Novel Agent Lowers Lp(a), Meets All End Points in Phase 2

Deborah Brauser

November 14, 2018

CHICAGO — A novel antisense agent is relatively safe and highly effective in lowering levels of lipoprotein(a) in patients with both elevated Lp(a) and established cardiovascular disease (CVD), new research suggests.

In a dose-finding phase 2b trial that examined five regimens in more than 200 patients with CVD and Lp(a) levels of 60 mg/dL or higher. Treatment with the subcutaneous injectable drug known as AKCEA-APO(a)-LRX (Akcea Therapeutics/Ionis Pharmaceuticals) was associated with a dose-dependent effect on these levels from baseline to week 25 to 27, meeting the primary end point.

In addition, for the patients receiving the highest active dose evaluated, 20 mg/week, there was a mean 80% reduction in Lp(a) from baseline.

Lead author Sotirios Tsimikas, MD, vice president of Global Cardiovascular Development at Ionis Pharmaceuticals and professor of medicine at the University of California, San Diego, noted that this is especially dramatic compared with currently available treatments, including proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors.

"Looking at current therapies, PCSK-9 inhibitors lower Lp[a] by about 15% to 25% and niacin can lower it by 20% to 30%. So this is two to three times more potent than what's currently available to lower Lp(a)," Tsimikas told | Medscape Cardiology.

Results also showed that 98% of the participants "got to goal," defined as Lp(a) less than 50 mg/dL. "This means almost everybody who got on the drug got to a level that we think has very low risk," Tsimikas said.

In addition, the 20 mg/week dose met all secondary outcomes, including mean change from baseline in low-density-lipoprotein cholesterol (LDL-C), ApoB, and oxidized phospholipids on apoB particles (OxPL-apoB and OxPl-apo[a]).

Tsimikas presented the results during a late-breaking science session here at the American Heart Association Scientific Sessions 2018.

Five-Regimen Cohort Study

Lp(a) "is an independent, genetic, and likely causal risk factor for CVD and aortic stenosis," Tsimikas told attendees during his presentation. "There are no approved pharmacological therapies to specifically lower Lp(a), and statins are ineffective."

AKCEA-APO(a)LRX "is an antisense oligonucleotide, or ASO, that contains a GalNac ligand that binds to asialoglycoprotein receptors on hepatocytes leading to enhanced intracellular uptake," he reported. Previous names of the drug have been IONIS-APO(a)-LRX and ISIS 681257.

Results from a phase 1 trial published in the Lancet in 2016 showed that healthy volunteers with elevated Lp(a) who received the drug had a mean 68% to 92% reduction in plasma Lp(a) levels, Tsimikas reported.

In addition, topline results for the current trial were released by the manufacturer in September.

"This was basically an efficacy phase 2b study in the kind of patient that would be reflected in a phase 3 outcomes trial," said Tsimikas.

"We also wanted to carefully evaluate safety, including any antiplatelet issues that were previously shown to be present in other older drugs, although not in this one; and we evaluated liver issues, renal issues, and general safety issues. We also wanted to look at appropriate dose," he added.

The investigators enrolled 286 participants and randomly assigned them to one of five cohorts. Each cohort included assignment of active treatment or placebo in a 5:1 design.

The pooled active-drug group was comprised of 239 participants (65.7% men; mean age, 60.1 years) and the pooled placebo group of 47 participants (68.1% men; mean age, 59.9 years). The estimated mean Lp(a) at baseline was 100.0 and 103.3 mg/dL, respectively.

The five cohorts were assigned to one of the following treatment regimens:

·       20 mg or matching placebo every 4 weeks (Q4W)

·       40 mg or placebo every 4 weeks

·       20 mg or placebo every 2 weeks (Q2W)

·       60 mg or placebo every 4 weeks

·       20 mg or placebo every week (QW)

Treatment duration lasted 6 to 12 months, with a 16-week follow-up.

Primary, Secondary Outcomes

The primary end point was met in a dose-dependent manner, as shown in the following table.

Table. Mean % Change in Lp(a) From Baseline to Week 25–27
Dose of AKCEA-APO Mean Reduction in Lp(a), % P Value
20 mg/Q4W 35 .003
40 mg/Q4W 56 <.0001
20 mg/Q2W 58 <.0001
60 mg/Q4W 72 <.0001
20 mg/QW 80 <.0001
Pooled placebo group 6 not significant

"The primary efficacy end point was not affected by baseline Lp(a) levels or use of statins or PCSK9s, Tsimikas reported.

The absolute reduction in Lp(a) from baseline to week 25 to 27 was 38.4, 46.8, 52.1, 59.8, and 75.1 mg/dL for the active dosing groups, respectively. The absolute change for the pooled placebo group was –6.1 mg/dL.

