MT-1

In CUV039, a randomised, double-blind, placebo-controlled phase 3 trial in 94 adults with erythropoietic protoporphyria in the United States, the median duration of pain-free time in direct sunlight after 6 months was 69.4 hours with the afamelanotide implant versus 40.8 hours with placebo (P=0.04).⁵

In CUV029, the companion randomised, double-blind, placebo-controlled phase 3 trial in 74 adults with erythropoietic protoporphyria in the European Union, median pain-free time in direct sunlight after 9 months was 6.0 hours versus 0.8 hours with placebo (P=0.005), and phototoxic reactions numbered 77 versus 146 (P=0.04). The two trials measured exposure over different periods, so their hour counts cannot be pooled or compared.⁵

In an uncontrolled before-and-after analysis of 39 Swiss patients with erythropoietic protoporphyria in routine care, the median maximum time in sunlight before a phototoxic reaction was 10 minutes (IQR 5-20) before afamelanotide and 180 minutes (IQR 120-240) during treatment, and the median pain score for the worst reaction fell from 10 before to 6 (IQR 3-7) during, on an 11-point scale.⁶

In an uncontrolled single-centre US cohort of 29 adults with erythropoietic or X-linked protoporphyria, among the 26 who received two or more implants the median time to phototoxic symptoms after sunlight exposure was 12.5 minutes (IQR 5-20) before afamelanotide versus 120 minutes (IQR 60-240) during it (P<0.001), while erythrocyte and plasma protoporphyrin and liver biochemistries did not improve.⁷

In a two-centre observational follow-up of 115 patients with erythropoietic protoporphyria treated in Rome and Zurich over a period of up to 8 years, disease-specific quality-of-life scores were 31 plus or minus 24% of maximum before afamelanotide, rose to 74% after starting it and stayed at that level; there was no untreated comparison group.⁸

In a placebo-controlled trial in 65 fair-skinned Caucasian volunteers, melanin density rose an average of 41% (2.55 to 3.59) in the subgroup with a low minimal erythemal dose, who burn most easily, versus 12% (4.18 to 4.70) in the high-MED subgroup, each P<0.0001 against placebo.⁹

In the same 65-volunteer placebo-controlled trial, epidermal sunburn cells after a 3-MED ultraviolet challenge fell by more than 50% after treatment in the volunteers with the lowest baseline minimal erythemal dose, and thymine dimer formation in the epidermal basal layer was reduced by 59% (P=0.002); both are reported as post-treatment comparisons rather than against placebo, and no skin-cancer outcome was measured in this 3-month study.⁹

In an uncontrolled study of seven volunteers with Fitzpatrick skin types III-IV, forearm eumelanin measured as PTCA was a mean 98% above baseline one week after Melanotan-I dosing ended (P=0.003), and forehead eumelanin was 49% above baseline in the three volunteers sampled there (P=0.019); pheomelanin did not change significantly, and the shift in the forearm eumelanin-to-pheomelanin ratio from 51:1 to 86:1 did not reach significance (P=0.054).¹⁰

In a randomised multicentre trial in 55 adults with nonsegmental vitiligo, adding the afamelanotide implant to narrowband UV-B gave 48.64% repigmentation (95% CI 39.49-57.80) at day 168 versus 33.26% (95% CI 24.18-42.33) with narrowband UV-B alone, intervals that overlap; the reported significant superiority was at day 56, and facial repigmentation came sooner with the combination (41.0 versus 61.0 days, P=0.001).¹¹

Restored sun exposure did not translate into better vitamin D status: in an observational multicentre cohort of 230 adults with erythropoietic protoporphyria, afamelanotide alone produced no significant change in vitamin D versus untreated patients (beta = 0.5, 95% CI -3.2 to 4.2) and deficiency below 50 nmol/L persisted in 71.8%, while cholecalciferol did raise levels (beta = 11.6, 95% CI 7.2-15.9).¹²

In an uncontrolled open study of five patients with solar urticaria tested in winter by monochromated light testing, weal area fell across responding wavelengths from 300 to 600 nm at day 60 after a single afamelanotide implant (P=0.049 versus baseline), while the greater than twofold overall rise in minimum urticarial dose did not reach significance (P=0.058); the authors call for study under ambient summer conditions.¹³