Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Gibbs, John P.; Slatter, J. Greg; Egbuna, Ogo; Geller, Michelle; Hamilton, Lisa; Dias, Clapton; Xu, Ren; Johnson, Jessica; Wasserman, Scott M.; Emery, Maurice G.

doi:10.1002/jcph.832

Cited by 21 publications

(31 citation statements)

References 32 publications

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“…14,15 In this study, evolocumab effectively lowered LDL-C levels in patients with severe RI or ESRD receiving hemodialysis; the magnitude and timing of LDL-C lowering were consistent with those reported recently in a hepatic impairment study 16 and in other evolocumab clinical trials. Mean baseline serum PCSK9 levels and the time course of PCSK9 lowering by evolocumab were similar in the normal renal function and renally impaired groups, indicating that target-mediated clearance of evolocumab is not affected by impaired renal function.…”

Section: Discussionsupporting

confidence: 89%

“…Patients with severe RI and ESRD had geometric mean C max and AUC last that were within 37% of patients with normal renal function with no adjustment for body weight and within 26% after adjustment for body weight. 4,9 AUC last , area under the drug concentration-time curve from time zero to time of last quantifiable concentration; AUC inf , area under the drug concentration-time curve from zero to infinity; C max , maximum observed drug concentration; ESRD, end-stage renal disease; Q, quartile; SD, standard deviation; t max , time to reach C max . Of note, least-squares geometric mean evolocumab exposure values in patients with normal renal function were higher than recently reported.…”

Section: Discussionmentioning

confidence: 99%

“…9 As the anti-idiotype antibodies bound to the antigen-combining site of evolocumab, these antibodies do not bind to evolocumab bound to PCSK9. 9 As the anti-idiotype antibodies bound to the antigen-combining site of evolocumab, these antibodies do not bind to evolocumab bound to PCSK9.…”

Section: Methodsmentioning

confidence: 99%

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Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety

Lee

Gibbs

Emery

et al. 2019

Clinical Pharm in Drug Dev

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We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open‐label, parallel‐design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end‐stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140‐mg dose of evolocumab. The effects of evolocumab treatment on low‐density lipoprotein cholesterol (LDL‐C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean C max and AUC last values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere‐Terpstra trend test; C max , P = .23; AUC last , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by C max and AUC last , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL‐C‐lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety

Lee

Gibbs

Emery

et al. 2019

Clinical Pharm in Drug Dev

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“…However, anti‐PCSK9 antibodies are proteins and are therefore not expected to be metabolised by the liver or kidneys; hence, no effects on the liver or kidneys are expected. For evolocumab, a small pharmacokinetics study reported no differences in efficacy or safety between healthy volunteers and in patients with mild or moderate hepatic impairment . Another evolocumab study reported no differences in LDL‐C lowering or safety among patients with normal renal function and those with severe renal impairment or end‐stage renal disease .…”

Section: Resultsmentioning

confidence: 99%

“…For evolocumab, a small pharmacokinetics study reported no differences in efficacy or safety between healthy volunteers and in patients with mild or moderate hepatic impairment. 66 Anotherevolocumab study reported no differences in LDL-C lowering or safety among patients with normal renal function and those with severe renalimpairmentorend-stagerenaldisease. 67 Therecentlypublished FOURIER study included patients with renal impairment (glomerular filtrationrateaslowas20mL/min) 26 and subgroup analyses examining the safety and efficacy of evolocumab in this population are expected.…”

Section: Safety Data For Anti-pcsk9 Antibodies and Other Lltsmentioning

confidence: 99%

Anti-PCSK9 antibodies for hypercholesterolaemia: Overview of clinical data and implications for primary care

