Evolocumab Research Articles

Abstract 15073: Response to PCSK9 Inhibition in Homozygous Familial Hypercholesterolemia Patients is Variable in Different Regions of the World and According to Age

Background: Reductions in LDL-C with PCSK9-inhibition in HoFH subjects are highly variable even within populations with the same pathogenic variants. Whilst initial studies were done in HoFH patients of European decent, recent studies from India and other countries with novel pathogenic variants as well as studies in paediatric patients have shown substantially less response to PCSK9 inhibition. In the global phase 3 LIBerate-HoFH trial, we evaluated two different PCSK9 inhibitors, lerodacibep (LIB) 300 mg SC QM and evolocumab (EVO) 420 mg SC QM in genetically confirmed HoFH patients on stable background lipid lowering therapy. Methods: Eligible patients (age ≥10 years) were randomized to either LIB or EVO for 24 weeks (Period A) followed by an 8 week ‘washout’ and crossed over to the alternate drug for the next 24 weeks (Period B). In a post-hoc analysis, the mean reduction in average LDL-C with both drugs were evaluated according to various world regions and age. Results: Of 65 who entered Period A, 56 completed both periods: 31 in USA/Europe/Israel/South Africa; 15 in India and 10 in Turkey. Mean baseline LDL-C was 401 mg/dL; 55% were female and 19(34%) were adolescents aged <18 years. For the total population, the mean (SE) reduction in average LDL-C was -9.6% (3.25) on LIB and -11.7% (3.65) on EVO (p=0.44, NS). LDL-C reductions varied considerably in different regions and response was poorer in the adolescent subjects. However, reductions in LDL-C of ≥15% were seen in 26.8% (n=15) with LIB and 37.5% (n=21) with EVO - Table. Conclusions: Reductions in LDL-C achieved with PCSK9-inhibition in HoFH subjects are highly variable and differ according to region and age. However, given the clinically significant reductions in LDL-C in 1/3 of patients including patients from India and Turkey with null/null or novel variants, PCSK9 inhibition should remain part of standard of care for HoFH patients who remain with elevated LDL-C levels despite treatment with statin and ezetimibe.

Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Podocytes in Mouse Nephrotic Syndrome

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to play a crucial role in dyslipidemia, and an increase in serum PCSK9 levels has also been reported in patients with nephrotic syndrome (NS). However, the specific effects of PCSK9 in kidney disease and the therapeutic potential of targeting PCSK9 in NS remain elusive. We thus investigated the effects of evolocumab (EVO) in mice with adriamycin (ADR)-induced NS. Male BALB/c mice were divided into the following 4 groups: Control, N = 11; EVO (monoclonal antibody for PCSK9), N = 11; ADR, N = 11; and ADR+EVO, N = 11. We also performed in vitro experiments using immortalized murine podocyte cells to validate the direct effects of PCSK9 on podocytes. EVO decreased urinary albumin levels and ameliorated podocytopathy in mice with ADR nephropathy. Further, EVO suppressed the Nod-like receptor protein 3 (NLRP3) inflammasome pathway in podocytes. PCSK9 expression upregulated CD36, a scavenger receptor of oxidized low-density lipoprotein (Ox-LDL), which in turn stimulated the absorption of Ox-LDL in vitro. EVO downregulated CD36 expression in podocytes both in vitro and in vivo. Immunofluorescence staining analysis reveals that CD36 and PCSK9 colocalized in the glomerular tufts of mice with ADR nephropathy. In the patients with focal segmental glomerulosclerosis, the CD36+ area in glomerular tufts increased compared with those diagnosed with minor glomerular abnormalities. This study revealed that EVO ameliorated mouse ADR nephropathy through the regulation of CD36 and NLRP3 inflammasome signaling. EVO treatment represents a potential therapeutic strategy for human NS.

PCSK9 Promotes Endothelial Dysfunction During Sepsis Via the TLR4/MyD88/NF-κB and NLRP3 Pathways.

