• Overview
• A-002
• A-623
• A-001
• A-003

BLyS/BAFF Peptibody for the Treatment of Lupus

Introduction

A-623 is a selective peptibody antagonist of the BLyS cytokine that is initially being developed as a treatment for lupus. BLyS, or BAFF, is a tumor necrosis family member and is critical to the development, maintenance and survival of B-cells. It is primarily expressed by macrophages, monocytes and dendritic cells and interacts with three different receptors on B-cells including BAFF receptor, or BAFF-R, B-cell maturation, or BCMA, and transmembrane activator and cyclophilin ligand interactor, or TACI. The BAFF-R receptor is expressed primarily on peripheral B-cells.

A-623, as a peptibody directed against BLyS, was developed as an alternative to antibodies and is produced in Escherichia coli. We believe A-623 may offer a number of potential differentiations over other BLyS antagonists such as:

• Dosing flexibility with both subcutaneous and intravenous routes of delivery
• Selective modulation and reduction of B-cell
• The ability to bind to both membrane-bound and soluble BLyS/BAFF
• Distinct intellectual property as a peptibody (relative to antibody and antibody-fragments), and structurally may confer different pharmacokinetics and pharmacodynamic characteristics

BLyS or BAFF in Autoimmune Diseases

Background

Systemic lupus erythematosus (SLE, also known as lupus) is an autoimmune disorder that involves inflammation that causes swelling, pain and tissue damage throughout the body. Lupus can affect any part of the body, but particularly the skin, heart, brain, lungs, joints and kidneys. The course of the disease is unpredictable, with periods of illness (called flares) alternating with remission. Patients with active lupus may have a broad range of symptoms related to inflammation. Inflammation of the brain may cause seizures and other neurologic abnormalities. Inflammation of the heart may cause heart failure or sudden death. Lung inflammation causes shortness of breath. Lupus may also cause swollen joints and severe rashes.

Epidemiology

Lupus primarily affects women, with a female to male ratio of about 10:1. Peak incidence occurs between ages 15 and 45, but ranges from infancy to advanced age. The Lupus Foundation estimates that approximately 1.5 million people in the United States and five million worldwide suffer from lupus.

Disease Management

No new therapies have been approved for lupus in the last 50 years. Current therapies such as non-steroidal anti-inflammatory drugs, or NSAIDs, corticosteroids and immunosuppressants generally act to hold back broadly the proliferation of many types of cells, including white blood cells. However, use of these agents is associated with significant adverse events and broad immune suppression.

BLyS or BAFF in Lupus and Other Autoimmune Diseases

B lymphocyte stimulator (BLyS), or B cell activating factor (BAFF), has been associated with a wide range of B-cell mediated autoimmune diseases, including SLE, lupus, lupus nephritis, rheumatoid arthritis, multiple sclerosis, Sjögren's Syndrome, Graves' Disease and others. BLyS, or BAFF, is a critical survival factor for B cells, and is required for B cell development and maintenance. Its involvement in B cell survival has been demonstrated in animal studies (Kalled 2005) and in human (Avery 2003) in vitro studies. BAFF is specifically up-regulated in human and animal models of autoimmune diseases, such as SLE, Sjögren's Syndrome, and rheumatoid arthritis (Gross 2000; Cheema 2001; Zhang 2001; Groom 2002; Kawasaki 2002). These finding suggests that high levels of BAFF may be link to various autoimmune diseases.

A-623 Program

A-623 is a fusion polypeptide protein (or peptibody) consisting of a novel BLyS, or BAFF, binding domain fused to the N-terminus of the Fc region of human antibody. A-623 binds to BLyS and inhibits the interaction of BLyS with its receptors.

The role of BLyS in lupus has recently been clinically validated in multiple late-stage clinical studies with an anti-BLyS antibody. We intend to advance the development of our BLyS antagonist, A-623, to exploit its broad potential clinical utility in autoimmune diseases, with initial focus on lupus. A-623 demonstrates anti-BLyS activity and has been shown to be safe and effective in selectively modulating and reducing B-cells in two Phase 1 clinical studies in lupus patients. We believe A-623 may offer a number of potential differentiations over other BLyS antagonists, as well as potentially other novel B-cell directed therapies including:

• Dosing flexibility with both subcutaneous and intravenous routes of delivery
• Selective modulation and reduction of B-cell
• The ability to bind to both membrane-bound and soluble BLyS/BAFF
• Distinct intellectual property as a peptibody (relative to antibody and antibody-fragments), and structurally may confer different pharmacokinetics and pharmacodynamic characteristics

Phase 1 Studies

Two randomized, dose-ranging, placebo-controlled Phase 1 clinical studies of A-623 in 119 lupus patients to evaluate the safety and pharmacokinetics of single and multiple doses of A-623 using intravenous and subcutaneous formulations have been completed. Results from these studies demonstrated A-623 generated anti-BLyS activity and showed statistically significant reductions in B-cells among lupus patients.

Prior to conducting Phase 1 clinical studies in lupus patients, a pre-Phase 1 clinical study was conducted to access individual B-cell subsets, such as mature naïve B-cells, activated B-cells and memory B-cells in order to characterize the specific B-cell subset abnormalities associated with lupus.

The randomized, placebo-controlled, dose-escalation Phase 1a clinical study evaluated A-623 as a single intravenous or subcutaneous therapy among 56 lupus patients. Intravenous doses included 1, 3 and 6 mg/kg, and subcutaneous doses included 0.1, 0.3, 1 and 3 mg/kg. Results from this clinical study indicated the safety and tolerability of A-623 administered as single dose of intravenous or subcutaneous was comparable to placebo. Single doses of A-623 exhibited linear pharmacokinetics after both intravenous and subcutaneous administration. There were comparable adverse events between the A-623 and placebo groups.

A-623 was also evaluated in a randomized, placebo-controlled, multi-dose Phase 1b clinical study as an intravenous or subcutaneous therapy among 63 lupus patients. The intravenous dose was 6 mg/kg, and subcutaneous doses included 0.3, 1 and 3 mg/kg. Results showed that multiple doses of A-623 exhibited dose proportional pharmacokinetics after both intravenous and subcutaneous administration. Further, results demonstrated a decrease in total B-cells as early as 15 days of treatment, and selective but significant reduction in total B-cells were achieved.

An experimental analysis was also conducted to assess B-cell subsets in patients following multiple doses. Results demonstrated that A-623 selectively modulate certain B-cell subsets and induced trends toward normal B-cell profiles that are consistent with findings in the pre-Phase 1 clinical study.

Current Phase 2b Study

Based on positive results in the Phase 1a and 1b clinical studies, as well as recent validation in multiple late-stage clinical studies of the role of BLyS in lupus, we have initiated the PEARL-SC, the Phase 2b study of A-623, for the treatment of Systemic Lupus Erythematosus (SLE). PEARL-SC is a randomized, double-blind, placebo-controlled, Phase 2b clinical study that will enroll up to 600 patients in up to 60 centers worldwide. Patients will be randomized into three active treatment arms and one placebo treatment arm for a minimum of 24 weeks. the primary endpoint of the PEARL-SC study is clinical improvement at 24 weeks in the SLE responder index, a recently recognized FDA endpoint for demonstrating clinical efficacy.