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The first Late Breaker Session highlighted novel treatments for lowering LDL cholesterol. Two of the presentations reported new data from the ORION clinical trial programme with inclisiran, an siRNA therapy. In contrast to PCSK9 monoclonal antibody therapy, inclisiran selectively targets the liver, preventing protein production and thus lowering LDL cholesterol levels.
Professor Kausik K. Ray (Imperial College London, UK) reported new findings from the ORION-11 study, a phase 3 trial in patients with either established atherosclerotic cardiovascular disease (ASCVD) or cardiovascular risk equivalents, and elevated LDL cholesterol levels despite maximally tolerated statin therapy (1). Overall, inclisiran given on day 1, day 90, and every 6 months thereafter to the end of study (day 510), effectively halved LDL cholesterol levels.
While most patients in the trial had ASCVD, 203 were high-risk primary prevention patients, the focus of this latest analysis. In this group, baseline LDL cholesterol levels were on average 3.6 mmol/L despite statin treatment (62% on high-intensity statin). At day 510, the placebo-corrected reduction in LDL was 47.2%, and the time-averaged LDL cholesterol reduction (day 90-540) was 42.3%; both were similar to changes observed in the overall study population (1). In addition, inclisiran significantly lowered other key lipid targets, including non-HDL cholesterol (39.5%) and apolipoprotein B (by 35.9%) at day 510, and lipoprotein(a) (by 28.5% on day 540).
These findings are relevant given that in routine clinical practice, high-risk primary prevention patients probably represent the majority of those seen for lipid lowering intervention. Many of these patients do not attain LDL cholesterol goals according to the 2019 ESC/EAS guidelines (2), highlighting a clinical need for additional efficacious LDL lowering therapies. Inclisiran, on top of statin treatment, offers the potential to improve goal attainment. Professor Ray discusses the analysis in this video.
In another report from the ORION trial programme, Professor Derick Raal (University of the Witwatersrand, Johannesburg, South Africa) presented results from a genotype analysis of the ORION-9 trial in patients with clinical diagnosis of heterozygous familial hypercholesterolaemia (FH) (3). Overall, 293 patients of the total 482 in the study had identified LDLR mutations. Surprisingly, a small proportion of patients had two LDLR mutations indicating that genetically they were either compound heterozygous or homozygous FH, even though clinically they were considered heterozygous FH. Across the range of LDLR mutations, including null and defective variants, the LDL cholesterol lowering response of inclisiran was similar, ranging from 37% to 56%. These findings provide reassurance that inclisiran is effective across the spectrum of genotypes causing FH. Similar results have been reported for the PCSK9 monoclonal antibodies – alirocumab and evolocumab – in patients with heterozygous FH. Professor Raal discusses the ORION-9 results in this video.
During the interactive session, there were questions regarding the intended patient populations for inclisiran, as well as use in children. Professor Raal commented that clinical trials are routinely conducted in adults before younger populations. However, at least in the case of homozygous FH, it would make sense to investigate treatments from an earlier age.
The PCSK9 therapeutics field is evolving. Last year’s Congress in Maastricht (4) showcased LIB003, a novel recombinant fusion drug targeting PCSK9. LIB003 combines a PCSK9-binding domain (adnectin) that blocks interaction with the LDL receptor, and human serum albumin that increases drug half-life. LIB003 is administered monthly as a small volume (1 mL) injection. In a 12-week dose-ranging study, LIB003 300 mg lowered LDL cholesterol by more 70% compared to placebo; this was the dose selected for further study. The latest report presented by Dr. Traci A. Turner (LIB Therapeutics) provides data from a 52-week study in 32 patients, over half on high intensity statin therapy, and with baseline LDL cholesterol on average 3.2 mmol/L (about 120 mg/dL).
At 52 weeks, LIB003 led to a sustained reduction in LDL cholesterol, on average by 64% (ranging from about 30% to more than 80%), as well as 83.4% suppression of free PCSK9. In addition, LIB003 also lowered apolipoprotein B (by 47.1%) and lipoprotein(a) (by 31.5%) at week 52. Importantly, LIB003 was well tolerated, with mild injection site reactions reported for only 1.4 per cent of all doses. Ongoing clinical development focuses on homozygous FH (5), ASCVD and high-risk primary prevention, as well as heterozygous FH. Dr Evan Stein (LIB Therapeutics and Metabolic & Atherosclerosis Research Center, Cincinnati, USA) who presented LIB003 data at Maastricht in 2019, comments on the 52-week study in this video.
