A phase 1 study to evaluate the safety and LDL cholesterol–lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9

Abstract

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates low‐density lipoprotein (LDL) receptors, thereby leading to a rise in circulating LDL cholesterol (LDL‐C). RG7652 is a fully human monoclonal antibody against PCSK9. This placebo‐controlled, phase 1 ascending‐dose study in healthy subjects evaluated the safety of RG7652 and its efficacy as a potential LDL‐C–lowering drug. Hypothesis Anti‐PCSK9 antibody therapy safely and effectively reduces LDL‐C. Methods Subjects (N = 80) were randomized into 10 cohorts. Six sequential single‐dose cohorts received 10, 40, 150, 300, 600, or 800 mg of RG7652 via subcutaneous injection. Four multiple‐dose cohorts received 40 or 150 mg of RG7652 once weekly for 4 weeks, either with or without statin therapy (atorvastatin). Results Adverse events (AEs) were generally mild; the most common AEs were temporary injection‐site reactions. No serious AEs, severe AEs, AEs leading to study‐drug discontinuation, or dose‐limiting toxicities were reported. RG7652 monotherapy reduced mean LDL‐C levels by up to 64% and as much as 100 mg/dL at week 2; the effect magnitude and duration increased with dose (≥57 days following a single RG7652 dose ≥300 mg). Exploratory analyses showed reduced oxidized LDL, lipoprotein(a), and lipoprotein‐associated phospholipase A2 with RG7652. Antidrug antibody against RG7652 tested positive in 2 of 60 (3.3%) RG7652‐treated and in 4 of 20 (20.0%) placebo‐treated subjects. Simultaneous atorvastatin administration did not appear to impact the pharmacokinetic profile or lipid‐lowering effects of RG7652. Conclusions Overall, RG7652 elicited substantial and sustained dose‐related LDL‐C reductions with an acceptable safety profile and minimal immunogenicity.

Usefulness of alirocumab and evolocumab for the treatment of patients with diabetic dyslipidemia

“…A phase 1 study of RG7652 (Roche Genentech), another fully human monoclonal antibody, revealed a substantial and sustained reduction of LDL-C, with an acceptable safety profile and minimal immunogenicity. 28 In conclusion, PCSK9 inhibitors are useful for the treatment of diabetic dyslipidemia. Research regarding the risk of developing diabetes mellitus following long-term exposure to PCSK9 inhibitors is warranted.…”

“…26 Because these anti-PCSK9 antibodies have already demonstrated their importance, a great effort has been made by pharmaceutical companies to develop additional PCSK9 inhibitors. 27 In 2017, Pfizer Inc. 27 and Genentech Inc. 28 reported the efficacy and safety of two new anti-PCSK9 antibodies, bococizumab 27 and RG7652 28 ; however, those trials were not specifically designed for subjects with diabetic dyslipidemia. It should be emphasized that different types of anti-PCSK9 drugs have distinct mechanisms of action.…”

PCSK9 monoclonal antibodies: An overview

“…Findings from PCSK9 monoclonal antibodies research did not find excess in muscle adverse symptoms or rise in creatinine kinase or liver enzyme levels which are commonly associated with statin therapy. [ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ] Nasopharyngitis and mild self-limited injection site reactions (e.g., itching, redness, and swelling) are considered the most frequent adverse reactions. [ 4 59 62 ]…”

“…Although bococizumab development was stopped in 2016, [ 7 ] trials on other potential monoclonal antibodies are ongoing with encouraging initial results. [ 8 9 10 11 ] The efficacy and the safety of PCSK9 monoclonal antibodies in the treatment of hypercholesterolemia will be discussed in this overview.…”

Efficacy and safety of PCSK9 monoclonal antibodies: an evidence-based review and update

“…After the completion of six bococizumab studies, an unexpected attenuation of effect on LDL-C over time was observed, in addition to high rates of injection-site reaction due to high immunogenicity 9 . However, the development of new investigational monoclonal antibodies to inhibit PCSK9 is well under way with promising initial results [10][11][12][13] . This review will discuss the efficacy and safety profile of PCSK9 monoclonal antibodies or inhibitors in the treatment of familial and non-familial hypercholesterolemia.…”