Targeting triglyceride-rich remnant lipoproteins

Dear colleagues, it’s my pleasure to briefly review today the therapeutic landscape and clinical innovations targeting TG-rich remnant lipoproteins. Here are my disclosures. You are all familiar with the fact that there are two metabolic pathways delivering fat to the body. The first one delivering fat after a meal is called the chylomicron pathway, Apo(b)48 dependent whereas the other one is the VLDL pathway. VLDL are being produced by the liver and the end product of VLDL pathway is the LDL particle, which is the main target for cardiovascular disease prevention. On top of LDL particles, there’s another class of very heterogenic lipoproteins which are called remnants. We can identify two kinds of remnants, the chylomicron remnants and the VLDL remnants. Both are heterogenic and a surrogate for these remnants are multiple. We can consider Apo(b), non-HDL cholesterol, TG levels, nonfasting or fasting and remnant cholesterol which is cholesterol or cholesterol minus LDL cholesterol minus HDL cholesterol. Looking at the size and density of these remnants, remnants are in the category of lipoproteins having a size approximately between 30 and 70 nanometers. Both chylomicron remnants and the VLDL remnants again are-can cross-in the intima, reach the arterial wall and contribute to atherosclerosis whereas the larger lipoproteins or chylomicrons remain in circulation and can contribute to pancreatitis risk instead of cardiovascular risk. The therapeutic landscape for TG-rich remnant lipoproteins include statins. The main target for statins, obviously, are LDL particles but they are, they are still able to contribute to TG reduction by approximately 10 to 20-percent and it’s dose dependent. PSK9 inhibitors also decrease TG at the same range as statins, maybe a little more. Whereas fibrates decrease TG levels by 25 to 50-percent with a variable effect on cardiovascular risk. Omega-3, looking at the results of both STRENGTH and REDUCE-IT Studies reduce TG levels by approximately 20-percent, a little less than that, similar to the decrease of CRP and it has nothing to do with the TG decrease in REDUCE-IT with the, the cardiovascular risk prevention. Emerging therapies targeting TG-rich lipoprotein remnants decrease TG by 50 to 80-percent. They include ApoC3 inhibitors, the ANGPTL3 inhibitors and other agents. Naturally occurring loss of function variance and clinical interest raise the clinical interest for both ApoC3 and ANGPTL3 inhibition. There were families where-which, in which there was lower cardiovascular risk and beneficial lipid profiles, so this led to the identification variants, naturally occurring variants in these genes, which led to the development of agents for cardiovascular disease prevention. Looking at the mechanism of action of ApoC3 and ANGPTL3 inhibitors, they cover a large, large spectrum of possibilities starting from the gene itself, the ANGPTL3 CRISPR-cas interventions are in preclinical development whereas the interference with the gene translation by using both or either oligonucleotide and, and single-stranded, or double-stranded iRNA and monoclonal antibodies are used and include quite advanced clinical development actually. Let’s start with ApoC3. ApoC3 is a glycoprotein which has a strong effect in inhibiting LPL, lipoprotein lipase, which is the key enzyme for TG metabolism. It also inhibits hepatic lipase and contributes to the clearance or removal of TG-rich lipoproteins by both canonical and uncanonical ways. ApoC3 is also an independent cardiovascular disease marker and risk. There are several clinical trials targeting ApoC3 actually, approximately 12. And some are completed and targeted rare disease associated with very, very high, extremely high TG levels whereas others are now looking at the efficacy and safety in TG-rich remnants. One of the first studies that have been conducted with ApoC3 inhibitor used volanesorsen which is a second-generation antisense oligonucleotide in patients with complete LPL deficiency. In this phase II study, it revealed that ApoC inhibition can decrease TG levels by both LPL dependent and LPL independent pathways for chylomicron and remnant removal. This-these results have been confirmed in a phase III study looking at the same patient population in larger sample size which a decrease of more than 60-percent of TG levels, which was sustained. Similar results were obtained in patients with some residual of LPL activity with severe hypertriglyceridemia with an important, more than 70-percent, TG reduction and an absolute number near 10 mmol/l which is huge. Volanesorsen, however, again, it’s a second-generation ASO and is not further developed because of some concerns about side effects, in particular, thrombocytopenia. So, it has been replaced and being replaced by a third-generation, which is using a system for internalization, cell internalization which is more potent and is associated with lower risk of side effects than prior versions. This applies both ASO and iRNA and both to ApoC3 and ANGPTL3 inhibitors. Looking at the results of ApoC3 inhibition by using a third-generation ASO, well, we, we-the lower dose at 60 mg instead of 300, we achieved results which are quite impressive in terms of TG reduction of more than 60-percent. Similar results are achieved with-by using ApoC-3-si-RNA whereas ANGPTL3 inhibitors might also decrease remnant cholesterol and TG remnants lipoproteins. ANGPTL3 acts in conjunction with ANGPTL4 and 8 and they are very important modulators of lipid metabolism. ANGPTL3 is produced in the liver, synthesized in the liver and it requires modification cleavage to be active. The effect of ANGPTL3 on LPL activity is more pronounced postprandially due to its interaction with the ANGPTL8. ANGPTL3 is an important inhibitor of LPL and endothelial lipase and this is critical when we