The percent of patients achieving an Lp(a) level of 50 mg/dL or below (≤125 nmol/L) was 6.4 for the placebo group vs 25.0 (P = .03), 62.5, 64.6, 80.9, and 97.7 for the active groups, respectively (P < .0001 for the latter four).

In addition, the 20mg/QW group showed an 81.8% reduction from baseline in OxPL-apoB compared with a 22.4% increase in the pooled placebo group (P < .001).

They also showed significantly greater changes in OxPL-apo(a) (–61.2% vs –17.6 ezetimibe%, P < .001), LDL-C (–20.5% vs +1.2%; P < .01), and ApoB (–14.5% vs +2.0%; P < .001).

All of these levels were also significantly lower in the 40 and 60 mg/Q4W and 20 mg/Q2W groups vs placebo. The 20 mg/Q4W group only showed a significant reduction vs placebo in OxPL-apoB.

"What you get with this drug a very massive reduction in Lp(a) and oxidized phospholipids, and then you have a more modest reduction in LDL and ApoB, which is in line with ezetimibe or methanoic acid," Tsimikas said. "So we feel very encouraged that this may provide a lot of clinical benefit in an outcomes trial."

Safety Analyses

In the safety analyses, 213 patients in the pooled active treatment group reported at least one treatment-emergent adverse event (TEAE) vs 39 patients in the pooled placebo group. The most common TEAE reported was injection-site erythema (25%). TEAEs leading to treatment discontinuation were reported by 11 and two group members, respectively.

There were only two related serious TEAEs, which occurred in the pooled active treatment group: one report of an auto accident and one report of "malaise." There were also two deaths in the same group: one from the aforementioned auto accident and one from depression/suicide.

In addition, "there were no safety concerns related to platelet counts, liver function, or renal function," Tsimikas said. There were no confirmed cases of platelet value less than 100,000 mm³, but there were 25 reports in the pooled active drug group of platelet values below 140,000 mm³ vs seven reports in the pooled placebo group.

No patient met a "Liver Safety Stopping Rule." In renal function analyses, one patient had unrelated prerenal azotemia and one had unrelated incomplete 24-hour urine collection, leading to a safety alert."

Overall, "this study provides a rationale for the initiation of a phase 3 outcomes trial to test the Lp(a) hypothesis, in which lowering Lp(a) levels will reduce cardiovascular events," Tsimikas concluded.

Asked by | Medscape Cardiology if he's currently feeling optimistic about the drug, Tsimikas said he'd rather wait for the phase 3 study.

"But this phase 2 went about as perfect as we could have hoped. There's never been a drug for this disorder; this will be the first specific drug for it," he said. "Safety is going to require a longer trial and more patients, and we'll have to wait for the outcomes trial to have more certainty about how much clinical benefit patients can accrue."

"A Very Big Deal"

When asked to comment on the findings, Steven E. Nissen, MD, chair of the Department of Cardiovascular Medicine at the Cleveland Clinic, told | Medscape Cardiology that "there was clearly a substantial reduction" in Lp(a) in this study.

"This is a very big deal because this has essentially been an untreatable abnormality that results in a lot of cardiovascular morbidity and mortality. So it's good news for patients and seems to be strong enough data to support moving quickly to a phase 3 definitive trial," said Nissen, who was not involved with the research.

"The other piece of information that's critically important is safety because this is a new kind of approach to therapy, and there appears…to be no major safety issues," he added.

Nissen noted that there had been some concern about possible reductions in platelet counts "based upon another product in the same general category. But it sounds like that didn't happen here."

"So, with good safety and strong efficacy, the data from phase 2 appear to support moving forward in developing this drug, which would be a huge benefit to patients," he said.

He added that efficacy expectations were quite high after the release of the phase 1 trial results, "but until you study this in people who actually have the disorder, you can't be sure" what the findings will show.

"This is one of those targets in cardiovascular medicine that we have not been able to address and I'm very excited that it looks like there's going to be a therapy approach that will address this unmet medical need," Nissen said.

Future Plans

Asked if he could share specifics about a future phase 3 trial, Tsimikas pointed out that "this is a bit of complicated issue." The drug was originally created by Ionis, which created Akcea as a subsidiary. These companies then potentially licensed the drug to Novartis.

"They haven't committed to it yet, but they have the option to license it," Tsimikas explained. "They'll do the phase  trial after they license it, which is in discussion now. Ionis and Akcea are too small to do a phase 3 study of this magnitude, but if everything goes smoothly, it'll start sometime in 2019."

The study was funded by Ionis Pharmaceuticals and Akcea Therapeutics. Tsimikas is an employee of Ionis and reports having patents with the University of California, San Diego and equity in Oxitop, and he has served on advisory boards for Boston Heart Diagnostics. Nissen reports no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2018: LBS.02. Presented November 10, 2018.

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