Erythropoietic protoporphyria (EPP) is an ultra-rare inborn error of metabolism characterised by painful phototoxic burn injuries after short exposure times to visible light. Patients with EPP are highly adapted to their condition which makes the quantification of their health-related quality of life (QoL) challenging. In the presented patient-initiated feasibility study, we describe a new approach to assess treatment benefits in EPP by measuring QoL with the generic EQ-5D instrument in five patients under long-term (≥two years) treatment with afamelanotide, the first approved therapy for EPP. For the study, we selected patients with EPP who in addition were affected by an involuntary treatment interruption (caused by a temporary reimbursement suspension) because we hypothesized that individuals who had previously unlearned their adaptation are better able to assess their life without treatment than treatment-naïve patients. QoL under treatment was comparable to the age-matched population norm, and retrospective results for a treatment interruption and phototoxic reaction time point were comparable to the QoL of patients with chronic neuropathic pain and acute burn injuries, respectively. The results were accepted by the National Institute for Health and Care Excellence in England for their evaluation of the cost-effectiveness of afamelanotide, i.e., the calculation of quality-adjusted life years.

The National Institute for Health and Care Excellence (NICE) in England uses quality-adjusted life years (QALYs) to assess the cost-effectiveness of treatments. A QALY is a measure that combines the size of the clinical benefit of a treatment with the time the patient benefits from it, i.e., the time horizon. We wanted to know how consistently QALY gains are calculated at NICE. Therefore, we have analysed information on the time horizons used for the QALY calculations of the concluded evaluations conducted under the Highly Specialised Technologies programme for treatments of very rare diseases at NICE. For treatments with final guidance published by December 2023 (n = 29), a time horizon of median 97.5 years (range: 35 to 125 years) was used to calculate the QALY gains. For most QALY calculations, the accepted time horizon was longer than either the expected treatment duration or the estimated life expectancy. In contrast, for the only technology with a final negative funding decision, i.e., afamelanotide for treating the lifelong chronic disease erythropoietic protoporphyria, a time horizon that was shorter than the expected treatment duration was used. The fairness and consistency of the evaluation process of treatments for very rare diseases at NICE should be reviewed.

Background: The erythropoietic protoporphyrias (EPP) are a group of ultra-rare (1:100.000) inborn errors of the heme biosynthesis characterised by painful phototoxic reactions in tissue exposed to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents phototoxic reactions and improves the quality of life of the patients. In the past years, several new potential treatment options for EPP have been identified, some of which are currently under investigation in clinical trials. While these developments could improve patient care, it is important to know how safety and efficacy of drug candidates compare to the existing treatment, i.e. afamelanotide. Methods: We identified pharmacotherapies (leaving out, for example, topical applications such as sunscreens or supplements such as iron) which are currently (that is, within the last 5 years) evaluated for EPP from clinical trial registries and investigated whether the trial designs allow a comparison of their treatment effects with each other and with afamelanotide. Therefore, we analysed the clinical trial protocols with emphasis on their trial designs, efficacy outcome measures, inclusion and exclusion criteria, safety aspects and, if available, published results. Results: Our search in the clinical trials registries retrieved 29 trials that included patients with EPP. From these, we identified 16 clinical trials evaluating afamelanotide and three new pharmacotherapies, i.e., dersimelagon, bitopertin and cimetidine. Safety and efficacy of all new pharmacotherapies are currently being investigated against placebo-control groups or against baseline. Because of differences in the outcome measures and included patient populations, the results of the trials cannot be directly compared. Moreover, methodically challenging aspects and ethical issues were identified in some of the trial protocols. Conclusion: Efficacy and safety of currently investigated treatments for EPP are not directly comparable. We wrote this manuscript as a call to action to Principal Investigators, Ethical Review Boards, Regulatory Authorities and the sponsors of trials because we are convinced that trials directly assessing new pharmacotherapies against afamelanotide would be the more informative, and methodological and ethically sounder trial design. Clinical trial number: Not applicable.