Endothelial dysfunction often accompanies sepsis. We aimed to explore the role of PCSK9 in septic endothelial dysfunction. Sepsis was induced by lipopolysaccharide (LPS) treatment of human umbilical vein endothelial cells (HUVECs) in vitro and cecal ligation and puncture (CLP) surgery in mice in vivo. Evolocumab (EVC) and Pep 2-8, PCSK9 inhibitors, were subsequently used to determine the role of PCSK9 in sepsis-induced endothelial dysfunction in vitro and in vivo, respectively. In addition, the TLR4 agonist, Kdo2-Lipid A ammonium (KLA), was used to determine the related mechanism. Protein expression of eNOS, VE-cadherin, PCSK9, TLR4, MyD88, p-p65, p65, NLRP3, ASC, and caspase-1 p20 in mice aortas and HUVECs was measured by western blotting, while mRNA expression of TNFα, IL-1β, and IL-18 was determined by qRT-PCR. The level of inflammatory cytokines of mouse aortas was visualized by immunohistochemistry. Vasodilation of the aorta was detected by vascular reactivity experiments. The 96-h survival rate after CLP was assessed. Our findings showed that the expression of eNOS and VE-cadherin decreased, and PCSK9 expression increased, in septic HUVECs or mice. Inhibition of PCSK9 increased eNOS and VE-cadherin expression. Activation of the TLR4/MyD88/NF-κB and NLRP3 pathways may be responsible for PCSK9-induced endothelial dysfunction in sepsis. Vascular reactivity tests and survival studies showed that inhibition of PCSK9 could prevent the decrease in endothelium-dependent vasodilation function and improve the survival rates of septic mice. In summary, our results suggested that increased PCSK9 expression during sepsis activated the TLR4/MyD88/NF-κB and NLRP3 pathways to induce inflammation, which resulted in vascular endothelial dysfunction and decreased survival rates. Thus, inhibition of PCSK9 may be a potential clinical therapeutic target to improve vascular endothelial function in sepsis.

Abstract 11043: Clinical Safety Outcomes in Relation to Lipoprotein(a) Concentration: Insights from the FOURIER Trial

Background: Lipoprotein(a) is believed to play a causal role in atherogenesis. Drugs are in development that directly target Lp(a) and lower levels by >75%. Thus, the safety of low Lp(a) levels is of importance. Methods: FOURIER randomized 27,564 patients w/ stable ASCVD to evolocumab (EVO) vs placebo on background statin (median f/up 2.2 y); EVO lowered Lp(a) levels by 27%. The relationships between Lp(a) levels, change in Lp(a) and 5 safety outcomes of interest based on prior reports (diabetes [DM], serious bleeding, hemorrhagic stroke, neurocognitive events, malignancy) were examined. Analyses were conducted in the overall population and by treatment arm. Multivariable models included age, sex, race, region, clinical predictors, high-intensity statin, ezetimibe, baseline hs-CRP, “Lp(a)-corrected” LDL-C, and treatment arm. Results: Lp(a) was assessed in 25,083 participants at baseline (median 37nM, range 5-1451) and 25,686 at week 12. There was no association between baseline or achieved Lp(a) levels and risk of serious bleeding, hemorrhagic stroke, neurocognitive events, or malignancy, even in the 3271 patients with Lp(a) levels ≤6nM. There was an inverse association between baseline Lp(a) levels and prevalent or incident DM [OR 1.09, 95%CI 1.07-1.12, for every 50nM lower Lp(a) below 250nM]. However, absolute change in Lp(a) with EVO was not associated with subsequent DM risk (HR 1.03, 0.91-1.16, per 50nM) and EVO did not increase the risk of DM irrespective of baseline Lp(a) (P int=0.97), even in participants in the top decile of baseline Lp(a) (HR 0.91, 0.51-1.62) in whom EVO reduced Lp(a) by 63nM. Conclusion: Lp(a) concentration and changes in Lp(a) were not associated with serious bleeding, hemorrhagic stroke, neurocognitive events, or malignancy. Levels were inversely correlated with having DM, but Lp(a) lowering over a median of 2.2 years with EVO did not further increase the risk. These findings provide new insights for ongoing trials of Lp(a)-lowering drugs.

