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News: Congress

EAS2019 - From the session on Familial hypercholesterolaemia, PCSK9, and bempedoic acid feature

Tuesday 28 May 2019   (0 Comments)
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The first late breaking session on Monday highlighted new therapeutic approaches focused on lowering low-density lipoprotein cholesterol (LDL-C). Among the studies reported was the ORION-2 study with inclisiran in homozygous familial hypercholesterolaemia (FH, inherited high cholesterol), a novel anti-PCSK9 agent LIB003, and a fixed combination of bempedoic acid and ezetimibe.  In addition, there were important insights from a new analysis of the Scandinavian Simvastatin Survival Study (4S), a gamechanger for statin therapy in the secondary prevention. None of these novel reports are published yet.

 

4S analysis: higher risk, greater benefit from LDL lowering

In 2019, it is not possible to quantify the benefit from statin treatment in secondary prevention patients with likely FH using a randomised clinical trial design. Delving into the 4S study1 database provided a unique opportunity to do so. As reported by Dr. Antonio J. Vallejo-Vaz (Imperial College London, UK), 2 the researchers stratified data for 4444 patients with established coronary artery disease (CAD) according to LDL-C level (<4.9 mmol/L or 4.9mmol/L), and the presence of premature CAD disease (i.e. onset <55 years in men and <60 years in women) in the patient, his/her sibling, or both. The combination of high LDL-C and premature CAD in the patient and siblings was considered suggestive of an ‘FH phenotype’ by the investigators. Overall, at one year, lowering LDL-C levels in people with baseline LDL-C levels of 4.9 mmol/L or higher resulted in about one-third reduction in the risk of major CAD events, as well as one-third reduction in the risk of death for any reason. The benefit in those with a likely genetic hypercholesterolaemia, with premature heart disease and in their siblings was greater, with over 80% reduction in the risk for all-cause death, and over 50% reduction in major CAD events. Individuals with elevated LDL-C levels and either a personal or family history of premature heart disease appeared to derive a similar benefit from statin treatment as those without clinical history of premature heart disease.

 

These findings highlight the importance of targeting elevated LDL-C in these very high-risk individuals with likely FH. Commenting on the results, Professor Chris Packard (University of Glasgow, UK) said: ‘As in other trials, there is the suggestion that if patients have evidence of a genetic or inherited tendency to high cholesterol levels and premature heart disease, then they are at greater risk of recurrent events. There is also the suggestion from a number of studies that these patients will receive greater improvement in risk from LDL-C reduction compared with those who do not have a strong genetic component of risk. From a practical viewpoint, if lipid testing in either primary or secondary prevention settings indicates a strong genetic component to the patient’s risk profile, then targeted intervention can effectively lower this risk.’

 

ORION-2: inclisiran in homozygous FH

In the second presentation, Professor Derick Raal (University of the Witwatersrand, Johannesburg, South Africa) reported the proof-of-concept ORION-2 study with inclisiran, an RNA interference agent targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) in four patients with a genetically confirmed homozygous FH.3 Inclisiran acts to silence the gene encoding PCSK9, thus blocking PCSK9 synthesis and lowering LDL-C levels.4 The effect is sustained allowing treatment to be given less frequently than with the dosing regimen for the PCSK9 monoclonal antibodies.5 All four patients had a genetically confirmed diagnosis of FH based on the presence of  mutations of LDLR gene on both alleles. Inclisiran 300 mg was administered subcutaneously on day 1 and again on day 90 if serum PCSK9 level at days 60 or 90 was reduced by more than 70% compared with baseline. Inclisiran was effective in three of these patients with LDL-C reductions averaging 30% (up to 37% at day 180 in one patient), similar to results seen in the TESLA study with evolocumab.6 The patient who did not respond to inclisiran had also failed to respond to either evolocumab or alirocumab.

Based on the results of this study, inclisiran is now being studied in a randomised design involving abut 50 patients with homozygous FH (ORION-5).7 Incidentally, it is recognised that a small proportion of patients do not respond to PCSK9 inhibition; estimates of prevalence are difficult to ascertain, although some studies suggest that this may affect <1% to about 10% of patients.8,9

 

Novel anti-PCSK9 agent: LIB003

In another presentation, Dr Evan Stein (LIB Therapeutics and Metabolic & Atherosclerosis Research Center, Cincinnati, USA) reported phase 2 for a novel therapeutic targeting PCSK9, LIB003. In this agent, an adnectin molecule (about 11 KD) with high potency in binding PCSK9 is fused to albumin (66 KD).10 The resulting formulation has a sustained half-life of 12 to 15 days, and increased solubility compared with the PCSK9 monoclonal antibodies, allowing the treatment to be given in a smaller volume.