et al. 2017

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SummaryObjectivesTo put data from our recent systematic review of phase 3 studies of anti‐proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies into the context of clinical practice.MethodsData from studies previously identified by a systematic review of phase 3 studies of alirocumab and evolocumab and additional references from non‐systematic literature searches were used. We evaluated the hypothetical cardiovascular (CV) benefit in cases of typical patients in whom anti‐PCSK9 antibodies may be recommended, using preliminary major CV event (CVE) rates from long‐term clinical trials of anti‐PCSK9 antibodies and from extrapolations derived from correlation between low‐density lipoprotein cholesterol (LDL‐C) reduction and CV benefit with other lipid‐lowering therapies (LLTs).ResultsRapid (within 1‐2 weeks) and persistent (8‐74 weeks) reductions in LDL‐C levels were achieved with anti‐PCSK9 antibodies. When combined with statins (± ezetimibe), high rates of LDL‐C goal achievement were observed (41%‐87% with alirocumab and 63%‐100% with evolocumab). In long‐term alirocumab and evolocumab studies, reductions in major CVEs of 48% and 53%, respectively, were observed. For every 38.7 mg/dL (1 mmol/L) reduction in LDL‐C, a 22% reduction in relative CVE risk is predicted. Applying these assumptions to typical patients who have high–very high risk (15%‐60% absolute 10‐year CVE risk) and elevated LDL‐C despite maximally tolerated statins, the 10‐year number needed to treat with an anti‐PCSK9 antibody to prevent one additional CVE varies from 4 to 26, depending on baseline LDL‐C levels and residual absolute CVE risk.ConclusionsAnti‐PCSK9 antibodies effectively lower LDL‐C levels in a broad patient population. While awaiting comprehensive data from CV outcome trials, these agents should be considered in very high risk patients, such as those in secondary prevention and those with familial hypercholesterolaemia who are already receiving maximally tolerated LLTs, have not achieved their LDL‐C goal and require substantial reductions in LDL‐C.

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Does Hepatic Impairment Affect the Exposure of Monoclonal Antibodies?

Sun

Seo

Zvada

et al. 2020

Clin Pharma and Therapeutics

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Limited information is available regarding the effect of hepatic impairment (HI) on the pharmacokinetics of monoclonal antibodies (mAbs). The results of an earlier report based on therapeutic proteins, including mAbs, approved through the end of 2012 were inconclusive due to limited HI data available at that time. New HI data for mAbs or antibody-drug conjugates (ADCs; with a focus on the mAb component) available between 2013 and 2018 were evaluated. The investigation indicates there is almost no data for severe HI, limited data for moderate HI, and abundant data for mild HI. A significant exposure decrease was found for several mAbs or ADCs and a trend for decreasing area under the concentration-time curve (AUC) was observed for other mAbs. Multiple potential mechanisms may contribute to the exposure decrease. Dose may need to be adjusted for patients with HI, after taking into account the exposure-response relationships for both efficacy and safety.There are increased efforts to evaluate monoclonal antibodies (mAbs) to treat various diseases and conditions, including, but not limited to, cancer, autoimmune diseases, infectious diseases, and inflammatory conditions. 1 Since 2014, about 30% of the approved new molecular entity drugs each year are therapeutic proteins (TPs), and the majority of them are mAbs (Figure 1). However, regulatory guidance and literature reports provide limited information regarding the effect of hepatic impairment (HI) on the pharmacokinetics (PK) of mAbs. Patients with HI are included in the targeted population for many mAbs, and patients may develop hepatic dysfunction as diseases progress (e.g., hepatitis, metastatic cancers). Therefore, it is essential to understand the effect of HI on PK of mAbs to provide an accurate dosing strategy for those patients.It is well known that the liver plays a vital role in the metabolism and transport of small molecule drugs by a variety of enzymes and transport proteins. Hepatic impairment may alter systemic exposure and affect clinical effectiveness and tolerability of small molecule drugs, if hepatic metabolism and/or excretion accounts substantially for their elimination. 2 TPs, including mAbs, are cleared through ubiquitous proteolytic catabolism by lysosomal degradation to amino acids, thus HI is generally thought to not affect the PK of mAbs. However, the elimination mechanisms for mAbs are far more complicated than nonspecific and unsaturable catabolism. Factors affecting the neonatal Fc (fragment crystallizable region) receptor (FcRn) binding, target-mediated drug disposition (TMDD), Fc gamma receptor (FcγR) binding, or other unknown mechanisms can alter the exposure of mAbs,

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Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Cited by 21 publications

References 32 publications

Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety

Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety

Anti-PCSK9 antibodies for hypercholesterolaemia: Overview of clinical data and implications for primary care

Does Hepatic Impairment Affect the Exposure of Monoclonal Antibodies?

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