Objectives: Acute Hepatic Porphyria (AHP) is a family of rare genetic diseases leading to an enzyme deficiency in the heme biosynthesis pathway, causing accumulation of neurotoxic heme intermediates, resulting in neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, is being evaluated for its ability to reduce the levels of neurotoxic intermediates thus decreasing attacks and disease manifestations.

BACKGROUNDUp-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.METHODSIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria.RESULTSA total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.CONCLUSIONSAmong patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

ALLE AN BORD Das Kongressmotto sagt es aus: wir wollen alle einladen sich an Bord zu begeben, um das Schiff „Notfallmedizin“ in sicheres Fahrwasser zu geleiten (. Abb. 1): Notfall-Youngster und Notfall-Erfahrene aus Rettungsdienst, Pflege und ärztlichem Dienst, notfallmedizinisch interessierte niedergelassene Kolleginnen und Kollegen, Gesundheitspolitiker, Geschäftsführer ... Neben dem gewohnt hochwertigen Kongressformat übernimmt am ersten Kongresstag mit „Notfallmedizin Direkt“ die Young DGINA das Ruder. Ein Tag. Eine Bühne. Ein Ziel: Internationale und nationale Größen und Experten präsentieren auf einer Bühne in neuem Format einen rasanten, inspirierenden und motivierenden notfallmedizinischen Rundumschlag. Freuen Sie sich auf einen erfrischenden Start in den DGINA-Kongress mit Updates und brandheißen Themen, Arbeitsalltag und Work-Life-Balance, Teamarbeit auf der Straße und in der Klinik. Zusätzlich zum Besuch von Fachvorträgen notfallmedizinischer Expertinnen und Experten möchten wir Sie auch dazu animieren, sich an den gesundheitspolitischen Diskussionen in diesen spannenden notfallmedizinischen Zeiten zu beteiligen! Lassen Sie es uns so sagen: die letzten Jahre waren für die Notaufnahmen und den Rettungsdienst nicht langweilig, und die aktuellen Entwicklungen lassen erahnen, dass dies auch in der Zukunft nicht der Fall sein wird: Notdienstreform, G-BA-Notfallstufen, Sachverständigen-Gutachten zur Notfallversorgung, Pflegepersonal-Untergrenzen, Fachkräftemangel etc. ... diese und andere Themen sorgen für viel Wind aus wechselnden Richtungen in den Segeln! Hochrangige Gesundheitspolitiker des Landes haben Ihr Kommen zugesagt, um den zukünftigen Kurs der Notfallmedizin in den Notaufnahmen des Landes mit uns zu diskutieren. Denn letztlich geht es uns allen um das Gleiche: eine qualitativ hochwertige Versorgung aller uns anvertrauter Akutund Notfallpatienten! In diesem Sinne wünschen wir allen Teilnehmenden eine spannende Jahrestagung mit reichlich Diskussionen und viel lehrreichem Input!

BACKGROUND:Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life.METHODS:We conducted two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide. Patients in the European Union (74 patients) and the United States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of five implants in the European Union study and three in the U.S study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. Quality of life was assessed with the use of validated questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. The primary efficacy end point was the number of hours of direct exposure to sunlight without pain.RESULTS:In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04). In both trials, quality of life improved with afamelanotide therapy. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug.CONCLUSIONS:Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).

In this volume a comprehensive review of membrane proteins that regulate complement and perforin-mediated cytolysis is presented. A detailed analysisis provided of the biochemical, molecular, and func