{"id":140006,"date":"2026-11-13T18:49:58","date_gmt":"2026-11-13T23:49:58","guid":{"rendered":"https:\/\/cardiologynownews.org\/?p=140006"},"modified":"2026-11-13T18:49:59","modified_gmt":"2026-11-13T23:49:59","slug":"aro-dimer-pa-ldl-c-and-triglycerides-fall-after-one-dose-of-pcsk9-apoc3-sirna-in-phase-1-study","status":"publish","type":"post","link":"https:\/\/cardiologynownews.org\/?p=140006","title":{"rendered":"ARO-DIMER-PA: LDL-C and Triglycerides Fall After One Dose of PCSK9\/APOC3 siRNA in Phase 1 Study"},"content":{"rendered":"\n<ul class=\"wp-block-list\">\n<li>ARO-DIMER-PA (Arrowhead Pharmaceuticals) is a liver-targeted small interfering RNA (siRNA) conjugate designed to silence both PCSK9 and APOC3 with one molecule.<\/li>\n\n\n\n<li>In the single-ascending-dose part of a phase 1\/2a trial, 31 adults with mixed hyperlipidemia received one dose of ARO-DIMER-PA (25 to 400 mg; n=21) or placebo (n=10).<\/li>\n\n\n\n<li>Across the five dose cohorts, mean LDL-C reductions from baseline ranged from 26% to 65%, and median triglyceride reductions ranged from 56% to 78%.<\/li>\n\n\n\n<li>No serious adverse events occurred; injection-site erythema occurred in 20 of 21 participants on ARO-DIMER-PA, and the only grade 3 event, syncope, followed a 400-mg dose.<\/li>\n<\/ul>\n\n\n\n<p>LDL-C fell by a mean of 26% to 65% and triglycerides by a median of 56% to 78% from baseline across five dose cohorts after a single dose of ARO-DIMER-PA in adults with mixed hyperlipidemia. The investigational siRNA is designed to silence both PCSK9 and APOC3. Luke Laffin, MD (Cleveland Clinic, OH), presented the phase 1 results at the American Heart Association (AHA) Scientific Sessions on November 7, 2026. The results have not yet been published in a peer-reviewed journal. &nbsp;<\/p>\n\n\n\n<p>Mixed hyperlipidemia involves elevated LDL-C and elevated triglyceride-rich lipoproteins, and current treatment typically requires more than one therapy, according to the investigators. PCSK9 promotes degradation of the LDL receptor. APOC3 inhibits the breakdown of triglyceride-rich lipoproteins by lipoprotein lipase and their clearance by the liver. Arrowhead&#8217;s plozasiran, a siRNA that targets APOC3 alone, is approved for familial chylomicronemia syndrome.<\/p>\n\n\n\n<p>The single-ascending-dose part of the randomized, double-blind, placebo-controlled phase 1\/2a trial (NCT07223658) enrolled adults with fasting triglycerides of 150 to 499 mg\/dL. Screening TG levels of 100\u2013149 mg\/dL were also permitted with a verifiable historical TG level of 150\u2013499 mg\/dL. Inclusion also required non-HDL cholesterol of at least 100 mg\/dL or LDL-C of at least 70 mg\/dL. Within each of five cohorts, participants were randomized 2:1 to a single dose of ARO-DIMER-PA (25, 50, 100, 200, or 400 mg) or placebo. A safety review on day 15 or day 30 preceded each dose escalation. The primary endpoint was the incidence, frequency, and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints were changes from baseline in PCSK9, APOC3, LDL-C, and triglycerides. Participants were enrolled at 11 sites in Australia, New Zealand, and Georgia in eastern Europe. The trial was sponsored by Arrowhead, and five of the 17 authors list Arrowhead as their affiliation.<\/p>\n\n\n\n<p>Of the 31 participants, 21 received ARO-DIMER-PA (four each at 25, 50, and 100 mg, six at 200 mg, and three at 400 mg) and 10 received placebo. Mean baseline LDL-C was 135 mg\/dL, and median baseline triglycerides were 170 mg\/dL. Five participants were taking a statin at baseline.<\/p>\n\n\n\n<p>No serious adverse events, grade 4 or 5 events, or deaths occurred. All 21 participants on ARO-DIMER-PA and 9 of 10 on placebo had at least one TEAE. Injection-site erythema occurred in 20 participants on ARO-DIMER-PA and in none on placebo. Pyrexia occurred in seven participants and headache in nine, all at doses of 100 mg or higher. The only participant with a grade 3 event had syncope 6 hours after a 400-mg dose, and another participant at 400 mg had a grade 2 influenza-like illness. High-sensitivity C-reactive protein increased early after dosing in several cohorts, most at day 2 in the 400-mg cohort, without sustained elevation. No participant met Hy&#8217;s law criteria, a measure of hepatic injury. The investigators concluded that tolerability was less favorable at 400 mg.