This installment of #amyloidosisJC examines the not-positive-enough results of a randomized trial comparing the effects of eprodisate to placebo in AA amyloidosis patients with amyloid-related renal disease. Click HERE for a link to the actual article. I’d like once again to thank Dr. Naresh Bumma (@NB191186) for his assistance preparing this post.
|Dember, Laura M., et al. “Eprodisate for thetreatment of renal disease in AA amyloidosis.” New England Journal of Medicine 356.23 (2007): 2349-2360.|
|AA Amyloidosis pathophysiology from T. Nakamura (click HERE for link to paper)|
Eprodisate (Kiacta), a negatively charged molecule with structural similarities to heparin sulfate, inhibits fibrillogenesis (fibril formation) by interfering with the interaction between SAA and GAGs. The premise of this trial was that if Eprodisate could inhibit fibril formation, organ damage would be prevented.
- Tissue diagnosed AA amyloidosis by histologic demonstration of Congo red staining and birefringence with the use of polarized microscopy and reactivity with anti-AA antibodies by IHC
- Kidney involvement (24hr urine protein >1g x 2 OR CrCl <60ml/min x 2)
- Kidney disease other than AA amyloidosis,
- Severe renal disease: CrCl <20ml/min OR SCr >3, DM
- Abnormal liver function: LFTs or alk phos >5 xULN, t bili >1.5xULN
- Diabetes Mellitus
- Nephrotic syndrome (Y/N)
- Treatment center
- Composite endpoint of worsening renal function (SCr >2x BL, CrCL <0.5 BL, or progression to dialysis-requiring ESRD) or death
- Slope of decline in CrCl over time
- Change in proteinuria
- Change in amyloid quantitation in abdominal fat
- Resolution or development of chronic diarrhea
Noted Patient Characteristics: F>M, ~1/3 pts had “normal” SAA levels, eprodisate group had slightly better baseline SCr (1.1 vs 1.3) but no statistically significant difference in CrCl, ~40% had nephrotic syndrome. The chronic underlying inflammatory condition was usually RA in both groups, but the eprodisate grp had a higher incidence of chronic infection as an alternative condition.
- Primary composite endpoint: 42% reduction in the risk of worsening renal function or death (HR 0.58 [95% CI 0.37 – 0.93; p=0.02]). Teasing this apart: renal function worsened in 27% of eprodisate-treated patients vs 40% placebo-treated pts (p=0.06). There was no difference in mortality (HR 0.95 [95% CI 0.27 – 3.29; p=0.94]).
- Secondary endpoints: Mean slope (+/- SE) of change in CrCl (in ml/min/1.73m2) was -10.9(+/-5.1) for the eprodisate grp versus -15.6(+/- 4.1) in the placebo grp (p=0.02), though no statistical difference in risk of progressing to ESRD (E: 7 pts, P: 13 pts, HR 0.54 ([95% CI 0.22 – 1.37; p=0.20]). Also, no difference in change in urine protein loss, change in abdominal fat amyloid content, or incidence of developing chronic diarrhea.
- Safety: Similar rates of AEs and SAEs between grps
- “Sample size…substantial for the rare disease,” but not large enough to be powered to assess differences in lower frequency events like progression to ESRD or death
- Finite versus indefinite therapy may have mattered
- PK analysis could have been informative, since more than half of eprodisate pts received modified doses of medication (authors posited that pts with less severe BL renal disease might have been more likely to benefit)
- Modest benefit may be in part due to mechanism of action: SAA oligomers and protofibril levels not reduced (predictably, since blocking SAA-GAG interaction should only affect mature AA fibril formation). Also, persisting albuminuria itself is nephrotoxic (as explained in an old post about kidney injury in AL amyloidosis) and therapy did not reduce proteinuria.
Have a great Easter (for those who celebrate) and hope a bunch of people can join us this coming Monday!