Study of Safety and Efficacy of LNP023 in Patients With Kidney Disease Caused by Inflammation

Study Overview
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Brief Summary
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Efficacy and safety of LNP023 in IgAN patients

Detailed Description
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This was a multicenter, randomized, double-blind, dose-ranging, parallel-group study with an adaptive design (Part 1 informed the design adaptations for Part 2). In Part 1, three doses of LNP023 (10 mg, 50 mg, and 200 mg) vs. placebo control were compared; In Part 2, four doses of LNP023 (10 mg, 50 mg, 100 mg, and 200 mg) vs. placebo control were compared. The study comprised a run-in phase in order that patients were on stable and maximally tolerated dose of Angiotensin-converting-enzyme inhibitor (ACEi) or Angiotensin II Receptor Blockers (ARB) for at least 90 days, a 90 days treatment phase in Part 1; a 180 days treatment phase in Part 2 and a 90 days follow-up phase in both Parts 1 and 2.

Official Title
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An Adaptive Seamless Randomized, Double-blind, Placebo-controlled, Dose Ranging Study to Investigate the Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients

Conditions
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IgA Nephropathy

Intervention / Treatment
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* Drug: LNP023
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female and male patients above 18 years of age with a biopsy-verified IgA nephropathy and where the biopsy was performed within the prior three years. Patients must weigh at least 35 kg to participate in the study, and must have a body mass index (BMI) within the range of 15 - 38 kg/m2. BMI = Body weight (kg) / [Height (m)]2 Measured Glomerular Filtration Rate (GFR) or estimated GFR (using the CKD-EPI formula) ≥30 mL/min per 1.73 m2 Urine protein ≥1 g/24hr at screening and ≥0.75 g / 24h after the run- in period Vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at least 30 days prior to first dosing with LNP023. Vaccination against N. meningitidis type B, S. pneumoniae and H. influenzae should be conducted if available and acceptable by local regulations, at least 30 days prior to first dosing with LNP023 All patients must have been on supportive care including a maximally tolerated dose of ACEi or ARB therapy for the individual, antihypertensive therapy or diuretics for at least 90 days before dosing Exclusion criteria Presence of crescent formation in ≥50% of glomeruli assessed on renal biopsy Patients previously treated with immunosuppressive agents such as cyclophosphamide or mycophenolate mofetil (MMF), or cyclosporine, systemic corticosteroids exposure within 90 days prior to start of LNP023/Placebo dosing Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations All transplanted patients (any organ, including bone marrow) History of immunodeficiency diseases, or a positive HIV (ELISA and Western blot) test result. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, excludes a patient. Patients with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject's medical history and/or clinical or laboratory evidence of any of the following: A history of invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus Splenectomy Inflammatory bowel disease, peptic ulcers, severe gastrointestinal disorder including rectal bleeding; Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; Pancreatic injury or pancreatitis; Liver disease or liver injury as indicated by abnormal liver function tests. ALT (SGPT), AST (SGOT), GGT, alkaline phosphatase and serum bilirubin will be tested. Any single parameter of ALT, AST, GGT, alkaline phosphatase or serum bilirubin must not exceed 3 x upper limit of normal (ULN) PT/INR must be within the reference range of normal individuals Evidence of urinary obstruction or difficulty in voiding any urinary tract disorder other than IgNA that is associated with hematuria at screening and before dosing; [If necessary, laboratory testing may be repeated on one occasion (as soon as possible) prior to randomization, to rule out any laboratory error] Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at screening or baseline: PR > 200 msec QRS complex > 120 msec QTcF > 450 msec (males) QTcF > 460 msec (females) History of familial long QT syndrome or known family history of Torsades de Pointes Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study History of severe allergic reactions as per Investigator decision Plasma donation (> 200mL) within 30 days prior to first dosing. