PHILADELPHIA — A novel anti-PCSK9 monoclonal antibody with a distinctive longer duration of action reduced cholesterol and other lipids in the phase III REMAIN-2 trial.
Recaticimab showed long-term efficacy as an add-on treatment for patients with non-familial hypercholesterolemia and mixed hyperlipidemia inadequately controlled by statins, reported Xin Du, MD, of Beijing Anzhen Hospital, at the American Heart Association (AHA) annual meeting.
In adults with hyperlipidemia who were already on moderate- or high-intensity statins, recaticimab was tested at various doses every 4, 8, and 12 weeks and was found to induce significant changes in lipid levels over placebo:
- 53-62% decrease in LDL cholesterol from baseline to week 24 (maintained through week 48)
- 47-56% decrease in non-HDL cholesterol
- 44-53% decrease in ApoB
- 28-36% decrease in Lp(a)
Du also showed that recaticimab was well-tolerated, as treatment-related adverse events — most commonly increased liver enzymes, increased blood creatine phosphokinase, and hyperuricemia — were similar with recaticimab and placebo (28.5% vs 26.6%). The rate of serious safety events was an identical 0.4% for both groups.
With REMAIN-2, recaticimab strengthened its position in the crowded arena of therapies targeting PCSK9.
Already available are the monoclonal antibodies alirocumab (Praluent) and evolocumab (Repatha) that need to be administered every few weeks. Twice-yearly injectable inclisiran (Leqvio) is also on the market as the first small interfering RNA therapy for lowering LDL cholesterol.
Then there are the other investigational therapies for LDL cholesterol lowering, including MK-101 as an oral inhibitor of PCSK9, the recombinant fusion protein lerodalcibep, and a gene editing treatment that had its first results also presented at this year’s AHA meeting.
“Each of these approaches will need to demonstrate ability to effectively and safely lower LDL cholesterol levels and cardiovascular risk, and they will further have to compete with other non-standard lipid lowering agents, whether that includes ezetimibe [Zetia], bempedoic acid [Nexletol], or the CTEP inhibitor obicetrapib, which is currently in clinical development,” said session discussant Stephen Nicholls, MBBS, PhD, of Monash Victorian Heart Institute in Melbourne, Australia.
“We have an increasing number of agents in our toolbox to achieve effective lipid control in the majority of high cardiovascular risk patients. What we need is to find better approaches to access that toolbox to more effectively reduce cardiovascular risk,” Nicholls emphasized.
High cholesterol is one of the key risk factors for cardiovascular disease. Statins remain the standard cornerstone therapy for lipid lowering, but the CDC estimates that they are only being used in 54.5% of eligible people. The persistent, population-level suboptimal control of cholesterol and other lipids suggests room for new therapies and advances in implementation.
Karol Watson, MD, of the University of California Los Angeles, remarked on the limited uptake and persistence in the available PCSK9 inhibitors.
“There are so many layers to this. In general, I’ve learned that people will do things that are cheap, easy, and advantageous. And you have to have at least two of those. The currently available therapies are not cheap. Some would say the every-2-week subcutaneous administration is not easy,” Watson commented during an AHA press conference.
“And then there’s been the one big thing that is nice: the dramatic reduction in LDL a patient sees. They love that. But again, that’s only one of three things, so I think we have to get cheap and easy going,” she continued. “Maybe if you spread out the administration schedule to every 3 months, that makes it easier, so you might get closer to getting two of those three. It might make it worse. We don’t know what the effects of this infrequent dosing [are].”
REMAIN-2 was a randomized phase III trial conducted at 62 Chinese centers. Investigators included adults with non-familial hypercholesterolemia (FH) and mixed hyperlipidemia who were on stable moderate- or high-intensity statin therapy with or without other background lipid-lowering therapies. Candidates had to pass a 4-6 week run-in period in which they maintained an LDL cholesterol of at least 1.8 mmol/L despite healthy lifestyle habits and lipid-lowering medications.
There were ultimately 692 patients randomized to various doses of recaticimab or placebo during a treatment period lasting 48 weeks. Average age was in the mid-50s, and over 60% of participants were men. The prevalence of atherosclerotic cardiovascular disease (ASCVD) was around 70%, and of type 2 diabetes 25%. About 90% of the cohort were on at least a moderate intensity statin, and over 10% on ezetimibe. LDL cholesterol averaged 2.8 mmol/L.
Across all dosing regimens, recaticimab’s efficacy was shown across subgroups by age, BMI, ASCVD, diabetes, or baseline LDL cholesterol.
Patients achieved their LDL cholesterol goal at week 24 in 85-95% of cases.
Du said that the results of the separate REMAIN-3 study of recaticimab in heterozygous FH are yet to come.
“It is important to note that these are still relatively short studies, and the short treatment period cannot exclude the formation of neutralizing anti-drug antibodies that have undermined the development of other humanized antibodies,” Nicholls warned.
“Therefore, longer studies will be required to determine whether this agent can produce durable reductions in LDL cholesterol and cardiovascular risk in a cost-effective fashion,” he told the audience.
Press conference moderator Donald Lloyd-Jones, MD, of Northwestern University Feinberg School of Medicine in Chicago, also alluded to cost being an important factor in people accessing the newer lipid-lowering therapies.
“The copays are often really, really high. And that is not the way to get access, and it certainly is not the way to get equitable access to these incredibly important medications,” he stressed.
The sponsor of the study was Jiangsu Hengrui Pharmaceuticals.
Du reported research funding from Sanofi, AstraZeneca, and Bayer.
Lloyd-Jones had no disclosures.
Nicholls reported relationship with AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, LipoScience, Amarin, Akcea, Omthera, Merck, Takeda, CSL Behring, Boehringer Ingelheim, Vaxxinity, and Seqirus.
Watson disclosed support from, and/or relationships with, the NIH, Amgen, Boehringer Ingelheim, Lilly, and Novartis.
American Heart Association
Source Reference: Du X “Recaticimab add-on therapy in patients with non-familial hypercholesterolaemia and mixed hyperlipidemia (REMAIN-2)” AHA 2023.
American Heart Association
Source Reference: Nicholls S “Next steps in PCSK9 inhibition” AHA 2023.