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Givosiran, a subcutaneously administered RNA interference therapeutic targeting liver ALAS mRNA, is approved for treating these disorders. This Phase 1\/2 open-label extension study (NCT02949830) evaluated the long-term safety and efficacy of givosiran in adults with acute intermittent porphyria, with follow-up of up to 48\u00a0months, which is the longest follow-up of givosiran treatment to date. Participants were adults aged 18\u201365\u00a0years who completed part C of the Phase 1 givosiran study (NCT2452372).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Enrollees received givosiran for up to 48\u00a0months. Primary and secondary endpoints included the incidence of adverse events, changes in urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, annualized rate of porphyria attacks, and annualized hemin use. Quality of life was assessed using the EQ-5D-5L instrument as an exploratory endpoint.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Sixteen patients (median age: 39.5\u00a0years) participated. Common adverse events included abdominal pain, nasopharyngitis, and nausea (50% each), with injection-site erythema (38%) and injection-site pruritus (25%) noted as frequent treatment-related reactions. Givosiran therapy reduced annualized rates of porphyria attacks and hemin use by 97% and 96%, respectively. From months\u2009&gt;\u200933 to 48, all patients were free from attacks requiring significant medical intervention and did not use hemin. There were substantial reductions in median urinary ALA and PBG of 95% and 98%, respectively. Additionally, a clinically meaningful improvement in quality of life was observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In the longest follow-up of givosiran-treated patients reported to date, the therapy maintained an acceptable safety profile and demonstrated sustained improvements in clinical outcomes over 4\u00a0years in patients with acute intermittent porphyria.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-024-03284-w","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T03:02:02Z","timestamp":1727924522000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Long-term follow-up of givosiran treatment in patients with acute intermittent porphyria from a phase 1\/2, 48-month open-label extension study"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2366-2213","authenticated-orcid":false,"given":"Eliane","family":"Sardh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Balwani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Rees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl E.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne T.","family":"Sweetser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,3]]},"reference":[{"issue":"2","key":"3284_CR1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.amjms.2021.03.004","volume":"362","author":"KE Anderson","year":"2021","unstructured":"Anderson KE, Lobo R, Salazar D, Schloetter M, Spitzer G, White AL, et al. 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This study was conducted in accordance with Good Clinical Practice as defined by the International Council on Harmonisation, the principles defined in the Declaration of Helsinki and its amendments, and all applicable national and international laws. All patients provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Eliane Sardh reports receiving grant support and consulting fees, advisory board fees, and lecture fees, paid to Karolinska Institutet, from Alnylam Pharmaceuticals, and is a member of the Ipnet Executive Board.Manisha Balwani reports receiving grant support, advisory board fees from Recordati Rare Diseases; grant support and advisory board fees from Mitsubishi Tanabe; and advisory board fees from Alexion, Genzyme\/Sanofi, and Takeda. In addition, Mount Sinai faculty are named Co-Inventors with Alnylam on a patent related to the development of givosiran, the study drug. The Icahn School of Medicine at Mount Sinai receives payments related to this patent from Alnylam, and a portion of these payments are also distributed to faculty and other co-inventors.David C. Rees reports receiving lecture fees from Alnylam Pharmaceuticals.Karl E. Anderson reports receiving grant support and consulting fees from Alnylam Pharmaceuticals, Recordati Rare Diseases, Mitsubishi Tanabe, and Disc Medicine and consulting fees from Moderna Therapeutics.Gang Jia and Marianne T. Sweetser are employed by and own stock and stock options in Alnylam Pharmaceuticals.Bruce Wang reports receiving consulting fees from Alnylam Pharmaceuticals, Recordati Rare Diseases, Mitsubishi Tanabe Pharma, and Disc Medicine; receiving grant support from Alnylam Pharmaceuticals and Mitsubishi Tanabe Pharma; and being a scientific advisor to Alnylam Pharmaceuticals and Recordati Rare Diseases.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"365"}}