The study included 81 patients who were randomised to subcutaneous treatment with LIB003 150 mg, 300 mg, 350 mg or placebo every 4 weeks for 12 weeks. Maximal mean LDL-C reduction at 12 weeks (versus placebo) was 77.3% (range 90.5% to 64.1%) with LIB003 300 mg. There was no further LDL-C lowering at the highest dose. Treatment with LIB003 appeared to be well tolerated and no patients developed neutralising drug antibodies. These findings support ongoing development of this agent in phase 3 trials.

Metabolomics, PCSK9 and statins

Dr Peter Würz (Nightingale Health, Science Team, Helsinki, Finland) compared metabolic profiling of a large randomised statin trial, PROSPER, with genetic inhibition of PCSK9 from a Mendelian randomisation study.11 For an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy. However, for very-low-density lipoprotein (VLDL) lipid measures, genetic inhibition of PCSK9 had weaker effects on lowering of VLDL-cholesterol compared with statin therapy. Dr Würz proposed that the findings reinforce the view that PCSK9 inhibitors are predominantly LDL- lowering treatments, that, unlike statins, have limited impact on remnant lipoproteins.

Fixed oral combination bempedoic acid-ezetimibe

In the final presentation, Dr. Christie Ballantyne (Baylor College of Medicine, Houston, Texas, USA) reported results from a phase 3 trial for a fixed combination of bempedoic acid and ezetimibe.12 Bempedoic acid is a first-in-class non-statin agent that inhibits ATP Citrate Lyase, an enzyme at a step preceding 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme that is inhibited by statins. As a result, bempedoic acid reduces cholesterol biosynthesis and lowers LDL cholesterol by up-regulating the LDL receptor.13 Given that bempedoic acid and ezetimibe are orally administered agents with complementary mechanisms of action, it makes sense to combine these two agents.

This double-blind study enrolled 301 evaluable patients at high risk of cardiovascular events who were not at guideline-recommended LDL-C goal despite maximally tolerated statin therapy. Patients who were unable to tolerate a statin were also included. Patients were randomly allocated to once-daily treatment with bempedoic acid 180 mg, ezetimibe 10 mg, the fixed combination, or placebo for 12 weeks. Overall, 65% of patients were on a statin. At the end of 12 weeks, the fixed combination of bempedoic acid plus ezetimibe reduced LDL-C by 36.2%, significantly greater than with either ezetimibe (23.2%) or bempedoic acid (17.2%). The placebo-corrected reduction in LDL-C with bempedoic acid plus ezetimibe was 38%. These findings offer a novel oral treatment for the management of high-risk patients unable to attain LDL-C goal, particularly those unable to tolerate statin therapy.  

References

1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.

2. Vallejo-Vaz AJ, Packard CJ, Ference BA et al. LDL-C lowering among patients with LDL-C above 4.9 mmol/L and features suggesting a genetic vulnerability to cardiovascular disease: analyses from the 4S Trial. Abstract EAS19-1136.

3. Raal F, Lepor N, Kallend D, Stoekenbroek R, Wijngaard P, Hovingh GK. Inclisiran durably lowers LDL-C and PCSK9 expression in subjects with homozygous familial hypercholesterolaemia: the ORION-2 pilot study. Abstract EAS19-1122.

4. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41-51.

5. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376:1430–40.

6. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341-50.

7. A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH) (ORION-5). ClinicalTrials.gov Identifier: NCT03851705.

8. Kohli M, Patel K, MacMahon Z et al. Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres. Int J Clin Pract 2017;71(11).

9. Hollstein T, Grenkowitz T, Spira D et al. Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies (pcsk9-i) Treatment of Cardiovascular High Risk Patients in Clinical Practice - New Data Regarding Safety and Effectivity. Abstract M1094. Poster presentation, AHA Scientific Sessions, Presented 13 November, 2017.

10. Stein E, Toth P, Butcher MB, Kereiakes D, Magnu P, Bays H, Zhou R, Turner TA. Safety, tolerability and LDL-C reduction with a novel anti-PCSK9 recombinant fusion protein (LIB003): Results of a randomized, double-blind, placebo-controlled, phase 2 study. Abstract EAS19-1100.

11. Würz P, Sliz E. Metabolomic consequences of PCSK9 inhibition compared with statin therapy. Abstract EAS19-1088.

12. Ballantyne C, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, Stroes ESG, MacDougal D, Zhao X, Catapano AL. Efficacy and safety of bempedoic acid + ezetimibe fixed-dose combination in patients at high CVD risk and with elevated LDL-C receiving maximally tolerated statin therapy. Abstract EAS19-1133.

13. Saeed A, Ballantyne CM. Bempedoic acid (ETC-1002): a current review. Cardiol Clin 2018;36:257-64.


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