Afamelanotid (1) – Scenesse®

• Clinical trials
  • The multicentre, double-blind, randomised, controlled trial CUV039 enrolled 93 patients with erythropoietic protoporphyria.

a) Prevention of phototoxicity in adult patients with erythropoietic protoporphyria (EPP)

• In summary, the additional benefit of afamelanotide is assessed as follows: non-quantifiable
• Due to the methodological limitations of the study and the overall limited evidence base, the G-BA classifies the extent of the additional benefit for afamelanotide, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition, the written submissions and the oral hearing, as non-quantifiable.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence currently does not permit a quantifiable assessment of the extent of the additional benefit for patient-relevant endpoints.
• mortality
  • No deaths were observed in the study; mortality was not an efficacy endpoint.
  • With regard to mortality, no conclusion can be drawn from the available results regarding the extent of the additional benefit.
• morbidity
  • The ITT population, comprising 46 patients in the afamelanotide arm and 43 patients in the placebo arm, was analysed.
  • The primary endpoint of the study was the time patients were able to spend in sunlight (between 10:00 and 18:00) on days when they did not experience EPP-related pain.
  • A statistically significant advantage of afamelanotide was observed. During the study duration, which was approximately 180 days long, patients in this arm spent 24 hours longer (estimated median difference) in the sun than patients in the placebo arm.
  • However, the test for individual patient differences in minutes per study day between the two treatment arms was not statistically significant; numerically, there was an advantage of 8.8 minutes per day (estimated median difference) for patients in the afamelanotide arm.
  • The time that patients were able to spend in sunlight (between 10:00 and 18:00) on days when they did not experience EPP-related pain is considered clinically relevant, as pain represents the symptoms perceived by the patient during or after exposure to sunlight.
  • However, the validity of the patient diary can only be assumed with reservations, as neither pre-test results nor psychometric properties are known.
  • It cannot be ruled out that – particularly for endpoints assessed subjectively via diaries – partial unblinding may have biased the results in favour of afamelanotide.
  • Other endpoints, which also take into account the components of pain and exposure to sunlight, did not reach statistical significance.
  • Due to the uncertainties described, the additional benefit of afamelanotide cannot be quantified on the basis of the morbidity results.
• quality of life
  • The pharmaceutical manufacturer presents the results of two health-related quality of life assessment tools in the CUV039 study.
  • Of these, only the data from the Dermatology Quality of Life Index (DLQI) can be used for the benefit assessment.
  • The questionnaire is validated and established for assessing the impact of skin diseases on quality of life; however, the generalisability of the results to patients with erythropoietic protoporphyria (EPP) is questionable.
  • Following statistical adjustment, there was no difference in the changes in the overall DLQI score between the two study arms.
  • The disease-specific EPP Quality of Life (EPP-QoL) questionnaire was used as a second tool for assessing quality of life. No information on the psychometric properties (validity, reliability, sensitivity to change) of this questionnaire was provided. The results of the questionnaire cannot therefore be used to assess the additional benefit.
  • Based on the available results on quality of life, the extent of the additional benefit of afamelanotide cannot be quantified.
• Side effects
  • With regard to the parameters of adverse events (AEs), moderate or severe AEs and serious AEs, there is a disadvantage for afamelanotide compared with placebo when considering the relative frequencies in each case.
  • Overall, only a few serious AEs occurred in both treatment arms, with no deaths and no AEs leading to discontinuation of the study medication.
  • The most common AEs with afamelanotide were headaches (40%), nausea (19%) and skin discolouration at the implantation site (19%).
  • The differences between the two arms were not statistically tested. A comparative assessment of the extent of the additional benefit is not possible on this basis.
• Overall assessment
  • In summary, it is not possible to quantify the additional benefit of afamelanotide on the basis of the mortality, morbidity and adverse event data.
  • The uncertain evidence base, resulting from the study’s high potential for bias, makes it difficult to interpret the data as a whole.

Courtesy translation only, please refer to the German original.