P0651 - Disease Characteristics of Acute Hepatic Porphyria Patients: ENVISION, a Phase 3 Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Presenting Author(s)

• 

  Karl Anderson, MD

  Galveston, Texas

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 neuropathy^3,4, hypertension^5,6, chronic kidney disease⁷, and hepatocellular carcinoma^8,9.

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.

References:

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.