Disease Analysis: Dyslipidemia

Disease Overview

Dyslipidemia refers to any increase or decrease in lipid levels from defined normal parameters, with physicians particularly focusing on the treatment of elevated low-density lipoprotein cholesterol (LDL-C) due to the well-established link between excessively elevated LDL-C and atherosclerosis. As such, LDL-C is a major modifiable risk factor for cardiovascular (CV) disease, one of the world’s leading causes of morbidity and mortality, though differences in LDL particle morphology can also play a role. Other lipid level deviations in dyslipidemia include elevated triglycerides, elevated lipoprotein(a) [Lp(a)], low levels of high-density lipoprotein cholesterol (HDL-C), elevated total cholesterol, and elevated non-HDL-C, a marker of cholesterol in all atherogenic lipoproteins.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2018, there were approximately 1.5 billion prevalent cases of dyslipidemia in adults aged 20 years and older worldwide, and forecasts that number to increase to 1.7 billion prevalent cases by 2027.
• The dyslipidemia market is well established, and the branded segment has seen declining sales due to generics. However, a number of novel drugs may help to spur growth, along with improved access with price competition, and new CV outcomes data with label expansions.
• In the hypercholesterolemia segment, the injectable PCSK9 inhibitors from Amgen and Regeneron have struggled due to payer restrictions. While declining net pricing in the US has improved access and growth somewhat, combined sales may only reach $1.6bn in 2021 despite a large potential market, hindered by prior authorization (PA), even though only physician attestation may be needed. The siRNA Leqvio, injected every six months, is slated to be approved at the end of 2021 in the US, and is likely to dominate the segment. Novartis plans to use Leqvio’s more convenient dosing to pursue administration in provider offices, with medical rather than pharmacy benefit coverage in the US, including Medicare Part B. Success will depend on whether the drug can avoid PA, how comfortable physicians feel about such prolonged dosing, and to what extent physicians are willing to adopt the buy-and-bill approach, which may be more suited to larger and possibly medium-sized integrated delivery networks/clinics. Leqvio’s cardiovascular outcomes trial (CVOT) is also designed to show a numerically stronger topline benefit, though the drug may well gain popularity prior to these results. The company is additionally open to innovative collaborations with healthcare systems outside the US, and has initiated one in the UK. AstraZeneca/Ionis do have what could be a more effective long-acting PCSK9 inhibitor (AZD8233) and LIB Therapeutics a fusion protein (LIB003) that is longer acting than the monoclonal antibodies, though these still require more frequent dosing than Leqvio (planned for around monthly dosing, though AZD8233 could be dosed less frequently), so the reimbursement strategy will not be as viable for them. There are also oral programs, though these are still early stage.
• Esperion’s oral Nexletol, approved in February 2020 and April 2020 in the US and Europe, respectively, has had only meager uptake. However, it is unclear how much is due to its modest LDL-C lowering (particularly on top of statins), poor marketing strategy, launch issues and physician inaction due to the COVID-19 crisis, or lack of CVOT results, which are expected Q1 2023, though they need to raise money to complete it. Its fixed-dose combination (FDC) with ezetimibe, Nexlizet, approved a few days after, has better efficacy and could be quite helpful in high-need statin-intolerant patients. The company is shifting its marketing to focus more on this FDC and instituted a system to help with PA, which they hope will become less burdensome after the CVOT. More real-world data are needed, though, on the efficacy of the FDC in patients on higher-dose statins, due to issues in its pivotal trial. The oral route of these drugs could lead them to be preferred initially in patients failing statins +/- ezetimibe, especially those who are not far from goal, and among primary care physicians, depending on the patient risk and whether the physician feels that reaching certain LDL-C targets is acceptable rather than driving it as low as possible. In the US, however, both drugs’ initial approvals, pending CVOT results, are in patients with atherosclerotic CV disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH). There is a large potential target market of hypercholesterolemia patients not meeting goal, either with or without statin intolerance, but much will depend on how Nexletol performs in its CVOT.
• Novartis is also testing a monthly antisense inhibitor of lipoprotein A [Lp(a)], pelacarsen, in a pivotal CVOT. While Lp(a) contributes to the cholesterol in LDL-C measurements, it is an independent risk factor and treatment could provide an important option to lower residual risk, though there is uncertainty in the outcome, as the mechanism is previously untested. Little data have been released on potential Phase II RNAi competitor AMG 890, but if it is similar to other Arrowhead drugs, it could have substantially longer dosing.
• In the hypertriglyceridemia segment (including mixed dyslipidemia), a CV label expansion in the US for Amarin’s omega-3 fatty acid (FA) Vascepa, a formulation of EPA, had been driving substantial growth. However, with a loss on an appeal of a US patent case, generics entered in November 2020. Amarin officials have claimed that manufacturing issues will keep this from being a typical generic market, and there has been some evidence of supply constraint, but this may not last in the longer term. Sales for the brand plus generics also appear to have plateaued in the US, but it is unclear how much of that is from the COVID-19 pandemic, and launches in Europe and potentially in China could help to spur additional growth. On the positive side for the drug, with the failure of Epanova, a mixture of DHA and EPA, physicians may believe that pure EPA is required to reduce CV risk, which should help Vascepa against DHA/EPA generics, though some experts have reiterated the concern that the mineral oil comparator in Vascepa’s CVOT caused adverse outcomes. Vascepa’s success has to some extent revived interest in triglycerides as a broader target, though its CV benefit may involve a number of other effects as well.
