A Phase III study (CUV039) evaluating the administration of Scenesse (afamelanotide 16mg) to patients diagnosed with erythropoietic protoporphyria (EPP) has shown a clinically meaningful treatment effect, according to Clinuvel Pharmaceuticals Limited. Independent Data Safety Monitoring Board stated that the drug treatment offered had been clinically meaningful and safe for use in patients.

EPP is a very rare disabling disease in which patients have learned to avoid light and sun exposure to prevent phototoxic pain and burns. Characteristic of EPP patients—and different from other photodermatoses—is that they experience prodromal symptoms upon light exposure, meaning that they are able to feel skin symptoms and burns developing. EPP patients are conditioned to avoid light from childhood and adapt their lives by remaining indoors and leading nocturnal existences.

The primary objective of evaluating Scenesse in EPP patients was to determine whether the prophylactic use of the drug would provide a clinically relevant benefit. The expected clinical benefit of treatment was to allow patients the ability to expose themselves to ambient light and to engage in outdoor activities that were not possible prior to treatment. A secondary objective was to assess whether treatment would improve their quality of life (QoL).

Scenesse is the first modern therapy to be evaluated for EPP.

CUV039 was a six-month, randomized, multicenter, double-blind, placebo-controlled Phase III study that recruited 93 adult EPP patients in the seven main US porphyria specialist centers (Alabama, California, Michigan, New York, North Carolina, Texas, and Utah). Patients were randomized into two treatment groups and given either Scenesse or placebo implants every two months (at days 0, 60 and 120). A final visit for safety follow-up was scheduled on day 210.

Patients kept written daily diaries recording light and outdoor exposure, as well as pain data. The impact on patient QoL was evaluated throughout the study using two validated questionnaires, DLQI and EPP-QoL (disease specific). As an objective measure of efficacy, a subset of patients (n=20) underwent photoprovocation testing on days 0, 30, 60, 90 and 120 utilizing an artificial light source under standardized laboratory conditions to determine the tolerance to light irradiation.

Of the 93 patients enrolled, 87 completed the study (93.5%), 45 on active treatment and 42 placebo recipients. Three from each group withdrew from the study due to reasons unrelated to drug administration.

The primary endpoint was to establish the extent to which patients exposed themselves to direct sunlight between 10am and 6pm as recorded daily in patient diaries. A strong trend towards greater direct sunlight exposure was seen in the active group compared to placebo recipients. Median total direct sunlight exposure was 64.13 hours (range 0 - 650.5 hours) in the active group compared with 47.5 hours (range 0 - 224 hours) for placebo recipients (p=0.107, Kruskal-Wallis test). The distribution of the number of days with sun exposure of various time intervals (30 min intervals) was significantly different between the treatment groups (p<0.001, Cochran-Mantel-Haenszel test). As an example, Scenesse recipients reported more days when they had pain-free exposure of 60 minutes or more (the time of greatest risk of burns).

As an objective measure, photoprovocation under standardized laboratory conditions was performed in 20 patients at Mount Sinai Hospital. The results showed that after receiving their second photoprovocation administration, patients had a significantly higher tolerance to light irradiation on the lower back and back of the hand (median change from baseline in minimum symptom dose on lower back at day 90, 227.5 versus -2.4 J/cm2; p<0.001, Wilcoxon test). Results for the lower back at day 120 and the back of the hand at days 90 and 120 showed similar significant differences.

As a secondary endpoint, QoL was evaluated using the validated EPP-QoL questionnaire. Active drug recipients showed significantly improved QoL scores in comparison to placebo recipients on days 60, 120 and 180 of the study (p=0.002, 0.002 and 0.004 respectively, Kruskal-Wallis test).

A further secondary endpoint looked at the distribution of days on which patients experienced mild, moderate, or severe phototoxic pain. The difference in the distribution of days during which pain was experienced was significant between the two treatment groups (p<0.0001, Cochran-Mantel-Haenszel test).

The safety profile of the drug was good, consistent with all previous trials in EPP. Headaches (nine patients receiving active treatment and five receiving placebo) and nausea (seven active and five placebo) after the first implant administration were the most common adverse events.

The study's independent Data Safety Monitoring Board confirmed that these results indicate that afamelanotide 16mg provides a safe, effective and clinically meaningful treatment for patients with EPP.

Clinuvel submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA) for Scenesse for the treatment of EPP in February2012, with data from previous Phase II and III studies forming the basis of the submission.

As part of the final regulatory review, the EMA has requested the results of CUV039 be made available. The EMA will evaluate the latest US data in a continuum with the results reported in the CUV029 and CUV030 studies.

According to the company, the final stage of EMA review of Scenesse is expected to continue in January 2014. The further EMA timeline will be known by Q1 2014.

The CUV039 results together with the earlier results in CUV010, CUV017, CUV029 and CUV030 will be discussed with the FDA Division of Dental and Dermatology Products in a meeting requested for Q1 2014.