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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Givosiran - LiverTox - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]">
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<meta name="citation_title" content="Givosiran">
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<meta name="citation_publisher" content="National Institute of Diabetes and Digestive and Kidney Diseases">
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<meta name="citation_date" content="2020/02/27">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK555105_"><span class="title" itemprop="name">Givosiran</span></h1><p class="fm-aai"><a href="#_NBK555105_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="Givosiran.OVERVIEW"><h2 id="_Givosiran_OVERVIEW_">OVERVIEW</h2><div id="Givosiran.Introduction"><h3>Introduction</h3><p>Givosiran is synthetic small interfering RNA (siRNA) molecule directed against 5-aminolevulinic acid synthase that is used to treat acute hepatic porphyria. Givosiran has been linked to mild-to-moderate ALT elevations during therapy, but has not been linked to instances of idiosyncratic acute liver injury with symptoms and jaundice.</p></div><div id="Givosiran.Background"><h3>Background</h3><p>Givosiran (giv” oh sir’ an) is a synthetic double stranded, small interfering RNA (siRNA) directed against 5-aminolevulinic acid synthase 1, which results in decreases in serum delta aminolevulinic acid (ALA) and porphobilinogen (PBG), intermediates in porphyrin metabolism which accumulate in patients with acute hepatic porphyrias and are believed to cause the neurologic and visceral symptoms of acute attacks. The siRNA molecule is covalently linked to three N-acetylgalactosamine residues which directs it to specific receptors found largely on hepatocytes. Once taken up by the hepatocyte, the siRNA is cleaved into smaller fragments and separated into single strands that bind and silence the mRNA of ALA synthase. In animal models, givosiran reduced ALA synthase mRNA levels in liver that was accompanied by a corresponding decline in urine and plasma ALA and PBG. In placebo controlled trials of givosiran in patients with recurring acute attacks, single infusions of givosiran resulted in dose related reductions in urinary ALA and PBG levels and, with monthly injections, annualized rates of attacks were reduced by 75% to 90%. Givosiran was approved for use in the United States for adults with acute hepatic porphyria in 2019. Current indications are limited to adults. Givosiran is available in solution in single dose vials of 189 mg/mL under the brand name Givlaari. The recommended regimen is 2.5 mg per kg body weight once monthly by subcutaneous injection. Givosiran is generally well tolerated but side effects can include nausea, injection site reactions, rash, fatigue and creatinine and serum aminotransferase elevations. Less common, but more severe side effects include severe injection reactions, anaphylaxis and recall reactions. In registration studies, immunogenicity was uncommon; only 1% of givosiran treated patients developed anti-drug antibodies.</p></div><div id="Givosiran.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>The acute hepatic porphyrias are rare, and the pivotal trials of givosiran were conducted in rather small numbers of patients, so the full spectrum of hepatotoxicity may not be fully known. Nevertheless, in the registration controlled trials, serum aminotransferase elevations arose in 13% of givosiran- versus 2% of placebo-recipients, but rose to levels above 5 times the upper limit of normal only rarely. One patient was reported as discontinuing givosiran therapy because of aminotransferase elevations, but no patient developed concurrent elevations in serum bilirubin or symptoms suggestive of hepatitis. Thus, givosiran has not been linked to instances of acute hepatitis or jaundice, but it has had limited clinical use.</p><p>Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).</p></div><div id="Givosiran.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>The cause of hepatic injury from the givosiran and other siRNA therapeutics is unknown. One possibility is that suppression of 5-aminolevulinic acid synthase may cause cell damage in some hepatocytes. The mRNA suppression appears to lower but not completely eliminate enzyme activity, but individual hepatocytes may vary in the sensitivity to the enzyme inhibition and effects of its loss. Givosiran is metabolized intracellularly by nucleases and is not a substrate of cytochrome P450 enzymes. On the other hand, the chronic inhibition of ALA synthase can result in decreases in CYP 1A2 and 2D6 synthesis and lead to supra-therapeutic or toxic levels of drugs that are metabolized by these enzymes.</p></div><div id="Givosiran.Outcome_and_Management"><h3>Outcome and Management</h3><p>The liver injury associated with givosiran therapy has invariably been mild, not associated with jaundice and rapidly resolving often without discontinuation or even dose adjustment. In prelicensure clinical trials, subjects received hemin therapy for acute attacks without evidence of liver injury, and there is no reason to suspect cross reactivity of hepatic injury with other therapies of acute porphyria. Monitoring of liver tests during therapy is recommended during givosiran therapy as well as interruption or discontinuation for significant elevations in serum aminotransferases.</p><p>Drug Class: Genetic Disorder Agents</p><p>Other Therapeutic siRNA and Antisense Agents: Eteplirsen, Golodirsen, Patisiran</p></div></div><div id="Givosiran.PRODUCT_INFORMATION"><h2 id="_Givosiran_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Givosiran – Givlaari®</p><p>
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<b>DRUG CLASS</b>
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</p><p>Genetic Disorder Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
