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

L. Gouya, P. Ventura, M. Balwani, DM. Bissell, DC. Rees, U. Stölzel, JD. Phillips, R. Kauppinen, JG. Langendonk, RJ. Desnick, JC. Deybach, HL. Bonkovsky, C. Parker, H. Naik, M. Badminton, PE. Stein, E. Minder, J. Windyga, R. Bruha, MD....

. 2020 ; 71 (5) : 1546-1558. [pub] 20191107

Language English Country United States

Document type Journal Article, Observational Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21020578

Grant support
U2C TR002818 NCATS NIH HHS - United States
U54 DK083909 NIDDK NIH HHS - United States
U54 DK110858 NIDDK NIH HHS - United States

BACKGROUND AND 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.

4th Internal Clinic General University Hospital Charles University Prague Czech Republic

Alnylam Pharmaceuticals Cambridge MA

Centre de Référence Maladies Rares Porphyries Colombes France

Clinica Universidad de Navarra Navarra Spain

Department of Hemostatic Disorders and Internal Medicine Institute of Hematology and Transfusion Medicine Warsaw Poland

Fondazione IRCCS Ca Granda University of Milan Milan Italy

Icahn School of Medicine at Mount Sinai New York NY

King's College Hospital King's College London London UK

Klinikum Chemnitz Porphyria Center Chemnitz Germany

Laboratory of Excellence GR Ex Paris France

Norwegian Porphyria Centre Haukeland University Hospital Bergen Norway

Porphyria Center Center for Lysosomal and Metabolic Disease Department of Internal Medicine Erasmus MC University Medical Center Rotterdam the Netherlands

Porphyria Centre Sweden Centre for Inherited Metabolic Diseases Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Section on Gastroenterology and Hepatology Wake Forest University NC Baptist Medical Center Winston Salem NC

St Ivan Rilski U Hospital Sofia Bulgaria

Stadtspital Triemli Zentrallabor Zurich Switzerland

Università degli Studi di Modena e Reggio Emilia Emilia Romagna Italy

University Hospital of Helsinki Helsinki Finland

University Hospital of Wales Cardiff UK

University of California San Francisco CA

University of Paris Paris France

University of Texas Medical Branch Galveston TX

University of Utah Salt Lake City UT

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$a EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks / $c L. Gouya, P. Ventura, M. Balwani, DM. Bissell, DC. Rees, U. Stölzel, JD. Phillips, R. Kauppinen, JG. Langendonk, RJ. Desnick, JC. Deybach, HL. Bonkovsky, C. Parker, H. Naik, M. Badminton, PE. Stein, E. Minder, J. Windyga, R. Bruha, MD. Cappellini, E. Sardh, P. Harper, S. Sandberg, AK. Aarsand, J. Andersen, F. Alegre, A. Ivanova, N. Talbi, A. Chan, W. Querbes, J. Ko, C. Penz, S. Liu, T. Lin, A. Simon, KE. Anderson
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$a BACKGROUND AND 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.
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