Lp(a), called the holy grail of prevention research, has been significantly reduced with SLN360 and should stimulate further research.
WASHINGTON, DC – Gene silencing therapy can significantly reduce the production of lipoprotein (a), a hot target in the field of atherosclerotic cardiovascular disease (ASCVD) prevention, according to early data.
Among people treated with the highest dose of a small interfering RNA (siRNA), the single subcutaneous injection reduced Lp(a) levels by up to 98%, reported Steven Nissen, MD (Cleveland Clinic, OH), at the end-session of breakthrough clinical trials at the 2022 Scientific Sessions of the American College of Cardiology.
“Historically, lipoprotein(a) has been considered an incurable abnormality, and it’s often not measured by many of our colleagues,” Nissen said. “The development of mRNA-targeting therapies has led to significant reductions in Lp(a) – whether these reductions may impact the incidence of ASCVD or prevent the progression of aortic stenosis remains to be determined, but we think the optimism is warranted.”
Historically, lipoprotein(a) has been considered an incurable abnormality and it is often not measured by many of our colleagues. Steven Nissen
Vera Bittner, MD (University of Alabama at Birmingham), who commented on the study during the session, said that the development of agents designed specifically for Lp(a) had been considered the ” Holy Grail” of ASCVD prevention. She pointed out that previous epidemiological studies have suggested that these drugs will need to greatly lower Lp(a) levels to have an impact on the event rates of SCAV or aortic stenosis. For this reason, APOLLO can be considered a successful phase I study of an mRNA with sufficiently potent Lp(a) lowering.
Michael Blaha, MD (Johns Hopkins University Medical Center, Baltimore, MD), was also impressed with the data, saying the field’s focus on Lp(a) is extremely exciting. “We know that’s something that explains a lot of the residual risk that we see in patients and the unexplained familial risk that we can’t do anything about,” he told TCTMD. “I love that we’re seeing several different approaches to lowering Lp(a).”
Like Bittner, Blaha noted that epidemiological data suggests that the treatment will require a very robust reduction in Lp(a) to be beneficial. “And we see that,” he said.
The study was simultaneously published on April 3, 2022 in JAMA.
Other agents in development too
SLN360 (Silence Therapeutics), as the siRNA is currently known, targets PLA, which is the gene that encodes apolipoprotein(a), the “dominant rate-limiting component” of hepatic Lp(a) production. SiRNA degrades apolipoprotein(a) mRNA, which in turn reduces Lp(a). Pelacarsen (Novartis), another Lp(a) lowering therapeutic currently in clinical trials, is an antisense oligonucleotide that also targets the mRNA of PLA.
Lp(a) is known to be associated with CVD, both in primary and secondary-prevention parameters, as well as in Mendelian randomization studies. In the US guidelines for the treatment of hypercholesterolemia, elevated Lp(a) is considered a risk-increasing factor to help physicians and patients make an informed decision regarding LDL-lowering therapy. In Europe, the clinical guidelines recommend checking Lp(a) for cardiovascular risk stratification in individuals at least once during the patient’s lifetime, although the recommendation is relatively weak.
I love that we are seeing several different approaches to lowering Lp(a). Michael Blah
In the APOLLO trial, researchers randomized 32 patients in four cohorts to different doses of SLN360. Each cohort included six patients randomized to receive active treatment and two participants treated with placebo. In the four cohorts, patients were treated with 30 mg, 100 mg, 300 mg, and 600 mg of SLN360, respectively. None of the participants had pre-existing cardiovascular disease, but all had Lp(a) concentrations ≥ 150 nmol/L at baseline, or about 60 mg/dL.
The median maximum reduction in Lp(a) was 20, 89, 185, 268, and 227 nmol/L for those treated with placebo and the 30, 100, 300, and 600 mg doses, respectively. The median maximum percent reduction from baseline was 10%, 46%, 86%, 96%, and 98%, respectively. The nadir reduction in Lp(a) occurred between 30 and 60 days after treatment with all doses. After this point, Lp(a) values increased again, but did not return to baseline values after 150 days. For the 300 and 600 mg doses, Lp(a) levels remained approximately 70% and 80% lower than baseline at 150 days.
