Afamelanotide Is Associated with Dose-Dependent Protective Effect from Liver Damage Related to Erythropoietic Protoporphyria

Abstract

In animal models, melanocyte-stimulating hormones (MSHs) protect the liver from various injuries. Erythropoietic protoporphyria (EPP), a metabolic disorder, leads to the accumulation of protoporphyrin (PPIX). In addition to the most prominent symptom of incapacitating phototoxic skin reactions, 20% of EPP patients exhibit disturbed liver functioning and 4% experience terminal liver failure caused by the hepatobiliary elimination of excess PPIX. Skin symptoms are mitigated through the application of the controlled-release implant afamelanotide, an α-MSH analog, every sixty days. Recently, we showed that liver function tests (LFTs) improved during afamelanotide treatment when compared to before treatment. The present study investigated whether this effect is dose-dependent, as the evidence of dose dependency would support a beneficial influence of afamelanotide. Methods: In this retrospective observational study, we included 2933 liver-function tests, 1186 PPIX concentrations and 1659 afamelanotide implant applications in 70 EPP patients. We investigated whether the number of days since the preceding afamelanotide dose or the number of doses during the preceding 365 days had an effect on LFTs and PPIX levels. In addition, we assessed the effect of global radiation. Results: Inter-patient differences exerted the most prominent effect on PPIX and LFTs. In addition, PPIX increased significantly with an increase in the number of days since the last afamelanotide implant (p < 0.0001). ALAT and bilirubin decreased significantly with an increasing number of afamelanotide doses in the preceding 365 days (p = 0.012, p = 0.0299, respectively). Global radiation only influenced PPIX (p = 0.0113). Conclusions: These findings suggest that afamelanotide ameliorates both PPIX concentrations and LFTs in EPP in a dose-dependent manner.

Afamelanotide for Treatment of the Protoporphyrias: Impact on Quality of Life and Laboratory Parameters in a US Cohort

“…In the present study, we did not detect any decreases in protoporphyrin levels or reductions in liver biochemistry values during treatment with afamelanotide, in contrast to one European cohort, although our study population was smaller and included fewer longitudinal values [13]. In fact, we found that metal-free erythrocyte protoporphyrin levels rose slightly during treatment compared with baseline levels, which we suspect to be related to natural variation and not a medication effect.…”

“…Furthermore, we only present data on AST, ALT, and total bilirubin, and these liver biochemistries may be within the normal range even in patients with protoporphyria-related liver disease [ 14 ]. We collected these labs for clinical reasons at least once yearly, but not with each afamelanotide dose, as performed in another study [ 13 ]. Moreover, metal-free protoporphyrin levels vary by as much as 25% within the same patient over time, which could influence the variability in these results, especially as our data are presented in aggregate [ 15 ].…”

Illuminating Dersimelagon: A Novel Agent in the Treatment of Erythropoietic Protoporphyria and X-Linked Protoporphyria

“…It has higher potency and stability than the natural MSH peptide. A recent observational animal study from Switzerland suggests the occurrence of a dose-dependent protective effect from liver damage related to EPP [ 32 ]. Afamelanotide is administered as a subcutaneous implant, which is injected every two months and gradually releases the active peptide.…”