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, or longer if required by local regulation Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug. Highly effective contraception methods include: Total abstinence from heterosexual intercourse (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject. Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure <1%), for example hormone vaginal ring or transdermal hormone contraception In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. If local regulations deviate from the contraception methods listed above and require more extensive measures to prevent pregnancy, local regulations apply and will be described in the ICF. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases History of any porphyria metabolic disorder History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and baseline. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo identical to LNP023 twice a day | Other: Placebo<br>* Matching placebo to LNP023<br>|
| Experimental: LNP023 10 mg BID<br>10 mg taken twice a day. | Drug: LNP023<br>* LNP023 5, 25, 100 mg capsles<br>|
| Experimental: LNP023 50 mg BID<br>50 mg taken twice a day. | Drug: LNP023<br>* LNP023 5, 25, 100 mg capsles<br>|
| Experimental: LNP023 100 mg BID - Part 2<br>100 mg taken twice a day. | Drug: LNP023<br>* LNP023 5, 25, 100 mg capsles<br>|
| Experimental: LNP023 200 mg BID<br>200 mg taken twice a day. | Drug: LNP023<br>* LNP023 5, 25, 100 mg capsles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MCP-Mod Estimates of the Ratio to Baseline of Urine Protein to Creatinine Ratio (UPCR) (g/Mol) - Parts 1 and 2 at Day 90 | The primary analysis of the dose-response effect of LNP023 versus placebo on the reduction in UPCR 24 hours at Day 90 was done using Multiple Comparison Procedure Modelling (MCP-Mod). The existence of a dose-response relationship was assessed at the MCP step at the one-sided 10% significance level vis a multiple contrasts test. In the Mod step, the mean predicted difference between each LNP023 dose and placebo were then estimated using parametric bootstrap model averaging. Results are presented on the original scale as geometric mean ratios. A ratio less than 1 indicates a reduction in proteinuria. Participants collected all urine over a 24 hour period for UPCR test. | Baseline and Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mixed Model of Repeated Measures (MMRM) of the Change From Baseline for Estimated Glomerular Filtration Rate (eGFR) - Parts 1 and 2 at Day 90 | eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The CKD-EPI equation is an established, widely used and Kidney Disease Improving Global Outcomes (KDIGO) guideline recommended method of GFR estimation based on serum creatinine, age, gender and race of the patient. It was derived and validated established from a meta-analyses of multiple studies including large number of patients. | Baseline and Day 90 | 
| Mixed Model of Repeated Measures (MMRM) of the Change From Baseline for Serum Creatinine - Parts 1 and 2 at Day 90 | Serum creatinine | Baseline and Day 90 | 
| Shift Table From Baseline for Hematuria Levels - Parts 1 and 2 at Day 90 | Hematuria levels were the number of erythrocytes/high-power-field (hpf) measured through microscopic examination. The table shows the shift in hematuria grade (Low: <9 rbc/hpf, Intermediate: >=9 to <= 50 rbc/hpf, High: >50 rbc/hpf) from baseline (rows) to Day 90 (columns). A lower grade corresponds to a better outcome. Only patients with both baseline and Day 90 hematuria values are presented. L=low, I=intermediate and H=high in column headings for doses and BL=baseline | Baseline and Day 90 | 
| Mixed Model of Repeated Measures (MMRM) of the Ratio to Baseline in 24hour Urine Protein (UP) - Parts 1 and 2 to Day 90 | Participants collected all of their urine over a 24-hour period. | Baseline and Day 90 | 
| Mixed Model of Repeated Measures (MMRM) of the Ratio to Baseline of 24 Hour Urine Albumin (UA) - Parts 1 and 2 to Day 90 | Participants collected all of their urine over a 24-hour period. | Baseline and Day 90 | 
| Mixed Model of Repeated Measures (MMRM) of the Ratio to Baseline in 24 Hour Urine Albumin to Creatinine (UACR) - Parts 1 and 2 to Day 90 | Participants collected all of their urine over a 24-hour period. | Baseline and Day 90 | 
