BEL114674: A 2 year study of efficacy and safety of intravenous belimumab versus placebo in subjects with idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN) is an autoimmune disease associated
with auto-antibody generation and elevated BLyS levels and is responsive to
B-cell depleting therapies.
Belimumab is a monoclonal antibody that binds soluble B lymphocyte stimulator
(BLyS), is used to treat Systemic Lupus Erythematosus and is being developed
for treatment of IMN. Existing therapies have significant toxicities and
relapses occur, leading to the need for safer, effective therapies.
Reduction of B-cells through BLyS neutralisation using belimumab, which has
already been shown to reduce auto-antibodies and have clinical efficacy in SLE,
is expected to be an effective therapy. The safety profile of belimumab, which
has already been demonstrated, suggests that treatment with belimumab should
overcome the adverse events (AE) previously encountered with other
immunosuppressive therapies and fulfill a high unmet need.
The primary purpose of this study is to evaluate the use of belimumab compared
to placebo for the treatment of IMN with nephrotic syndrome, when added to
supportive therapy (excludes immunosuppressants) as well as the effect of
initiating therapy earlier than would be recommended with more toxic
immunosuppressive agents.

Primary: efficacy of belimumab for the treatment of IMN.
Secondary: safety and tolerability, PK, PD, quality of life, benefit of earlier
treatment initiation.

Multi-center, Randomized Parallel Group, Placebo-Controlled Double-Blind phase
II Trial.
Randomisation (1:1) to
• Belimumab 10 mg/kg infusion
• Placebo infusion
In addition to supportive treatment with MTD ACE or AT inhibitor (unless
contra-indicated) +/- statins, diuretics, salt restriction).
Preparation by unblended pharmacist.
Dosing day 1, 14, 28 and every 4 weeks thereafter.
Treatment duration 104 weeks (27 infusions in total).
Possibility to increase dosing frequency to every 2 weeks.
Early termination study treatment in case of progressive deterioration in renal
function attributable to IMN or worsening proteinuria or reduction in serum
albumin and provision of rescue immunosuppressive treatment (with continuation
of study follow-up).
Long term outcome data from subjects beyond two year trial end is planned to be
collected on at least an annual basis and entered into a membranous nephropathy
registry database.
Approx. 100 patients.
Interim-analyses, see protocol page 45.
IDMC, see protocol page 91.

Treatment with belimumab or placebo.

Risk: adverse events of study treatment.
Burden: Study visits screening, day 1, 14, 28, thereafter every 4 weeks until
week 104.
Belimumab infusions or placebo every 2 weeks (3 times) and thereafter every 4
weeks. Duration at least 1 h.
Blood draws every visit, 7-20 ml/occasion.
Urine collection every visit.
ECG at screening.
6 min walk test: screening, day 1, every 24 weeks and end of treatment.
Questionnaires 6 times in 104 weeks.
Diary co-morbidity, signs and symptoms co-medication, entire study period.
Optional pharmacogenetic research (10 ml blood)
After end of study: at least annually: collection of outcome data.