SO076EVOLOCUMAB HAS THERAPEUTIC EFFECTS ON EXPERIMENTAL MODEL OF FSGS

Abstract Background and Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9), which accelerates LDL-receptor degradation, plays a central role in dyslipidemia in nephrotic syndrome (NS). Intracellular LDL-C accumulation is supposed to damage podocytes through oxidative stress, foam cell formation, and apoptosis. In the present study, we investigate the effects of evolocumab (EVO), which is anti-PCSK9 monoclonal antibody, on a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with NS in order to clarify the potential of EVO as a therapeutic agent in FSGS. Method Male BALB/c mice aged 9 to 11 weeks were divided into vehicle and intervention groups. The mice underwent subcutaneous injection of normal saline (FSGS-Vehicle group) or EVO (30 mg/kg) (FSGS-EVO group) and immediately after that, they were administered adriamycin (11.5 mg/kg) from tail vein. All mice were sacrificed on Day 14, and then morphological and functional analyses were performed. Results EVO treatment significantly reduced serum levels of LDL-C (mg/dl, 305.3±77.1 vs. 159.1±31.7, p<0.01) and PCSK9 (ng/ml, 652.9±230.0 vs 311±116.5, p<0.001). In addition, EVO treatment significantly improved renal function, including albuminuria (albumin/creatinine (Cr), 15.73±1.26 vs. 7.32±1.02, p<0.001), serum Cr (mg/dl, 0.48±0.13 vs. 0.18±0.044, p<0.001) and BUN (mg/dl, 80.08±20.22 vs. 46.86±9.60, p<0.05). Compatibly with the clinical data, the severity of glomerulosclerosis score (semi-quantification, 2.44 vs. 1.95, p<0.001) was ameliorated and podocyte density (number of podocyte/glomerulus, 2.61 vs. 7.54, p<0.001) was maintained in the FSGS-EVO mice compared with the FSGS-Vehicle mice. Conclusion Our findings provided novel insights into the protective effects of EVO on adriamycin nephropathy, indicating EVO as a potent therapeutic agent for FSGS.

Abstract 11946: Effect of Evolocumab on Non-high-density Lipoprotein Cholesterol and Apolipoprotein B Levels: An Analysis of Double-blind and Open-label Extension Studies

Introduction: Dyslipidemia guidelines have recommended non-HDL-C and ApoB either as co-primary or secondary targets of therapy. Objective: To evaluate the effect of evolocumab on non-HDL-C and ApoB...

Phase 3 Study to Evaluate the Efficacy and Safety of LIB003 With Evolocumab in HoFH

Phase 3 Study to Evaluate the Efficacy and Safety of LIB003 With Evolocumab in HoFH

Abstract 545: Evolocumab Alters LDL-cholesterol Levels but Not Glycemic Profile and Liver Lipids in Chow Fed and High fat/Cholesterol/Fructose Fed Golden Syrian Hamsters

