Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial
Open accessAbstract
BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C–lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was −1.68% (95% CI, −29.19% to 25.83%; P =0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was −60.6% with inclisiran treatment ( P <0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non−high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03851705.
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Inclisiran improved multiple lipid parameters including non-HDL-C, apoB, triglycerides, and lipoprotein(a) in addition to LDL-C.
“Inclisiran improved multiple lipid parameters including non-HDL-C, apoB, triglycerides and lipoprotein(a) in addition to LDL-C which makes it beneficial for complete lipid management [39, 43, 49].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [43]
In ORION-5 patients with homozygous familial hypercholesterolemia, the Results (Primary End Point) found no statistically significant LDL-C benefit over placebo. The Results (Other Secondary End Points) likewise found no statistically significant differences for apoB, non-HDL-C, or lipoprotein(a) at any time point. These findings run contrary to the unqualified claim that inclisiran improved those lipid parameters; the cited passages do not report a triglyceride benefit. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe lack of significant LDL-C reduction in ORION-5 was because most participants had either completely or nearly no LDL receptor function.
“The overall LDL-C reduction was not statistically significant at −1.68% (P = 0.90) because most participants had either completely or nearly no LDL receptor function [43].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [43]
The Results (Primary End Point; page unavailable) report −1.68% (P=0.90), with no statistically significant LDL-C reduction. The Discussion (page unavailable) says genetic variation and an imbalance in null/null patients might have affected the result, not that this was the established cause. It reports 13 null/null patients among 56, so it does not support the claim that most participants had little or no LDL receptor function. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe overall LDL-C reduction in ORION-5 was not statistically significant at −1.68% (P = 0.90).
“The overall LDL-C reduction was not statistically significant at −1.68% (P = 0.90) because most participants had either completely or nearly no LDL receptor function [43].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [43]
The Results (Primary End Point; page unavailable) report the exact placebo-corrected LDL-C change of −1.68% (P=0.90) and say it was not statistically significant. The citing sentence’s explanation is not supported: the Discussion reports 13 null/null patients, not most participants, and says their uneven distribution between groups might have confounded the result rather than establishing its cause. (LLM, conf=0.91)
Experimental — accuracy not yet measuredThe analysis of 11 RCTs for quantitative synthesis included more than 13,000 participants and showed inclisiran produces significant LDL-C reduction versus placebo treatment.
“The analysis of 11 RCTs for quantitative synthesis included more than 13,000 participants showed inclisiran produces significant LDL-C reduction versus placebo treatment [24, 25, 38–44, 46, 49].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [43]
The Methods identify ORION-5 as a randomized, placebo-controlled inclisiran trial in 56 patients, so it supports citing this paper as one trial relevant to the synthesis. It does not report an analysis of 11 RCTs or more than 13,000 participants. Its Results > Primary End Point instead found no statistically significant LDL-C difference between inclisiran and placebo (P=0.90); that individual result does not establish or rule out the claimed pooled result. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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- Authors
- Raal, F., Durst, R., Bi, R., Talloczy, Z., Maheux, P., Lesogor, A., Kastelein, J. J. P., & on behalf of the ORION-5 Study Investigators
- Affiliations
- University of the Witwatersrand (ZA)
- Hebrew University of Jerusalem (IL)
- Novartis Pharmaceuticals Corporation, East Hannover, NJ (R.B., Z.T.).
- Novartis (Switzerland) (CH)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Raal, Frederick
- Venue
- Circulation
- Published
- 2024-01-30
- Volume
- 149
- Issue
- 5
- Pages
- 354-362
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC10815002
- OpenAlex
- W4387728648
- Cited by
- 96
- References
- 27
- Citations by year
- 2026: 33 · 2025: 30 · 2024: 32 · 2023: 1
- FWCI
- 25.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Circulation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Funders
- Novartis Pharma
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- homozygous familial hypercholesterolemia, PCSK9 inhibition, siRNA, LDL cholesterol lowering, statins, ezetimibe, lipoprotein apheresis, cardiovascular risk, treatment efficacy and safety, tolerability
- MeSH terms
- Proprotein Convertase 9, Homozygous Familial Hypercholesterolemia, Adult, Anticholesteremic Agents, Cholesterol, Female, Humans, Cholesterol, LDL, Male, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Small Interfering
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