Beyond pigmentation: signs of liver protection during afamelanotide treatment in Swiss patients with erythropoietic protoporphyria, an observational study

Abstract

Erythropoietic protoporphyria (EPP) is an ultra-rare inherited disorder with overproduction of protoporphyrin in maturating erythroblasts. This excess protoporphyrin leads to incapacitating phototoxic burns in sunlight exposed skin. Its biliary elimination causes cholestatic liver injury in 20% and terminal liver failure in 4% of EPP patients. Thereby, the risk of liver injury increases with increasing erythrocyte protoporphyrin concentrations. Afamelanotide, an α-melanocyte-stimulating hormone (MSH) analog inducing skin pigmentation, was shown to improve sunlight tolerance in EPP. Beyond this well-known effect on pigmentation, the MSHs have liver-protective effects and improve survival of maturating erythroblasts, effects described in animal or in vitro models to date only. We investigated whether afamelanotide treatment in EPP has effects on erythropoiesis, protoporphyrin concentrations, and liver injury by analyzing retrospectively our long-term safety data. Methods: From the 47 Swiss EPP-patients treated at our center since 2006, we included those 38 patients in the current analysis who received at least one afamelanotide dose between 2016 and 2018 and underwent regular laboratory testing before and during the treatment. We compared the means of pretreatment measurements with those during the treatment. Results: Protoporphyrin concentrations dropped from 21.39 ± 11.12 (mean ± SD) before afamelanotide to 16.83 ± 8.24 µmol/L ( p < .0001) during treatment. Aspartate aminotransferase decreased from 26.67 ± 13.16 to 22.9 ± 7.76 IU/L ( p = .0146). For both entities, patients with higher values showed a more progressive decrease, indicating a risk reduction of EPP-related liver disease. The pre-existing hypochromia and broad mean red-cell distribution width were further augmented under afamelanotide. This was more likely due to an influence of afamelanotide on maturating erythroblasts than due to an exacerbated iron deficiency, as mean zinc-protoporphyrin decreased significantly and ferritin remained unchanged. No serious afamelanotide-related adverse events were observed for a total of 240 treatment years. Conclusion: Our findings point to a protective effect of afamelanotide on erythroblast maturation and protoporphyrin-induced liver injury. Plain Language summary Afamelanotide, a skin tanning hormone, may protect patients with erythropoietic protoporphyria not only from skin burns, but also from liver injury associated with the disease. Patients with erythropoietic protoporphyria (EPP), an inherited metabolic disease, suffer from light-induced skin burns and liver injury elicited by the accumulated light sensitizer protoporphyrin. The excess protoporphyrin is produced in red cell precursors in the bone marrow, and it is eliminated from the body via the liver and bile. A high protoporphyrin excretion burden damages the liver cells, the risk for this increases with higher protoporphyrin concentrations. About 20% of EPP patients show some sign of liver injury and 4% develop life-threatening liver dysfunction. Afamelanotide, closely related to natural α-melanocyte stimulating hormone (MSH), induces skin tanning. This effect protects EPP patients from light-induced skin burns as shown in previous studies. We have treated Swiss EPP patients with afamelanotide since 2006, and we regularly perform safety tests of this treatment. Recent in vitro and animal studies demonstrated α-MSH effects other than skin tanning, including an improved synthesis of red blood cell precursors in the bone-marrow and protection of the liver from experimentally induced damage. Until now, it is unknown whether afamelanotide has similar effects in the human organism. To study this question, we analyzed retrospectively the safety laboratory data of 38 Swiss patients, who received at least one dose of afamelanotide from 2016 to 2019. We found that both, the average protoporphyrin concentrations and aspartate aminotransferase, a test for liver function, improved during afamelanotide treatment as compared to before. We concluded that afamelanotide applied to EPP patients to protect them from light-induced skin burns also may reduce their risk of liver injury.

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

“…These effects improve light tolerance in EPP, as proven by multiple clinical and observational trials and studies [7,8,[21][22][23][24][25]. We recently published the positive effect of afamelanotide on LFTs in humans for the first time in a retrospective analysis of the safety data of our EPP cohort treated with afamelanotide [5], with patients who had been observed since 1993 and treated with afamelanotide since 2006. We found a significant decrease in aspartate transaminase (ASAT) and PPIX during afamelanotide treatment.…”

“…Afamelanotide induces skin pigmentation and has anti-inflammatory as well as anti-oxidative properties [20]. These effects improve light tolerance in EPP, as proven by multiple clinical and observational trials and studies [7,8,[21][22][23][24][25]. We recently published the positive effect of afamelanotide on LFTs in humans for the first time in a retrospective analysis of the safety data of our EPP cohort treated with afamelanotide [5], with patients who had been observed since 1993 and treated with afamelanotide since 2006.…”

“…One patient, for whom all patient data have been included in the study, intermittently had a strong increase in his liver enzymes due to a histologically verified allergic drug reaction of the liver to acetaminophen, which subsided after its discontinuation. Thirty-eight patients were identical to those included in our previous study [5]. However, we included additional data from these patients, as we extended the data collection time up to the end of 2020.…”

“…Although the above-mentioned data from animal studies, indicating the potential therapeutic effectiveness of the MSHs on a variety of liver diseases, have been known for years, to our knowledge, no study addressing this potential in humans has been performed so far-apart from our recently published retrospective study in erythropoietic protoporphyria (EPP) [5]. This may, in part, be due to the specific pharmacological characteristics of MSHs.…”

A feasibility and safety study of afamelanotide in acute stroke patients – an open label, proof of concept, phase iia clinical trial

“…Afamelanotide is currently licenced in United States, Europe and Australia for treatment of EPP. Post marketing surveillance over several years has confirmed the positive safety profile of afamelanotide with no significant drug related adverse effects [ 18 , 21 , 22 ]. Implant site reaction and nausea were the most common side effects with incidence rate of up to 21% [ 23 ].…”