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Antisense Drug Cuts Lp(a) in Midstage Study
- Up next: phase III trial probing clinical outcomes
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January 2, 2020
An investigational antisense drug targeting LPA gene expression successfully reduced levels of lipoprotein(a), or Lp(a), in a dose-ranging study aimed at informing a future outcomes trial.
People randomized to one of five dosing regimens of APO(a)-LRx had large drops in Lp(a) by the sixth month, the reduction ranging from 35% from baseline (at a dose of 20 mg every 4 weeks) to 80% (at 20 mg every week) compared with a 6% drop in the saline placebo arm (P=0.003 and P<0.001, respectively).
Genes determine the plasma concentration of Lp(a), an atherogenic and thrombogenic low density lipoprotein. APO(a)-LRx works as a subcutaneous injection that blocks Lp(a) production in hepatocytes via an antisense mechanism aimed at disabling LPA mRNA.
"Most LDL-lowering drugs do not substantially lower lipoprotein(a), and statins often have a neutral or modest lipoprotein(a)-increasing effect," Tsimikas' group wrote, adding that the patients in the FOURIER outcomes trial who could not achieve very low LDL cholesterol on PCSK9 inhibition tended to have elevated Lp(a).
Lp(a) lowering was dose-dependent and observed as early as the first month, reaching near-maximal effect by week 16, according to the AKCEA-APO(a)-LRx Study team, led by Sotirios Tsimikas, MD, of the University of California San Diego and Ionis Pharmaceuticals (majority owner of Akcea Therapeutics, maker of the APO(a)-LRx drug).
A whopping 98% of patients in the highest APO(a)-LRx dosing group (20 mg every week) achieved Lp(a) levels of 50 mg/dL or under by 6 months.
The phase II study was conducted as a randomized double-blind trial assigning patients to 6-12 months of APO(a)-LRx (at various doses) or placebo on top of their usual lipid-lowering medications.
The cohort averaged age 60 and was over 30% women. Median Lp(a) ended up ranging from 205 to 247 nmol/L across groups. At trial entry, about 80-90% of patients were on statins, half were on ezetimibe, and 20% were on a PCSK9 inhibitor.
The AKCEA-APO(a)-LRx investigators noted that these patients were generally younger than the ones included in other cardiovascular trials, consistent with Lp(a) being genetically determined and "therefore a lifelong risk factor."
A good outcomes trial may look to the PCSK9 trials as a model where patients already treated with maximally effective therapies are enrolled, targeting people who have very high Lp(a) to begin with, Huggins suggested.
Indeed, the pivotal phase III Lp(a)HORIZON trial plans to include 7,680 patients with established cardiovascular disease and Lp(a) ≥70 mg/dL over 4-5 years of monthly APO(a)-LRx or placebo injections. The trial is sponsored by Novartis, which licensed the drug from Akcea in 2019, and is expected to start in about 2 weeks. It's anticipated to finish in April 2024.
The phase II study was conducted as a randomized double-blind trial assigning patients to 6-12 months of APO(a)-LRx (at various doses) or placebo on top of their usual lipid-lowering medications.
Study participants were 286 adults with established atherosclerotic cardiovascular disease and Lp(a) levels at least 60 mg/dL at baseline. Exclusion criteria included recent acute coronary syndrome, major cardiac surgery, or stroke; uncontrolled hypertension; and impaired kidney function.
Most study participants experienced adverse events, the most common ones being injection-site reactions (such as myalgia, arthralgia, and post-injection general discomfort). Serious adverse events were noted in 10% and 2% of the APO(a)-LRx and placebo arms, respectively. Events were not dose-dependent.
Platelet counts, liver and renal measures, and influenza-like symptoms were no different between the experimental and control groups.
That nearly all of the patients were white is a limitation of the trial, the authors cautioned.
Nevertheless, Bhatt said, "This appears to be a very promising approach to cardiovascular risk reduction. The mechanism of action is fascinating. These data show excellent effectiveness at lowering Lp(a), with very good safety as well."
