Landmesser, Ulf

Abstract Background Patients (pts) with hyperlipidaemia and established cerebrovascular disease (CeVD) are at an increased risk of future strokes or other cardiovascular events.[1] In ischaemic stroke survivors, statins and inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) reduce recurrent cardiovascular events including stroke.[2–4] With guidelines increasingly advocating lower LDL-C goals, add-on lipid lowering therapies to statins may be needed. Inclisiran, a first-in-class small interfering RNA (siRNA) targeting PCSK9 messenger RNA, when added to maximally tolerated statin therapy, may provide further LDL-C lowering with a convenient, infrequent dosing schedule in pts with established CeVD. Purpose To assess efficacy and safety of inclisiran in pts with established CeVD. Methods Pts with HeFH, ASCVD or its risk equivalents from ORION-9 (NCT03397121]), ORION-10 (NCT03399370), and ORION-11 (NCT03400800) were randomised 1:1 to receive inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) or placebo (pbo) at Days 1, 90 and 6-monthly thereafter to Day 540. This post hoc analysis included pts with established CeVD (ischaemic stroke, and/or carotid artery stenosis by angiography or ultrasound >70%, and/or prior percutaneous or surgical carotid artery revascularisation). Percentage LDL-C change from baseline to Day 510 and corresponding time-averaged percentage change from baseline after Day 90 to Day 540 were evaluated. Safety was assessed over 540 days. Results Of 202 pts with established CeVD, 110 and 92 received inclisiran and pbo, respectively. At baseline, 90.0% (99/110) of pts in inclisiran and 84.8% (78/92) in pbo group reported prior ischaemic stroke(s); others had carotid artery stenosis and/or carotid revascularisation (Table 1). Mean (95% CI) pbo-corrected LDL-C percentage change from baseline at Day 510 with inclisiran was −55.2% (−64.5 to −45.9); corresponding time-averaged change from baseline after Day 90 to Day 540 was −55.2% (−62.4 to −47.9) (P<0.0001 for each; Table 2). Treatment-emergent adverse event (TEAE) and treatment-emergent serious adverse event (TESAE) were more frequent in the inclisiran vs pbo group but were consistent with the overall pooled (N=3655) population of the combined trials. Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran (3.6% [4/110]) vs pbo (0% [0/92]), but none were severe. Percentage of pts with clinically relevant laboratory measurements was low and similar between treatment groups and consistent with the overall pooled population (Table 2). Conclusions In pts with established CeVD, a twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided sustained additional LDL-C reduction of ∼55%. A modest excess of mild/moderate TEAEs at the injection site were reported with inclisiran. The cardiovascular benefits of inclisiran among patients with established CeVD are being evaluated in ongoing trials. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG, Basel, Switzerland.

Abstract Background Approximately 25% of patients (pts) with atherosclerotic cardiovascular disease (ASCVD) have polyvascular disease (PVD), which involves ≥2 coronary, cerebrovascular, and peripheral artery beds. PVD is an independent predictor of major adverse cardiovascular (CV) events (MACE) and death.[1,2] Agents that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) resulted in reduced low-density lipoprotein cholesterol (LDL-C) concentration and MACE incidence in pts with PVD.[3,4] Inclisiran is a small interfering RNA (siRNA) agent targeting PCSK9 messenger RNA that provided effective and sustained reduction in LDL-C concentration and was well tolerated.[5] Purpose To describe the effect inclisiran versus placebo (pbo) in pts with and without PVD. Methods This was a post hoc analysis from the ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800) trials. Pts with heterozygous familial hypercholesterolaemia, ASCVD or risk equivalents were randomised 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or pbo at baseline, Day 90, and 6-monthly thereafter. LDL-C percentage change from baseline to Day 510 and corresponding time-averaged change from Day 90 and to Day 540 were evaluated by presence or absence of PVD (intention-to-treat population). Safety was assessed over 540 days (safety population). Results Of 3454 pts, 470 (13.6%) had PVD and 2984 (86.4%) did not. Baseline characteristics were generally balanced between treatment arms in both groups (Table 1). A greater proportion of pts with vs without PVD had CV risk factors at baseline. Mean LDL-C concentration at baseline was lower in pts with vs without PVD (Table 1). Mean (95% CI) pbo-corrected LDL-C percentage change from baseline to Day 510 with inclisiran was −48.9 (−55.6 to −42.2) in pts with PVD and −51.5 (−53.9 to −49.1) in pts without PVD (Table 2). Proportions of pts with treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events (TESAE) were similar between treatment arms irrespective of PVD status although reported TESAEs were numerically greater in both treatment arms for pts with PVD (Table 2). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo in both groups but all were mild or moderate (Table 2). Proportions of pts with clinically relevant laboratory measurements were low and similar between treatment arms for both groups (Table 2). Conclusions Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering in pts, irrespective of their PVD status, with a safety profile similar to pbo, except for a modest excess of mainly mild TEAEs at the injection site. Notably, TESAEs were reported more frequently in pts with PVD, which was likely due to their more advanced disease. Since pts with PVD are at high risk of CV events, intensive LDL-C lowering may be beneficial to reduce this risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG, Basel, Switzerland

