Antoine Poli1,2,3, Caroline Schmitt1,2,3, Boualem Moulouel2, Arienne Mirmiran2, Neila Talbi2, Sophie Rivière4, Diane Cerutti5, Isabelle Bouchoule6, Anthony Faivre7, Vincent Grobost8, Claire Douillard9, Francis Duchêne10, Valeria Fiorentino1, Thierry Dupré1, Hana Manceau1,11, Katell Peoc'h1,11, Hervé Puy1,2,3, Thibaud Lefebvre1,2, Laurent Gouya1,2,3. 1. Université de Paris, INSERM U1149, Centre de Recherche sur l’Inflammation, F-75018 Paris, France 2. AP-HP, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France 3. Laboratory of Excellence Gr-Ex, Paris 4. CHU Montpellier, Médecine interne, Hôpital St Eloi, Montpellier, France 5. CH Toulon, Médecine polyvalente, La Seyne-sur-Mer, France 6. CHI Elbeuf Louviers Val de Reuil, Néphrologie, Saint-Aubin-lès-Elbeuf, France 7. HIA St-Anne, Neurologie, Toulon, France 8. CHU Estaing, Médecine interne, Clermont-Ferrand, France 9. CHRU Lille, Endocrinologie-diabétologie-métabolisme-nutrition, hôpital Huriez, Lille, France 10. Hôpital Nord Franche-Comté, Médecine interne, Trévenans, France 11. AP-HP, Biochimie, Hôpital Beaujon, Clichy, France
Abstract
BACKGROUND: In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase. OBJECTIVES: To describe the efficacy and safety of givosiran based on a personalized medical approach. METHODS: We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events. RESULTS: Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism. CONCLUSION: The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient.
BACKGROUND: In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase. OBJECTIVES: To describe the efficacy and safety of givosiran based on a personalized medical approach. METHODS: We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events. RESULTS: Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism. CONCLUSION: The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient.
Authors: Chaudry Nasir Majeed; Christopher D Ma; Ted Xiao; Sean Rudnick; Herbert L Bonkovsky Journal: Drug Des Devel Ther Date: 2022-06-16 Impact factor: 4.319