Noted Steven Nissen, MD, of the Cleveland Clinic and chairman of the upcoming phase III trial, "We have no therapy whatsoever for this disorder that affects 20% or so of the population. That's 1.5 billion people with high Lp(a). A therapy that reduces levels up to 80% is a really important development and has enormous [clinical] potential. That will, of course, need to be proven in an outcomes trial."
"I'm very optimistic and very hopeful," Nissen said. "This is one of the last really important frontiers in cardiovascular risk reduction."
https://www.medpagetoday.com/cardiology/dyslipidemia/84185
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https://www.nejm.org/doi/full/10.1056/NEJMoa1905239?query=featured_home
Abstract
Background
Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels.
Methods
We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).
Results
The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo/b> (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.
Conclusions
APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics;
Lipoprotein(a) is composed of a low-density lipoprotein (LDL)–like moiety bound covalently to apolipoprotein(a).1,2 Lipoprotein(a) potentially contributes to cardiovascular disease through proatherogenic effects of its LDL-like moiety, proinflammatory effects of its oxidized phospholipid content, and prothrombotic effects through its inactive, plasminogen-like protease domain on apolipoprotein(a). Mechanistic, epidemiologic, and genetic evidence reported over the past 20 years provides support for the idea that elevated plasma lipoprotein(a) is an independent genetic risk factor for cardiovascular disease and calcific aortic-valve stenosis.3,4 In contrast, genetically determined low levels of lipoprotein(a) (<30 mg per liter [<75 nmol per liter]) are associated with a decreased risk of cardiovascular disease but not of other non–cardiovascular disease adverse phenotypes.5
There are currently no approved pharmacologic therapies that specifically target lipoprotein(a). Antisense oligonucleotides (ASOs) inhibit the production of apolipoprotein(a) in the hepatocyte, the source of approximately 99% of plasma lipoprotein(a).6 Preclinical proof-of-concept studies have established that ASOs targeting hepatic LPA messenger RNA (mRNA) specifically reduce plasma levels of lipoprotein(a).7,8
Subsequent phase 1 and 2 studies of a non–hepatocyte-targeted, second-generation ASO showed lowering of lipoprotein(a) levels in healthy participants who had elevated lipoprotein(a), as well as in patients with established cardiovascular disease and elevated plasma levels of lipoprotein(a).9,10 Advances in directing ASOs to hepatocytes by conjugation with a triantennary N-acetylgalactosamine (GalNAc3) moiety, a high-affinity ligand for the asialoglycoprotein receptor on the surface of hepatocytes, have resulted in large increases (by a factor of 15 to 30) in their potency,10 with implications for improvements in the side-effect profile and safety of ASOs.11,12 AKCEA-APO(a)-LRx - here referred to as APO(a)-LRx and previously called IONIS-APO(a)-LRx - is a GalNAc3-conjugated 2′-methoxyethyl chimeric second-generation ASO drug targeted to LPA mRNA. In a phase 2a trial, APO(a)-LRxwas shown to result in a dose-dependent reduction of 66 to 92% in circulating lipoprotein(a) in participants with elevated lipoprotein(a) levels.10 The long half-life of APO(a)-LRx (approximately 1 month) that was observed in that trial prompted us to consider longer dosing intervals in the trial we report here.
Discussion
APO(a)-LRx treatment resulted in dose-dependent reductions in lipoprotein(a) levels in patients with cardiovascular disease; these reductions were significant at all doses studied, with a mean 80% reduction at the highest dose (20 mg weekly). At the highest cumulative dose regimen, which was equivalent to 80 mg monthly, 98% of patients attained a lipoprotein(a) level of 50 mg per deciliter (125 nmol per liter) or lower, a target value supported by European15 and U.S.16 guidelines and by empirical data from patients treated with statins.17 We found reductions in levels of oxidized phospholipids on apolipoprotein B and oxidized phospholipids on apolipoprotein(a), both of which are proinflammatory components that are present on lipoprotein(a) and on apolipoprotein(a) and are linked to a higher atherothrombotic risk.18-20 Finally, we noted reductions in LDL cholesterol and apolipoprotein B in patients receiving APO(a)-LRx, beyond those achieved with aggressive background lipid-lowering therapy.