• While fibrates have mixed CVOT data and failed to show a benefit in combination with statins in ACCORD, if the PROMINENT trial of pemafibrate is positive it could bolster subgroup analyses of ACCORD, suggesting a benefit in patients with high triglycerides and low HDL-C. If the data are strong, it could take substantial share from Vascepa, though this could be hampered by Vascepa generics.
• A number of injectable triglyceride-lowering drugs targeting ANGPTL3 and ApoC-III are being developed for a variety of indications, though questions have recently come up about the liver safety of ANGPTL3 inhibition, at least with certain candidates. Drugs targeting ANGPTL3 may not lower triglycerides quite as much and may have efficacy difficulties in certain related genetic conditions, but they also moderately lower LDL-C, likely through an impact on VLDL precursors and without the need for LDL receptors, as required for currently approved hypercholesterolemia agents. Hence, Regeneron’s anti-ANGPTL3 monoclonal antibody Evkeeza being approved for homozygous familial hypercholesterolemia (HoFH), where it is expected to take share from oral Juxtapid due to safety and tolerability issues with the latter. However, it will still face some competition from the lower-priced PCSK9 inhibitors in patients with residual LDL receptor activity, given its orphan pricing. Evkeeza’s HoFH trial also involved inconvenient IV dosing, but SC dosing was similarly successful in a Phase II trial in patients with persistent hypercholesterolemia despite treatment even with PCSK9 inhibitors. For high triglycerides, however, Evkeeza failed to show a benefit in familial chylomicronemia syndrome (FCS), which could have implications for the mechanism in general, so Regeneron is only pursuing an indication in severe hypertriglyceridemia patients without genetic FCS.
• However, Phase IIb data from Pfizer/Ionis’s vupanorsen, an antisense targeting ANGPTL3, have raised questions about the prospects of the mechanism, especially for large indications such as mixed dyslipidemia, with reports of elevated liver enzymes and liver fat. Details have not been released and Pfizer has only said it is reviewing the data to determine next steps, so it remains to be seen whether an effective dose can be carried forward. The drug had been planned to be studied in a pivotal CVOT, where it has been hoped that its impact on non-HDL-C, which includes cholesterol in triglyceride-rich particles like VLDL, as well as LDL, would improve residual risk. Vupanorsen had also been planned to reach the market earlier with a severe hypertriglyceridemia indication, including a trial against Vascepa. If vupanorsen can still be developed in a broader population and consequently has lower pricing, it could take share from Evkeeza in HoFH, assuming vupanorsen likewise has substantial LDL-C lowering in that indication. As an injectable, vupanorsen may have stronger triglyceride and LDL-C lowering than oral pemafibrate, but could still face competition from the latter, though pemafibrate has a disadvantage of twice-daily dosing.
• In terms of drugs targeting ApoC-III, the antisense drug Waylivra may not be approved in the US for familial chylomicronemia syndrome due to safety issues. However, Ionis’s olezarsen (AKCEA-APOCIII-LRx) is hoped to avoid these issues, though it remains to be seen if it does so completely. Drugs targeting ApoC-III may lower triglycerides somewhat more than those targeting ANGPTL3, especially when levels are extremely high, though that remains to be proven with these next-generation drugs and sorted out by genetic conditions. As noted above, Evkeeza failed to show a benefit in FCS patients, which could have implications for the mechanism. However, depending on the magnitude of the difference, if drugs targeting ANGPTL3 are able to be developed for a broad population and hence are priced lower, they could still be used before ApoC-III inhibitors in certain patients.
• Arrowhead’s ARO-APOC3 and ARO-ANG3 have numerically greater reductions in triglycerides in the most recent data than those from Ionis, but this may be due to variability in their earlier-stage, uncontrolled, smaller studies. However, they may also have the advantage of quarterly or semi-annual dosing rather than monthly, though Ionis argues that some physicians may be hesitant about such prolonged dosing in case there are safety issues. Nevertheless, this could change as more experience is gained with such drugs.
• Given limited budgets for many patients, there will be indirect competition between drugs targeting LDL-C and those targeting triglycerides, if patients are eligible for both, as well as with diabetes drugs that have CV and renal benefits.
• In the US, different specialties and primary care physicians may use dyslipidemia guidelines with varying approaches to lipid targets.
• The overall likelihood of approval of a Phase I dyslipidemia/hypercholesterolemia asset is 8.5%, and the average probability a drug advances from Phase III is 60%. Dyslipidemia/hypercholesterolemia drugs, on average, take 7.7 years from Phase I to approval, compared to 10.2 years in the overall CV space.