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Disease Analysis: Dyslipidemia

  • Report
  • 101 Pages
  • November 2020
  • Region: Global
  • Pharma Intelligence
  • ID: 4895486
Latest Key Takeaways

The publisher 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, the market is poised to resume steady growth due to the introduction of novel agents, 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 $1.3bn in 2020 despite a large potential market, hindered by prior authorization, even though only physician attestation may be needed. The siRNA inclisiran, injected every six months, is slated to be approved in late 2020 and is likely to dominate the segment. Novartis plans to use inclisiran’s more convenient maintenance dosing to pursue administration in healthcare provider offices, with medical rather than pharmacy benefit coverage, including Medicare Part B. Success will depend on whether the drug can avoid prior authorization, 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 integrated delivery networks. Inclisiran’s cardiovascular outcomes trial (CVOT) is also designed to show a numerically stronger top-line benefit, though the drug may well gain popularity prior to these results. The company is also open to innovative collaborations with healthcare systems outside the US, and has initiated one in the UK.

Esperion’s oral Nexletol (bempedoic acid), approved in February 2020 and April 2020 in the US and Europe, respectively, has had only meager uptake so far. However, it is still early in the launch, and it is unclear how much of that is due to its relatively modest LDL-C lowering, particularly on top of statins, versus launch issues and physician inaction due to the COVID-19 crisis or lack of CVOT results, which are expected in H2 2022. 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 too far from goal, and among primary care physicians, depending on the risk of the patient and whether the particular 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 could depend on details of 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 that is not reduced by statins, and the 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, has been driving substantial growth. However, with a loss on an appeal of a US patent case in September 2020, generics are likely to enter the US soon, depending on further developments in the case. Amarin officials have claimed, though, that manufacturing issues will keep this from being a typical generic market. 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 details from Epanova’s trial are still needed to see if there are other explanations. 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. Drugs targeting ANGPTL3 may not lower triglycerides quite as much, 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 evinacumab has initially been submitted 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, assuming evinacumab has orphan pricing. Evinacumab’s HoFH trial also involved inconvenient IV dosing, but SC dosing is being studied in a Phase II trial in patients with persistent hypercholesterolemia despite treatment even with PCSK9 inhibitors.

On the other hand, after completing a Phase IIb trial, Pfizer/Ionis’s vupanorsen, an antisense targeting ANGPTL3, is planned to be studied in a pivotal CVOT in a broader mixed dyslipidemia population, where it is hoped that its impact on non-HDL-C, which includes cholesterol in triglyceride-rich particles like VLDL, as well as LDL, will improve residual risk. Vupanorsen is also planned to reach the market earlier with a severe hypertriglyceridemia indication, including a trial against Vascepa. If vupanorsen is priced lower for a broader population and does have substantial LDL-C lowering in HoFH, it could displace evinacumab. While vupanorsen may have stronger triglyceride and LDL-C lowering, as an injectable, it could still face competition from oral pemafibrate, though the latter 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 earlier-stage AKCEA-APOCIII-LRx is hoped to avoid these issues, as is vupanorsen, though it remains to be seen if they avoid them 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. However, depending on the magnitude of the difference, if vupanorsen is priced lower for a broad population, it could be used first 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 asset is 8.9%, and the average probability a drug advances from Phase III is 62.1%. Dyslipidemia drugs, on average, take 7.6 years from Phase I to approval, compared to 10.0 years in the overall CV space.

Table of Contents

  • Latest key takeaways

  • Definition
  • Patient segmentation

  • Treatment guidelines vary across regions
  • Treatment recommendations focus on risk groups
  • Recommendations on specific classes

  • Daiichi Sankyo Enters Europe’s Cholesterol Market
  • Amarin Seeks EU Fast-Track For Potential Cardiovascular Blockbuster
  • YouTube Video Suggesting Livalo Is Safer Than Other Statins Is Dinged By US FDA

  • Deal Watch: NewAmsterdam To Take On Amgen’s Stalled CETP Inhibitor
  • Alnylam Secures $2bn Financing From Blackstone By Monetizing Inclisiran Royalties
  • Novartis To Pay $9.7bn For The Medicines Company
  • Pfizer Reaffirms CV Disease Commitment With Deal For Akcea's ANGPTL3 Drug

  • Sponsors by status
  • Published on 06 November 2020
  • Sponsors by phase
  • Recent events

  • Cholesterol-lowering drugs
  • Triglyceride-lowering drugs
  • Lp(a)-lowering drugs
  • HDL-increasing drugs

  • New launches and CVOT data will drive growth in the dyslipidemia market over the forecast period
  • Novel reimbursement strategy for inclisiran could salvage the PCSK9 segment
  • Price pressures and affordability will continue to be major factors limiting growth

  • CaPre for Dyslipidemia (August 31, 2020)
  • Multiple Drugs for Dyslipidemia (August 31, 2020 and August 29, 2020)
  • Nexletol for Dyslipidemia (June 14, 2020)
  • Vupanorsen for Dyslipidemia (January 28, 2020)
  • Dalcetrapib for Dyslipidemia (January 27, 2020)
  • CaPre for Dyslipidemia (January 13, 2020)
  • Inclisiran for Dyslipidemia (November 16, 2019 and November 18, 2019)
  • Vascepa for Dyslipidemia (November 18, 2019)
  • Vascepa for Dyslipidemia (November 14, 2019)
  • Vascepa for Dyslipidemia (November 12, 2019)
  • ARO-ANG3 for Dyslipidemia and ARO-APOC3 for Lipoprotein Lipase Deficiency (September 16, 2019)
  • Inclisiran for Dyslipidemia (September 2, 2019)

  • Interviews with physicians at the ADA conference regarding Vascepa
  • Interview regarding PCSK9 reimbursement with a KOL from a large US payer

