Tafolecimab, a novel potential long-acting PCSK9 monoclonal antibody: efficacy and safety in healthy and hypercholesterolemia subjects
Authors: Cui Y , Huo Y , Li X , Yang G , Huang Z , Zhao X , Qi L , Deng H , Zheng S , An P , Sun X , Li H , Wu X , Qian L 
Published: November 2020

Abstract

Background
LDL cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease. PCSK9 binds LDL receptors, targeting them for degradation. The dosing intervals for currently available PCSK9 monoclonal antibodies are once every 2 or 4 weeks. Tafolecimab, a novel recombinant human PCSK9 monoclonal antibody, was found to have higher affinity with PCSK9 and show longer LDL-C reduction compared to evolocumab in preclinical studies.

Purposes
The objectives for the SAD and MAD studies were to investigate the safety and efficacy of tafolecimab and explore the optimal dosing schedule.

Methods
The phase 1 study was a randomized, placebo-controlled, double-blind, single-ascending dose study (SAD) in Chinese healthy subjects, who were randomized 3:1 to tafolecimab and placebo (n=58). SAD subjects received tafolecimab subcutaneously at 25/75/150/300/450/600mg, or intravenously at 75/450mg, monitored up to day 84. The phase 2 study was a randomized, double-blind, placebo-controlled, repeated-dosing, multiple ascending dose (MAD) study in patients with hypercholesterolemia, who were randomized 4:1 to tafolecimab and placebo (n=60). MAD subjects received tafolecimab subcutaneously at 75/140mg every 2 weeks, 300/420mg every 4weeks, 450/600mg every 6 weeks up to day 84 or 98 with 3 months follow-up.

Results
In the SAD, the maximum mean reduction in LDL-C ranged from 52.2% to 72.1% and was achieved as early as 5 days (figure 1a). The duration of LDL-C reduction was tafolecimab dose dependent. In the MAD, the mean LDL-C concentrations were reduced by tafolecimab for each dose at 12 weeks relative to baseline (ranging from 54.30% to 72.26%; p&lt;0.001). Particularly, a 56.52% (−72.50%, −40.54%) reduction of LDL-C was observed in the cohort of 600mg Q6W. The effect sustained till week 14 (8 weeks after the last dose) where there was still a 43.46% (−60.96%, −25.96%) reduction from baseline (figure 1b). The mean reduction of Lp(a) at week 12 ranged from 24.04% to 50.59% relative to baseline. Tafolecimab reduced the other lipids when comparing with placebo. The pharmacokinetics/pharmadynamics (LDL-C) profiles of tafolecimab were well characterised and support the potential dosing interval of 6–8 weeks subcutaneously.
Both healthy and hypercholesterolemia subjects are generally tolerable to tafolecimab. Reported treatment-emergent adverse events (TEAEs) were: tafolecimab 23 (52.3%) vs. placebo 8 (57.1%); tafolecimab 34 (70.8%) vs. placebo 9 (75.0%) in the SAD and MAD respectively. There were no serious TEAEs or events leading to death or treatment discontinuation in both SAD and MAD.

Conclusions
Tafolecimab was well tolerated in both healthy and hypercholesterolemia in Chinese subjects, and improved lipid profile including LDL-C, Lp(a) and other lipids. The sustained effects on LDL-C suggests the potential of tafolecimab as a long-lasting PCSK9 inhibitor with dosing interval of 6–8 weeks or beyond.
Figure 1. LDL-C: Percent change from baseline

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): Innovent Biologics (Suzhou), China