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Efficacy of an orphan drug: The patient perspective Cornelia Dechant 1 , MD; Francesca Granata 2 , PhD; Jasmin Barman:Aksözen, PhD 3 1 [email protected] 2 [email protected] 3 [email protected] THE DISEASE: ERYTROPIOETIC PROTOPORPHYRIA Afamelanotide is a hormon analogon, which induces skin pigmentation and scavenges radicals, was approved ”under exceptional circumstances” by EMA. In 2014 to reduce the excruciating pain caused by severe phototoxic reactions in patients suffering from erythropoietic protoporphyria (EPP). THE MEDICAMENT Two phase II and three phase III clinical trials with 347 participants and a longTterm observational study with 115 patients from the Swiss and Italian compassionate use and early access schemes showed a significant extension of sun exposure time, a reduction of phototoxic reactions and an improvement of quality of life under the therapy with afamelanotide. THE STUDIES EPP patients under therapy describe the effect of the treatment as transformative and life changing. During the approval process, EPP patients for the first time in the history of EMA were allowed to participate at a full committee meeting and their description of the clinical benefit contributed to the positive opinion for approval. However, in their final assessment report, EMA claims that afamelanotide was able to extent sun exposure for 8 minutes per day only For standardization, EMA in a first step recalculated the median and in a second step divided the resulting 24h (median) additional pain free sunlight exposure through the whole period of the study (6 Month), not regarding that they included rainy weather periods or working days. In addition, based on their own recalculation, the benefit is questioned in the report by EMA, although such a standardization obviously cannot capture the entire benefit of the treatment RESULTS BASED ON QOL AND SUN EXPOSURE TIME EPP is an ultraTrare congenital disease, which results from a reduced activity of ferrochelatase, an enzyme of the heme biosynthesis. The enzyme deficiency leads to an accumulation of the heme precursor protoporphyrin IX in the whole body, but especially in blood, bone marrow and in the liver. Protoporphyrin IX reacts with the blue part of the visible light (400T410 nm) and causes acute photototoxic reactions due to formation of oxygen radicals in vessels and subcutaneous tissue, leading to unbearable pain and a severely reduced quality of life. Patients with EPP have to wear protective clothing to prevent phototoxic reactions, or remain indoors,which leads to social isolation as well. INTERPRETATION OF THE EMA SINGLE PERSON OBSERVATION FOR 2 MONTH EACH WITH & WITHOUT AFAMELANOTIDE CONCLUSION The pivotal study describes a significant prolongation of sun exposure time of 55h (mean/ patient; 28.6 h median) over 6 months .The quality of life (QoL) scores, measured by an EPPTspecific questionnaire, were 31 ± 24% of maximum prior to afamelanotide treatment, rose to 74% after starting afamelanotide and remained at this level during the entire observation period. Only minor adverse events attributable to afamelanotide, predominantly nausea, were recorded. 0 1 2 3 4 5 6 10.04 17.04 24.04 01.05 08.05 15.05 22.05 29.05 05.06 12.06 19.06 26.06 03.07 10.07 17.07 24.07 31.07 07.08 14.08 Schmerzen in Relation zur Wetterlage vor und nach Therapiebeginn Wetterlage: 0- Regen, 1- bewölkt/tlw. Regen, 2- tlw. bewölkt, 3- Sonne Schmerzen: 0- keine, 1- gering, 2- belastend, 3- sehr belastend, 4- nicht mehr arbeitsfähig, 5- verrücktmachend Therapiebeginn 0 1 2 3 4 5 6 10.04 17.04 24.04 01.05 08.05 15.05 22.05 29.05 05.06 12.06 19.06 26.06 03.07 10.07 17.07 Vermummung in Relation zur Wetterlage vor und nach Therapiebeginn Wetterlage: 0- Regen, 1- bewölkt/tlw. Regen, 2- tlw. bewölkt, 3- Sonne Schutzbekleidung: 0- keine Vermummung, 1- nur Hut und Schal, 2- volle Montur Therapiebeginn Pain irelation to the weather conditions before and after treatment with afamelanotide Blue: Weather condition 0: Rain, 1: cloudy/ rainy; 2:cloudy /sunny; 3: Sun Red: Pain: 0: no pain; 1: mild pain; 2: moderate pain; 3: very painful; 4: not possible to work because of pain; 5: to be out of ones mind with pain Based on the PainTDiary of Cornelia Dechant 2017 Protection clothes in relation to the weather conditions before and after treatment with afamelanotide Blue: Weather condition 0: Rain, 1: cloudy/ rainy; 2:cloudy /sunny; 3: Sun; Yellow: protection/clothes : 0: none , 1: hat and scarf, 2: full protection(hat , scarf, gloves, socks...) Based on the PainT Diary of Cornelia Dechant 2017 Although EPPTPatients report about a significant longer sun exposition time and an eminent improvement of quality of life under therapy with afamelanotid, the postT hoc recalculations of the EMA and the associated seemingly short prolongation of sun exposure time led to a severe impairment of the reimbursement process of afamelanotideTtherapy in most of the countries of the EU. We think that a more patientTcentered approach to describe the benefit is necessary to avoid such situations, especially in rare diseases. SINGLE PERSON OBSERVATION FOR 2 MONTH EACH WITH & WITHOUT AFAMELANOTIDE Literature: Biolcati, G., Marchesini, E., Sorge, F., Barbieri, L., SchneiderTYin, X., & Minder, E. I. (2015). LongTterm observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. British Journal of Dermatology, 172(6), 1601T1612. Langendonk, Janneke G., et al. "Afamelanotide for erythropoietic protoporphyria." New England Journal of Medicine 373.1 (2015): 48T59. «Patients involved in discussions on benefits and risks of a medicine at CHMP for the first time» http://www..ema.E urope.eu/docs/en_GB/document_library/Press_release//2014/10/WC500176355.pdf European Public Assessment report (EPAR) afamelanotide: 23 October 2014,EMA/CHMP/709396/2014 Rev.1 Committee for Medicinal Products for Human Use (CHMP)http://www.ema.Europe.eu/docs/en_GB/document_library/EPARTPublic_assessment_report/human/002548/WC500182309.pd Quality of life (QoL) scores vs. treatment duration. The treatment period is indicated on the abscissa and the QoL scores on the ordinate LongTterm observational study of afamelanotide in 115 patients with erythropoietic protoporphyria This private „painTdiary“ written by an EPP Patient, used as documetation for the insurance ,shows an impressive effect on the daily life of this patient( with regard to the pain and the protection clothes)
