Karl Anderson, MD1, Manisha Balwani, MD2, Eliane Sardh, MD, PhD3, Laurent Gouya, MD, PhD4, David Rees, MD5, Penelope Stein, MB, PhD5, Ulrich Stolzel, MD6, Paula Aguilera, MD, PhD7, D. Montgomery Bissell, MD8, Herbert Bonkovsky, MD9, Sioban Keel, MD10, Charles Parker, MD11, John Phillips, PhD11, Samuel Silver, MD, PhD12, Jerzy Windyga, MD, PhD13, Delia D'Avola, MD, PhD14, Gayle Ross, MD15, Peter Stewart, MD16, Bruce Ritchie, MD17, Jeeyoung Oh, MD, PhD18, Pauline Harper, MD, PhD3, Jiaan-Der Wang, MD, PhD19, Janneke Langendonk, MD, PhD20, Aneta Ivanova, MD, PhD21, Yutaka Horie, MD22, Elisabeth Minder, MD23, Daphne Vassiliou, MD24, Ilja Kubisch, MD6, Encarna Guillen-Navarro, MD, PhD25, David Coman, MBBS, MPhil26, Bruce Wang, MD8, Hung-Chou Kuo, MD27, Sushama Scalera, MD28, Craig Penz, MA29, Zoe Hua, PhD29, Amy Simon, MD29, John J. Ko, PharmD, MBA29, Paolo Ventura, MD30
1University of Texas Medical Branch, Galveston, TX; 2Mt. Sinai Icahn School of Medicine, New York, NY; 3Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Stockholms Lan, Sweden; 4Centre Français des Porphyries, Paris, Centre, France; 5King’s College Hospital, London, England, United Kingdom; 6Klinikum Chemnitz, Chemnitz, Sachsen, Germany; 7Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain; 8University of California San Francisco, San Francisco, CA; 9Wake Forest University Baptist Medical Center, Winston-Salem, NC; 10University of Washington, Seattle, WA; 11University of Utah, Salt Lake City, UT; 12University of Michigan Medical Center, Ann Arbor, MI; 13Instytut Hematologii i Transfuzjologii, Warsaw, Podlaskie, Poland; 14Clinica Universidad de Navarra, Madrid, Navarra, Spain; 15Melbourne Health - Royal Melbourne Hospital, Melbourne, Victoria, Australia; 16Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; 17University of Alberta Hospital, Edmonton, AB, Canada; 18Konkuk University Hospital, Konkuk University Medical Center, Seoul, Seoul-t'ukpyolsi, Republic of Korea; 19Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taichung, Taiwan; 20Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Zuid-Holland, Netherlands; 21St. Ivan Rilski University Hospital, Sofia, Sofiya, Bulgaria; 22Tottori University School of Medicine, Tottori, Tottori, Japan; 23Stadtspital Triemli, Zurich, Zurich, Switzerland; 24Karolinska Institutet, Karolinska University Hospital, Stockholm, Stockholms Lan, Sweden; 25Hospital Clínico Universitario Virgen de la Arrixaca, University of Murcia, IMIB-Arrixaca, Murcia; CIBERER-ISCIII, Madrid, Murcia, Spain; 26The Wesley Hospital, Queensland, Queensland, Australia; 27Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taoyuan, Taiwan; 28Alnylam Pharrmaceuticals, Cambridge, MA; 29Alnylam Pharmaceuticals, Cambridge, MA; 30Università degli Studi di Modena e Reggio Emilia, Modena, Emilia-Romagna, Italy
Introduction: Acute Hepatic Porphyria (AHP) is a family of rare genetic diseases due to enzyme deficiencies in heme biosynthesis in the liver that can lead to neurovisceral attacks and chronic symptoms.1,2 AHP is also associated with multiple long-term complications, including neuropathy3,4, hypertension5,6, chronic kidney disease7, and hepatocellular carcinoma8,9.
Methods: ENVISION (NCT03338816) was a Phase 3 global, multicenter, randomized, double-blind, placebo-controlled trial with an open label extension to evaluate the efficacy and safety of subcutaneous givosiran in AHP. Eligible patients had an AHP diagnosis and ≥2 attacks within the prior 6 months. At baseline detailed medical history and laboratory assessments were obtained.
Results: Ninety-four AHP patients enrolled, median (range) age 37.5 (19-65) years, 89% female, and median (range) of 6.5 (0.1-43) years since diagnosis. Patients had a median of 4 composite attacks in the preceding 6 months and 40% were on hemin prophylaxis prior to study. Half the patients experienced daily chronic symptoms and 29% used opioids daily/most days between attacks. Comorbidities reported on medical history included neuropathy (38%), central venous access complications (71%), iron overload (33%), liver disease (28%), and chronic kidney disease (18%). At baseline 17% of patients had liver transaminases > ULN and 34% had an eGFR < 60 mL/min/1.73m2.
Discussion: The baseline disease characteristics of the Phase 3 study population are consistent with findings reported in the AHP literature, underscoring the high rate of liver disease and central venous access complications in these patients, and highlighting the multi-systemic nature of AHP and the medical challenge it presents for diagnosis and treatment.
1. Gouya et al. EASL Meeting, Apr 2018. 2. Bonkovsky, et al., Am J Med. 2014;127:1233-41. 3. Puy H et al. Lancet 2010;375:924–37. 4. Pischik E. Kauppinen R. Cell Mol Biol 2009;55:72–83 5. Pallet N et al. Clin Kidney J 2018;11:191–197. 6. Stewart MF J Clin Pathol 2012;65:976–80. 7. Pallet N et al. Kidney Int 2015;88:386–95. 8. Peoc’h K et al. Mol Genet Metab 2018;S1096-7192(18)30482–7 9. Baravelli CM et al. J Intern Med 2017;282:229–240.
Citation: Karl Anderson, MD; Manisha Balwani, MD; Eliane Sardh, MD, PhD; Laurent Gouya, MD, PhD; David Rees, MD; Penelope Stein, MB, PhD; Ulrich Stolzel, MD; Paula Aguilera, MD, PhD; D. Montgomery Bissell, MD; Herbert Bonkovsky, MD; Sioban Keel, MD; Charles Parker, MD; John Phillips, PhD; Samuel Silver, MD, PhD; Jerzy Windyga, MD, PhD; Delia D'Avola, MD, PhD; Gayle Ross, MD; Peter Stewart, MD; Bruce Ritchie, MD; Jeeyoung Oh, MD, PhD; Pauline Harper, MD, PhD; Jiaan-Der Wang, MD, PhD; Janneke Langendonk, MD, PhD0; Aneta Ivanova, MD, PhD; Yutaka Horie, MD; Elisabeth Minder, MD; Daphne Vassiliou, MD; Ilja Kubisch, MD; Encarna Guillen-Navarro, MD, PhD; David Coman, MBBS, MPhil; Bruce Wang, MD; Hung-Chou Kuo, MD; Sushama Scalera, MD; Craig Penz, MA; Zoe Hua, PhD; Amy Simon, MD; John J. Ko, PharmD, MBA; Paolo Ventura, MD0. P0651 - DISEASE CHARACTERISTICS OF ACUTE HEPATIC PORPHYRIA PATIENTS: ENVISION, A PHASE 3 GLOBAL, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL. Program No. P0651. ACG 2019 Annual Scientific Meeting Abstracts. San Antonio, Texas: American College of Gastroenterology.