Key papers ✓ 4✗ 2? 1

• ✓ Positive human RCTN Engl J Med · 2015

  Afamelanotide for Erythropoietic Protoporphyria.

  Humanssize not reportedRandomizedPlacebo-controlledDouble-blind180 days (EU) and 270 days (US)

  Two multicenter randomized double-blind placebo-controlled trials of 16 mg afamelanotide implants every 60 days

  Two placebo-controlled RCTs in EPP (74 EU and 94 US patients) with 16 mg implants: pain-free time in direct sunlight increased (US median 69.4 vs 40.8 h, P=0.04; EU 6.0 vs 0.8 h, P=0.005), phototoxic reactions fell and quality of life improved; adverse events were mostly mild.

  Key resultUS: median pain-free time 69.4 vs 40.8 hours (P=0.04); EU: 6.0 vs 0.8 hours (P=0.005); phototoxic reactions 77 vs 146 (P=0.04)

  Study details

  Studied

  Patients with erythropoietic protoporphyria

  Compared with

  Placebo implant

  Main outcome

  Hours of direct sunlight exposure without pain

  Sample

  Two RCTs: 74 patients (EU) and 94 patients (US)

  Authors' conclusion

  Afamelanotide had an acceptable side-effect profile and increased pain-free sun exposure and quality of life in erythropoietic protoporphyria.

  DOI 10.1056/NEJMoa1411481PubMed 26132941Free full text
• ✓ Positive human RCTJAMA Dermatol · 2015

  Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: a randomized multicenter trial.

  Humanssize not reportedRandomizedAfamelanotide monthly for 4 months; repigmentation assessed to day 168

  Randomized multicenter trial

  55 adults with vitiligo randomized to narrowband UV-B plus afamelanotide or UV-B alone: repigmentation was faster and greater with the combination (48.6% vs 33.3% at day 168), mainly in darker skin types; nausea and minor infections occurred in the combination group.

  Key resultRepigmentation at day 168 was 48.64% (95% CI 39.49%-57.80%) with combination vs 33.26% (95% CI 24.18%-42.33%) with NB-UV-B alone

  Study details

  Studied

  Adults with Fitzpatrick skin phototype III to VI and nonsegmental vitiligo involving 15% to 50% of body surface area

  Compared with

  Narrowband UV-B monotherapy

  Main outcome

  Vitiligo Area Scoring Index and VETF repigmentation

  Sample

  55 randomized (28 combination, 27 NB-UV-B alone)

  Authors' conclusion

  Afamelanotide implant plus NB-UV-B gave faster, statistically superior repigmentation than NB-UV-B alone, more noticeably in skin phototypes IV to VI.

  Limitations

  Small trial; adverse events included erythema, minor infections and nausea.

  DOI 10.1001/jamadermatol.2014.1875PubMed 25230094
• ✓ Positive reviewAm J Clin Dermatol · 2016

  Afamelanotide: A Review in Erythropoietic Protoporphyria.

  No new data

  Drug review of efficacy and tolerability in erythropoietic protoporphyria

  Review of EPP trials: in phase III CUV039, afamelanotide increased time in direct sunlight without pain vs placebo; generally well tolerated, with headache and implant-site reactions commonly reported.

  Study details

  Compared with

  Placebo (in the reviewed trials)

  Main outcome

  Light tolerance

  Authors' conclusion

  Afamelanotide improved light tolerance versus placebo in EPP, was generally well tolerated, and is a useful addition to EPP management.

  DOI 10.1007/s40257-016-0184-6PubMed 26979527
• ✓ Positive reviewJ Drugs Dermatol · 2021

  Afamelanotide: An Orphan Drug with Potential for Broad Dermatologic Applications.

  No new data

  Literature review of afamelanotide in cutaneous diseases

  Review: RCT evidence supports use beyond EPP in polymorphic light eruption and vitiligo, with smaller studies in acne and other conditions; no serious adverse effects reported, but diffuse hyperpigmentation occurs in almost all patients. Larger studies are needed.

