The year in lipids: Progress in Lp(a) management and a blow to the ‘HDL hypothesis’
Key takeaways:
- A speaker highlighted key advances in lipid treatment in 2024.
- Topics included triglyceride and lipoprotein(a) management as well as another setback to the “HDL hypothesis.”
In 2024, there were numerous trials and a few regulatory moves related to advancements in lipid management for the prevention of major adverse CV events.
At the Cardiometabolic Health Congress in October, Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, chief of the section of cardiovascular research and professor of medicine at Baylor College of Medicine, discussed the following developments in lipidology, in no particular order.
Managing triglycerides: Trials and regulatory moves
At the 2024 National Lipid Association Scientific Sessions, Ballantyne presented the results of the phase 3 BALANCE trial of olezarsen (Tryngolza, Ionis Pharmaceuticals), an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III, for patients with familial chylomicronemia syndrome (FCS).
Olezarsen reduced triglycerides at 6 months in patients with FCS without excessive adverse events, Ballantyne reported.
As Healio previously reported, based on these data, the FDA subsequently approved olezarsen in December for the treatment of FCS when used on top of an appropriate low-fat diet.
“If we look at the reduction in pancreatitis, it was really quite impressive, with a mean rate ratio being 0.12 for all of the patients. So it’s a therapy that is very effective targeting ApoC-III-lowering triglycerides,” Ballantyne said during the presentation.
Another novel RNA interference agent, plozasiran (Arrowhead Pharmaceuticals), was granted breakthrough therapy designation by the FDA on top of diet for the reduction of triglycerides in patients with FCS.
Granting of the breakthrough designation was based on the phase 3 top-line results of the PALISADE trial, also presented at the National Lipid Association in 2024. Read more in Healio’s coverage here.
The full phase 3 results of the PALISADE trial were presented at the 2024 European Society of Cardiology Congress, in which plozasiran reduced triglycerides and risk for pancreatitis in patients with persistent chylomicronemia.
Read Healio’s coverage of this trial.
Ballantyne also highlighted the results of two phase 2b trials of RNA interference agents for the reduction of triglycerides vs. placebo for patients with mixed hyperlipidemia: the final results of the MUIR trial of plozasiran and of the ARCHES-2 trial of zodasiran (Arrowhead Pharmaceuticals). Read more about the results of both trials here.
The year in PCSK9 inhibition
In June, AstraZeneca announced the interim results of its phase 1 trial of AZD0780, an oral small molecule PCSK9 inhibitor, which evaluated the safety and tolerability of the drug in healthy adults.
Ballantyne reported that AZD0780, after a rosuvastatin run-in period, was associated with a 52% reduction in LDL.
The phase 2b study of AZD0780 in adults with LDL between 70 mg/dL and 190 mg/dL was completed in September, but the results have not yet been reported, according to the presentation.
Ballantyne also highlighted the results of the LIBerate studies that evaluated monthly lerodalcibep (LIB003, LIB Therapeutics), an investigational biologic PCSK9 inhibitor and alternative to monoclonal antibodies.
The researchers reported that monthly lerodalcibep, when added on top of maximally tolerated oral lipid-lowering therapy, was associated with and maintained LDL reductions of more than 60% through 72 weeks among adults at high or very high CVD risk.
Also highlighted by Ballantyne was the FDA approval of alirocumab (Praluent, Sanofi/Regeneron) for patients aged 8 to 17 years with heterozygous familial hypercholesterolemia (HeFH) and LDL of 130 mg/dL or more already treated with LDL-lowering therapies.
Experimental cholesteryl ester transfer protein inhibitor
There are currently multiple ongoing trials evaluating the effects of obicetrapib 10 mg (NewAmsterdam Pharma) with HeFH and/or atherosclerotic CVD on maximally tolerated lipid-lowering therapies.
The results of the first of these trials — the BROOKLYN trial — were presented at the AHA Scientific Session in November 2024.
As Healio previously reported, among participants with HeFH and high LDL already taking optimal medical therapy, obicetrapib was associated with greater reductions compared with placebo.
Healio wrote about this trial as well as the top-line results of two others evaluating obicetrapib in patients with ASCVD or ASCVD risk factors and/or HeFH: TANDEM and BROADWAY. Check out our full coverage of all three trials.
