A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety
of Ravulizumab in Adult Participants With Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy
(IgAN)

Lupus nephritis occurs in approximately 50% of patients with systemic lupus
erythematosus (SLE), an autoimmune disorder caused by loss of tolerance to
self-antigens, the production of autoantibodies, and deposition of
complement-fixing immune complexes (ICs) in injured tissues
(Bao, 2015). The diagnosis of LN is determined by kidney biopsy according to
the 2018 International Society of Nephrology/Renal Pathology Society (ISN/RPS)
nomenclature and classification revised from the 2003 report (Bajema, 2018;
Markowitz, 2007). In total there are 6 classes of LN: Classes I to VI
(Markowitz, 2007). The subset of patients with SLE that develop LN have the
worst prognosis (Hoover, 2016). Lupus nephritis leading to CKD is an
independent major risk factor for overall mortality and morbidity attributed to
cardiovascular disease and
septic shock. With current induction and maintenance therapies, the 5-year
mortality is approximately 20% and the risk of developing ESRD at 5, 10, and 15
years are 11%, 17%, and 22%, respectively (Mageau, 2019). Recurrence of LN
after treatment (renal flare) occurs within
1 year in up to 25% of patients and is associated with increased risk of CKD
progression (Almaani, 2017).

The pathophysiology of LN involves multiple overlapping pathways where
complement serves as a mediator of an abnormal immune response (Bao, 2015;
Pickering, 2000; Schur, 1988). The terminal complement components (C5a and
terminal complement complex [C5b-9]) trigger acute
cellular inflammatory responses through activation of interleukin and cytokine
signaling. Complement also serves to fix immunoglobulins and ICs in the kidney.
In fact, complement and complement split products are a prominent histologic
finding in kidney biopsies of LN (Biesecker, 1981; Wilson, 2019). Serum levels
of these autoimmune and complement biomarkers are linked with disease activity
(Birmingham, 2015; Dall*Era, 2011). Decreases in complement components 3, 4,
and 1q (C3, C4, and C1q) are associated with de novo LN and LN flares.
Likewise, levels of complement biomarkers correlate with disease activity in
SLE (Kim, 2019). Restoring complement regulation may improve renal responses
through acute anti-inflammatory effects and lasting effects on IC deposition in
the kidney. Thus, anti-C5 therapy is promising for both induction treatment for
active proliferative LN and maintenance treatment of chronic LN.

The American College of Rheumatology (ACR), and joint recommendations from the
European League Against Rheumatism (EULAR) and European Renal
Association-European Dialysis and Transplant Association (ERA-EDTA), recommend
immunosuppression treatment for Class III,
IV, III/V, and IV/V LN also called *proliferative* LN (Bertsias, 2012). The
guidelines agree on induction treatment with glucocorticoids plus mycophenolate
mofetil (MMF) or cyclophosphamide. For maintenance therapy, the guidelines
agree on MMF or azathioprine, with
or without low dose glucocorticoids. In patients with LN, the main goal of
therapy is prevention of CKD progression, ESRD, and death. Lack of achievement
of remission, in particular complete remission, is one of the major risk
factors for progression of renal disease. Hence, short-term
complete and partial renal remissions are used to assess the efficacy of
standard of care and novel therapies. However, after 6 to 12 months of
treatment, only 10% to 40% of patients achieve a Complete Renal Response (CRR)
with standard of care (Parikh, 2016).

This study has been transitioned to CTIS with ID 2023-507977-16-00 check the CTIS register for the current data.

To evaluate the efficacy of ravulizumab compared with placebo to reduce
proteinuria in adult participants with LN or IgAN.