Background: Beside its effect on LDL-cholesterol levels, proprotein convertase subtilisin/kexin9 (PCSK9) could also be linked to glucose metabolism and non-alcoholic fatty liver diseases. Here we evaluated whether Evolocumab (EVO), a monoclonal antibody targeting PCSK9, may alter glycemic profile and liver lipids in hamsters. Methods: Hamsters were maintained on either a control chow (CC) or high fat/cholesterol/fructose (HFCF) diet for 5 weeks. After 2 weeks of diet, hamsters were randomized into 2 groups, control or EVO at 30mg/kg s.c. once weekly for 3 weeks, to evaluate the effects on lipoprotein/glycemic profiles, and liver lipids. Results: When compared with CC diet, HFCF diet significantly increased total cholesterol and LDL-cholesterol levels by 87% and 102%. Hamsters fed the HFCF diet also showed higher HOMA-IR index of insulin resistance, higher blood glucose area under the curve (AUC) during an oral glucose tolerance test (OGTT), and higher liver lipids (triglycerides: +197%, total cholesterol: +421%, both p<0.001 vs. CC). However, plasma PCSK9 levels were markedly reduced by 47% in HFCF fed hamsters (p<0.001 vs. CC). As expected, treatment with EVO significantly increased hepatic LDL-receptor protein levels by 1.74-fold and reduced plasma LDL-cholesterol by up to 28% in CC fed hamsters (p<0.01 vs. CC control). The LDL-cholesterol reduction was also observed in HFCF fed hamsters treated with EVO, but to a lesser extent (up to 16%). In both CC and HFCF fed hamsters, EVO did not alter fasting glycemia and plasma insulin levels. IN CC fed hamsters, EVO transiently reduced blood glucose levels by 15% at time 15 minutes (p<0.01 vs. CC control) after an oral glucose load. However, EVO did not change blood glucose levels AUC or plasma insulin levels during the OGTT, in neither CC nor HFCF fed hamsters. As well, no change in liver lipids levels was observed in CC or HFCF fed hamsters treated with EVO. Conclusion: Our data indicate that diet-induced insulin resistance and liver steatosis in hamsters are not associated with elevated plasma PCSK9 levels, and are not altered by Evolocumab. Whether these results are specific to our hamster model and can translate to humans remains to be further investigated.

INSIDE INDUSTRY

Drug development companies in APAC need to raise their game to capitalise on the $33bn+ immuno-oncology treatment opportunity Singapore’s pharmaceutical market value to reach $1.15 billion by 2021 Ryzodeg reduces hypoglycaemia in type 2 diabetic fasting patients FDA approves Amgen’s Repatha (evolocumab) to prevent heart attack and stroke FDA approves first drug for rare disease, eosinophilic granulomatosis with polyangiitis FDA approves first biosimilar for the treatment of certain breast and stomach cancers FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss Singapore institutes collaborate with Samsung Medical Center to improve treatment of liver cancer Globavir announces partnership with Singhealth Duke-NUS Academic Medical Centre to study dengue treatment Mundipharma secures exclusive license for the development and commercialisation of PAION’s remimazolam in Japan

Outcomes-based pricing: effects on evolocumab

Outcomes-based pricing: effects on evolocumab

Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a post-commercialization study

BackgroundEfficacy-safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO), have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in 69 patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated LDLC therapy, we assessed efficacy and safety of ALI and EVO.MethodsPost-commercially, we started 29 patients on ALI 75 mg, 18 on ALI 150 mg, and 22 on EVO 140 mg every 2 weeks added to a maximally tolerated LDLC-lowering regimen. Since LDLC lowering did not differ between ALI 150 and EVO 140 mg, ALI 150-EVO 140 data were pooled (ALI-EVO). Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed.ResultsOf the 69 patients, 25 had HeFH, 25 CVD, and 19 had both. At entry, 23 (33%) took statins and 46 (67%) were statin-intolerant. Mean ± SD and median follow-up were 49 ± 13 and 49 weeks on ALI 75 mg, and 37 ± 12 and 33 weeks on ALI-EVO. In the ALI-EVO group (n = 40), median LDLC fell from 165 mg/dl at entry to 70 mg/dl (median − 59%, p < .0001). AHA 10-year calculated CVD risk fell from 10.2 to 5.5% (median − 28%, p < .0001), and by the NIH calculator from 14.2 to 3.6% (median − 78%, p < .0001). In the ALI 75 mg group (n = 29), entry LDLC fell from 115 to 68 mg/dl (median − 39%, p < .0001). AHA 10-year calculated CVD risk fell from 11.5 to 7.3% (median − 20%, p = .004), and NIH 10-year risk from 12.9 to 5.1% (median 67%, p < .0001). Absolute and percent change in LDLC was independent of statin use. There were flu-like symptoms in 14% of patients. Adverse events did not differ (p > 0.05) between ALI 75 mg and ALI-EVO.ConclusionIn patients with HeFH and/or CVD, LDLC decreased from 115 to 68 mg/dl (39%) on ALI 75 mg with mean follow-up of 49 weeks, and from 165 to 70 mg/dl (59%) on ALI-EVO over 37 weeks, p < .0001 for both. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering.