| Mixed Model of Repeated Measures (MMRM) of the Ratio to Baseline in Urine Protein to Creatinine (UPCR) From 1st Morning Void - Parts 1 and 2 at Day 90 | A midstream urine sample was obtained from the first morning void (FMV) on the visit day. | Baseline and Day 90 | 
| Plasma Pharmacokinetics (PK) of Area Under the Curve at Steady State (AUCtau,ss and AUClast,ss) at Day 30 | AUClast,ss: the area under the plasma concentration-time curve from time zero to last quantifiable concentration at steady state AUCtau,ss: the area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady state | Baseline (0 hr), Day 15 (0 hr) Day 30 (0, 0.25, 0.5, 1, 2, 4, 6, 8 hrs) | 
| Plasma Pharmacokinetics (PK) of Pre-dose Trough at Steady State (Ctrough,ss) and Maximum Concentrations (Cmax,ss) at Day 30 | Cmax,ss: the observed maximum plasma concentration following drug administration at steady state (ng/mL) Ctrough,ss: the pre-dose plasma concentration observed during a dosing interval at steady state (ng/mL) | Baseline (0 hr), Day 15 (0 hr) Day 30 (0, 0.25, 0.5, 1, 2, 4, 6, 8 hrs) | 
| Plasma Pharmacokinetics (PK) of Time to Maximum Concentration at Steady State (Tmax,ss) at Day 30 | Tmax,ss: the time to reach the maximum concentration after drug administration at steady state (h) | Baseline (0 hr), Day 15 (0 hr) Day 30 (0, 0.25, 0.5, 1, 2, 4, 6, 8 hrs) | 
| Amount of LNP023 Excreted Into Urine (Ae,ss) at Day 30 | Ae,ss: the total cumulative urinary excretion at steady state | Baseline and Day 30 | 
| Percent of LNP023 Excreted Into Urine at Day 30 | Percent of drug excreted into the urine | Baseline and Day 30 | 
| Renal Clearance From Plasma at Steady State (CLr,ss) at Day 30 | The renal clearance from plasma at steady state | Baseline and Day 30 | 
| Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb) and Soluble Terminal Complement Complex (sC5b-9) Biomarkers for Parts 1 and 2 to Day 90 | The complement AP biomarkers Bb and sC5b-9 were evaluated as potential pharmacodynamics and mode-of-action markers. Both biomarkers were measured using validated enzyme-linked immunosorbent assays (ELISAs). | Baseline, Days 8, 15, 30, 60, 90 | 
| Estimation of the Lowest Dose Providing Maximal Reduction of Proteinuria as Measured by the Ratio to Baseline in UPCR at Day 90 | The table shows the ratio to baseline in UPCR at Day 90 by treatment group. The lowest dose providing maximal reduction of proteinuria is the dose with the smallest UPCR ratio to baseline estimate (i.e. LNP023 200mg), | Baseline up to Month 3 | 
| Mixed Model of Repeated Measures (MMRM) of the Change From Baseline for Estimated Glomerular Filtration Rate (eGFR) - Part 2 up to Day 180 | eGFR; estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | Baseline and Day 180 | 
| Mixed Model of Repeated Measures (MMRM) of the Ratio to Baseline Protein to Creatinine (UPCR) From 1st Morning Void - Part 2 up to Day 180 | A midstream urine sample was obtained from the first morning void (FMV) on the visit day. | Baseline and Day 180 | 
| Shift Table From Baseline for Hematuria Levels - Part 2 at Day 180 | Hematuria levels were the number of erythrocytes/high-power-field (hpf) measured through microscopic examination. The table shows the shift in hematuria grade (Low: <9 rbc/hpf, Intermediate: >=9 to <= 50 rbc/hpf, High: >50 rbc/hpf) from baseline (rows) to Day 180 (columns). A lower grade corresponds to a better outcome. Only patients with both baseline and Day 90 hematuria values are presented. L=low, I=intermediate and H=high in column headings for doses and BL=baseline | Baseline and Day 180 | 
| Mixed Model of Repeated Measures (MMRM) of the Change From Baseline in Protein Level Urine Using the Urine Protein-creatinine Ratio (UPCR) From 24 Hour Urine Collection - Part 2 up to Day 180 | For UPCR test, participants collected all of their urine over a 24-hour period | Baseline, Days 30, 90 and 180 | 
| Mixed Model of Repeated Measures (MMRM) of the Ratio to Baseline in 24 Hour Urine Albumin to Creatinine (UACR) - Part 2 up to Day 180 | The 24-hour urine collection was started 1 day prior to the clinic visit, after participant urinated for the first time, than all urine was collected for the next 24 hours and refrigerated prior to clinic visit. | Baseline and Day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glomerunephritis, complement driven, chronic kidney disease