Melanotan 1 10 mg

Melanotan 1, also catalogued as afamelanotide and as NDP-alpha-MSH, is a synthetic 13-residue analogue of alpha-melanocyte-stimulating hormone. The sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. It differs from the native human hormone at two positions. Methionine at position 4 is replaced by norleucine, and the L-phenylalanine at position 7 is replaced by its D-enantiomer. The chain is acetylated at the N-terminus and amidated at the C-terminus. Molecular formula C78H111N21O19; CAS 75921-69-6. The FDA prescribing information for the approved product containing this peptide gives the molecular weight as 1646.85 for the anhydrous free base.

The formula and mass above are for the free base. The approved drug substance of the same peptide is registered as an acetate salt, written by the FDA as C78H111N21O19 with 3 to 4 equivalents of acetic acid, and synthetic peptides of this class are generally isolated as acetate or trifluoroacetate salts. Counter-ion and water content for any individual lot are properties of that lot and belong on its certificate of analysis, not in a catalogue entry.

Norleucine lacks the sulfur-containing side chain of methionine, and substituting D-phenylalanine at position 7 places a non-natural stereocentre in the chain. Sawyer and colleagues first reported the analogue in 1980, titling it a highly potent alpha-melanotropin with ultralong biological activity; their abstract records that the compound was 26 times as potent as alpha-MSH in the adenylate cyclase assay and was resistant to degradation by serum enzymes (Sawyer et al., Proc Natl Acad Sci USA 1980). The FDA multi-discipline review for application 210797 states that the code names used for the product are CUV1647, Melanotan, Melanotan-1 (MT-1), [Nle4, D-Phe7]-alpha-MSH and EPT1647. It should not be confused with Melanotan 2, a structurally different molecule: a cyclic lactam heptapeptide, CAS 121062-08-6, molecular formula C50H69N15O9, rather than a linear 13-mer.

The compound is supplied here as a lyophilised powder in a sealed vial, for laboratory research use only and not for human consumption. The pharmaceutical form of the same molecule is a 16 mg controlled-release subcutaneous implant marketed as SCENESSE, which received European Commission marketing authorisation on 22 December 2014 and FDA approval on 8 October 2019. That is a regulatory fact about a different, finished dosage form; it says nothing about the material in this vial, which is neither a medicine nor an implant.

Receptor binding has been characterised directly. Schioth and colleagues expressed melanocortin MC1, MC3 and MC5 receptor subtypes in COS cells and used radioiodinated [Nle4, D-Phe7]-alpha-MSH as the radioligand. They reported binding to a single saturable site with a Kd of 85.1 +/- 8.0 pmol/l at the MC1 receptor and 396 +/- 65 pmol/l at the MC3 receptor, with a third value of 5.05 +/- 1.00 nmol/l (Schioth et al., Eur J Pharmacol 1995). The published abstract names the MC3 receptor twice in that list, so the third figure cannot be assigned to a named subtype from the abstract alone and is reported here without one. Separately, the FDA prescribing information for the approved product states that afamelanotide is a melanocortin receptor agonist and binds predominantly to MC1-R. Those two records sit alongside each other in the literature and are presented as written rather than reconciled.

The first controlled human study was reported by Levine and colleagues in 1991. Twenty-eight healthy white men with differing tanning histories received ten subcutaneous injections of either purified NDP-MSH or saline over twelve days, followed by a seven-week observation period, with high-potency sunscreen used throughout. The authors reported a significant parabolic curve of skin darkening in both skin-type groups receiving the peptide (P < 0.001 for skin types I and II) and no darkening in placebo recipients, with peak changes one to three weeks after the injection course (Levine et al., JAMA 1991).

Barnetson and colleagues ran a larger trial with instrumented endpoints. Sixty-five subjects completed subcutaneous abdominal injection across three 10-day cycles over three months. Melanin density measured by reflectance spectroscopy rose by an average of 41% in low-minimal-erythemal-dose subjects (2.55 to 3.59, P < 0.0001 versus placebo) and by 12% in high-MED subjects (4.18 to 4.70, P < 0.0001 versus placebo), averaged across eight skin sites. Epidermal sunburn cells following exposure to 3 MED of UV radiation were reduced by more than 50% in the low-baseline-MED volunteers, and thymine dimer formation in the epidermal basal layer was reduced by 59% (P = 0.002) (Barnetson et al., J Invest Dermatol 2006).

The phase 3 programme used the implant rather than injected peptide. Langendonk and colleagues reported two randomised, double-blind, placebo-controlled trials in erythropoietic protoporphyria using subcutaneous implants containing 16 mg of afamelanotide, with patients assigned in a 1:1 ratio: a European Union trial of 74 patients receiving five implants over a 270-day period, and a United States trial of 94 patients receiving three implants over a 180-day period. The primary endpoint was hours of direct sunlight exposure without pain. In the US trial the median was 69.4 hours with afamelanotide versus 40.8 hours with placebo (P = 0.04); in the European trial, 6.0 versus 0.8 hours (P = 0.005). Phototoxic reactions in the European study numbered 77 versus 146 (P = 0.04) (Langendonk et al., N Engl J Med 2015). The FDA prescribing information describes the same two studies under the codes CUV039 and CUV029, gives the enrolment as 93 and 74 subjects, and reports medians of 64.1 versus 40.5 hours and 6.0 versus 0.75 hours under its own endpoint definitions. The two sets of figures differ because the analyses differ, and both are stated here rather than one being chosen.

Two further findings define the edges of the record. In a randomised multicentre vitiligo trial, 28 participants received monthly 16 mg afamelanotide implants alongside narrowband UV-B and 27 received narrowband UV-B alone; repigmentation at day 168 was 48.64% (95% CI 39.49-57.80) in the combination arm versus 33.26% (95% CI 24.18-42.33) in the monotherapy arm (Lim et al., JAMA Dermatol 2015). A pharmacokinetic review by Minder and colleagues reported full bioavailability by the subcutaneous route, and stated that neither oral nor transdermal application resulted in measurable plasma concentrations or a pigmentation response (Minder et al., Clin Pharmacokinet 2017). Note also what the record does not contain: the human literature above rests on either the pharmaceutical controlled-release implant or standardised injection of purified peptide under trial conditions. No peer-reviewed study characterises reconstituted research-grade lyophilised material of the kind supplied here, and none of the work cited was conducted on this product.