Successful early studies reported for two Lp(a)-lowering therapies
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Key takeaways:
- Muvalaplin, the first oral therapy developed to lower lipoprotein(a), did so in a phase 1 study.
- An extended phase 2 study of olpasiran showed it lowered Lp(a) for nearly 1 year after final dose.
The first oral treatment to lower lipoprotein(a) safely lowered Lp(a) in a phase 1 study, whereas an extended phase 2 study showed durable Lp(a) lowering by an injectable treatment, researchers reported.
Results of the phase 1 study of muvalaplin (Eli Lilly) and the extension of the phase 2 OCEAN(a)-DOSE study of olpasiran (Amgen) were presented at the European Society of Cardiology Congress.
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Muvalaplin phase 1 study
Muvalaplin is an oral investigational selective small molecule inhibitor of Lp(a) formation that works by blocking the interaction between apolipoprotein(a) and apolipoprotein B-100, Stephen J. Nicholls, MBBS, PhD, director of the Victorian Heart Hospital and Institute and professor of cardiology at Monash University in Melbourne, Australia, said during a presentation.
“Lp(a) therapies that are in clinical development involve injectable agents that target Apo(a) mRNA,” Nicholls said during the presentation. “Muvalaplin is the first oral agent specifically developed to lower Lp(a) levels.”
For the phase 1 study, simultaneously published in JAMA, the researchers enrolled 114 participants. The single-ascending dose portion included 55 people with any Lp(a) level (mean age, 29 years; 64% women; mean Lp(a) at baseline, 10.3 mg/dL) who were randomly assigned on a 6:2 basis to muvalaplin 1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, 800 mg or placebo. The multiple-ascending dose portion included 59 people (mean age, 32 years; 58% women) with Lp(a) at least 30 mg/dL (mean at baseline, 58.3 mg/dL) who were randomly assigned to once per day for 14 days muvalaplin 30 mg, 100 mg, 300 mg, 500 mg, 800 mg or placebo.
Nicholls and colleagues observed no tolerability issues or clinically significant adverse effects associated with muvalaplin.
The range of elimination half-life of muvalaplin went from 70.9 hours in the 30 mg group to 414 hours in the 500 mg group, according to the researchers.
Muvalaplin lowered Lp(a) levels within 24 hours of first dose, with greater reductions on repeated dosing, Nicholls and colleagues found. The maximum placebo-adjusted Lp(a) reduction was 63% to 65% at doses of muvalaplin 100 mg or more on days 14 and 15, and Lp(a) returned to baseline levels by day 29 for the 30 mg dose, day 43 for the 100 mg dose and day 64 for the doses of 300 mg or higher, according to the researchers, who found that 93% of participants with elevated Lp(a) who were given high doses of muvalaplin achieved Lp(a) less than 50 mg/dL.
Muvalaplin did not affect levels of LDL, HDL, total cholesterol, triglycerides or ApoB, and did not significantly impact plasminogen levels or activity, Nicholls said during the presentation.
“Muvalaplin disrupts interaction between ApoA and ApoB and is the first once-daily oral agent developed to specifically lower Lp(a) levels,” Nicholls said during the presentation. “Muvalaplin resulted in dose-dependent lowering of Lp(a) of up to 65% with no discernible effects on plasminogen activity. An ongoing phase 2 study is assessing muvalaplin in patients with elevated Lp(a) levels, and the longer-term impact of muvalaplin on Lp(a) and cardiovascular outcomes will require additional studies.”
OCEAN(a)-DOSE extended study
Michelle L. O’Donoghue, MD, MPH, cardiovascular medicine specialist and senior investigator of the TIMI Study Group at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, presented findings from an extension period of the phase 2 OCEAN(a)-DOSE study of olpasiran, an injectable small interfering RNA agent directed to the liver, in patients with atherosclerotic CVD and elevated Lp(a).
As Healio previously reported, in the 36-week on-treatment results of OCEAN(a)-DOSE, olpasiran 75 mg or greater dosed subcutaneously every 12 weeks reduced Lp(a) concentration by more than 95%.
The goals of the study, O’Donoghue said, “were to examine the effects of olpasiran on levels of oxidized phospholipids on apolipoprotein B-100, to examine the effects of olpasiran on Lp(a) concentration after administration of the last dose, and to examine the extended safety profile of olpasiran, again after last dose.”
The median follow-up time was 86 weeks from randomization (50 weeks after last administered dose). The overall cohort included 281 patients (mean age, 62 years; 32% women; median Lp(a) at baseline, 261 nmol/L).
The researchers observed a dose-dependent effect “such that patients on higher doses of olpasiran at both week 36 and week 48 had more than a 90% reduction in oxidized phospholipids on apolipoprotein B,” O’Donoghue said.
At nearly 1 year after the last dose, Lp(a) levels remained approximately 40% to 50% lower in patients given the higher doses of olpasiran, “so the effects on Lp(a) remained quite sustained over time,” she said.
During the extension period, adverse events did not differ among groups and there was no increase in serious adverse events in the olpasiran groups, O’Donoghue said, noting that safety data combined from the treatment period and the extended period did not suggest “an imbalance of adverse events between active groups and placebo, other than the previously reported mild injection-site reactions.”
“Olpasiran leads to a marked and durable reduction in pro-atherogenic oxidized phospholipid species on apolipoprotein B,” O’Donoghue said during the presentation. “Subjects who were dosed at 75 mg or greater every 12 weeks sustained a 40% to 50% placebo-adjusted reduction in Lp(a) concentration close to 1 year after the last dose.”
She said the phase 3 OCEAN(a)-OUTCOMES trial evaluating the long-term clinical safety and efficacy of olpasiran has begun.
References:
- Nicholls SJ, et al. JAMA. 2023;doi:10.1001/jama.2023.16503.
- O’Donoghue ML, et al. Clinical trial updates on prevention and lipid lowering. Presented at: European Society of Cardiology Congress; Aug. 25-28, 2023; Amsterdam (hybrid meeting)
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Nicholls SJ, et al. Late-breaking science on pharmacology. Presented at: European Society of Cardiology Congress; Aug. 25-28, 2023; Amsterdam (hybrid meeting).
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