{"id":138200,"date":"2023-11-15T14:04:10","date_gmt":"2023-11-15T19:04:10","guid":{"rendered":"https:\/\/cardiologynownews.org\/?p=138200"},"modified":"2023-11-15T14:04:10","modified_gmt":"2023-11-15T19:04:10","slug":"novel-rna-interference-therapeutic-zilebesiran-results-in-dose-dependent-sustained-bp-reduction","status":"publish","type":"post","link":"https:\/\/cardiologynownews.org\/?p=138200","title":{"rendered":"Novel RNA interference therapeutic Zilebesiran results in dose-dependent sustained BP reduction"},"content":{"rendered":"<p><span style=\"font-weight: 400;\">Key Points:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Uncontrolled hypertension is a major public health concern, and this condition is often primarily driven by the renin-angiotensin (RAAS) pathway.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">A new RNA interference therapy, Zilebesiran, was developed to target to most upstream precursor of the RAAS pathway (angiotensinogen). This study was a Phase 2 study examining the safety and efficacy of zilebesiran.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">A single dose of subcutaneous zilebesiran resulted in sustained BP reduction with low rates of adverse events over 6 months.<\/span><\/li>\n<\/ul>\n<p><!--more--><\/p>\n<p><span style=\"font-weight: 400;\">Uncontrolled hypertension is a major contributor to long-term morbidity and mortality, with major contributions from the renin-angiotensin system (RAAS). There has yet to be a therapy directly targeting angiotensinogen (AGT), the most upstream precursor of the RAAS pathway. In a breaking presentation at the 2023 AHA Scientific Sessions today,\u00a0 <\/span><a href=\"https:\/\/www.uchicagomedicine.org\/find-a-physician\/physician\/george-bakris\"><span style=\"font-weight: 400;\">Dr. George Bakris (University of Chicago)<\/span><\/a><span style=\"font-weight: 400;\"> and his team presented their study: \u201cSustained BP reduction with the RNA interference therapeutic, Zilebesiran,\u201d or the KARDIA-1 study.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">The KARDIA-1 study <\/span><a href=\"https:\/\/clinicaltrials.gov\/study\/NCT04936035\"><span style=\"font-weight: 400;\">(NCT04936035)<\/span><\/a><span style=\"font-weight: 400;\"> randomized 394 adults (18-75 years) with a daytime mean sBP 135-160 mm Hg by ambulatory BPM, after washout of prior antihypertensive medication for 2-4 weeks prior to enrollment. Relevant exclusion criteria were secondary hypertension, elevated liver enzymes, hyperkalemia, and eGFR &lt;30ml\/min. Patients were randomized 1:1:1:1:1 to placebo and zilebesiran doses of 150mg q6M SC, 300mg q6M SC, 300mg q3M SC, and 600mg q6M SC. The primary outcome was change from baseline at month 3 in 24-hour ambulatory SBP. Secondary outcomes included change from baseline at month 6 in 24-hour ambulatory SBP, change from baseline in office SBP at month 3 or 6, and proportion of patients with 24-hour mean SBP &lt;130mm Hg or reduction \u2265 20 mm Hg at month 6, without additional antihypertensives. Safety endpoints (frequency of adverse events) were also observed.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">The median age was 57, with 44% women. A sustained, dose-dependent reduction in serum angiotensinogen, AGT, was observed through 6 months, with a peak reduction observed at 2 months. At 6 months, there were reductions of 88% for 150mg q6<\/span> <span style=\"font-weight: 400;\">M, 93% for 300mg q6M, 98% for 300mg q3M, and 96% for 600mg q6M. At 6 months there were also sustained BP reductions observed across all doses compared to placebo, with observed reductions of 11.1 (-15.8, -6.4) mm Hg, 14.5 (-19.1, -9.9) mm Hg, 14.1 (-18.9, -9.4) mm Hg, and 14.2 -18.9, -9.5) mm Hg observed for escalating doses of zilebesiran (all p&lt;0.05). Similar results were obtained for office SBP readings at 6 months (p&lt;0.05 for all doses). The proportion of patients achieving a 24-hour mean SBP &lt;130mm Hg or reduction \u2265 20 mm Hg at month 6 was higher across all doses (all p&lt;0.05). Zilebesiran also had a favorable safety profile over 6 months, with no serious or severe drug-related adverse events noted. Drug-related adverse events which resulted in drug discontinuation included orthostatic hypotension (n=2), ISR (n=1), and BP elevation (n=1).<\/span><\/p>\n<p><span style=\"font-weight: 400;\">When discussing the clinical implications of the study at the Scientific Sessions, Dr. Bakris stated: \u201cIn KARDIA-1, single subcutaneous doses of zilebesiran resulted in clinically meaningful and significant reductions in 24-hour mean SBP compared with placebo at Month 3, that were sustained through Month 6\u2026these data further support the potential for quarterly or biannual dosing of SC zilebesiran in achieving a consistent pharmacodynamic effect and effective BP reduction through 6 months\u2026..it is being further evaluated as an add-on therapy for the treatment of hypertension in the ongoing KARDIA-2 study.\u201d<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Key Points: Uncontrolled hypertension is a major public health concern, and this condition is often primarily driven by the renin-angiotensin (RAAS) pathway. A new RNA interference therapy, Zilebesiran, was developed to target to most upstream precursor of the RAAS pathway (angiotensinogen). This study was a Phase 2 study examining the safety and efficacy of zilebesiran. [&hellip;]<\/p>\n","protected":false},"author":40603,"featured_media":138201,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[883,8],"tags":[885,45,47,185],"ppma_author":[1029],"class_list":{"0":"post-138200","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-aha-2023","8":"category-news","9":"tag-aha-2023","10":"tag-conference","11":"tag-featured","12":"tag-news","13":"author-leah-kosyakovsky"},"authors":[{"term_id":1029,"user_id":40603,"is_guest":0,"slug":"leah-kosyakovsky","display_name":"Leah Kosyakovsky","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/864bde69f6f1f80e91e4a97f0a0ba8daa64c2bb702be09ed787444c7dfa045bb?s=96&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138200","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/users\/40603"}],"replies":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=138200"}],"version-history":[{"count":1,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138200\/revisions"}],"predecessor-version":[{"id":138202,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138200\/revisions\/138202"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/138201"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=138200"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=138200"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=138200"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=138200"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}