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EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

Publication Details

Hepatology

November 2019

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Author(s)

Laurent Gouya^{1 2 3}, Paolo Ventura⁴, Manisha Balwani⁵, D Montgomery Bissell⁶, David C Rees⁷, Ulrich Stölzel⁸, John D Phillips⁹, Raili Kauppinen¹⁰, Janneke G Langendonk¹¹, Robert J Desnick⁵, Jean-Charles Deybach^{1 2 3}, Herbert L Bonkovsky¹², Charles Parker⁹, Hetanshi Naik⁵, Michael Badminton¹³, Penelope E Stein⁷, Elisabeth Minder¹⁴, Jerzy Windyga¹⁵, Radan Bruha¹⁶, Maria Domenica Cappellini¹⁷, Eliane Sardh¹⁸, Pauline Harper¹⁸, Sverre Sandberg¹⁹, Aasne K Aarsand¹⁹, Janice Andersen¹⁹, Félix Alegre²⁰, Aneta Ivanova²¹, Neila Talbi ^{1 23}, Amy Chan²², William Querbes²², John Ko²², Craig Penz²², Shangbin Liu²², Tim Lin²², Amy Simon²², Karl E Anderson²³

Affiliations

¹Centre de Référence Maladies Rares Porphyries, Colombes, France; ²University of Paris, Paris, France; ³Laboratory of Excellence GR-Ex, Paris, France; ⁴Università degli Studi di Modena e Reggio Emilia, Emilia-Romagna, Italy; ⁵Icahn School of Medicine at Mount Sinai, New York, NY; ⁶University of California, San Francisco, CA; ⁷King's College Hospital, King's College London, London, UK; ⁸Klinikum Chemnitz Porphyria Center, Chemnitz, Germany; ⁹University of Utah, Salt Lake City, UT; ¹⁰University Hospital of Helsinki, Helsinki, Finland; ¹¹Porphyria Center, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands; ¹²Section on Gastroenterology & Hepatology, Wake Forest University/NC Baptist Medical Center, Winston-Salem, NC; ¹³University Hospital of Wales, Cardiff, UK; ¹⁴Stadtspital Triemli, Zentrallabor, Zurich, Switzerland; ¹⁵Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; ¹⁶4th Internal Clinic, General University Hospital, Charles University, Prague, Czech Republic; ¹⁷Fondazione IRCCS, Ca Granda, University of Milan, Milan, Italy; ¹⁸Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; ¹⁹Norwegian Porphyria Centre, Haukeland University Hospital, Bergen, Norway; ²⁰Clinica Universidad de Navarra, Navarra, Spain; ²¹St. Ivan Rilski U Hospital, Sofia, Bulgaria; ²²Alnylam Pharmaceuticals, Cambridge, MA; ²³University of Texas Medical Branch, Galveston, TX

Abstract

Background & Aims:

Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.

Approach and Results:

EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0‐52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0‐37.0]). Elevated levels of hepatic δ‐aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ‐aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization.

Conclusions:

Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day‐to‐day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.