Tafolecimab, A Novel Member of PCSK9 Monoclonal Antibodies, Is Worth Expecting in a Chinese Population

Corresponding Author

Low-density lipoprotein cholesterol (LDL-C), a well-established and modifiable risk factor, has indubitably been recognized as a causal association with the development of atherosclerotic cardiovascular disease (ASCVD). More importantly, there are a mass of studies demonstrating that reduction in LDL-C is among the most powerful tools available to decrease adverse events including cardiovascular morbidity and mortality.¹ Although statins and ezetimibe are currently available in clinical practice for cholesterol management around the world covering a Chinese population, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, including alirocumab and evolocumab, have been on the market for several years and are becoming an important treatment option for patients at highest risk of ASCVD who are unable to reach their target values with current treatment for optimal LDL-C control.

In this issue of JACC: Asia, Qi et al² reported the efficacy and safety of tafolecimab, a novel member of PCSK9 monoclonal antibodies, in Chinese patients with hypercholesterolemia. The data were from a randomized, double-blind, placebo-controlled phase III trial, CREDIT-4 (Clinical Research of Developing PCSK9 Inhibitor as Cholesterol-Lowering Therapy in Chinese Patients with Dyslipidemia-4).² In their study, 303 patients diagnosed with heterozygous familial hypercholesterolemia or at high or very-high cardiovascular risk with non-familial hypercholesterolemia, with a screening LDL-C level ≥1.8 mmol/L, were randomized 2:1 to receive tafolecimab or placebo 450 mg every 4 weeks in the 12-week double-blind treatment period. The study revealed that the LDL-C level from baseline to week 12 was –68.9% in the tafolecimab group and –5.8% in the placebo group. In addition, more patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C <1.8 mmol/L, and LDL-C <1.4 mmol/L at week 12 than the placebo group. The investigators concluded that tafolecimab was safe and showed robust lipid-lowering efficacy in Chinese patients at high or very high cardiovascular risk with hypercholesterolemia. I am happy for having an opportunity to make a comment on this original and brilliant work that is involved in developing a novel lipid-lowering medication in China.

Firstly, tafolecimab is a fully human immunoglobulin G2 (IgG2) PCSK9 monoclonal antibody developed in China. According to my knowledge, it may also be a new member of the PCSK9 monoclonal antibodies around the world developed in Asia that have already completed a phase III trial. Currently, PCSK9 monoclonal antibodies have widely been considered powerful drugs for lowering LDL-C concentration, besides their feature of being well-tolerated in real-world clinical practice.³ In the 2023 China Guidelines for the Management of Blood Lipids, it is recommended that ultra-high-risk patients with high baseline LDL-C levels (LDL-C ≥2.6 mmol/L in those taking statins and LDL-C ≥4.9 mmol/L in those not taking statins) who are expected to have difficulty achieving the target goal with a statin combined with a cholesterol absorption inhibitor may be initiated directly on a statin combined with PCSK9 inhibitor therapy.⁴ This recommendation originates from the fact of the lower rate of LDL-C target achievement in the Chinese population at high or very high risk and the concept that “the earlier the better” for cholesterol management.⁵ Therefore, tafolecimab is worth expecting as another option for the lipid management in Chinese population in the near future. Notably, similar to the well-known PCSK9 monoclonal antibodies alirocumab and evolocumab, tafolecimab markedly reduces LDL-C concentration approximately 70% accompanied by the reduction in non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels.^6,7 Those lipid-related markers are highly perceived as the novel lipid targets in the prevention and treatment of ASCVD in recent years.⁸ More interestingly, tafolecimab drug appeared to have a significant advantage in that it maintains an extended period of reduction in LDL-C concentration (an injection for every 4 weeks) than alirocumab and evolocumab (an injection for every 2 weeks). This trait, obviously, may help to improve medication compliance of patients, reduce both the numbers of injections and treatment cost to some extent, especially for patients in developing countries among Asia.

Moreover, tafolecimab has no serious adverse reactions according to the investigators’ data presented in this small sample size study, and even patients who achieved very low LDL-C did not have any significant untoward effects.² Hence, tafolecimab may be another promising therapeutic option of PCSK9 inhibitors for LDL-C control in the Chinese population around the corner. Nevertheless, as noted by the investigators, several concerns may need to be addressed. Firstly, the investigators reported that the most commonly reported adverse events in their phase III study were urinary tract infections (5.9% with tafolecimab vs 4.1% with placebo) and hyperuricemia (3.4% vs 4.1%) during the double-blind treatment period. Even though the investigators indicated that these adverse effects were mild in severity, and all were judged to be unrelated to the study drug, no explanation was given why the patients enrolled in this study experienced a relative higher rate of urinary tract infections and hyperuricemia, which effects have not been reported before in developing PCSK9 monoclonal antibodies. Whether there is a possibility that in the trial there exists an unclear factor that resulted in this uncommon effect may warrant further attention. Furthermore, the impact of tafolecimab on cardiovascular outcomes is still lacking; further study is needed. Besides, although the latest FOURIER-OLE (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk Open Label Extension) study suggested that ASCVD patients on evolocumab for up to 8.4 years (median 5 years) with a median LDL-C level of 0.78 mmol/L had no serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death. The long-term safety of tafolecimab is another open concern that should be demonstrated in a large sample size population. Finally, the usefulness of tafolecimab with regard to the efficacy and safety in other ethnic patients (white race and black race) also raises questions for this novel PCSK9 monoclonal antibody.⁹ Therefore, more study is needed to explore this novel PCSK9 monoclonal antibody before approving it in the clinical practice.

In summary, tafolecimab, a novel member of PCSK9 monoclonal antibodies dosed at 450 mg every 4 weeks, was safe and effective for lowering LDL-C, which may provide a novel treatment option for patients with hypercholesterolemia in a Chinese population and is worth expecting. Larger sample sizes and longer double-blind treatment period studies concerning the impact on cardiovascular events in different ethnic individuals are needed.

Funding Support and Author Disclosures

The author has reported that he has no relationships relevant to the contents of this paper to disclose.