▾ Evolocumab as an adjunct to statins for CVD

▾ Evolocumab as an adjunct to statins for CVD

Evolocumab cost effective in patients with HeFH

Evolocumab cost effective in patients with HeFH

Evolocumab Improves Cardiovascular Outcomes

Prior research on evolocumab — a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) — has shown that this now

Efficacy, safety, Low density lipoprotein cholesterol lowering, and calculated 10-year cardiovascular risk reduction of alirocumab and evolocumab in addition to maximal tolerated cholesterol lowering therapy: a post-commercialization study

BackgroundEfficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO) have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated cholesterol lowering therapy, we assessed efficacy and safety of ALI and EVO.MethodsPost-commercially, we started 25 patients on ALI 75 mg, 15 on ALI 150 mg, and 32 on EVO 140 mg bi-weekly added to entry LDLC lowering regimen, with follow-up for a median 24 weeks. History, physical exam, demographics, and adverse event data were collected. Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed on ALI and EVO.ResultsOf 72 patients, 25 had HeFH only, 25 CVD only, 22 had both, median age was 65 years, 63% females, 38% males, 86% Caucasian, 11% African-Americans, 17% diabetics, 63% on anti-hypertensives, and 7% smokers. At entry, 30 (42%) were on a statin and 42 (58%) could not tolerate any statins.At 24-weeks, median LDLC decreased on ALI 75 mg from 117 to 62 mg/dL (−54%), on ALI 150 mg from 175 to 57 mg/dL (−63%), and on EVO 140 mg from 165 to 69 mg/dL (−63%), p <0.0001 for all. Absolute and percent LDLC reduction did not differ (p >.05) between ALI 150 and EVO 140 mg, but were less on ALI 75 mg vs ALI 150 mg and EVO 140 mg (p <.05).Percent reductions in 10-year CVD risks by AHA and NIH calculators, respectively were ALI 75 mg −22 and −44%, ALI 150 mg −31 and −50%, and EVO 140 mg −29 and −56%, p ≤.002 for all.The three most common adverse events included flu-like myositis 10%, respiratory tract symptoms 8%, and injection site reaction 6%.ConclusionIn patients with HeFH and/or CVD, LDLC was lowered by 63% on EVO and ALI 150 mg, and 54% on ALI 75 mg. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering. Long term, post-commercial safety and efficacy remain to be determined.

Research progress in proprotein convertase subtilisin/kexin type 9 monoclonal antibody

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in lipid regulation through interaction with low-density lipoprotein cholesterol receptors, and several types of PCSK9 inhibitors are gradually becoming research hotspots due to their lipid lowering effect. Among them PCSK9 monoclonal antibodies are the closest to clinical application, and a number of phase Ⅲ clinical trials in PCSK9 monoclonal antibodies have been completed in recent years. We systemically reviewed the current clinical research on PCSK9 monoclonal antibodies in this paper, in order to understand their efficacy and long-term safety in reducing the risk of cardiovascular diseases. Key words: Proprotein convertase subtilisin/kexin type 9; Monoclonal antibody; Dyslipidemia; Evolocumab; Alirocumab; Bococizumab

Alirocumab and evolocumab recommended by NICE

Alirocumab and evolocumab recommended by NICE

PCSK9 inhibitors: new treatment to lower cholesterol

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors appear to represent an important development in the management of hypercholesterolemia. US Food and Drug Administration and European Medicines Agency approved alirocumab and evolocumab, injected drugs administered subcutaneously every 2 or 4 weeks, for patients with hypercholesterolemia, such as those who not reached the cholesterol targets or those with intolerance to statin, especially in secondary prevention or familial hypercholesterolemia. This decision is based on several clinical trials suggesting that these drugs have a powerful effect on levels of LDL-cholesterol with an acceptable safety compared to placebo. Large clinical studies are currently performed to assess the impact of PCSK9 inhibitors on major adverse cardiovascular events in secondary prevention.

Evolocumab: Second-in-class agent for lowering cholesterol

Evolocumab: Second-in-class agent for lowering cholesterol