The patients enrolled in this trial all had established cardiovascular disease, even though two thirds of the patients were under 65 years of age, which is generally younger than is typical in cardiovascular trials. This age profile was consistent with the lipoprotein(a) level being genetically determined and therefore a lifelong risk factor. Other ways in which the patients in the pooled trial population differed from participants in other cardiovascular trials were the relatively high percentages of patients with premature cardiovascular disease (40%) and familial hypercholesterolemia (approximately 30%) and the relatively low body-mass index and likelihood of having type 2 diabetes. That 97% of the patients were white is a limitation of the trial.
Patients with elevated lipoprotein(a) levels often cannot reach very low LDL cholesterol levels even with aggressive LDL-lowering therapy, because lipoprotein(a) cholesterol is comeasured with LDL cholesterol.21 Consistent with this observation is the fact that, in the current trial, mean LDL cholesterol levels at baseline were approximately 70 to 80 mg per deciliter despite treatment with up to three drugs. In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, patients in whom very low LDL cholesterol levels could not be achieved had markedly elevated lipoprotein(a) levels.22 Most LDL-lowering drugs do not substantially lower lipoprotein(a), and statins often have a neutral or modest lipoprotein(a)-increasing effect.17,23
Evidence from studies of primary prevention indicate that elevated lipoprotein(a) levels are associated with an increased atherothrombotic risk - in particular, an increased risk of myocardial infarction.4 The role of lipoprotein(a) in the context of secondary prevention remains controversial. Although meta-analyses have intrinsic limitations, we would note that in a patient-level meta-analysis of statin outcomes trials that included 5751 events and 95,576 person-years at risk, the risk of elevated lipoprotein(a) was almost linearly associated with the risk of cardiovascular disease, and lipoprotein(a) levels greater than 50 mg per deciliter (125 nmol per liter) among patients who were taking statins were associated with significantly higher risk.17 Furthermore, a recent analysis of data from the placebo group in the FOURIER trial showed that higher levels of lipoprotein(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease, irrespective of LDL cholesterol levels.24
Among lipoproteins, lipoprotein(a) is the highest-capacity carrier of oxidized phospholipids,25 which are responsible for many of its proinflammatory effects.26-28 In our trial, dose-dependent reductions were noted in oxidized phospholipids on apolipoprotein B and oxidized phospholipids on apolipoprotein(a) in plasma which, we posit, reflects effects of APO(a)-LRx on the oxidized phospholipid content of lipoprotein(a). In previous studies, oxidized phospholipids on apolipoprotein B, primarily reflecting the oxidized phospholipid content of lipoprotein(a), predicted first and recurrent myocardial infarction, stroke, and aortic stenosis.18-20
The reduction in LDL cholesterol and apolipoprotein B levels by ASOs targeting LPA mRNA, in the presence of aggressive lipid-lowering therapy, has been documented in previous studies.9,10 Such findings may indicate that, when the synthesis of apolipoprotein(a) is inhibited in the liver, apolipoprotein B lipoproteins - which would otherwise be destined to become lipoprotein(a), with relatively low plasma clearance as a result of weak interactions with the LDL receptor - are converted to LDL particles with relatively strong affinity for the LDL receptor and hence a relatively quick and efficient clearance from the blood.10
We did not observe marked changes in platelet, renal, or liver function, nor a between-group difference in the risk of influenza-like symptoms. The most common adverse events among patients who received APO(a)-LRx were injection-site reactions, which were generally mild.
Elevated levels of lipoprotein(a) are a cardiovascular risk factor for which no effective pharmacological therapy currently exists. In this trial, we found that APO(a)-LRx provided potent reductions in levels of lipoprotein(a) in patients with cardiovascular disease.
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