Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited. Methods: Here, we report on all adults who received at least one dose of afamelanotide at the Massachusetts General Hospital Porphyria Center from 2021 to 2022. Changes in the time to phototoxic symptom onset, QoL, and laboratory parameters were assessed before and during treatment with afamelanotide. Results: A total of 29 patients with protoporphyria were included, 26 of whom (72.2%) received ≥2 afamelanotide implants. Among the patients who received ≥2 implants, the median time to symptom onset following sunlight exposure was 12.5 min (IQR, 5–20) prior to the initiation of afamelanotide and 120 min (IQR, 60–240) after treatment (p < 0.001). Improvements in QoL during afamelanotide treatment were measured using two QoL tools, with good correlation observed between these two instruments. Finally, we found no improvements in the median levels of metal-free erythrocyte protoporphyrin, plasma protoporphyrin, or liver biochemistries during versus prior to the initiation of afamelanotide treatment. Conclusions: This study highlights a dramatic clinical benefit of afamelanotide in relation to light tolerance and QoL in protoporphyria, albeit without improvement in protoporphyrin levels or measures of liver function.

Introduction: Erythropoietic protoporphyria and X-linked protoporphyria, collectively known as the protoporphyrias, are inherited disorders of heme biosynthesis characterized by the accumulation of protoporphyrin IX in the skin and other organs. Clinical manifestations include severe pain with exposure to sunlight, as well as liver disease in a subset of patients. Approximately half of patients with protoporphyria have mild microcytic anemia, which is not well understood but thought to be related either to decreased iron availability or to decreased heme biosynthesis. Several reports have described mild thrombocytopenia in patients with protoporphyria (Delaby et al., 2009, Wensink et al., 2022), although thrombocytosis would be expected with iron deficiency as low iron biases megakaryocyte-erythroid progenitors to the megakaryocyte lineage (Xavier-Ferrucio et al., 2019). We sought to further characterize the relationship between erythrocyte metal-free protoporphyrin IX (PPIX) levels, platelet count, and iron status in patients with protoporphyria. Methods: We conducted a single-center cohort study of adults with protoporphyria treated at the Massachusetts General Hospital Porphyria Center from March 2021 through June 2023. Patient-level data across multiple time points were collected, including platelet count, ferritin, and alanine transaminase (ALT). Generalized Estimating Equation (GEE) models with an identity link and gaussian family distribution were performed to determine the association, accounting for within-participant associations. Results: A total of 38 patients with protoporphyria were included in the analysis. The median PPIX level was 1169.5ug/dl (interquartile range [IQR] 729.50 - 2069.75, reference range <20). The median platelet count was 208 x10 9/L (IQR, 171-243, reference range 150-400). Only 3 patients had a platelet count <150 x10 9/L and none <100 x10 9/L. A 1ug/dl increase in protoporphyrin level was associated with an 0.02 x10 9/L decrease in platelet count on average (p= < 0.00001, Figure). We next sought to evaluate whether the relationship between PPIX and platelet count was affected by iron status (assessed by ferritin) or liver disease (assessed by ALT). When adjusting for ferritin and ALT, the relationship between PPIX and platelet count remained statistically significant (p= < 0.00001). When adjusting for PPIX and ferritin, an increase in platelets was associated with an increase in ALT (p=0.002), but there was no significant relationship between ferritin and PPIX when adjusting for the other variables in the model. Conclusion: In this study of 38 patients with protoporphyria, higher levels of PPIX were associated with lower platelet counts. This association was independent of markers of iron status or hepatic dysfunction. Only 3 patients had thrombocytopenia, which was mild in all cases. Although increased PPIX was not associated with clinically significant thrombocytopenia, the reason for the relationship between PPIX and platelets in this patient population remains unclear. Considering the well-described risk of anemia in protoporphyria, there may exist some unknown effect on hematologic cells and their precursors, either due to the accumulation of PPIX or variants in heme biosynthetic enzymes. Understanding this fundamental biology may pave the way for further treatment targets in protoporphyria and other hematologic conditions.