Therapies targeting PCSK9 have undoubtedly changed the management of patients with FH, notably homozygous FH, reducing the requirement for lipoprotein apheresis (6,7). However, as these treatments require residual LDL receptor function (>2%), they are not effective in homozygous FH patients with null LDLR mutations. Clearly, there is an unmet clinical need for new options in these patients. Another novel therapy – evinacumab targeting ANGPTL3 (angiopoietin-like protein 3) – offers potential, according to the results of another presentation by Professor Raal.
Evinacumab was investigated in a phase 3 trial in 65 homozygous FH patients on stable lipid lowering therapy – the ELIPSE HoFH study (8). Treatment with evinacumab (15 mg/kg intravenously every 4 weeks) for 24 weeks halved LDL cholesterol levels compared with baseline. This latest report investigated the response to evinacumab in 10 patients with little (<2%) to no residual LDL receptor activity, 8 of whom received evinacumab. Compared with baseline, evinacumab lowered LDL cholesterol levels by 53.5% at 24 weeks, whereas the two patients on placebo experienced an increase of 18.8%. These findings show that the response to evinacumab is independent of functional LDLR receptor activity and suggest potential for this treatment in these very difficult-to-treat patients. Professor Raal discusses the results in this video.
Other late breaker news
Dr Alexey Meshkov (National Medical Research Center for Preventive Medicine of the Ministry of Healthcare, Moscow, Russian Federation) presented data from the ESSE-RF study, a general population study of 21,300 people aged 25-54 years from 13 regions of the Russian Federation differing in climatic, geographic, economic, and demographic characteristics (about 1600 per region). Overall, 2,304 people had LDL cholesterol levels >4.9 mmol/L, or <4.9 mmol/L on statin therapy. FH was diagnosed based on the Dutch Lipid Clinic Network Criteria, and all underwent genetic testing. Overall, the prevalence of definite or probable FH was 1:173 people. Of these people (n=105), 63% were on statins but only three attained target LDL cholesterol levels.
Dr Sergio de Carvalho (Laboratory of Data for Quality of Care and Outcomes Research, Brasilia, Brazil) presented the results from a meta-analysis showing that there was no excess risk of major adverse cardiovascular events (MACE) following treatment with bupropion alone or in combination with naltrexone. The investigation was necessary given early termination of the LIGHT trial (9), meaning that physicians were no closer to knowing if the combination medication posed a cardiovascular risk for obese and overweight patients, the intended patient group. This meta-analysis of 12 randomised controlled trials included 19,176 patients, 68.5% of whom were included in trials aiming at weight loss and 29.1% in trials of smoking cessation. With the combination of bupropion and naltrexone the odds ratio for MACE was 0.97 (95% CI 0.75–1.24), p=0.79; results were similar for either agent individually. In conclusion these findings showed no increased risk of MACE with this combination.
Presentations in this session
- Ray KK et al. Effect of inclisiran on atherogenic lipoproteins in high-risk primary prevention populations: Analysis from the Phase III ORION-11 trial.
- Raal FJ et al. Inclisiran reduces LDL-cholesterol independent of genotype in subjects with heterozygous familial hypercholesterolaemia.
- Turner TA et al. Results of a 52-week open-label phase 2b study to assess long-term safety, immunogenicity and LDL-C efficacy of monthly dosing with LIB003 a novel anti-PCSK9 recombinant fusion protein.
- Raal FJ et al. The efficacy and safety of evinacumab in homozygous familial hypercholesterolaemia (HoFH) patients with little to no Low-Density Lipoprotein Receptor (LDLR) activity.
- Meshkov AN et al. The prevalence of heterozygous familial hypercholesterolemia in selected regions of the Russian Federation
- de Carvalho LSF et al. Bupropion and/or naltrexone are not associated with increased risk of major adverse cardiovascular events: a network meta-analysis of additive effects.
- Ray KK, et al; ORION-10 and ORION-11 Investigators. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507-19.
- Mach F, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-188.
- Raal FJ, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med 2020;382:1520-30.
- Stein EA. Late Breaking Session of EAS Congress, 26-29 May, Maastricht, The Netherlands.
- Phase 3 Study to Evaluate the Efficacy and Safety of LIB003 With Evolocumab in HoFH. ClinicalTrials.gov Identifier: NCT04034485. https://clinicaltrials.gov/ct2/show/NCT04034485
- Baum SJ, et al. Effect of evolocumab on lipoprotein apheresis requirement and lipid levels: Results of the randomized, controlled, open-label DE LAVAL study. J Clin Lipidol 2019;13:901-909.
- Moriarty PM, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J 2016;37:3588-3595.
- Raal FJ, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020;383:711-720.
- Sharfstein JM, Psaty BM. Evaluation of cardiovascular risk of naltrexone-bupropion. JAMA. 2016;315:984-986.