  • Improved options for statin-intolerant patients
  • A well-tolerated oral drug with LDL-C lowering as good as the current injectable PCSK9 inhibitors when added to a statin
  • Addressing the residual risk remaining in higher-risk patients despite well-controlled LDL-C levels
  • A way to motivate patients to stick with treatment if their lipid levels are elevated

  • Prescription information

List of Figures
  • Figure 1: Hypercholesterolemia treatment recommendations in the US
  • Figure 2: Hypercholesterolemia treatment recommendations in Europe and Japan
  • Figure 3: Hypercholesterolemia recommendations for specific drug classes
  • Figure 4: Hypertriglyceridemia recommendations for specific drug classes
  • Figure 5: Usage of major drug classes
  • Figure 6: Trends in prevalent cases of dyslipidemia, 2018-27
  • Figure 7: Overview of pipeline drugs for dyslipidemia in the US
  • Figure 8: Pipeline drugs for dyslipidemia, by company
  • Figure 9: Pipeline drugs for dyslipidemia, by drug type
  • Figure 10: Pipeline drugs for dyslipidemia, by classification
  • Figure 11: Probability of success in the dyslipidemia/hypercholesterolemia pipeline
  • Figure 12: Clinical trials in dyslipidemia
  • Figure 13: Top 10 drugs for clinical trials in dyslipidemia
  • Figure 14: Top 10 companies for clinical trials in dyslipidemia
  • Figure 15: Trial locations in dyslipidemia
  • Figure 16: Dyslipidemia trials status
  • Figure 17: Dyslipidemia trials sponsors, by phase
  • Figure 18: Datamonitor Healthcare’s drug assessment summary for dyslipidemia
  • Figure 19: Dyslipidemia CVOTs in the statin era - MACE/primary endpoint reductions
  • Figure 20: Major statin comparison - LDL-C lowering
  • Figure 21: Ezetimibe and bempedoic acid franchise - LDL-C lowering
  • Figure 22: PCSK9 comparison - LDL-C lowering
  • Figure 23: Inclisiran - LDL-C lowering in Phase III: ASCVD patients (ORION-10, -11) and HeFH (ORION-9)
  • Figure 24: Homozygous familial hypercholesterolemia comparison - LDL-C lowering
  • Figure 25: Omega-3 FA comparison - triglyceride lowering
  • Figure 26: Fenofibrate - triglyceride lowering
  • Figure 27: ApoC-III and ANGPTL3, antisense oligonucleotides and RNAi - triglyceride lowering
  • Figure 28: Hypercholesterolemia and Lp(a) segment - current and future market dynamics analysis
  • Figure 29: Hypertriglyceridemia and low HDL-C segment - current and future market dynamics analysis
  • Figure 30: Future trends in dyslipidemia
  • Figure 31: CaPre for Dyslipidemia (August 31, 2020): Phase III - TRILOGY 2
  • Figure 32: Vupanorsen for Dyslipidemia (August 29, 2020): Phase II - Hypertriglyceridemia, T2DM, & NAFLD
  • Figure 33: AKCEA-APOCIII-LRx for Dyslipidemia (August 29, 2020): Phase II - ISIS 678354-CS2
  • Figure 34: Vupanorsen for Dyslipidemia (January 28, 2020): Phase II - Hypertriglyceridemia, T2DM, & NAFLD
  • Figure 35: CaPre for Dyslipidemia (January 13, 2020): Phase III - TRILOGY 1
  • Figure 36: Inclisiran for Dyslipidemia (November 16, 2019): Phase III - ORION-10 (US)
  • Figure 37: Inclisiran for Dyslipidemia (November 18, 2019): Phase III - ORION-9 (Heterozygous FH Subjects)
  • Figure 38: Vascepa for Dyslipidemia (Cardiovascular Disease indication; November 18, 2019): Phase IV - EVAPORATE
  • Figure 39: ARO-ANG3 for Dyslipidemia and ARO-APOC3 for Lipoprotein Lipase Deficiency (September 16, 2019): Phase I - SAD/MAD (AROAPOC31001); Phase I - AROANG1001 (Australia)
  • Figure 40: Inclisiran for Dyslipidemia (September 2, 2019): Phase III - ORION-11 (EU)
  • Figure 41: Key upcoming events in dyslipidemia

List of Tables
  • Table 1: Prevalent cases of dyslipidemia, 2018-27
  • Table 2: Marketed drugs for dyslipidemia
  • Table 3: Pipeline drugs for dyslipidemia in the US
  • Table 4: Historical global sales, by drug ($m), 2015-19
  • Table 5: Forecasted global sales, by drug ($m), 2020-24
  • Table 6: CaPre for Dyslipidemia (August 31, 2020)
  • Table 7: Multiple Drugs for Dyslipidemia (August 31, 2020 and August 29, 2020)
  • Table 8: Nexletol for Dyslipidemia (June 14, 2020)
  • Table 9: Vupanorsen for Dyslipidemia (January 28, 2020)
  • Table 10: Dalcetrapib for Dyslipidemia (January 27, 2020)
  • Table 11: CaPre for Dyslipidemia (January 13, 2020)
  • Table 12: Inclisiran for Dyslipidemia (November 16, 2019 and November 18, 2019)
  • Table 13: Vascepa for Dyslipidemia (November 18, 2019)
  • Table 14: Vascepa for Dyslipidemia (November 14, 2019)
  • Table 15: Vascepa for Dyslipidemia (November 12, 2019)
  • Table 16: ARO-ANG3 for Dyslipidemia and ARO-APOC3 for Lipoprotein Lipase Deficiency (September 16, 2019)
  • Table 17: Inclisiran for Dyslipidemia (September 2, 2019)