Resumen

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.

Descripción detallada

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.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

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.

Criterios de exclusión

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.

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

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

LNP023

Rituximab

Ubicaciones

Novartis Investigative Site

Novartis Investigative Site

Novartis Investigative Site

Patrocinadores