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Eprodisate Sodium Reduces Risk of Renal Deterioration in Patients With Amyloid A Amyloidosis: Presented at EULAR

By Chris Berrie

AMSTERDAM, THE NETHERLANDS -- June 27, 2006 -- The new anti-amyloid agent eprodisate sodium (NC-503) is safe and exerts a clinically meaningful and statistically significant effect on amyloid A (AA) amyloidosis that can result in loss of tissue and organ function in patients with underlying inflammatory conditions, according to a combined international, multicenter, randomized, double-blind, placebo-controlled, phase 2/3 trial.

This study was presented here on June 23^rd at the Annual European Congress of Rheumatology (EULAR) on behalf of the Fibrillex Amyloid Secondary Trial (FAST) Group by Bouke P.C. Hazenberg, MD, coinvestigator and consultant in rheumatology, rheumatology, and clinical immunology at the University Medical Centre Groningen in Groningen, The Netherlands.

Amyloidosis is a protein-folding disorder that can occur in diseases characterized by extracellular deposition of insoluble fibrillar proteinaceous material, thereby resulting in loss of function of the tissue or organ involved.

AA amyloidosis occurs in 1% to 5% of patients with sustained high levels of serum AA, and it is characteristic of idiopathic inflammatory diseases (eg, rheumatoid arthritis, JIA, Crohn's disease), chronic infections (eg, tuberculosis, leprosy, bronchiectasis), and hereditary fevers (eg, familial Mediterranean fever).

While current treatment strategies target the initial causes of inflammation that can lead to increased levels of serum AA precursor protein, the new anti-amyloid agent eprodisate more directly prevents polymerization of AA into the aggregates that show resistance to proteolysis.

The treatment protocol was designed with an initial 24-month, randomized, placebo versus eprodisate stage, followed by a 36-month, open-label, eprodisate extension. The initial randomization was according to nephrotic status, and eprodisate dosing was for 400, 800, or 1,200 mg BID, as needed to achieve the same blood concentration in all patients treated with eprodisate.

The aim of the study was to assess the safety and efficacy of eprodisate for the treatment of AA amyloidosis.

The final primary composite endpoint was for assessment of renal function or death. Renal function was "improved" if a patient achieved a greater than or equal to 50% increase in creatinine clearance (CrCl) and no parameter obtained a worse category. A "stable" status was defined as none of the milestones met, while a "worse" prognosis was defined as a greater than or equal to 50% reduction in CrCl, a greater than or equal to 100% increase in serum creatinine, or progression to dialysis/end-stage renal disease (ESRD) or death.

The inclusion criteria consisted of: age greater than or equal to 18 years; positive biopsy for AA amyloidosis; proteinuria greater than or equal to 1 g/day or CrCl less than or equal to 60 mL/min; CrCl greater than or equal to 20 mL/min and serum creatinine less than or equal to 3 mg/dL; no other potential causes of renal disease; stable therapy reached for the underlying inflammatory condition for 3 months prior to screening; and stable acetylcholine esterase inhibitor therapy reached for 3 months prior to screening and during the study.

Of 261 patients screened, 183 were randomized to placebo (n = 94; mean age, 52 years; 61% female) or eprodisate (n = 89; mean age, 50 years; 55% female). Their baseline characteristics included, respectively: median C-reactive protein (CRP), 15.3, 9.2 mg/L; median serum AA: < 10 mg/L, 25%, 33%; 10-50 mg/L, 41%, 45%; > 50 mg/L, 24%, 17%; mean proteinuria, 4.2, 4.1 g/day; CrCl, 71.6, 80.6 mL/min/1.73 m²; serum creatinine, 1.4, 1.2 mg/dL; nephritic syndrome, 42%, 38%.

The major underlying inflammatory condition was arthritides, comprising some 65% to 70% of patients, with some 20% showing hereditary fevers.

For the primary endpoint, with stable/improved versus worse categories for placebo at 59.6% versus 40.4% and for eprodisate at 73.0% versus 27.0%, this represented a 13.4% improvement with eprodisate, with a trend toward a relative risk of being worse of 0.68 (95% confidence interval [CI], 0.45-1.02; P = .063). Dr Hazenberg stressed that, with the more recent increased data collection, this now shows significance.

In the Cox model analysis that includes patient status and time to first event, this primary composite endpoint was significantly different, with a hazard ratio of 0.58 (95% CI, 0.37-0.93; P = .025). This thus represented a significant 42% reduction in risk of renal decline or death for eprodisate treatment, which was primarily defined by a doubling of serum creatinine (P = .019) and a 50% decrease in CrCl (P = .008).

For the secondary endpoints, all parameters used to measure decline in renal function were in favor of eprodisate. Of note, there were an equal number of deaths in each treatment arm (5 patients).

Dr Hazenberg also stressed the effects of eprodisate on the slope of CrCl. Here, a significant difference was seen from placebo to eprodisate, representing an improvement of 9.4 mL/min/1.73 m² for eprodisate after 24 months. This represents a clinically meaningful measure of improved renal function that can also be used to predict progression to ESRD.

For safety considerations, there were no significant differences between placebo and eprodisate treatment.

After consideration of the clinical relevance of eprodisate use as compared to other treatments for renal function, Dr Hazenberg concluded by saying, "Eprodisate is an effective drug; it is a safe drug. AA amyloidosis is an awful disease with high morbidity and mortality, and there is no alternative specific treatment, so my final conclusion is: eprodisate is the first effective therapy for this disease."

The study was sponsored by Neurochem, Inc.


[Presentation title: Treatment for Amyloid A (AA) Amyloidosis With Eprodisate Disodium (NC-503): 2-Year Results of Efficacy and Safety From a Multicentre, International Trial. Abstract OP0153]

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