KRAKEN: Oral Muvalaplin Safely Lowers Lp(a) in Early-Stage Trial

Competition is already heating up in a drug class where therapies are not yet approved, as findings for the first oral drug to lower lipoprotein(a) (Lp[a]) showed promise in a presentation today at the 2024 American Heart Association (AHA) Scientific Sessions, which drew to a close in Chicago, Illinois.

Stephen Nicholls, MBBS, PhD | Image credit: Cardiology Society of Australia

In a phase 2 study, muvalaplin was found to significantly reduce Lp(a) using both the traditional test for measuring these particles in the blood, and a new test that more accurately assesses how muvalaplin works to disrupt them, according to lead study author Stephen Nicholls, MBBS, PhD, director of the Victorian Heart Institute at Monash University in Melbourne, Australia.

Lp(a) is a genetically driven variant of low-density lipoprotein (LDL) cholesterol, that is known to be an independent risk factor for cardiovascular disease (CVD) and currently has no approved treatments. As commenter Erin D. Michos, MD, MHS, of Johns Hopkins noted at a press briefing, Lp(a) affects about 1 in 5 people worldwide.

Erin D. Michos, MD, MHS | Image credit: Johns Hopkins

The 2 major protein components of Lp(a) are apolipoprotein(a), or Apo(a), associated with high-density lipoprotein or “good” cholesterol and apolipoprotein(b), or ApoB, associated with LDL or “bad” cholesterol. Muvalaplin works, Nicholls explained at the press briefing, by disrupting the bonding of apo(a) to apoB, which does not allow Lp(a) to form.

The study examined 3 different doses, at 10 mg, 60 mg, and 240 mg vs placebo over 12 weeks. To enroll, patients had to have serum level Lp(a) of at least 175 mmol/L.

In addition, the study team measured how well muvalaplin reduced oxidized phospholipids; Nicholls explained that Lp(a) acts as a “reservoir” for oxidized phospholipids, and “there is a school of thought that this is plays a particular mechanistic role in driving the relationship between Lp(a) and atherosclerotic disease.”

Results showed the study drug significantly reduced oxidized phospholipids as well, he demonstrated. Detailed results showed:

• In the traditional blood test, muvalaplin reduced Lp(a) by 70% compared with placebo, and it reduced Lp(a) by 85.5% in a new test that evaluates “intact” Lp(a) particles, accounting for those particles that might attach to the drug, Nicholls explained.
• Treatment with muvalaplin helped 97% of participants to bring Lp(a) levels below 125 nmol/L, as measured by the intact Lp(a) particle test, or about 82% of what they measured with the traditional blood test.
• Compared with placebo, muvalaplin lowered ApoB by as much as 16% with no change in high-sensitivity C-reactive protein, which would have indicated heart attack or stroke risk.
• The percentage of serious adverse events was about the same in the placebo arm (6%) as the 10 mg arm (5.9%) , and the percentages were lower in the other arms, with 60 mg at 3.2% and 240 mg at 2.9%.

Muvalaplin, being developed by Eli Lilly, is the latest of the therapies targeting Lp(a) to generate interest at recent cardiology conferences, but the first that would not require injection. Nicholls said these data follow up on previously reported phase 1 results, which showed a reduction of 65% for muvalaplin compared with placebo using the traditional blood test and were reported in JAMA in 2023.

Nicholls emphasized that Lp(a) is a distinct, independent risk factor from others that might be treated by primary care physicians and cardiologists; current recommendations call for adults to be tested at least once in their lifetime to learn whether they have elevated levels. But Michos said right now, even when clinicians know a patient has high Lp(a) there is only so much they can do.

“Our current approach is to take an account to both the patient's global cardiovascular risk—so their other risk—as well as their absolute lipoprotein(a) level.”

By contrast, when treating LDL cholesterol, although there are certain thresholds between intermediate and high risk, she said, “it’s really a continuous threshold,” and “we try to treat all their risk factors the best we can, get their LDL as low as possible. But the reason why this is so important is that even in patients who are treated very intensively and get their LDL less than 70 on a statin, having high Lp(a) still carries some independent risks that can't be fully eliminated by our other risk modifying strategies.”

Black individuals of African descent and South Asian populations frequently have the highest Lp(a) levels, according to the AHA’s 2021 scientific statement “Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease.”

Lp(a) levels of 50 mg/dL (125 nmol/L) or higher contribute to clotting and inflammation, and significantly elevate the the risk of heart attack, stroke, peripheral artery disease; the presence of Lp(a) is especially dangerous for those who have existing CVD or a history of familial hypercholesterolemia.

Multiple Lp(a) therapies are under development; those in the later stages include:

• Pelacarsen, an antisense oligonucleotide given once a month. Developed by Ionis/Novartis, its phase 3 HORIZON outcomes trial is expected to be complete in 2025.
• Olpasiran, an siRNA therapy given every 3 months. Developed by Amgen, its phase 3 OCEAN(a) outcomes trial is scheduled to be complete in 2027.

Nicholls said the next steps for muvalaplin are phase 3 trials and cardiovascular outcomes trials before the therapy could reach the market. But while studies continue, he said, the first step is knowing who are the patients with high levels of Lp(a). “In most countries around the world, Lp(a) testing is not covered by payers. It's largely an out-of-pocket expense to patients, and that presents an enormous barrier. Many of us in the field are advocating strongly to payers around the world to have Lp(a) testing included in prevention—to be covered—because it is an important tool, as Dr. Michos has already suggested, in terms of the way that we assess risk today, in terms of the way that we try to manage established cardiovascular risk factors.

“These therapies will come to the clinic, and we need to be able to target the right patient to the right therapy.”

Reference

Nicholls SJ, Wei N, Rhodes GM, et al. Phase 2 trial of an oral small molecule inhibitor of lipoprotein(a) formation. Presented at: American Heart Association Scientific Sessions; November 16-18, 2024; Chicago, IL. Abstract LBS 08.