Disease Analysis: Dyslipidemia
Author: Peter Chang
Publisher: Datamonitor Healthcare
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Latest key takeaways
- Datamonitor Healthcare estimates that in 2019, 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 cardiovascular outcomes data with label expansions.
- In the hypercholesterolemia segment, the injectable PCSK9 inhibitors have struggled due to payer restrictions, and while declining net pricing in the US has improved access and growth somewhat, sales are still relatively modest, 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, 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 topline benefit, though the drug is likely to already gain popularity prior to those results. The company is also open to innovative collaborations with healthcare systems outside the US, and has initiated one in the UK.
- Oral Nexletol (bempedoic acid), approved in February and April 2020 in the US and Europe respectively, could be limited by modest low-density lipoprotein cholesterol (LDL-C) lowering, particularly on top of statins. However, its fixed-dose combination (FDC) with ezetimibe, Nexlizet, approved a few days after, has better efficacy and could be an important addition, especially in high-need statin-intolerant patients. More real-world data are needed, though, on efficacy of the FDC in patients on higher-dose statins, due to issues in its pivotal trial. In addition, its oral route could lead it 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 cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH). Ultimately, given the large number of hypercholesterolemia patients not meeting goal, either with or without statin intolerance, Nexletol should still be fairly successful despite its modest efficacy, though it still needs to demonstrate positive CVOT results.
- In the hypertriglyceridemia segment (including mixed dyslipidemia), a CV label expansion in the US for the omega-3 fatty acid (FA) Vascepa, a formulation of EPA, should drive substantial growth, though with a loss on a patent case in March 2020, there are questions about when generics may enter, pending appeals. 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 could revive 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.
- In the orphan drug segment, anti-ANGPTL3 monoclonal antibody evinacumab is expected to take share from oral Juxtapid in homozygous familial hypercholesterolemia (HoFH) due to safety and tolerability issues with the latter, but will still face some competition from the lower-priced PCSK9 inhibitors in eligible patients, 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, and the drug additionally lowers triglycerides, so it could expand to other orphan dyslipidemia indications as well. The antisense drug Waylivra, which targets ApoC-III, may not be approved in the US for familial chylomicronemia syndrome due to safety issues. However, other earlier-stage antisense and RNAi drugs targeting ANGPTL3, ApoC-III, and Apo(a) may avoid these safety issues, and selected drugs have gained large pharma interest, including plans for a CVOT for a broader indication.
- 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 8.7%, and the average probability a drug advances from Phase III is 60.7%. Dyslipidemia drugs, on average, take 7.6 years from Phase I to approval, compared to 10 years in the overall CV space.
CONTENTS
8 OVERVIEW
8 Latest key takeaways
10 DISEASE BACKGROUND
10 Definition
10 Patient segmentation
11 TREATMENT