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</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div><div id="Givosiran.CHEMICAL_FORMULA_AND_STRUCTURE"><h2 id="_Givosiran_CHEMICAL_FORMULA_AND_STRUCTURE_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figGivosiranTc"><a href="/books/NBK555105/table/Givosiran.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figGivosiranTc" rid-ob="figobGivosiranTc"><img class="small-thumb" src="/books/NBK555105/table/Givosiran.Tc/?report=thumb" src-large="/books/NBK555105/table/Givosiran.Tc/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="Givosiran.Tc"><a href="/books/NBK555105/table/Givosiran.Tc/?report=objectonly" target="object" rid-ob="figobGivosiranTc">Table</a></h4></div></div></div><div id="Givosiran.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Givosiran_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 27 February 2020</p><p>Abbreviations: ALA, aminolevulinic acid; ALAS, aminolevulinic acid synthetase; PBG, porphobilinogen; siRNA, small interfering RNA.</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Givosiran.REF.yasuda.2014.7777">Yasuda M, Gan L, Chen B, Kadirvel S, Yu C, Phillips JD, New MI, et al. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2014;<span class="ref-vol">111</span>:7777–82.</span> [<a href="/pmc/articles/PMC4040563/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4040563</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24821812" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24821812</span></a>]<div>
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<i>(Screening of multiple small interfering RNAs [siRNA] for activity in suppressing aminolevulinic acid synthetase [ALAS] in cell culture identified several with potent activity which were formulated into lipid nanoparticles and shown to lower ALAS activity and decrease serum levels of aminolevulinic acid (ALA) and porphobilinogen (PBG) in mice and to protect against acute attacks of porphyria in mouse models of the disease).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.bonkovsky.2014.1233">Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, Phillips JD, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. <span><span class="ref-journal">Am J Med. </span>2014;<span class="ref-vol">127</span>:1233–41.</span> [<a href="/pmc/articles/PMC4563803/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4563803</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25016127" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25016127</span></a>]<div>
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<i>(Among 108 subjects with acute porphyria enrolled in a U.S. prospective clinical cohort study, 90 had acute intermittent porphyria, 9 hereditary coproporphyria and 9 variegate porphyria; most were women [81%], non-Hispanic and white, and delay in diagnosis after onset of symptoms was common [mean delay=15 years]).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.bissell.2015.313">Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. <span><span class="ref-journal">Am J Med. </span>2015;<span class="ref-vol">128</span>:313–7.</span> [<a href="/pmc/articles/PMC4339446/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4339446</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25446301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25446301</span></a>]<div>
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<i>(32 year old woman using several Ayurvedic medications developed recurrent abdominal pain and had elevations in serum ALA but not PBG, subsequent testing demonstrating lead poisoning and symptoms improving with hemin infusions but ultimately resolving after chelation of excess lead; these results suggest that ALA rather than PBG is the cause of neurologic and visceral symptoms in acute hepatic porphyria).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.chalasani.2015">Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52e7. [<a href="/pmc/articles/PMC4446235/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4446235</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25754159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25754159</span></a>]<div><i>(Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to siRNA therapies or medications for porphyria).</i></div></div></li><li><div class="bk_ref" id="Givosiran.REF.sardh.2019.549">Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, Desnick R, et al. Phase 1 Trial of an RNA interference therapy for acute intermittent porphyria. <span><span class="ref-journal">N Engl J Med. </span>2019;<span class="ref-vol">380</span>:549–58.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30726693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30726693</span></a>]<div>
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<i>(A phase 1 trial of ascending, single doses of givosiran followed by studies of the two optimal doses vs placebo either once monthly or quarterly in 40 patients with acute intermittent porphyria demonstrated rapid and marked declines in urinary ALA and PBG levels and decreases in annualized acute attack rates of 75-90%; there were no liver related severe adverse events and “no clinically significant changes in laboratory measures”).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.setten.2019.421">Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. <span><span class="ref-journal">Nat Rev Drug Discov. </span>2019;<span class="ref-vol">18</span>:421–46.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30846871" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30846871</span></a>]<div>
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<i>(Extensive review of gene silencing using RNA interference pathways and the potential of RNAi therapeutics which have promise in many genetic and acquired diseases including transthyretin amyloidosis [transthyretin], HIV infection [CCR5], HBV [HBV mRNA], alpha-1-antitrypsin deficiency [zz A1AT], hypercholesterolemia [PCSK9]).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.chen.2019.2605">Chen B, Whatley S, Badminton M, Aarsand AK, Anderson KE, Bissell DM, Bonkovsky HL, et al. International Porphyria Molecular Diagnostic Collaborative. an evidence-based database of verified pathogenic and benign variants for the porphyrias. <span><span class="ref-journal">Genet Med. </span>2019;<span class="ref-vol">21</span>:2605–13.</span> [<a href="/pmc/articles/PMC7229570/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7229570</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31073229" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31073229</span></a>]<div>
