Glomerulonephritis, Membranous

Interventions

Rituximab

Condition Hierarchy (Ancestors)

Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Per protocol, participants randomized to the former LNP023 low dose arm (LNP023 10/50 mg b.i.d.) were included in the safety and PK analyses but not in the PD/efficacy analyses as the low number of subjects would not have allowed for a meaningful analysis and interpretation of PD/efficacy data.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open label study for treatment (LNP023 or rituximab).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2019
• First Posted: November 6, 2019
• Study Start: November 23, 2019
• Primary Completion: January 20, 2023
• Study Completion: January 20, 2023
• Last Updated: October 9, 2024
• Results First Posted: July 5, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share

Locations

IN (2); TW (1); AR (3); GB (3); NL (1); ES (2); CN (1); DE (4); CZ (1)