Afamelanotide for Erythropoietic Protoporphyria

Ashley Choi, Mercer University College of Pharmacy

Erythropoietic protoporphyria (EPP) is considered an inherited inborn error of porphyrin metabolism characterized clinically by photosensitivity to visible light.1  A review of multiple clinical studies stated that EPP is usually initiated during early infancy or childhood, upon the first sun exposure and manifested by an immediate painful photosensitivity with skin stinging, prickling, and burning on sun exposure but without blisters.2

 Scenesse® (afamelanotide) is noted to be a synthetic tridecapeptide and a structural analogue of endogenous α-melanocyte stimulating hormone (α-MSH).  Afamelanotide is also classified as a melanocortin receptor agonist and binds predominantly to the melanocortin-1 receptor (MC1R).  It is indicated for prevention of phototoxicity in adult patients with erythropoietic protoporphyria (EPP).3

Title: Afamelanotide for Erythropoietic Protoporphyria4
Design Two multicenter, randomized, double-blind, placebo-controlled trials
Objective To evaluate the safety and efficacy of afamelanotide, to decrease pain, and improve quality of life
N=168 N=74 in the European Union (E.U.) trial
N=94 in the United States (U.S.) trial
Study Groups E.U. trial (1)  Subjects receiving afamelanotide (n=38)
(2)  Subjects receiving placebo (n=36)
U.S. trial* (1)  Subjects receiving afamelanotide (n=48)
(2)  Subjects receiving placebo (n=45)
* 1 patient discontinued the study before receiving a study drug
Methods Patients were randomly assigned, in a 1:1 ratio, to receive either implant formulation of afamelanotide 16 mg subcutaneously or a placebo containing poly (D, L-lactide-co-glycolide).  An implant was inserted on days 0, 6, and 120 in both trial, but also in days 180 and 240 in E.U. trial using a 14-gauge catheter needle and a 16-gauge stylet.  The intensity and duration of pain and exposure to sunlight and shade were recorded daily by the patients, and time spent outdoors was recorded in 15-minute intervals.  Pain was scored on an 11-point Likert pain-intensity scale (higher scores indicating greater severity of symptoms).  Quality of life was assessed with the use of the Erythropoietic Protoporphyria Quality-of-Life (EPP-QOL) questionnaire (higher scores indicating a better quality of life).
Duration E.U. trial January 2010 through May 2011
U.S. trial May 2012 through July 2013
Primary Outcome Measure The primary end point was the duration of direct exposure to sunlight without pain between 10 a.m. and 3 p.m. in the E.U. trial or between 10 a.m. and 6 p.m. in the U.S. trial.
Baseline Characteristics All patients were at least 18 years of age, had biochemically confirmed erythropoietic protoporphyria, and did not have clinically significant hepatic or other organ dysfunction, skin cancer, or premalignant lesion or other photodermatoses.
E.U. trial U.S trial
Afamelanotide Placebo Afamelanotide Placebo
Age 38±13.0 38.6±11.6 40.4±12 39.1±16.2
Body-mass index 24.0±3.0 26.5±5.2 26±4.8 26.7±5.4
White race 100% 97% 98% 96%
Results E.U. trial U.S. trial
Afamelanotide Placebo p-value Afamelanotide Placebo p-value
Median hours in direct sunlight 6.0 0.8 0.005 69.4 40.8 0.04
Mean hours in direct sunlight 20.4±40.5 5.6±9.3 115.6±140.6 60.6±60.6
Adverse Events (AE) Common AE: E.U. trial U.S trial
Afamelanotide Placebo Afamelanotide Placebo
Headache 34% 39% 40% 29%
Nausea 18% 17% 19% 18%
Nasopharyngitis 21% 22% 12% 22%
Back pain 5% 11% 12% 13%
Serious AE: Afamelanotide: subcapital humerus fracture with uncomplicated repair, herniated disk, abdominal pain, and benign compound nevus Placebo: pulmonary embolus and melanoma
E.U. trial U.S trial E.U. trial U.S trial
3% 6% 0% 4%
Percentage that Discontinued due to Adverse Event: N/A
Study Author Conclusions Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria.

Although there were differences in U.S trial and E.U. trial with regards to the end points, (such as the duration of the trial, the recruitment periods, and the data collected from the diaries), the pain-free time in direct sunlight was longer among afamelanotide receiving patients than among placebo receiving patients in both trials.  With the adequate side-effect profile and enhanced tolerance to sunlight, afamelanotide provided photo-protection that enabled patients to have more exposure to visible light in patients with erythropoietic protoporphyria.  Patients who received afamelanotide also had decreased the consequences of photo-toxicity and improved quality of life.

References

  1. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. 1994;131(6):751-66.
  2. Lecha M, Puy H, Deybach JC. Erythropoietic protoporphyria. Orphanet J Rare Dis. 2009;4:19.
  3. Scenesse® [Product Information]. London, United Kingdom: Penn Pharmaceutical Services Ltd; 2015.
  4. Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for Erythropoietic Protoporphyria. N Engl J Med. 2015;373(1):48-59.
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