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C >70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p<0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

Abstract Introduction Inclisiran, an investigational siRNA, has been shown to effectively and durably lower LDL-C in Phase 3 trials. Inter-individual variability in LDL-C reductions has been documented for statin therapy and ezetimibe. Purpose To evaluate the inter-individual variability in LDL-C lowering with inclisiran. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) who had LDL-C >70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. Co-primary endpoints were the LDL-C reduction from baseline to Day 510 and the time adjusted average % change in LDL-C reduction after Day 90 and up to Day 540. Measures of response variability were pre-specified secondary endpoints. This analysis examines the inter-individual variability of LDL-C reductions at day 510 using pooled data from both trials. Results The analysis included 3178 individuals (92% on statins). At Day 90, 97% of inclisiran-treated patients had an LDL-C reduction. At Day 510, the median percent reduction in LDL-C levels from baseline was 57.3% in the inclisiran group (interquartile range, 44%-70%). An LDL-C reduction ≥50% was reached by 1359 (86.6%) inclisiran-treated patients versus 97 (6.2%) placebo patients at any visit (odds ratio [OR] 97.6, 95% confidence interval [CI] 76–126). An LDL-C reduction ≥30% was reached by 1523 (97.0%) inclisiran-treated patients versus 371 (23.7%) placebo patients (OR 104.5, 95% CI 76–143). At Day 510, 921 patients (65.1%) in the inclisiran group had a reduction ≥50% in LDL-C compared to 34 patients (2.4%) in the placebo group, and 1228 (86.8%) had a reduction ≥30% compared to 148 (10.5%), respectively. Among placebo-treated patients, there was a substantial proportion with notable increases in LDL-C at Day 510 (figure). Conclusion In Phase 3 trials, inclisiran on top of maximally tolerated statins provided reliable, consistent and durable reductions in LDL-C. A large percentage of subjects randomized to inclisiran achieved substantial reductions (>50%) in LDL-C and nearly all achieved at least a 30% reduction suggesting inclisiran is potentially a promising novel therapy for patients needing sustained LDL-C reductions. Waterfall plot of pooled trials Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

Abstract Introduction Elevated triglyceride (TG) levels contribute to the total burden of circulating atherogenic lipoprotein levels and are associated with increased cardiovascular (CV) risk. LDL-C underestimates risk in patients with elevated TG. Therefore, 2019 ESC/EAS guidelines recommend apoB or non-HDL-C as secondary lipid goals for patients with TG >150mg/dL. Purpose To assess the impact of inclisiran on apoB and non-HDL-C goal attainment across a range of TG levels among patients with atherosclerotic CV disease (ASCVD). Methods The ORION-10 and ORION-11 trials included 3178 patients with ASCVD and LDL-C >70mg/dl despite maximally tolerated statins randomized to inclisiran or placebo (1:1). Pre-specified secondary endpoints were placebo-corrected changes in lipids at Day 510. For this analysis patients were stratified by TG quartiles at baseline within each trial. The proportion of individuals attaining apoB <55 mg/dL or non-HDL-C <70mg/dl within each trial were assessed across TG strata and the likelihood of goal attainment within TG strata assessed using logistic regression. Results In ORION-10, TG quartiles were ≤94, 94 to ≤128, 128 to ≤181 and >181mg/dl respectively and in ORION-11 corresponding values were ≤101, 101 to ≤135, 135 to ≤183 and >183mg/dl. As compared to placebo a significantly greater proportion of patients randomised to inclisiran attained apoB goals within each TG strata (Table). Similar results were observed for non-HDL-C. Conclusion Among patients with ASCVD on maximally tolerated statin and high TG levels, attainment of apoB and non-HDL-C secondary lipid targets was more likely with inclisiran than placebo. Inclisiran may be a useful therapeutic option for patients with atherogenic dyslipidaemia. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

Abstract Aims Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. Methods and results The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: −0.5%; 500 mg: −1.8%; DD: 100 mg: 1.3%; 200 mg: −0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. Conclusion In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.