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<i>(Announcement of a collaborative international effort to define phenotypes and genotypes of the 4 acute hepatic porphyrias, 3 being autosomal dominant [acute intermittent porphyria, hereditary coproporphyria and variegate porphyria] and 1 autosomal recessive, the genetic variation and clinical expression of each being highly variable).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.gouya.2019">Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, Phillips JD, et al. EXPLORE: A prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. <span><span class="ref-journal">Hepatology. </span>2019 Sep 12;</span> [Epub ahead of print] [<a href="/pmc/articles/PMC7255459/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7255459</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31512765" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31512765</span></a>]<div>
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<i>(Among 112 patients with acute hepatic porphyria and recurrent attacks followed for at least 6 months, 98 [88%] had a total of 483 attacks, 371 [77%] requiring hemin therapy and, compared to baseline, urinary levels of ALA, PBG and ALAS mRNA increased during acute attacks).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.naik.2020.590">Naik H, Overbey JR, Montgomery GH, Winkel G, Balwani M, Anderson KE, Bissell DM, et al. Evaluating the patient-reported outcomes measurement information system scales in acute intermittent porphyria. <span><span class="ref-journal">Genet Med. </span>2020;<span class="ref-vol">22</span>:590–7.</span> [<a href="/pmc/articles/PMC7060090/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7060090</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31690837" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31690837</span></a>]<div>
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<i>(Analysis of symptom scores in a cohort of 259 patients [75% with symptoms] with acute intermittent porphyria).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.scott.2020.335">Scott LJ. Givosiran: first approval. <span><span class="ref-journal">Drugs. </span>2020;<span class="ref-vol">80</span>:335–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/32034693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32034693</span></a>]<div>
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<i>(Review of the mechanism of action, history of development, clinical efficacy and safety of givosiran shortly after its approval for use in acute hepatic porphyria in the US and Europe mentions that in the registration trial, the median composite annualized attack rate at 6 months was decreased by 90% and adverse events in treated vs control subjects included nausea [27% vs 11%], injection site reactions [25% vs 0%], rash [17% vs 4%], creatinine increase [15% vs 4%], aminotransferase elevations [13% vs 2%] and fatigue [10% vs 4%]).</i>
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</div></div></li><li><div class="bk_ref" id="Givosiran.REF.givosiran.2019">FDA. Givosiran. Multi-Disciplinary Review and Evaluation. 2019. Available at: <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212194Orig1s000MultidisciplineR.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.accessdata<wbr style="display:inline-block"></wbr>​.fda.gov/drugsatfda_docs<wbr style="display:inline-block"></wbr>​/nda/2019/212194Orig1s000MultidisciplineR.pdf</a>.<div><i>(The FDA clinical review of givosiran for efficacy and safety reported ALT elevations above 3 times ULN arose in 6 of 48 [13%] givosiran treated vs 1 of 46 [2%] controls, one patient discontinuing therapy because of enzyme elevations after 3 doses [ALT 172 U/L, AST 95 U/L] which reportedly resolved rapidly upon stopping).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK555105_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">February 27, 2020</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="https://www.niddk.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute of Diabetes and Digestive and Kidney Diseases</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Givosiran. [Updated 2020 Feb 27].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Ginseng/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/livertox/Glasdegib/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobGivosiranTc"><div id="Givosiran.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK555105/table/Givosiran.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Givosiran.Tc_lrgtbl__"><table><tbody><tr><th id="hd_b_Givosiran.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_b_Givosiran.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAS REGISTRY NO</th><th id="hd_b_Givosiran.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_b_Givosiran.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">STRUCTURE</th></tr><tr><td headers="hd_b_Givosiran.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Givosiran</td><td headers="hd_b_Givosiran.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/313371338" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1639325-43-1</a>
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</td><td headers="hd_b_Givosiran.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C78-H139-N11-O30</td><td headers="hd_b_Givosiran.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/313371338" title="View this structure in PubChem" class="img_link" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem"><img src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&sid=313371338" alt="image 313371338 in the ncbi pubchem database" /></a>
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