番茄社区

The alpha-melanocyte-stimulating hormone analogue, afamelanotide, appears to be safe and efficacious in the treatment of erythropoietic protoporphyria -- the rare condition whose sufferers become people of the night.

Afamelanotide had an acceptable side-effect and adverse-event profile and improved the quality of life for patients with this severe photodermatitis, allowing them to tolerate more sun exposure without pain due to phototoxicity, , of the department of genetics and genomic sciences, Icahn School of Medicine at Mount Sinai, New York, NY, and colleagues reported in two studies published in the . "The main results, which were concordant and consistent across the two trials, indicated that afamelanotide was safe and effective," said the researchers.

Prior to this, there was for erythropoietic protoporphyria, noted Desnick. "Although several treatments, including beta carotene, N-acetyl-L-cysteine, and vitamin C, have been described in the literature, a of more than 20 studies showed little to no benefit," he said.

"For the first time, there is a treatment (afamelanotide) that results in improvement of quality of life of patients with erythropoietic protoporphyria," , Chairman, department of dermatology at Henry Ford Hospital, Detroit, MI, told 番茄社区. Lim was also a co-investigator in the study.

As a result of these clinical trials, which were held in both the European Union and the U.S., the use of afamelanotide in patients with confirmed erythropoietic protoporphyria, now has been approved for use in the European Union by the European Medicines Agency and the European Commission, said the investigators. It has not been approved for use in the U.S., confirmed Lim.

The long-term side effects of afamelanotide are not yet known.

In patients with erythropoietic protoporphyria, photosensitivity usually manifests in early childhood as severe burning pain that lasts from 1- 20 minutes after exposure to direct sunlight. The neurologic pain, which is often accompanied by swelling and redness, can last for days and , including narcotic analgesics.

Patients quickly learn to recognize early symptoms and avoid sun exposure, an adaptive behaviour that has a major effect of quality of life, opportunities for work and lifestyle choices, noted Desnick.

A total of 168 patients were enrolled in the two trials: 74 patients in the five-dose, 9-month European Union trial (conducted from January 2010 through May 2011 and completed before the initiation of the U.S. trial) and 94 patients in the three-dose, 6-month U.S. trial (conducted from May 2012 to July 2013).

Although similar protocols were followed in the two trials, results of the European Union trial led to changes to the U.S. trial such as a shortening of the inclusion period from 9 months to 6.

The was conducted at eight European centers with membership in the European Porphyria Network.

Similarly, the U.S. trial was conducted at seven porphyria centers in the U.S. Eligibility criteria for both trials included:

• 18 years of age or older;
• biochemically confirmed erythropoietic protoporphyria;
• no clinical significant hepatic or other organ dysfunction, skin cancer, or premalignant lesions or other photodermatoses.

Patients were , in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide 16 mg or placebo every 50 days. The placebo implants, which were introduced into the subcutaneous fat above the iliac crest and then pushed into the fat tissue, were identical to the afamelanotide implants except that they contained only poly (D,L-lactide-co-glycolide. Study investigators, research staff, and patients were all blinded to the study-drug assignments.

U. S. study participants received a total of three implants while those in the European Union study received a total of five. Over the respective 180-day and 270-day study periods, the type and duration of sun exposure, the number and severity of phototoxic reactions, and adverse events were recorded. A subgroup of U.S. patients also underwent photo-provocation testing.

Quality of life was assessed using validated questionnaires: the Erythropoietic Protoporphyria Quality-of-Life (EPP-QOL) questionnaire in which scores range from 0 to 100, with the higher scores indicating a better quality of life; and the Dermatology Life Quality Index, in which scores range from 0 to 30, with lower scores indicating an improved quality of life.

"The EPP-QOL questionnaire, which was designed specifically for patients with this disorder, showed significant differences between the afamelanotide and placebo groups and favored afamelanotide in both trials for all questions," said Desnick. "These findings further support the favorable effect of afamelanotide on the patients' daily lives."

Pain was scored on an 11-point Likert pain-intensity scale with scores ranging from 0 to 10, and higher scores indicating greater severity of symptoms. The duration of any phototoxic reactions was defined as pain on a Likert score of 4 or higher.

In both trials, the primary end point -- the length of time during which patients were pain-free in direct sunlight -- was significantly longer among patients who received afamelanotide than among patients who received placebo. In the U.S. trial, the pain-free time in direct sunlight was 70% longer among patients on active treatment (median 69.4 hours) than for those who received placebo (median 40.8 hours; P=0.04). In addition, after 9 months in the European Union trial, the duration of pain-free time was significantly longer in those who received afamelanotide (median 6.0 hours) than among patients receiving placebo (median 0.8 hours; P=0.005).

Although the total number of phototoxic reactions after 9 months was reduced among patients in the European Union trial (77 for those receiving active treatment versus 146 for those receiving placebo; P=0.04), there were no significant changes seen between the active treatment (46 reactions) and placebo groups (43 reactions) after 6 months in the U.S. trial (P=0.60).

In both trials, quality of life improved with afamelanotide therapy and adverse events were mostly mild. The most common adverse events recorded in both trials were headache, nausea, nasopharyngitis and back pain. "There were no clinically relevant between-group differences in the incidence of severity of adverse events, except for mild hyper-pigmentation at the implant site in one third of patients who received afamelanotide and moles that darkened in a few patients who received the drug," said Desnick.

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