11 Treatment guidelines vary across regions
11 Treatment recommendations focus on risk groups
12 Recommendations on specific classes
16 EPIDEMIOLOGY
20 MARKETED DRUGS
28 PIPELINE DRUGS
37 KEY REGULATORY EVENTS
37 Daiichi Sankyo Enters Europe’s Cholesterol Market
37 Amarin Seeks EU Fast-Track For Potential Cardiovascular Blockbuster
37 YouTube Video Suggesting Livalo Is Safer Than Other Statins Is Dinged By US FDA
38 PROBABILITY OF SUCCESS
39 LICENSING AND ASSET ACQUISITION DEALS
39 Alnylam Secures $2bn Financing From Blackstone By Monetizing Inclisiran Royalties
39 Novartis To Pay $9.7bn For The Medicines Company
39 Pfizer Reaffirms CV Disease Commitment With Deal For Akcea’s ANGPTL3 Drug
41 CLINICAL TRIAL LANDSCAPE
42 Sponsors by status
43 Sponsors by phase
44 Recent events
47 DRUG ASSESSMENT MODEL
47 Cholesterol-lowering drugs
50 Triglyceride-lowering drugs
51 HDL-increasing drugs
57 MARKET DYNAMICS
62 FUTURE TRENDS
62 New launches and CVOT data will drive growth in the dyslipidemia market over the forecast period
63 Novel reimbursement strategy for inclisiran could salvage the PCSK9 segment
63 Price pressures and affordability will continue to be major factors limiting growth
64 CONSENSUS FORECASTS
69 RECENT EVENTS AND ANALYST OPINION
69 AKCEA-ANGPTL3-LRx for Dyslipidemia (January 28, 2020)
70 Dalcetrapib for Dyslipidemia (January 27, 2020)
71 CaPre for Dyslipidemia (January 13, 2020)
72 Inclisiran for Dyslipidemia (November 16, 2019 and November 18, 2019)
76 Vascepa for Dyslipidemia (November 18, 2019)
78 Vascepa for Dyslipidemia (November 14, 2019)
80 Vascepa for Dyslipidemia (November 12, 2019)
82 ARO-ANG3 for Dyslipidemia and ARO-APOC3 for Lipoprotein Lipase Deficiency (September 16, 2019)
85 Inclisiran for Dyslipidemia (September 2, 2019)
87 Nexlizet for Dyslipidemia (August 29, 2019)
89 Inclisiran for Dyslipidemia (August 26, 2019)
91 Evinacumab for Dyslipidemia (August 14, 2019)
92 Vascepa for Dyslipidemia (August 8, 2019)
94 Inclisiran for Dyslipidemia (May 18, 2019)
96 Nexletol for Dyslipidemia (May 5, 2019)
98 KEY UPCOMING EVENTS
99 KEY OPINION LEADER INSIGHTS
101 Interviews with physicians at the ADA conference regarding Vascepa
101 Interview regarding PCSK9 reimbursement with a KOL from a large US payer
103 UNMET NEEDS
103 Improved options for statin-intolerant patients
103 A well-tolerated oral drug with LDL-C lowering as good as the current injectable PCSK9 inhibitors when added to a statin
103 Addressing the residual risk remaining in higher-risk patients despite well-controlled LDL-C levels
103 A way to motivate patients to stick with treatment if their lipid levels are elevated
104 BIBLIOGRAPHY
105 Prescription information
106 APPENDIX
LIST OF FIGURES
12 Figure 1: Hypercholesterolemia treatment recommendations in the US
12 Figure 2: Hypercholesterolemia treatment recommendations in Europe and Japan
14 Figure 3: Hypercholesterolemia recommendations for specific drug classes
14 Figure 4: Hypertriglyceridemia recommendations for specific drug classes
15 Figure 5: Usage of major drug classes
19 Figure 6: Trends in prevalent cases of dyslipidemia, 2018–27
28 Figure 7: Overview of pipeline drugs for dyslipidemia in the US
29 Figure 8: Pipeline drugs for dyslipidemia, by company
29 Figure 9: Pipeline drugs for dyslipidemia, by drug type
30 Figure 10: Pipeline drugs for dyslipidemia, by classification
38 Figure 11: Probability of success in the dyslipidemia pipeline
41 Figure 12: Clinical trials in dyslipidemia
41 Figure 13: Top 10 drugs for clinical trials in dyslipidemia