Abstract Background PCSK9 inhibitors and statins both lower LDL-C by increasing LDL-receptor (LDLR) function. PCSK9 inhibitors lower Lp(a) by 20–30%, whereas statins do not lower Lp(a). The mechanism by which PCSK9 inhibitors lower Lp(a) is unclear. We assessed the role of the LDLR in Lp(a) reductions produced by inclisiran, an siRNA which prevents hepatic synthesis of PCSK9. Methods ORION-1 was a phase 2 trial of inclisiran in subjects at high ASCVD risk with elevated LDL-C on optimized statin therapy. Subjects received one dose of inclisiran (200, 300, or 500 mg) or two doses at days 1 and 90 (100, 200, or 300 mg). We assessed the correlations between % change in Lp(a) and LDL-C at Day 180 for the inclisiran groups using Spearman correlation coefficients. We additionally assessed the correlation between % change in Lp(a) and absolute change in LDL-C as a proxy for LDLR expression. Lp(a) was measured using an isoform-independent assay and LDL-C with β-quantification. Results ORION-1 included 501 subjects; mean age 63; 65% male; 73% on statins. Median baseline Lp(a) was 37.0 nmol/l (IQR: 11.5–142.0 nmol/l), median LDL-C was 117.0 (IQR: 92.5–149.5 mg/dL). Inclisiran dose-dependently lowered Lp(a) by 14% to 26%. Overall, there was a significant but weak correlation between % change in Lp(a) LDL-C (Spearman coefficient 0.35, p<0.001). This correlation appeared to be stronger at higher inclisiran doses and with repeat dosing (table), as well as in statin-users versus non-users (Spearman coefficient 0.37 vs. 0.21). The correlation between % Lp(a) change and absolute LDL-C change was weaker (0.27, p<0.001). Correlation coefficients LDL-C – Lp(a) Single-dose groups Two-dose groups Inclisiran overall 200 mg (n=60) 300 mg (n=60) 500 mg (n=60) 100 mg (n=59) 200 mg (n=60) 300 mg (n=59) Lp(a) ∼ % change LDL-C 0.22 0.26 0.22 0.29 0.47 0.51 0.35 Lp(a) ∼ absolute change LDL-C 0.35 0.12 0.04 0.22 0.45 0.24 0.27 Lp(a) ∼ % change LDL-C - Statin users 0.16 0.28 0.28 0.31 0.45 0.55 0.37 Lp(a) ∼ % change LDL-C - Non statin users 0.80 -0.08 0.09 0.10 0.63 0.09 0.21 Conclusion The dose-dependent correlation between % changes in LDL-C and Lp(a) suggests that the LDLR may be partially responsible for Lp(a) reductions produced by inclisiran. The numerically stronger correlation in statin-users supports the idea that LDL-C may compete with Lp(a) for LDLR binding especially at low LDL-C levels. Acknowledgement/Funding The Medicines Company

Abstract Background Cachexia has significant impact on the patients' quality of life and prognosis. It is frequently observed in patients with cancer, especially in advanced stages, but prevalence data for the overall population are lacking. Good quality estimates of cancer cachexia in general and for each of the major cancer types would be highly relevant for potential treatment development efforts in this field. Both the USA and European Union (EU) have implemented special clinical development rules for such rare disorders what are called ‘orphan diseases’. The cut‐off level for a disease to be considered an orphan disease in the USA is 200 000 people (0.06% of the population) and EU is 5 per 10 000 people (0.05% of the population). Methods For this systematic review, we searched at PubMed (from inception to 31 January 2018) to identify clinical studies that assessed the prevalence of cachexia in cancer patients at risk. Studies reporting the prevalence of either cancer cachexia or wasting disease in the top‐10 cancer types and 4 other selected cancer types known to be particularly commonly complicated by cachexia were included in this analysis (i.e. prostate cancer, breast cancer, colorectal cancer, melanoma, endometrial cancer, thyroid cancer, urinary bladder cancer, non‐hodgkin lymphoma, lung cancer, kidney and renal pelvis cancer, head and neck cancer, gastric cancer, liver cancer, and pancreatic cancer). We calculated the current burden of cancer cachexia, disease by disease, in the USA and in the EU and compared them to the current guidelines for the definition of orphan disease status. Results We estimate that in 2014 in the USA, a total of 527 100 patients (16.5 subjects per 10 000 people of the total population), and in 2013 in the EU, a total of 800 300 patients (15.8 subjects per 10 000 people of the total population) suffered from cancer cachexia (of any kind). In the 14 separately analysed cancer types, the prevalence of cancer cachexia in the USA ranged between 11 300 (0.4/10 000, gastric cancer) and 92 000 patients (2.9/10 000, lung cancer) and in the EU between 14 300 (0.3/10 000, melanoma of the skin) and 150 100 (3.0/10 000, colorectal cancer). Conclusions The absolute number of patients affected by cancer cachexia in each cancer group is lower than the defined thresholds for orphan diseases in the USA and EU. Cancer cachexia in each subgroup separately should be considered an orphan disease.

OBJECTIVE To evaluate the efficacy and safety of inclisiran by diabetes status. RESEARCH DESIGN AND METHODS ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C–lowering therapies, to one or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared. RESULTS Inclisiran was associated with marked declines in LDL-C (median −28% to −52%, P &lt; 0.0001 and −28% to −55%, P &lt; 0.005 for all doses in the without- and with-diabetes groups, respectively) and PCSK9. The inclisiran-treated groups also had lower apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL cholesterol. Inclisiran had an adverse profile similar to that of placebo, and adverse events were proportionally balanced in the baseline with- and without-diabetes groups. CONCLUSIONS PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option for managing dyslipidemia in the presence and absence of diabetes.