Primary IgA Nephropathy

Primary objective(s) To evaluate the dose response relationship of LNP023 on the reduction in proteinuria versus placebo after 90 days of treatment Secondary objective(s) To evaluate the safety and tolerability of LNP023 To assess the effect of LNP023 on renal function up to 90 days of treatment (combining Part 1 and Part2 of the study) To assess the pharmacokinetics of LNP023 To assess the effect of LNP023 on alternative complement pathway To estimate the lowest dose that provides maximal reduction of proteinuria To assess the effect of LNP023 on renal function up to Day 180 (Part 2 of the study) Exploratory objective(s) To assess the effect of LNP023 on complement factors and other soluble biomarkers associated with mode of action and response in urine and plasma To explore the relationship between LNP023 systemic drug exposure (free drug as well as total drug) pharmacodynamic and mode-of-action markers, and clinical efficacy To assess the effect of LNP023 on urine markers of inflammation or renal damage To perform genetic research to better understand the safety and efficacy of LNP023 To assess quality of life Assess the systemic FB levels at baseline and on treatment and correlation to PK/PD

LNP023

LNP023

hard gelatin capsule

5mg, 25mg, 100mg

Primary
The primary variable for the statistical analysis is the ratio
to baseline of urine protein to creatinine concentration
ratio (UPCR based on 24h urine collection) at 90 days

Secondary
-Assessment of safety based on vital signs, physical
examination, ECGs, laboratory assessments, and
collection of AEs assessed from baseline until the end of
the study visit.
-Estimated glomerular filtration rate (eGFR; estimated by
the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation)
Serum creatinine
Hematuria (number of erythrocytes/high-power-field (hpf)
measured through microscopic examination)
24h-UP, 24h-UA, UACR (urine albumin to creatinine
concentration ratio)
UPCR (urine protein to creatinine concentration ratio)
from first morning void.
-Plasma: Non-compartmental parameters related to total
parent drug, including but not limited to Tmax, Cmax,
AUClast and AUCtau will be calculated for each dose
level.
Urine: Non-compartmental parameters, including but not
limited to total cumulative urinary excretion (Ae) and renal
plasma clearance (CLr)
-Plasma levels of alternative pathway biomarkers including
Bb and sC5b-9
-Ratio to baseline of UPCR
-Estimated glomerular filtration rate (eGFR; estimated by
the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation)
UPCR from 24 hour sample and first morning void
Hematuria (number of erythrocytes/high-power-field (hpf)
measured through microscopic examination)
UACR (urine albumin to creatinine concentration ratio).

Inclusion criteria
IgA nephropathy patients eligible for inclusion in this study must fulfill all of the following
criteria:
1. Written informed consent must be obtained before any study-specific assessment is
performed.
2. Female and male patients ≥18 years of age with a biopsy-verified IgA nephropathy and
where the biopsy was performed within the previous three years. If the most recent renal
biopsy was performed more than three years ago, a new biopsy should be performed.
3. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
4. 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
5. Measured GFR or estimated GFR calculated using the CKD-EPI formula (or modified
MDRD formula according to specific ethnic groups and local practice guidelines
(Imai et al 2011)) ≥30 mL/min per 1.73 m2
6. Urine protein to creatinine ratio (UPCR) ≥0.8 g/g (≥90 mg/mmol) sampled from first
morning void (FMV) or urine protein ≥0.75 g/24hr from a 24h urine collection at
screening and urine protein ≥0.75 g / 24h from a 24h urine collection at the completion of
the run-in period.
7. Vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at least 4
weeks prior to first dosing with LNP023. Vaccination against N. meningitidis type B
should be conducted if available and acceptable by local regulations, at least 4 weeks prior
to first dosing.
8. Vaccination for the prevention of S. pneumoniae and H. influenzae, if available and
acceptable by local regulations, at least 4 weeks prior to first dosing.
9. 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.
10. Laboratory values must meet the following criteria:
hemoglobin ≥ 9.0 g/dL
platelet count ≥ 100,000/mm3
11. Vital signs should be within the following ranges
body temperature between 35.0-37.5 °C
systolic blood pressure, 90-160 mm Hg
diastolic blood pressure, 50-90 mm Hg
pulse rate, 40-90bpm, below 50bpm if no other clinically significant ECG abnormalities as
per Investigator decision. For subjects with heart rates less than 50 bpm, evidence should
be provided that they have no history of (i) moderate or severe valvular disease;
(ii) history of coronary artery disease, myocardial infarction, hypertension or diabetes
mellitus; (iii) history of cardiomyopathy, congenital heart defect, open heart surgery, or
ongoing arrhythmia; (iv) family history of sudden death in a first degree relative.

Exclusion criteria
IgA nephropathy patients fulfilling any of the following criteria are not eligible for inclusion in
this study:
1. Presence of crescent formation in ≥50% of glomeruli assessed on renal biopsy
2. Patients previously treated with immunosuppressive agents such as cyclophosphamide,
mycophenolate mofetil (MMF) or mycophenolate sodium, cyclosporine, tacrolimus,
sirolimus or systemic corticosteroids exposure within 90 days prior to start of
LNP023/Placebo dosing
3. Patients who previously have received LNP023. 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.
4. All transplanted patients (any organ, including bone marrow)
5. 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
6. 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 2 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 IgAN 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]
7. 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.
8. 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
9. History of severe allergic reactions as per Investigator decision
10. Plasma donation (> 200 mL) within 30 days prior to first dosing.
11. 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
12. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using effective methods of contraception from first
dosing until an additional one week following cessation of study drug. 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.
 Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal
suppository
 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.
13. 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
14. History of any porphyria metabolic disorder
15. 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.
16. History of hypersensitivity to any of the study treatments or excipients or to drugs of
similar chemical classes