<\/p>\n\n\n\n<p>Mean reductions from baseline ranged from 50% to 89% for PCSK9 and from 43% to 95% for APOC3. Mean reductions ranged from 32% to 66% for apolipoprotein B and from 52% to 73% for remnant cholesterol. Mean LDL-C reductions from baseline ranged from 26% to 65%. Each cohort had three to six participants on ARO-DIMER-PA. In the 400-mg cohort, LDL-C data is limited to two participants through day 29 and one at day 43, while LDL-C data for the other cohorts were available through day 85<\/p>\n\n\n\n<p>The phase 2b MUIR trial used the same lipid entry criteria and randomized 353 participants (Ballantyne et al., <em>New England Journal of Medicine<\/em>, 2024). Two doses of plozasiran 12 weeks apart lowered fasting triglycerides at week 24 by 49.8 to 62.4 percentage points more than placebo. At the same AHA meeting, a first-in-human study of FB7023, an siRNA that targets PCSK9 and LPA, reported mean LDL-C reductions of 34.9% and 38.5% at week 8.<\/p>\n\n\n\n<p>The investigators stated that longer-term studies are needed to establish optimal dosing and to characterize safety, durability of effect, and potential cardiovascular benefit. The results for this trial&#8217;s multiple-dose part, with four cohorts of 12 participants dosed on day 1 and week 12, are still awaited.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>LDL-C fell by a mean of 26% to 65% and triglycerides by a median of 56% to 78% from baseline across five dose cohorts after a single dose of ARO-DIMER-PA in adults with mixed hyperlipidemia. The investigational siRNA is designed to silence both PCSK9 and APOC3. Luke Laffin, MD (Cleveland Clinic, OH), presented the phase [&hellip;]<\/p>\n","protected":false},"author":40604,"featured_media":140007,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"aside","meta":{"footnotes":"","_ppma_block_editor_authors":""},"categories":[1093,8],"tags":[1096,47,185],"tmauthors":[1085],"ppma_author":[1031],"class_list":{"0":"post-140006","1":"post","2":"type-post","3":"status-publish","4":"format-aside","5":"has-post-thumbnail","7":"category-aha-2026","8":"category-news","9":"tag-aha-2026","10":"tag-featured","11":"tag-news","12":"post_format-post-format-aside","13":"author-basir-gill"},"authors":[{"term_id":1031,"user_id":40604,"is_guest":0,"slug":"basir-gill","display_name":"Basir Gill MD","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/05064ea2c277f8906826ab0662151459a584dc4b50046758e59dbf39135256c6?s=96&r=g","avatar_alt":"","avatar_decorative":"","author_category":"1","first_name":"Basir","last_name":"Gill","user_url":"","job_title":"Clinical Specialist, Baim Institute for Clinical Research","description":""}],"_links":{"self":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/140006","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\/40604"}],"replies":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=140006"}],"version-history":[{"count":1,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/140006\/revisions"}],"predecessor-version":[{"id":140008,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/140006\/revisions\/140008"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/140007"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=140006"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=140006"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=140006"},{"taxonomy":"tmauthors","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftmauthors&post=140006"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=140006"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}