42 Figure 14: Top 10 companies for clinical trials in dyslipidemia
42 Figure 15: Trial locations in dyslipidemia
43 Figure 16: Dyslipidemia trials status
44 Figure 17: Dyslipidemia trials sponsors, by phase
47 Figure 18: Datamonitor Healthcare’s drug assessment summary for dyslipidemia
52 Figure 19: Dyslipidemia CVOTs in the statin era
52 Figure 20: Major statin comparison – LDL-C lowering
53 Figure 21: Ezetimibe and bempedoic acid franchise – LDL-C lowering
53 Figure 22: PCSK9 comparison – LDL-C lowering
54 Figure 23: Inclisiran – LDL-C lowering in Phase III: ASCVD patients (ORION-10, -11) and HeFH (ORION-9)
54 Figure 24: Heterozygous familial hypercholesterolemia comparison – LDL-C lowering
55 Figure 25: Omega-3 FA comparison – triglyceride lowering
56 Figure 26: Fenofibrate – triglyceride lowering
62 Figure 27: Future trends in dyslipidemia
70 Figure 28: AKCEA-ANGPTL3-LRx for Dyslipidemia (January 28, 2020): Phase IIb – Hypertriglyceridemia, T2DM, & NAFLD
72 Figure 29: CaPre for Dyslipidemia (January 13, 2020): Phase III – TRILOGY 1
76 Figure 30: Inclisiran for Dyslipidemia (November 16, 2019): Phase III – ORION-10 (US)
76 Figure 31: Inclisiran for Dyslipidemia (November 18, 2019): Phase III – ORION-9 (Heterozygous FH Subjects)
78 Figure 32: Vascepa for Dyslipidemia (Cardiovascular Disease indication; November 18, 2019): Phase II – EVAPORATE
85 Figure 33: ARO-ANG3 for Dyslipidemia and ARO-APOC3 for Lipoprotein Lipase Deficiency (September 16, 2019): Phase I – SAD/MAD (AROAPOC31001); Phase I – AROANG1001 (Australia)
87 Figure 34: Inclisiran for Dyslipidemia (September 2, 2019): Phase III – ORION-11 (EU)
89 Figure 35: Nexlizet for Dyslipidemia (August 29, 2019): Phase II – 1002-058 (T2DM & Elevated LDL-Cholesterol)
91 Figure 36: Inclisiran for Dyslipidemia (August 26, 2019): Phase III – ORION-11 (EU)
92 Figure 37: Evinacumab for Dyslipidemia (August 14, 2019): Phase III – ELIPSE HoFH
96 Figure 38: Inclisiran for Dyslipidemia (May 18, 2019): Phase II – ORION-3 (OLE)
98 Figure 39: Key upcoming events in dyslipidemia
LIST OF TABLES
17 Table 1: Prevalent cases of dyslipidemia, 2018–27
21 Table 2: Marketed drugs for dyslipidemia
31 Table 3: Pipeline drugs for dyslipidemia in the US
58 Table 4: Hypercholesterolemia segment – current and future market dynamics analysis
60 Table 5: Hypertriglyceridemia and low HDL-C segment – current and future market dynamics analysis
65 Table 6: Historical global sales, by drug ($m), 2014–19
67 Table 7: Forecasted global sales, by drug ($m), 2020–25
69 Table 8: AKCEA-ANGPTL3-LRx for Dyslipidemia (January 28, 2020)
70 Table 9: Dalcetrapib for Dyslipidemia (January 27, 2020)
71 Table 10: CaPre for Dyslipidemia (January 13, 2020)
73 Table 11: Inclisiran for Dyslipidemia (November 16, 2019 and November 18, 2019)
77 Table 12: Vascepa for Dyslipidemia (November 18, 2019)
79 Table 13: Vascepa for Dyslipidemia (November 14, 2019)
81 Table 14: Vascepa for Dyslipidemia (November 12, 2019)
83 Table 15: ARO-ANG3 for Dyslipidemia and ARO-APOC3 for Lipoprotein Lipase Deficiency (September 16, 2019)
86 Table 16: Inclisiran for Dyslipidemia (September 2, 2019)
88 Table 17: Nexlizet for Dyslipidemia (August 29, 2019)
90 Table 18: Inclisiran for Dyslipidemia (August 26, 2019)
91 Table 19: Evinacumab for Dyslipidemia (August 14, 2019)
93 Table 20: Vascepa for Dyslipidemia (August 8, 2019)
94 Table 21: Inclisiran for Dyslipidemia (May 18, 2019)
97 Table 22: Nexletol for Dyslipidemia (May 5, 2019)
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