Study ALXN1210-NEPH-202 is a Phase 2, randomized, double-blind,
placebo-controlled, multicenter study of ravulizumab in addition to background
therapy consistent with the standard-of-care in 120 adult participants (18 to
75 years of age) with either LN or IgAN. All participants must be naive to
complement inhibitor treatment and have either a diagnosis of LN with an active
flare or IgAN based on kidney biopsy, estimated glomerular filtration rate
(eGFR) >= 30 mL/min/1.73m2, and proteinuria [defined as urine protein to
creatinine ratio (UPCR) >= 1 g/g from one 24-hr urine collection (LN cohort) or
as mean protein >= 1 g/24-hr from 2 valid 24-hr collections (IgAN cohort)].
Participants in the IgAN cohort must have been treated with stable doses of the
maximum tolerated renin-angiotensin system (RAS)-inhibiting medications and
have controlled, stable blood pressure (< 140/90 mmHg) for >= 3 months prior
to Screening. Approximately 60 participants in each disease cohort will be
randomly assigned in a 2:1 ratio to receive ravulizumab or placebo (40
ravulizumab, 20 placebo). Randomization will be stratified by whether
corticosteroid induction treatment was initiated prior to Screening versus
during the Screening Period for participants in the LN cohort and by mean
proteinuria (1 to 2 g/day versus > 2 g/day) from 2 valid 24-hr urine
collections during Screening Period for participants in the IgAN cohort. The
study consists of an up to 6-week Screening Period, a 26-week Initial
Evaluation Period, a 24-week Extension Period, and a 36-week post-treatment
Follow-up Period.

Ravulizumab is formulated at pH 7.0 and is supplied in 30 mL single-use vials.
Each vial of ravulizumab contains 300 mg of ravulizumab (10 mg/mL) in 10 mM
sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and water for
injection. The comparator product (placebo) is formulated as a matching
sterile, clear, colorless solution with the same buffer components, but without
active ingredient.

The dosing regimen consists of a loading dose followed by maintenance dosing
administered q8w. The maintenance dosing will be initiated 2 weeks after the
loading dose administration. Weight-based dosing will be based on the
participant*s body weight recorded at the day of the
infusion visit. If the weight at the day of the infusion cannot be obtained,
the weight recorded during the most recent prior study visit may be used.

During the Initial Evaluation Period (Day 1 through Week 26), participants in
each cohort will be randomized 2:1 to receive blinded doses of ravulizumab or
placebo.
- Ravulizumab group: participants will receive a blinded loading dose of
ravulizumab via IV infusion on Day 1, followed by a blinded maintenance doses
at Week 2 then q8w thereafter through the end of the Initial Evaluation Period
- Participants in the placebo group will receive a blinded matching placebo
dose via IV infusion on Day 1, followed by a blinded matching placebo dose at
Week 2, then q8w thereafter through the end of the Initial Evaluation Period.

During the Extension Period (Week 26 through Week 50), participants in the LN
cohort will continue on the same maintenance regimen. In the IgAN cohort,
participants in the placebo group will switch to receive a blinded loading dose
of ravulizumab at Week 26 and participants in the ravulizumab group will
receive a blinded ravulizumab dose of 900 mg at Week 26. Starting at Week 28,
all participants in the IgAN cohort will receive open-label weight-based doses
of ravulizumab (Table 9) q8w until the end of the Extension Period.

-The study will take about 86 weeks in total for patients.
-Additional visits to the hospital
-Extra physical exams and pregnancy testing
-Around 468 mL blood will be taken. This amount won't cause any problem (to
compare: A blood donation involves 500mL of blood tests. Possible side effects
of blood draws are are fainting, confisions, sore spot and sensitive area at
the injection site and, in rare cases, an infection.
-Meningococcal Infection: Patients receiving the study drug, even after a
single dose, are at increased risk of developing serious infections caused by
the bacteria Neisseria meningitidis. The infection can affect the tissues that
surround the brain and spinal cord (meningococcal meningitis) or can develop in
the blood (meningococcal sepsis). Meningococcal infections can rapidly become
life-threatening or fatal. It is very important that the infection is diagnosed
and treated early. If patients have not been vaccinated recently, they will be
given a vaccine to protect against the bacteria that causes meningococcal
infections. Vaccination alone may not be sufficient to prevent infection with
Neisseria meningitidis. The study doctor may also prescribe antibiotics to help
protect patients from infection.
-Possible rash or superficial irritation of the skin by the ECG stickers.