inhibit ANGPTL3 to understand its efficacy. Looking at the results of preclinical and clinical studies with ANGPTL3 inhibitors are compatible with the following mechanism of actions. Once and since, once the VLDL particles are secreted, LPL is importantly upregulated. This leads to the clearance, the removal of the small VLDL particles and remnants due to endothelial dependent mechanisms of action. So, as a consequence, LDL particles are not produced and the ANGPTL3 acts upstream LDL production so it’s LDL receptor independent. Clinical targets for ANGPTL3 inhibitors in trials are-cover a very wide spectrum of dyslipidemia, starting from extreme hypercholesterolemia, specifically homozygous FH to extreme hypertriglyceridemia till TG levels above 10 mmol/L multifactorial chylomicronemia. So, in clinical trials looking at the different trials that are ongoing or I think recently been completed with the ANGPTL3 inhibitors, they cover a large spectrum again of unmet medical needs. Clinical trials targeting ANGPTL3 for hyperTG are very active. There are approximately 13, actually, trials ongoing or which will start very soon looking at some of the agents, most import-more advanced agents. One of them is vupanorsen. Vupanorsen is a third-generation GalNAc ANGPTL3 antisense oligonucleotide and its effect on triglycerides and atherogenic lipoproteins has been studied in phase IIa study in patients with hypertriglyceridemia, hepatic steatosis and diabetes. So, in this study, TG levels decreased significantly by 44-percent, which was the primary endpoint. Obviously, ANGPTL3 level is decreased but ApoC3 levels decreased as well. This phase IIa study has been followed by a phase IIb study which is called the Translate-TIMI 70 Phase IIb Study with vupanorsen which used different dosage and different drug regimen to evaluate the safety and efficacy of vupanorsen, the ANGPTL3-Lx ASO, the primary target being non-HDL cholesterol. And very recently, preliminary results of this study, which is not published yet which has just been completed very few days ago. You can find at the PACE-CME website some preliminary results of this IIb trial. Apparently, it shows efficacy and it has been different, depending on the dosage, very well tolerated. Looking at decreasing TG levels by using ANGPTL3 monoclonal antibody instead with evinacumab-and by the way, evinacumab is an agent which has been recently, which recently succeeded in filing in the U.S. for treatment of homozygous FH, and actually it’s assessed to evaluate its safety and efficacy in patients with severe hypertriglyceridemia. So, looking at the efficacy of evinacumab on TG levels in patients with severe hypertriglyceridemia, it [inaudible 00:10:14] works, it works quite well with a very significant decrease in TG levels provided that you have some LPL residual activity. On the right panel, you see in very small sample size of seven individuals, two on placebo, five being treated, that there are variability in TG response and this is due to the fact that some patients here were, didn’t have, or they lacked, completely lacked LPL activity because they, they were homozygous for [inaudible 00:10:41] LPL gene variance. Another study with a little more individuals has been, has been completed to assess, again, the efficacy and safety of evinacumab in severe hypertriglyceridemia. In this study, patients were distributed in three groups, the first one being those with loss of function LPL mutations and thus being entirely or lacking LPL activity and being, being suffering by disease called familial chylomicronese-chylomicronemia syndrome. The second group were heterozygous for same, the same mutations whereas the third group was defined according to the phenotype, not the genotype. Looking at the results, again, if you have LPL or some residual LPL activity, you will achieve a huge decrease of TG levels. The only situation where ANGPTL3 inhibitor might not work is, is in the situation, which is rare, when LPL activity is completely lacking due to familial chylomicronemia syndrome. So, looking at the effects and mechanisms of action of ApoC3 and ANGPTL3 inhibitors on TG-rich lipoproteins, first of all, both agents or both classes are very effective in clearing or removing TG-rich remnants. Second, it also works in the presence of chylomicronemia provided there is still some LPL activity when you’re using ANGPTL3 inhibitors. Whereas for those lacking, completely lacking LPL activity, while an ApoC3 inhibitor will still work, both agents, both classes are using LPL upregulation as a mechanism of action and they also use some clearance mechanisms to, to increase their efficacy on clearing the TG-rich lipoproteins. One of the main differences between the two classes, first of all, is that ApoC3 inhibitors are able to work by using LPL independent mechanism of action, which is not the case for ANGPTL3 inhibitors. In contrast, ANGPTL3 inhibitors are able to work completely independently of LDL receptor due to the endothelial lipase mechanism, which is not the case for ApoC3. So, there is a niche for both classes and there is no, honestly, no situations where we would, in the future, be unable to clear or manage adequately the risk associated with remnant particles. So, in conclusion, both ANGPTL3 and ApoC3 inhibitors reduce plasma TG by, by clearing TG-rich remnants. ApoC3 inhibitors involve LPL-dependent and LPL-independent mechanisms of action to succeed in achieving TG reduction. Whereas ANGPTL3 inhibitors are LPL-dependent but LDL receptor independent so being able to clear LDL particles and remnants at the same level of efficacy. So, the efficacy of ANGPTL3 or ApoC3 blockade to treat patients with severe hypertriglyceridemia and being at high cardiovascular risk is still under study and clinical investigation and is quite advanced for several agents. I thank you very much for your attention.