Recaticimab Monotherapy in Patients With Nonfamilial Hypercholesterolemia and Mixed Hyperlipemia - REMAIN-1

Oct 15, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Anthony A. Bavry, MD,MPH,FACC
Trial Sponsor:
Jiangsu Hengrui Pharmaceuticals
Date Published:
10/09/2024
Original Posted Date:
10/15/2024
References

Contribution To Literature:

The REMAIN-1 trial showed that in a Chinese cohort of elevated LDL-C and low-to-moderate ASCVD risk, recaticimab monotherapy significantly lowered LDL-C compared with placebo even with extended intervals between doses.

Description:

The goal of the trial was to assess the lipid-lowering efficacy and safety of recaticimab, a long-acting monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9).

Study Design

  • Randomized
  • Double-blind
  • Placebo-controlled
  • Multicenter (China)
  • Phase 3

Patients with elevated low-density lipoprotein cholesterol (LDL-C) at low-to-moderate risk of atherosclerotic cardiovascular disease (ASCVD) were randomized in 2:2:2:1:1:1 fashion to receive subcutaneous recaticimab at 150 mg every 4 weeks (n = 157), 300 mg every 8 weeks (n = 156), or 450 mg every 12 weeks (n = 155) or matching placebo (n = 78, 79, and 78 for every 4, 8, and 12 weeks, respectively) in the absence of other lipid-lowering agents. Blinded treatment was performed for 12 weeks in the 4- and 12-week dosing groups and for 16 weeks in the 8-week groups. Treatment was subsequently extended to 24 weeks, with the placebo arms crossing over to the corresponding recaticimab dosing strategy.

  • Total number of enrollees: 703
  • Duration of follow-up: 24 weeks
  • Median patient age: 42-48 years
  • Percentage female: 47%

Inclusion criteria:

  • Age 18-80 years
  • Fasting LDL-C ≥100 mg/dL (2.6 mmol/L) and <190 mg/dL (4.9 mmol/L)
  • Fasting triglyceride ≤500 mg/dL (5.6 mmol/L)
  • 10-year ASCVD risk score <10% based on the 2016 Chinese dyslipidemia guidelines

Exclusion criteria:

  • Definite familial hypercholesterolemia according to the Simon Broome Criteria
  • Prior ASCVD history
  • Type 1 diabetes mellitus (DM)
  • Hemoglobin A1c >8.5%

Other salient features/characteristics:

  • Type 2 DM: 1%
  • Mean baseline LDL-C: 143 mg/dL (3.7 mmol/L)
  • Median baseline lipoprotein(a) [Lp(a)]: 18.5-32.3 nmol/L
  • Median baseline triglyceride: 133-151 mg/dL (1.5-1.7 mmol/L)

Principal Findings:

The primary outcome, percentage change in LDL-C, for recaticimab vs. placebo at 12 or 16 weeks:

  • 150 mg every 4 weeks: -50.4% vs. -0.8%, treatment difference -49.6% (95% confidence interval [CI] -54.9 to -44.2), p < 0.0001
  • 300 mg every 8 weeks: -50.5% vs. +2.3%, treatment difference -52.8% (95% CI -57.2 to -48.3), p < 0.0001
  • 450 mg every 12 weeks: -45.6% vs. -0.6%, treatment difference -45.0% (95% CI -49.0 to -41.0), p < 0.0001

Secondary outcomes for recaticimab vs. placebo at 12 or 16 weeks:

  • Absolute LDL-C reduction treatment difference: -69.6 mg/dL (150 mg every 4 weeks), -73.5 mg/dL (300 mg every 8 weeks), -61.9 mg/dL (450 mg every 12 weeks), p < 0.0001 for all
  • LDL-C <100 mg/dL (2.6 mmol/L): 88.2% vs. 7.5% (150 mg every 4 weeks), 91.0% vs. 8.2% (300 mg every 8 weeks), 86.9% vs. 3.9% (450 mg every 12 weeks)
  • Percentage Lp(a) reduction treatment difference: -32.4% (150 mg every 4 weeks), -28.5% (300 mg every 8 weeks), -18.3% (450 mg every 12 weeks), p < 0.0001 for all

Percentage LDL-C reduction for recaticimab vs. placebo-recaticimab crossover at 24 weeks:

  • 150 mg every 4 weeks: -53.1% vs. -52.8%
  • 300 mg every 8 weeks: -51.7% vs. -45.9%
  • 450 mg every 12 weeks: -47.3% vs. -45.7%

Safety outcomes for recaticimab vs. placebo at 12 or 16 weeks:

  • Any adverse event: 14.1% vs. 11.1%
  • Injection site reaction: 3.0% vs. 1.7%
  • Antidrug antibody positivity: 5.4% vs. 0.5%

Interpretation:

PCSK9 inhibition, both alone and in conjunction with other lipid-lowering therapy, has become a key target in ASCVD reduction across a range of patient risk profiles. Recaticimab is a novel PCSK9-inhibiting monoclonal antibody engineered to resist intracellular degradation, resulting in an extended half-life. Recaticimab monotherapy resulted in significant reductions in LDL-C and other atherogenic lipids, such as Lp(a), across dosing intervals extending out to 12 weeks with no adverse safety signal. Such infrequent dosing may be preferable in patients at higher risk for medication nonadherence.

Cardiovascular events were not examined in this short-term study, although the lipid-lowering effect was comparable to similar monoclonal PCSK9 inhibitors with demonstrated cardiovascular benefit. Extended treatment studies, such as the REMAIN-2 trial, may provide further insight into clinical efficacy and safety of infrequent-dosing strategies with recaticimab across a range of ASCVD risk profiles.

References:

Xu M, Wang Z, Zhang Y, et al., on behalf of the REMAIN-1 Investigators. Recaticimab Monotherapy for Nonfamilial Hypercholesterolemia and Mixed Hyperlipemia: The Phase 3 REMAIN-1 Randomized Trial. J Am Coll Cardiol 2024;Oct 9:[Epub ahead of print].

Editorial Comment: Santos RD, Nasir K, Shapiro MD. A Step Forward for Long-Acting PCSK9 Inhibition: Improvements Without a Breakthrough. J Am Coll Cardiol 2024;Oct 9:[Epub ahead of print].

Clinical Topics: Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Prevention

Keywords: Atherosclerosis, Cholesterol, LDL, Hypercholesterolemia, Hyperlipidemias, PCSK9 Inhibitors


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