{"id":138316,"date":"2024-04-09T17:13:00","date_gmt":"2024-04-09T21:13:00","guid":{"rendered":"https:\/\/cardiologynownews.org\/?p=138316"},"modified":"2024-04-09T17:13:00","modified_gmt":"2024-04-09T21:13:00","slug":"shasta-2-novel-rnai-therapeutic-plozasiran-results-in-sustained-reduction-in-triglycerides-in-severe-hypertriglyceridemia","status":"publish","type":"post","link":"https:\/\/cardiologynownews.org\/?p=138316","title":{"rendered":"SHASTA 2: Novel RNAi Therapeutic Plozasiran Results in Sustained Reduction In Triglycerides in Severe Hypertriglyceridemia"},"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;\">Severe hypertriglyceridemia portends high risk of both CVD and acute pancreatitis, but there are limited effective treatment options.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">A novel RNA interference (RNAi) therapeutic plozasiran can reduce APOC3, a mediator of triglyceride elevation.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">In the Phase 2B trial SHASTA-2, two doses of plozasiran were compared with placebo in long-term (24 and 48 week) reduction of triglycerides and other cholesterol pathway mediators.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">All doses of plozasiran was well-tolerated and resulted in sustained reduction in triglycerides, APOC3, and remnant cholesterol with increased HDL-C by 24 weeks, with a still-significant but attenuated effect at 48 weeks.<\/span><\/li>\n<\/ul>\n<p><!--more--><\/p>\n<p><span style=\"font-weight: 400;\">Severe hypertriglyceridemia (SHTG) is characterized by triglyceride (TG) levels &gt;500 mg\/dL and is associated with high risk of cardiovascular events as well as pancreatitis. Unfortunately, there are limited treatment options that specifically target SHTG. In Phase 2 trials, the RNA interference (RNAi) therapeutic plozasiran (ARO-APOC3) successfully reduced APOC3, a mediatory of elevated triglycerides. In a breaking presentation at the 2024 ACC conference today, Dr. Daniel Gaudet <\/span><a href=\"https:\/\/eas-society.org\/contributor\/daniel-gaudet\/\"><span style=\"font-weight: 400;\">(University de Montreal)<\/span><\/a><span style=\"font-weight: 400;\"> and his team presented their study: \u201cSHASTA 2: A Double-blind, Phase 2b Placebo-Controlled, Dose Ranging Study Of Plozasiran In Subjects With SHTG.\u201d<\/span><\/p>\n<p><span style=\"font-weight: 400;\">The <\/span><a href=\"https:\/\/jamanetwork.com\/journals\/jamacardiology\/fullarticle\/2817469\"><span style=\"font-weight: 400;\">SHASTA-2<\/span><\/a><span style=\"font-weight: 400;\"> trial <\/span><a href=\"https:\/\/www.clinicaltrials.gov\/study\/NCT04720534\"><span style=\"font-weight: 400;\">(NCT04720534)<\/span><\/a><span style=\"font-weight: 400;\"> was a double-blind, placebo-controlled trial examining the efficacy and safety of plozasiran vs placebo in lowering TGs and the risk of acute pancreatitis. Participants were required to have a history of SHTG (TG &gt; 500 mg\/dL and fasting TG of 500-4,000 mg\/dL). Key exclusion criteria were active pancreatitis within 12 weeks, ACS within 24 weeks, or any planned coronary intervention. The primary outcome was % change in TG from baseline to weeks 24 and 48. Key secondary outcomes included percent change from baseline in APOC3, nonHDL-C, LDL-C, HDL-C, APOB, and remnant cholesterol.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">A total of 226 patients were 1:1:1:1 randomized to either pooled placebo or 10, 25, or 50 mg of plozasiran, respectively. Plozasiran was administered in two doses at 0 and 12 weeks. The mean age was 56, and 23% were women; the mean baseline APO3 level was 33 mg\/dL and the mean baseline TG level was 679 mg\/dL. Plozasiran resulted in a significant reduction in triglycerides and APOC3 at 24 and 48 weeks across all 3 doses (p&lt;0.001 for all). Specifically, individuals receiving plozasiran experienced a 66% reduction in TGs in the 10mg group, 70% reduction in the 25mg group, and 74% reduction in the 50mg group at 24 weeks relative to a 17% reduction in the placebo arm, with attenuated but still significant reduction at 48 weeks. The majority of patients achieved TG &lt;500mg\/dL by 24 weeks (88%, 93% and 91% for increasing doses of plozasiran, respectively, relative to 54% of the placebo arm). Maximum dose plozasiran also reduced LDL-C by 78% (p&lt;0.001), remnant cholesterol by 57% (p&lt;0.0001), and non-HDL-C by 22% (p=0.0001) by 24 weeks, in addition to raising HDL-C by 68% (p&lt;0.0001).\u00a0 Serious adverse events occurred in 16.4% of the placebo arm and 7.8% of individuals receiving plozasiran; none were deemed to be related to the treatment itself.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">When discussing the clinical implications of the study at the ACC conference, Dr. Gaudet stated: \u201cPlozasiran decreases mean serum APOC3, TGs, and remnant cholesterol while increasing HDL-C at 24 weeks for all dose levels\u2026with a favorable safety profile at 48 weeks\u2026these data support further development of plozasiran in planned phase 3 programs for the treatment of chylomicronemia and SHTG.\u201d<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Key Points: Severe hypertriglyceridemia portends high risk of both CVD and acute pancreatitis, but there are limited effective treatment options. A novel RNA interference (RNAi) therapeutic plozasiran can reduce APOC3, a mediator of triglyceride elevation. In the Phase 2B trial SHASTA-2, two doses of plozasiran were compared with placebo in long-term (24 and 48 week) [&hellip;]<\/p>\n","protected":false},"author":40603,"featured_media":138317,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[888,8],"tags":[889,45,47,185],"ppma_author":[1029],"class_list":{"0":"post-138316","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-acc-2024","8":"category-news","9":"tag-acc-2024","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\/138316","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=138316"}],"version-history":[{"count":1,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138316\/revisions"}],"predecessor-version":[{"id":138318,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138316\/revisions\/138318"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/138317"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=138316"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=138316"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=138316"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=138316"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}