In addition, Menarini Group, which has a license from NewAmsterdam Pharma to commercialize obicetrapib in Europe, announced the positive top-line data from the phase 3 BROADWAY trial in December, with significant LDL reduction of 33% (P < .0001) among participants assigned to obicetrapib monotherapy compared with placebo.
Lipoprotein(a): Discoveries and trial updates
Early in 2024, a novel genetic analysis published in the Journal of the American College of Cardiology showed that lipoprotein(a) was significantly more atherogenic compared with LDL per particle. Therefore, the researchers stated that Lp(a) may represent a key therapeutic target for the prevention of CHD.
“You’ve got to put this into perspective,” Ballantyne said. “A high level of Lp(a) would be about 250 nmol/L. If you have an LDL level that’s around 200 mg/L plus, that would be over 2,000 nmol/L. So there are a lot more LDL particles than Lp(a) particles. So reducing LDL is still the correct one for most people.”
Two therapeutic approaches to Lp(a) lowering are currently under investigation.
Injectable RNA-based therapies that prevent translation of LPA messenger RNA may block the production of ApoA used in Lp(a) synthesis.
Ballantyne first highlighted the small interfering RNA injection, zerlasiran, formerly known as SLN360 (Silence Therapeutics), for which the phase 2 results of the ALPACAR trial were presented at the 2024 AHA Scientific Sessions.
As Healio previously reported, zerlasiran lowered Lp(a) by more than 80% at 36 weeks compared with placebo in patients with an Lp(a) concentration of at least 125 mmol/L and stable ASCVD. Read Healio’s in-depth coverage.
Ballantyne also highlighted a second Lp(a) therapeutic currently under evaluation: oral small molecule inhibitor therapy. This approach is designed to prevent the formation of Lp(a) by not allowing the bonding of ApoA and ApoB100, according to the presentation.
The first oral small molecule inhibitor to show benefit in treating high Lp(a) was muvalaplin (Eli Lilly) in the KRAKEN trial, also presented at the 2024 AHA Scientific Sessions.
Among adults with elevated Lp(a) and high CV risk, muvalaplin was associated with a more than 80% reduction in Lp(a) at the highest dose over 12 weeks compared with placebo. Read Healio’s full coverage of the phase 2 results from the KRAKEN trial.
“We have a lot in the pipeline. Nothing approved for Lp(a) yet. We’re a little behind everybody else,” Ballantyne said.
Another blow to the ‘HDL hypothesis’
The “HDL hypothesis” was a theory that improving HDL function after MI can stabilize atherosclerotic plaque, thereby reducing risk for future events, according to C. Michael Gibson, MD,MS, interventional cardiologist, CV researcher and CEO of the combined nonprofit Baim and PERFUSE research institutes at Harvard Medical School, who presented the results of the AEGIS II trial at the 2024 ACC Scientific Session.
The AEGIS II trial tested the HDL hypothesis using the investigational infusion CSL112 (CSL Behring) to boost ApoA-I levels, increasing cholesterol efflux capacity and potentially improving HDL particles.
As Healio previously reported, enhancing HDL function did not reduce the composite primary endpoint of MI, stroke or CV death over 90 days of follow-up among adults with acute MI, multivessel disease and CV risk factors.
However, Ballantyne highlighted a post hoc analysis of the AEGIS II trial, published in the European Heart Journal, which showed that although the difference was not statistically significant, participants treated with CSL112 had numerically lower incidences of CV death and MI, type 1 MI and stent thrombosis-related MI compared with placebo.
References:
- AstraZeneca. A study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD0780 in healthy subjects. https://www.astrazenecaclinicaltrials.com/study/D7960C00001/. Published June 2024. Accessed Jan. 14. 2025.
- Björnson E, et al. J Am Coll Cardiol. 2024;doi:10.1016/j.jacc.2023.10.039.
- Gibson CM, et al. Eur Heart J. 2024;doi:10.1093/eurheartj/ehae614.
Collapse
Ballantyne CM. FDA update and late breaking trials. Presented at: Cardiometabolic Health Congress; Oct. 17-19, 2024; Boston.