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Vol. 42. Issue S2.
Pages 27 (November 2020)
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Vol. 42. Issue S2.
Pages 27 (November 2020)
43
DOI: 10.1016/j.htct.2020.10.044
Open Access
TWELVE-MONTH INTERIM ANALYSIS OF EFFICACY AND SAFETY OF GIVOSIRAN, AN INVESTIGATIONAL RNAI THERAPEUTIC FOR ACUTE HEPATIC PORPHYRIA, IN THE ENVISION OPEN LABEL EXTENSION
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R. Marchia, L. Duartea, S. Eb, B. Mc, R. Dcd, S. Pd, S. Ue, A.P. Pf, B. Dmg, E. Ala, K. Sh, P. Ci, P. Jdi
a Alnylam Brasil Farmacêutica Ltda, São Paulo, SP, Brazil
b Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
c Icahn School of Medicine at Mt. Sinai, New York, United States
d King's College Hospital, London, United Kingdom
e Klinikum Chemnitz, Chemnitz, Germany
f Hospital Clinic Barcelona, Barcelona, Spain
g University of California, San Francisco, United States
h University of Washington, Seattle, United States
i University of Utah, Salt Lake City, United States
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Goals: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, can lead to accumulation of toxic heme intermediates 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), causing neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, targets liver ALAS1 to reduce ALA/PBG and ameliorate attacks and clinical manifestations. ENVISION (NCT03338816) is an ongoing study, evaluating efficacy and safety of givosiran in symptomatic AHP patients in a 6-month double blind (DB) period and a 30-month open label extension (OLE) period. While the efficacy and safety profile of givosiran has previously been reported in the DB period, here its effect through Month 12 of the OLE period is reported. Materials and methods: ENVISION is an ongoing Phase 3 global, multicenter, randomized, placebo-controlled trial. During the OLE, patients received either 2.5mg/kg or 1.25mg/kg monthly givosiran. Outcome measures included composite annualized attack rate (AAR) requiring hospitalization, urgent care, or IV-hemin at home, ALA/PBG levels, hemin use, daily worst symptoms, and quality of life (QoL). Analyses were descriptive. Results and discussion: As of July 23, 2019, 93 patients entered the OLE: 56 (placebo/givosiran=29; givosiran/givosiran=27) received 2.5mg/kg monthly givosiran, and 37 (placebo/givosiran=17; givosiran/givosiran=20) received 1.25mg/kg. In givosiran patients (both doses), median AAR was 1.1 (range: 0–20.5) through Month 12. In placebo patients who crossed over to givosiran in the OLE, median AAR (DB=10.65; OLE=1.81) and proportion of attack-free patients (DB=17.4%; OLE=42.2%) were similar to the givosiran group in the DB period (median AAR=1.04; attack free patients=48.9%). In addition, sustained lowering of ALA/PBG in the OLE was accompanied by reductions in hemin use, daily worst pain and analgesic use, and improvements in QoL. Among patients on givosiran through Month 12, 62% had ≥1 drug-related adverse event (AE) and 3% had ≥1 drug-related serious AE. There were no new AEs leading to discontinuation and no deaths. No new safety concerns occurred in the OLE. There was a trend toward increased efficacy with the 2.5mg/kg dose compared to 1.25mg/kg dose, and safety was acceptable at both doses. Conclusion: In an ongoing Phase 3 study, givosiran 2.5mg/kg monthly demonstrated maintenance or enhancement of clinical efficacy and an acceptable safety profile consistent with that observed in the 6-month DB period.

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Hematology, Transfusion and Cell Therapy

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