Renal Decline from Amyloidosis Slowed by Eprodisate

BOSTON, June 6 -- Decline in renal function associated with Amyloid A (AA) amyloidosis can be slowed by eprodisate (Kiacta), a drug that inhibits the deposit of the complex protein in tissues.

In a multicenter study, patients randomly assigned to receive eprodisate had a 42% lower risk that their renal disease would worsen than patients on placebo, reported Laura M. Dember, M.D., of Boston University, and colleagues.

Eprodisate slowed the decline in creatinine clearance compared with placebo, but did not have an effect on either decline to end-stage renal disease or on risk of death, the authors reported in the June 7 issue of the New England Journal of Medicine.

AA amyloidosis is a serious, frequently fatal disorder involving deposits of amyloid fibrils in various organs and tissues. It is a complication of many chronic inflammatory disorders, but little is known about its etiology or natural history, noted Helen J. Lachmann, M.D., and colleagues of the National Amyloidosis Centre at Royal Free and University College Medical School in London, in a separate article in the same issue of the journal.

In a study of the natural history and clinical outcomes in patients with the disease, they found that more than 97% of patients had renal dysfunction, with excretion of more than 500 mg of protein per day, or a serum creatinine concentration more than 1.5 mg per deciliter (133 ?mol per liter), or both. At the time of diagnosis, 41 patients (11%) were in end-stage renal failure, Dr. Lachmann said.

Therapy for inflammatory diseases was administered to suppress the production of serum amyloid protein A (SAA). They found that mortality and renal prognosis significantly correlated with the (SAA) concentration during follow-up. Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 mg per liter, and survival among those patients was superior to survival among those in whom amyloid deposits did not regress (P=0.04).

Given the paucity of therapies for AA amyloidosis, the study of eprodisate is encouraging, commented S. Vincent Rajkumar, M.D., and Morie A. Gertz, M.D. from the Mayo Clinic in Rochester, Minn., in an accompanying editorial.

Although the eprodisate study has some methodological flaws, the editorialists said, this trial "is a milestone in which hypothesis-driven, direct targeting of amyloid fibrils has shown some benefit."

"Eprodisate should be investigated as an adjuvant to existing treatments in patients with immunoglobulin-light-chain-related amyloidosis and forms of familial amyloidosis with renal involvement," they said. "Since AA amyloidosis rarely involves the heart or peripheral nerves, it is not possible to comment now on the drug's effect on forms of amyloidosis that affect these structures."

There is evidence to suggest that glycosaminoglycans (long unbranched polysaccharides) are involved in amyloidosis, Dr. Dember and colleagues wrote. Eprodisate is structurally similar to the glycosaminoglycan heparan sulfate and therefore appears to interfere with polymerization of amyloid fibrils, they said. In mouse models of AA amyloidsosis, the drug was shown to inhibit the development of amyloid deposits.

To see whether the drug might be beneficial in humans with AA amyloidosis, they conducted a multicenter, double-blind, placebo-controlled trial involving 183 patients with AA amyloidosis treated at 27 centers in North America, Europe, and the Middle East.

The patients were randomly assigned to receive oral eprodisate twice daily or placebo for 24 months. The primary study endpoint was a composite of renal function or death. The researchers classified worsening of disease as a reduction of 50% or more in creatinine clearance, progression to end-stage renal disease, or death.

They found that, at 24 months, only 27% of patients on eprodisate had worsening of renal disease, compared with 40% of patients on placebo (P=0.06). The hazard ratio for worsening disease among patients taking eprodisate vs. placebo was 0.58 (95% confidence interval, 0.37 to 0.93, P=0.02).

Patients on eprodisate also had a significantly slower rate of decline in creatinine clearance, at 10.9 per minute per 1.73 m² of body-surface area per year, compared with 15.6 ml per minute per 1.73 m² of body-surface area per year in the placebo group (P=0.02).

Eprodisate had no significant effect on either progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or on risk of death (hazard ratio, 0.95, P=0.94).

The incidence of adverse events was similar in the two groups, the researchers found. Five patients in each group died during the study or within 15 days after the last administration of the drug.

Among patients on eprodisate, Dr. Dember said, the causes of death were ischemic stroke in two patients and one case each of the nephrotic syndrome, gastrointestinal hemorrhage, and pneumonia. Among patients on placebo the deaths were caused by ischemic stroke, amyloid cardiomyopathy, bowel perforation, sepsis, and pancytopenia. None of the deaths was thought to be related to eprodisate, the authors noted.

"Eprodisate delays the progression of AA amyloidosis-associated renal disease," the investigators concluded. "The drug directly targets formation of AA amyloid rather than the underlying inflammatory condition and is a member of a new class of compounds designed to interfere with amyloid-glycosaminoglycan interactions.

"This treatment approach has potential applicability to other types of amyloidosis, including AL amyloidosis, familial amyloidosis, and Alzheimer's disease," they said

In their editorial, Dr. Rajkumar and Dr. Gertz noted that, despite randomization, there were some imbalances in the two treatment groups that may have tilted results in favor of eprodistate.

"Patients in the eprodisate group had a significantly greater number of chronic infections (presumably treatable with antibiotics) than did those in the placebo group, and there was a trend toward lower levels of C-reactive protein in the eprodisate group," they wrote. "Moreover, the effect on the analysis of classifying patients with no follow-up after baseline as 'worsened status' of disease is unclear, since twice as many patients withdrew or were lost to follow-up in the placebo group as in the eprodisate group (eight patients versus four). Ideally, data from these patients should have been censored."