Study of the Safety and Efficacy of NC-503 in Secondary (AA) Amyloidosis

A Phase II/III Study of the Safety and Efficacy of NC-503 in Patients Suffering From Secondary (AA) Amyloidosis

The main objective of this study is to evaluate the safety and efficacy of NC-503 compared to placebo in patients with secondary (AA) amyloidosis using a composite assessment of clinical improvement/worsening of both renal and gastrointestinal functions.

AA amyloidosis is associated with chronic inflammatory conditions (rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease), chronic infection (tuberculosis, osteomyelitis), and Familial Mediterranean Fever. Rheumatoid arthritis is the major cause of AA amyloidosis in Western Europe and North America. The most common clinical feature of AA amyloidosis is renal dysfunction manifested as nephrotic-range proteinuria or renal insufficiency at the time of diagnosis. End-stage renal failure is the cause of death in 40-60% of cases. Gastrointestinal involvement is also frequent and is usually manifested as chronic diarrhea, body weight loss and malabsorption. Enlargement of the liver and spleen may also occur in some patients. The median survival time from diagnosis varies from 2 to 8 years depending on the stage of the disease at time of diagnosis. The goal of the current therapy in AA amyloidosis is the control of the associated disease. However, the current approaches for the treatment of AA amyloidosis are unspecific, toxic, invasive, and not sufficiently effective in many cases. NC-503 was specifically designed to compete with the naturally occurring sulfated GAGs for the binding to amyloidogenic precursor proteins, and to inhibit amyloid deposition into tissues. The proposed therapy with NC-503 is based on the prevention of the amyloid fibril formation. The objective of this clinical phase II/III study is to determine the efficacy and safety of NC-503 compared to a placebo in patients suffering from secondary (AA) amyloidosis by the assessment of clinical improvement/ worsening of both renal and gastrointestinal functions.

PROTOCOL INCLUSION CRITERIA

• Patients must be 18 years of age or older.
• Males and females. If women of childbearing potential (i.e., not surgically sterilized or post-menopausal greater than one year) the patient must be using effective birth control.
• Diagnosis of AA amyloidosis demonstrated by positive biopsy (Congo red staining) and immunohistochemistry or immunoelectron microscopy at screening visit. Tissue from previous biopsy can be used for confirmation of diagnosis, if available.
• Persistent proteinuria defined as urinary protein excretion ? 1g/24h in two distinct 24-h urine collections at least 1 week apart within 3 months prior to study entry (baseline, Month 0 visit) without evidence of urinary tract infection or overt heart failure (NYHA class III or more); OR creatinine clearance ? 60 mL/min in two distinct measures at least 1 week apart within 3 months prior to study entry (baseline, Month 0 visit).
• Creatinine clearance ? 20 mL/min AND serum creatinine ? 3 mg/dl within 3 months prior to study entry (baseline, Month 0 visit).
• Written informed consent.

PROTOCOL EXCLUSION CRITERIA

• Evidence or suspicion of renal or renovascular diseases other than renal AA amyloidosis.
• Presence of diabetes mellitus (Type I and II).
• Evidence of a cause of potentially reversible reduced renal function, such as accelerated hypertension or drug nephrotoxicity.
• AST, ALT, or ALP > 5 times the upper limit of normal, or total bilirubin 50% above upper limits of normal.
• Presence of any other clinically significant diseases that could interfere with the interpretation of study results or compromise patient safety or any conditions that could reduce life expectancy to less than two years.
• Use of an investigational drug within thirty days prior to the screening visit.
• Active alcohol and/or drug abuse.
• Initiation of or any changes in ACE inhibitor therapy within 3 months prior to the screening visit.
• Initiation of or any changes in cytotoxic agents/colchicine therapy within 3 months prior to the screening visit.
• Inability to provide legal consent.