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 2021, there were approximately 1.6 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 are poised to spur growth, though this will depend on a variety of payer and physician factors.
• 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 remained close to $1.6bn in 2021 despite a large potential market, hindered by prior authorization (PA), even though only physician attestation may be needed, as well as patient co-pays and reluctance for regular injections. The siRNA Leqvio, injected every six months, was approved at the end of 2020 in Europe and in 2021 in the US, and is likely to dominate the segment, though initial uptake has been slow. Novartis is using Leqvio’s prolonged dosing to pursue administration in provider offices, with medical rather than pharmacy benefit coverage in the US, for less burdensome reimbursement and co-pays under traditional Medicare Part B (unless there are legislative changes), though Medicare Advantage and commercial plans will still have obstacles. Success will depend on physician willingness to adopt the buy-and-bill approach, which is more suited to large and possibly medium-sized integrated delivery networks/clinics. Physicians will also need to become comfortable with such prolonged dosing, which may depend on safety data from Leqvio’s cardiovascular outcomes trials (CVOTs). One of the CVOTs allows less strict LDL-C control and may show a numerically stronger topline benefit. Physicians could realize that was due to the trial design, but it still may help them feel comfortable. The company is open to innovative collaborations with healthcare systems outside the US, initiating one in the UK. LIB Therapeutics is developing a fusion protein (lerodalcibep), though it requires more frequent dosing than Leqvio (planned for monthly), so the reimbursement strategy will not be as viable. There are also oral programs, albeit they are at an 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 this 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 a lack of CVOT results, which are expected in Q1 2023. The company instituted a system to help with PA, but also scaled back its commercial organization, pending CVOT results, which could help with both PA and physician views. 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. 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.
• For the much narrower indication of homozygous familial hypercholesterolemia (HoFH), Regeneron’s anti-ANGPTL3 monoclonal antibody Evkeeza 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. ANGPTL3 inhibition lowers both triglycerides and LDL-C, so Evkeeza is also being studied in severe hypertriglyceridemia (see below).
• 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 importantly lower residual risk, though there is uncertainty in the outcome as the mechanism is previously untested. Since the target population is smaller, reimbursement may be easier than for the PCSK9 inhibitors, though that remains to be seen. Preliminary data on RNAi competitor AMG 890 have shown stronger and longer-lasting Lp(a) lowering – though Phase II details are pending – which should lead to substantially longer dosing and mean that in the US it can be reimbursed as a provider-administered drug.
• In the hypertriglyceridemia segment (including mixed dyslipidemia), a CV label expansion in the US for Amarin’s omega-3 fatty acid 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. While supply constraints have limited the generics to some extent, it is unclear how long this will last, and even with only a moderate decline in prescriptions, sales have decreased dramatically due to lower net pricing to retain exclusive formulary positions and reduced wholesaler inventory. Prescriptions for the brand plus generics have also plateaued in the US, though it is unclear how much of that is from the COVID-19 pandemic. Launches in Europe and potentially in China could help, but initial sales in Europe have been sluggish. 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 lowers triglycerides, but its CV benefit most likely involves a number of other effects as well. In line with that, the failure of triglyceride-lowering pemafibrate in its CVOT adds further evidence regarding the difficulty of using triglyceride lowering to impact CV risk through triglyceride-rich atherogenic particles (though trial details are still pending) – arguing against the hypothesis that prior fibrate CVOT failures, on top of statins, were due to not selecting the proper patients. Fibrates still have a role, though, in pancreatitis prevention in severe hypertriglyceridemia.
• A number of injectable triglyceride-lowering drugs targeting ANGPTL3 and ApoC-III have been under development for a variety of indications, but the most prominent of these, vupanorsen, an antisense inhibitor of ANGPTL3, was suspended due to insufficient lowering of non-HDL-C and apparent liver toxicity, with increased liver fat and enzymes, disrupting plans for a CVOT for mixed dyslipidemia. The increase in liver fat raises questions about an on-target effect. This is not seen with loss-of-function mutations in ANGPTL3 (familial hypobetalipoproteinemia-2; FHBL2), but there may be differences with gene silencing (eg vupanorsen did not reduce free fatty acids in a study, whereas homozygous LOF mutations do). Liver toxicity also was not an issue for monoclonal antibody Evkeeza, though it is not clear if that could similarly be due to differences in the mechanisms or if the liver effects may show up if Evkeeza is studied in more patients. In any case, there are serious concerns for other gene silencers of ANGPTL3.
• Vupanorsen’s suspension also raises questions about liver safety for drugs targeting ApoC-III, since there is some overlap in mechanisms, but Waylivra, an antisense drug with that target, substantially lowered hepatic fat in familial partial lipodystrophy (FPL), suggesting that will not be an issue. There are significant differences in the mechanisms, since targeting ApoC-III does not generally have the same effects on LDL-C as ANGPTL3.
• In terms of drugs targeting ApoC-III, Waylivra was approved in Europe for familial chylomicronemia syndrome (FCS), but was not approved in the US due to safety issues. It is hoped that Ionis’s olezarsen (AKCEA-APOCIII-LRx) can 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 is yet to be proven with these next-generation drugs and sorted out by genetic conditions. For example, Evkeeza, which as noted targets ANGPTL3, failed to show a benefit in FCS, which could have implications for the mechanism in general, so Regeneron is only pursuing an indication in severe hypertriglyceridemia patients without genetic FCS.
• 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, and there are concerns that ARO-ANG3 will run into similar issues as vupanorsen. Arrowhead’s approach may also have the advantage of three-monthly or six-monthly 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.
• Olezarsen and ARO-APOC3 are slated to be first approved for FCS and then severe hypertriglyceridemia, where pancreatitis is a concern. While they could start out with ultra-orphan drug pricing, they would need to reduce net pricing to gain access in the larger population (except under traditional Medicare Part B if ARO-APOC3 is positioned as provider-administered, though there may not be as high a percentage of FCS or severe hypertriglyceridemia patients on Medicare as there is in more routine dyslipidemia, and keeping orphan pricing could spur changes in Medicare’s regulations). Unless they are priced more like other dyslipidemia drugs, they are likely to be restricted to patients with severe refractory hypertriglyceridemia, possibly with volume-discounted pricing in some geographies. They could also face competition in severe hypertriglyceridemia from FGF21 analog pegozafermin, which if also approved in NASH, may be priced more competitively.
• 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 8.6%, and the average probability a drug advances from Phase III is 58.1%. Dyslipidemia/hypercholesterolemia drugs, on average, take 8.0 years from Phase I to approval, compared to 10.4 years in the overall cardiovascular space.