Trial Information

A Phase I Dose Escalation Study of B-Lymphocyte Stimulator (BLyS) Administered Subcutaneously in Patients With Selective IgA Deficiency

B Lymphocyte Stimulator (BLyS (Trademark)) is a member of the tumor necrosis factor (TNF)
superfamily of cytokines that is expressed on peripheral blood monocytes and dendritic
cells. Cellular receptors for BLyS are detected on mature immunoglobulin (Ig) expressing
B-lymphocytes. In vitro studies show that BLyS increases B cell number, Ig production,
antigen-specific immunoglobulin response, and induces production of secretory IgA.

B-cells collected from patients with Common Variable Immune Deficiency show evidence for
BLyS binding to B cells and enhanced immunoglobulin secretion.

In 28-day toxicology studies in mice, pharmacological effects were restricted to B lymphoid
tissues including B lymphocyte hyperplasia, increased splenic weight without significant
increase in spleen size, and increased immunoglobulin production. Murine models suggest
that all of the pharmacological effects are fully and rapidly reversible.

The biological profile of BLyS suggests that it may have therapeutic utility in the
treatment of immunodeficiency disorders characterized by low or absent immunoglobulin such
as selective IgA deficiency (IGA-D).

Risk that BLyS might contribute to IGA-D complications has been assessed. A series of
special in vitro and short-term in vivo studies have shown BLyS does not enhance
tumorigenicity or allergy/hypersensitivity. Enhanced autoimmunity with immune complex
formation could not be ruled out in two mouse studies in which BLyS was administered at
higher doses on multiple dosing schedules. Renal changes with glomerular protein deposits
were noted in a subset of mice treated at 0.1 and 1.0 mg/kg in the first study and 0.3 and
3.0 mg/kg in the second study. Renal changes have not been reproducible in either of 2
repeat mouse studies designed to replicate conditions on the first study. Renal changes
were not observed in the GLP toxicity study in which mice were treated for 4 weeks with BLyS
followed by a 2-week recovery period, or in an exploratory monkey study.

This study is a phase I; single-dose, open-label, non-randomized, dose escalation study of
BLyS administered subcutaneously to a total of 20 evaluable subjects with IgA-D. Each
subject will receive a single dose of BLyS.

The proposed study consists of a screening phase, a 1-day treatment phase with
pharmacokinetic sampling, day 2 and day 3 follow-up, and 1, 2, 4, 8, and 12-week acute
safety evaluations. Dose escalation to the next cohort is dependent on results of the
2-week acute safety evaluation. Autoimmunity and interim infection history will be
evaluated 4-6 weeks and 6 and 12 months. Long-term data will be collected on incidence of
malignancy for a minimum of one year.