Afamelanotid (2) – Scenesse®

• Clinical trials
  • The multicentre, double-blind, randomised, controlled CUV039 trial enrolled 93 patients with erythropoietic protoporphyria. Participants were randomised in a 1:1 ratio to two treatment arms (afamelanotide and placebo).
  • The PASS study is a non-interventional study, ongoing since 2016, involving individuals receiving afamelanotide treatment.

Adult patients with erythropoietic protoporphyria for the prevention of phototoxicity

• Hint for a non-quantifiable additional benefit, as the available scientific data do not permit quantification.
• Due to the high potential for bias in the CUV039 study and the non-comparative nature of the data from the PASS study, the evidence is classified as a hint.
• mortality
  • No deaths were observed in the studies.
• morbidity
  • In the CUV039 study, the ITT population was analysed, comprising 46 participants in the afamelanotide arm and 43 participants in the placebo arm, comprising all randomised subjects who had received at least one dose of the study medication and for whom at least one post-baseline efficacy assessment was available.
  • The primary endpoint of the study was 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.
  • A statistically significant advantage of afamelanotide was observed. Over 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.
  • By contrast, the test for individual patient differences in minutes per study day between the two treatment arms was not statistically significant.
  • The time that could be spent in sunlight (between 10:00 and 18:00) on days when no EPP-related pain was experienced is considered clinically relevant, as pain represents the symptoms perceived by the patient perceived symptoms 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 recorded 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 (phototoxic episodes and pain during phototoxic episodes), did not reach statistical significance.
  • In the PASS study, phototoxicity was also assessed via patient diaries and a recall-based assessment of the previous two months at the respective study visits.
  • The results must be regarded as potentially highly biased, given that participants were required to report the number of phototoxic reactions over the past two months solely on the basis of their memory.
  • Data on the patient diaries are not available (at least at baseline, due to a lack of compliance). Owing to these ambiguities in operationalisation, the endpoint cannot be used to assess the extent of the additional benefit.
  • Daily activity is, in principle, relevant to patients and was assessed in the PASS study using the ‘Daily Activity Inventory’; however, there is insufficient information available to validate this measure.
• quality of life
  • The pharmaceutical manufacturer presents the results of two assessment tools for health-related quality of life 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 well-established for assessing the impact of skin diseases on quality of life; however, the generalisability of the results to individuals with erythropoietic protoporphyria (EPP) is questionable.
  • Following statistical adjustment, there was no difference in the changes to the overall DLQI score between the two study arms.
  • As a second tool for assessing quality of life, the disease-specific EPP Quality of Life (EPP-QoL) questionnaire was used in both studies. No information is available regarding the validation or psychometric properties of this questionnaire.
  • The results of the questionnaire cannot therefore be used to assess the additional benefit.
• Side effects
  • The differences between the study arms with regard to moderate or severe AEs and serious AEs in the CUV039 study were not statistically tested.
  • Overall, only a few serious AEs occurred in both treatment arms, and there were no AEs that led to discontinuation of the study medication.
  • The most common AEs at the PT level under afamelanotide were headaches (40%), nausea (19%) and skin discolouration at the implantation site (19%); however, no statistical analysis is available for these either.
  • An assessment with regard to quantifying the additional benefit is not possible on this basis.
  • The data from the PASS study show side effect frequencies of a similar magnitude and no indications of specific risks not observed in the CUV039 study. As only single-arm data are available, a comparative assessment is not possible here either.
• Overall assessment
  • In summary, it is not possible to quantify the additional benefit of afamelanotide on the basis of the mortality, morbidity, quality of life and adverse event data.
  • The uncertain evidence base, resulting from the high potential for bias in the CUV039 study, makes the interpretation of the data difficult overall.
  • A statistically significant result in favour of afamelanotide is available for only a single operationalisation of the endpoint ‘sunlight exposure’ (duration of direct sunlight exposure between 10:00 and 18:00 on pain-free days, total time for each individual patient in the study).
  • There is no statistically significant confirmation of this effect in other operationalisations or in other patient-relevant endpoints.
  • Consequently, and because no statistical analyses of the data on side effects are available, the results are insufficient to quantify the additional benefit.
  • There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit a quantifiable statement on the extent of the additional benefit.

Courtesy translation only, please refer to the German original.