  Study details

  Authors' conclusion

  RCT evidence supports use beyond EPP (polymorphic light eruption, vitiligo); no serious adverse effects reported but diffuse hyperpigmentation is nearly universal; larger studies are needed.

  DOI 10.36849/JDD.5526PubMed 33683075
• ? Inconclusive human trialBMC Neurol · 2023

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

  Humans6 peopleOpen-labelFollow-up to Day 42

  Open-label proof-of-concept phase IIa feasibility and safety trial

  Open-label phase IIa in 6 acute stroke patients: implants were tolerated; one fatal recurrent stroke was judged unrelated; neurological scores improved but there was no control group.

  Key resultMedian NIHSS improved from 6 to 2 on D7 in surviving patients; one fatal recurrent stroke judged unrelated to study drug

  Study details

  Studied

  Acute ischemic stroke patients within 24 h of onset, ineligible for revascularisation

  Compared with

  None

  Main outcome

  Treatment-emergent adverse events and neurological assessments

  Sample

  6 acute ischemic stroke patients

  Authors' conclusion

  Afamelanotide was well tolerated and safe in this small sample, with apparent good recovery and radiological improvement that needs testing in randomized studies.

  Limitations

  Six patients, open-label, no control group.

  DOI 10.1186/s12883-023-03338-9PubMed 37496004Free full text
  Fig. 3 Fig. 1
• ✗ Negative human observationalBr J Dermatol · 2024

  The effects of cholecalciferol and afamelanotide on vitamin D levels in erythropoietic protoporphyria: a multicentre cohort study.

  Humans230 people2005 to 2021 data

  Multicentre observational cohort study using routinely collected data

  Cohort of 230 EPP patients: afamelanotide alone did not raise vitamin D levels (beta = 0.5, 95% CI -3.2 to 4.2) and vitamin D deficiency remained common; only cholecalciferol raised levels.

  Key resultAfamelanotide alone: beta = 0.5 (95% CI -3.2 to 4.2); cholecalciferol beta = 11.6 (95% CI 7.2-15.9); combined beta = 15.2 (95% CI 12.3-18.1)

  Study details

  Studied

  Adults with erythropoietic protoporphyria from two centers (Netherlands, Germany)

  Compared with

  Untreated vs cholecalciferol vs afamelanotide vs combined

  Main outcome

  Vitamin D levels

  Sample

  230 patients, 1774 vitamin D measurements

  Authors' conclusion

  Afamelanotide did not affect vitamin D levels; cholecalciferol remains essential for vitamin D deficiency in EPP.

  Limitations

  Observational, routinely collected data.

  DOI 10.1093/bjd/ljae148PubMed 38634774
• ✗ Negative reviewHautarzt · 2015

  [Undesirable pigmentation].

  No new data

  Narrative review of hyperpigmentation

  Dermatology review on unwanted pigmentation: case reports describe activation of dysplastic nevi by unlicensed melanotan I, which the authors describe as dangerous.

  Study details

  Authors' conclusion

  Melanotan I can activate dysplastic nevi, and melanotan I and bleaching creams are dangerous; hyperpigmentation is best treated with combination therapy.

  Limitations

  No guidelines established.

  DOI 10.1007/s00105-015-3671-4PubMed 26315100

Reported side effects

• commonHeadache [ref] [ref]
• commonNausea [ref] [ref]
• commonFatigue [ref]
• commonImplant-site reactions [ref]
• commonDiffuse skin darkening (hyperpigmentation) [ref]
• reportedMinor infections [ref]
• reportedActivation of dysplastic moles (unlicensed melanotan I) [ref]

Approved afamelanotide implants have trial safety data; unlicensed injectable 'Melanotan I' products have not been tested.

✓ positive · ✗ negative · ~ mixed · ? inconclusive, judged on each paper's own main outcome. Grades: A strong human evidence → D little or none. Papers and verdicts are drawn from PubMed, Europe PMC and Russian journals (CyberLeninka); not medical advice.