At the maximum doses of SLN360, LDL cholesterol and apolipoprotein B were reduced by 26% and 24%, respectively.
In terms of safety, headaches were reported by nine participants, five of whom were treated with the 600mg dose. Neutrophil counts increased in three patients, as did C-reactive protein levels. There was one serious adverse event – a patient receiving the 30mg dose hospitalized with fever and severe headache – but these effects were attributed to the COVID-19 vaccine he had received a week earlier. The same patient had a triple elevation in liver enzymes, and again this was attributed to the COVID-19 vaccine. Overall, treatment-emergent adverse events were mild and were most often low-grade injection site events. None led to withdrawal from the study.
The researchers point out, however, that the current study was too small to truly determine the safety of this therapeutic siRNA and further studies are needed, including those with a more diverse patient population, such as those with cardiovascular disease.
Anthony DeMaria, MD (UC San Diego Health, La Jolla, CA), who commented on the study, first listed its shortcomings, namely that it was a small, single-center study using a surrogate endpoint . Nonetheless, he imagines the game will change soon enough. “In the past, I would say every adult should know at least two numbers: their blood pressure and their cholesterol,” he said. Going forward, however, knowing your LDL and HDL levels will not be enough. “People aren’t used to measuring Lp(a) levels,” DeMaria said, “but I think we need to start doing that because we’re going to have to identify patients at risk.”
The first step, Blaha said, is to determine whether lowering Lp(a) reduces ASCVD event rates. Pelacarsen, the most advanced antisense oligonucleotide in clinical development, is currently being tested on a large scale Lp(a)HORIZON study, of which Nissen is the chair of the study. That said, Blaha is also optimistic about the future for patients with elevated Lp(a).
“The data lines up perfectly,” he said. “In fact, if the [CVD event] the trials are not positive, I think there will be a lot of thought about how this is possible. Of course, you never know, though.
More data to come
Speaking to the media, Nissen said patients with elevated Lp(a) levels are frequently seen in the cardiac care unit after a myocardial infarction. Although Lp(a) is a strong risk factor for ASCVD, it is only currently considered a risk factor and is not often on doctors’ radar. Like DeMaria, Nissen believes that at least once in a person’s lifetime, preferably when they are young, Lp(a) should be measured. In their prevention clinic, all patients are tested for Lp(a), he said.
“As these therapies mature, we will need to know who to treat,” Nissen said.
When patients with elevated Lp(a) are identified today, Nissen said, the goal should be to treat other risk factors as aggressively as possible. This includes keeping LDL cholesterol as low as possible, controlling blood pressure and physical activity in overweight/obese patients. “We will take all other risk factors off the table until we have drugs on the market that can treat Lp(a) – that’s why we need to measure it,” he told TCTMD.
Blaha takes a similar approach when he discovers that a patient has significantly elevated Lp(a), such as those with levels above 150 nmol/L. “I will advise patients that they have inherited a family risk that we can’t do much about at the moment, so we need to reduce their other risk factors even further,” he said. . “I also advise them on cascade screening, particularly if they have adult children who should also be screened, especially if they have a strong family history.”
Finally, Blaha said he would counsel patients on the possibility of enrolling in a clinical trial, noting that his center was enrolling patients in Lp(a) HORIZON, despite it being a prevention trial. secondary. If they are not eligible, he will tell them that there may one day be a therapy to treat their high Lp(a) levels.
During the discussion, Bittner said that in previous studies of PCSK9 inhibitors – which have also been shown to lower Lp(a) levels – the greatest reduction in Lp(a) has been observed. in people with the highest baseline levels. Nissen said they were unable to analyze Lp(a) reduction based on starting Lp(a), but that is an interesting question. However, since the therapy is so effective in degrading the mRNA of PLA“it is highly likely that we will see robust plasma suppression [Lp(a)] whatever the baseline, it’s not proven, but I think it’s very likely,” Nissen predicted.