RNA interference therapies safely lower atherosclerotic cholesterol
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Key takeaways:
- Three phase 2 trials demonstrated the efficacy and safety of RNA interference therapy for the treatment of mixed dyslipidemia.
- Two trials assessed ApoC-III inhibition and the third studied ANGPTL3 inhibition.
PHILADELPHIA — Three phase 2 trials, two of apolipoprotein C-III inhibition and one of angiopoietin-like protein 3 inhibition, demonstrated the efficacy and safety of dyslipidemia treatment via RNA interference.
The results of the SHASTA-2, MUIR and ARCHES-2 trials were presented at the American Heart Association Scientific Sessions.
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The SHASTA-2 trial
“Apolipoprotein C-III inhibits triglyceride clearance by reducing lipoprotein lipase-mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits ApoC-III messenger ribonucleic acid expression, lowering triglyceride levels,” Daniel Gaudet, MD, PhD, professor of medicine at Université de Montréal, and colleagues wrote in the background of a phase 1 study evaluating the safety of plozasiran, formerly ARO-APOC3 (Arrowhead Pharmaceuticals), published in NEJM Evidence, that served as the foundation of the three phase 2 trials discussed at the meeting.
For the randomized controlled phase 2b SHASTA-2 trial, Gaudet and colleagues enrolled 229 patients with severe hypertriglyceridemia and randomly assigned them 3:1 to subcutaneous plozasiran 10 mg, 25 mg or 50 mg, or placebo. Across the groups, the mean age ranged from 53 to 56 years and the percentage of women ranged from 15% to 28%.
The primary endpoint was percent change in fasting triglycerides from baseline to 24 weeks.
At 24 weeks, plozasiran was associated with reduced mean serum ApoC-III by up to 79% (P = .007), according to the presentation.
The median range in triglycerides was 598 mg/dL to 696 mg/dL.
Gaudet reported that triglycerides were reduced by 66% to 74% from baseline in the plozasiran group (P < .0001) and more than 90% of patients in the 25 mg dose and 50 mg dose groups achieved triglyceride levels of less than 500 mg/dL by week 4, which were sustained through week 24.
Fifty percent to 72% of participants in the plozasiran groups achieved a triglyceride level of less than 150 mg/dL, according to the presentation.
In addition, mean non-HDL was reduced up to 30% and mean serum HDL increased up to 68%.
The most common treatment-emergent adverse events were SARS-CoV-2 infection, headache and worsening glycemic control, according to the presentation.
“These data support further development of plozasiran in planned phase 3 programs for the treatment of [familial chylomicronemia syndrome and severe hypertriglyceridemia],” Gaudet said during the presentation. “Based on these results, RNA interference-mediated silencing of hepatic ApoC-III expression via plozasiran is a promising potential treatment for subjects with [severe hypertriglyceridemia].”
The MUIR trial
For the MUIR trial, Gaudet, Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, chief of the section of cardiovascular research and professor of medicine at Baylor College of Medicine, and colleagues evaluated the effects of plozasiran in patients with mixed dyslipidemia, defined as fasting triglycerides between 150 mg/dL and 499 mg/dL and either LDL of at least 70 mg/dL or non-HDL of at least 100 mg/dL.
Overall, 353 participants already on optimal lipid-lowering therapy were randomly assigned 3:1 to subcutaneous plozasiran or placebo at the same doses and duration as were used in the SHASTA-2 trial. The primary endpoint was also the same.
At 24 weeks, plozasiran was associated with reduced mean serum ApoC-III by up to 80% in a dose-dependent manner (P = .0001), according to the presentation.
From baseline, the mean reduction in triglycerides was 52% to 64% (P < .0001).
Additionally, non-HDL was reduced up to 27%, apolipoprotein B was reduced up to 19%, remnant cholesterol was reduced up to 55% and mean HDL increased by up to 51%.
The most common treatment-emergent adverse events were SARS-CoV-2 infection, worsening of glycemic control and upper respiratory infection, according to the presentation.
“The compelling data ... support the further development of plozasiran in phase 3 studies, including in patients with severe hypertriglyceridemia, and potentially in a clinical outcomes trial for patients with increased risk for atherosclerotic CVD due to elevated triglyceride-rich lipoproteins (TRLs),” Ballantyne said in a press release issued by Arrowhead. “Numerous epidemiologic studies have shown an association between higher TRLs and an increased risk of ASCVD. Despite potent LDL-C lowering therapies, residual ASCVD risk persists due in part to high levels of atherogenic TRLs. Importantly, plozasiran is the first investigational RNA [interference]-based molecule to demonstrate substantial reductions in TRLs in a mixed dyslipidemia population.”
The ARCHES-2 trial
For the phase 2 ARCHES-2 trial, Gaudet, Ballantyne and Robert S. Rosenson, MD, director of metabolism and lipids for the Mount Sinai Health System and professor of medicine in cardiology at the Icahn School of Medicine at Mount Sinai, and colleagues evaluated the effects of zodasiran, formerly ARO-ANG3 (Arrowhead Pharmaceuticals), designed to inhibit hepatic angiopoietin-like protein 3 (ANGPTL3) in patients with mixed dyslipidemia.
For ARCHES-2, mixed dyslipidemia carried the same definition as it did in the MUIR trial.
For the present trial, researchers enrolled patients with mixed dyslipidemia and randomly assigned them 3:1 to subcutaneous zodasiran 50 mg, 100 mg or 200 mg, or placebo. Participants received injections on day 1 and week 12 of the study and were followed out to week 24.
The primary endpoint was the same as for SHASTA-2 and MUIR.
At 24 week, zodasiran was associated with reductions in ANGPTL3 of up to 77%.
The researchers reported reductions in remnant cholesterol of up to 56%, ApoB up to 20%, LDL up to 19.9%, non-HDL up to 36.4%, lipoprotein(a) up to 20% and HDL up to 24.5%, according to the presentation.
Similar reductions in liver fat were observed in both the zodasiran and placebo groups.
The observed treatment-emergent adverse events were reported to be consistent with what was expected in this patient population.
“ARCHES-2 data demonstrate ARO-ANG3 significantly lowers [triglycerides], ANGPTL3 and atherogenic TRLs, LDL and total ApoB in patients with mixed dyslipidemia,” Rosenson and colleagues wrote in the conclusion section of their poster presentation. “The reductions in serum lipids and lipoproteins and favorable safety profile seen in ARCHES-2 support the potential of ARO-ANG3 to treat residual ASCVD risk in patients with elevated TRLs not at LDL-C goal.”
References:
- Ballantyne CM, et al. Abstract Mo3206. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
- Rosenson RS, et al. Abstract Mo3213. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
- Arrowhead presents new phase 2 data on plozasiran and zodasiran at AHA 2023. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-presents-new-phase-2-data-plozasiran-and-zodasiran-aha. Published Nov. 13, 2023. Accessed Nov. 28, 2023.
- Gaudet D, et al. NEJM Evid. 2023;doi:10.1056/EVIDoa2200325.
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Gaudet D, et al. Abstract 302. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
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