Nature Reviews Drug Discovery | AOP, published online 17 October 2014; doi:10.1038/nrd4475
N E W S & A N A LY S I S
FROM THE ANALYST’S COUCH
The dyslipidaemia market Victoria Hudson It is estimated that the annual global number of deaths that are attributable to cardiovascular diseases (CVDs) will rise to 23.3 million by 2030 (REF. 1). Dyslipidaemia, which refers to any deviations in lipid levels from defined normal parameters, is a major modifiable risk factor for CVDs. The most common deviations include elevated low-density lipoprotein (LDL) cholesterol (LDL‑C; also known as ‘bad’ cholesterol), elevated triglycerides, and reduced high-density lipoprotein (HDL) cholesterol (HDL‑C; also known as ‘good’ cholesterol). Excessively elevated LDL‑C levels can lead to atherosclerosis when cholesterol is deposited in plaques in arterial walls. These plaques can rupture, leading to myocardial infarctions or ischaemic strokes. Although the underlying biological association between the other biomarkers (elevated triglycerides and low HDL‑C levels) and CVDs is less clear, there are strong epidemiological correlations that justify the treatment of those deviations. Current therapeutic options The efficacious statin class dominates the treatment of dyslipidaemia. Statins inhibit 3‑hydroxy‑3‑methylglutaryl-coenzyme‑A (HMG‑CoA) reductase, a rate-limiting enzyme involved in the hepatic synthesis of cholesterol. By reducing cholesterol synthesis, LDL receptors are upregulated, leading to increased LDL‑C endocytosis. Accordingly, the statin class has been shown to lower LDL‑C by 30–50%. A large body of randomized clinical trials demonstrate the efficacy of statins in reducing CVD outcomes (defined as death from coronary heart disease, myocardial infarction, unstable angina or stroke). The key statins are atorvastatin (Lipitor; Pfizer) and rosuvastatin (Crestor; AstraZeneca), either of which can lower LDL‑C by 50% or more. Other statin therapies commonly prescribed include simvastatin and pravastatin, which have been shown to lower LDL‑C levels by 30–50%. A number of drug classes that target non‑LDL‑C biomarkers are used as add‑on therapies with statins. Different formulations of niacin (also known as vitamin B3), anti-atheroma preparations of natural origin (for instance, from fish oils), and ezetimibe (Zetia; Merck & Co.) all demonstrate a
Yellow sofa, image from iStock.
beneficial impact on their respective target lipids, but they have been unable to demonstrate a clear impact on CVD outcomes. Niacin preparations target HDL‑C, whereas the fish-oil-derived products target triglycerides. Ezetimibe, an inhibitor of the transmembrane Niemann–Pick C1‑like protein 1 (NPC1L1), increases clearance of LDL‑C from the blood. It is positioned as an add-on therapy to statins or as an alternative treatment for statin-intolerant patients. However, the post-marketing ENHANCE trial did not show a slower progression of atherosclerosis in individuals with heterozygous familial hypercholesterol aemia, questioning its impact on CVDs despite its efficacy in reducing LDL‑C. A fixed-dose combination (FDC) of ezetimibe and simvastatin (Vytorin; Merck & Co.) is currently being investigated in the IMPROVE‑IT Phase IV study. Another FDC, which comprises ezetimibe and atorvastatin (Liptruzet; Merck & Co.), is also available, but its uptake has been limited given the uncertainty of ezetimibe’s impact on CVD outcomes. Other drugs that are used to treat dyslipidaemia include fibrates and ion-exchange resins; several FDCs of marketed antidyslipidaemic drugs; and cross-disease-area FDCs that involve antidyslipidaemic and antihypertensive therapies.
Fibrates increase HDL‑C levels as well as lowering triglycerides, and are mostly used in individuals with hypertriglycerid aemia or mixed dyslipidaemia. They activate peroxisome proliferator-activated receptors (PPARs), which are transcription factors for various genes encoding proteins that facilitate lipid metabolism. Ion-exchange resins tend to be used in statin-intolerant patients, but gastrointestinal side effects limit their uptake. These therapies disrupt the enterohepatic circulation of bile acids, leading to an upregulation of hepatic bile acids, which are produced from cholesterol. This in turn leads to increased clearance of LDL‑C from the plasma. Pipeline analysis The key late-stage pipeline therapies target statin-intolerant patients (approximately 10–15% of patients); patients with serious genetic causes of hypercholesterolaemia, (known as familial hypercholesterolaemia) in whom LDL‑C levels remain elevated in spite of high‑dose statin therapy; and other patients who remain at an elevated risk of having a CVD event. There are two main pipeline classes vying for these subpopulations: the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and the cholesteryl ester transport protein (CETP) inhibitors ▶ (TABLE 1).
Table 1 | Overview of the key compounds in development for dyslipidaemia Drug
Developer
Drug type
Status
Evolocumab
Amgen
Biologic
Filed (USA, EU)
Alirocumab
Sanofi/Regeneron
Biologic
Phase III
Bococizumab
Pfizer
Biologic
Phase III
LY3015014
Eli Lilly
Biologic
Phase II
Anacetrapib
Merck & Co.
Small molecule
Phase III
Evacetrapib
Eli Lilly
Small molecule
Phase III
DRL 17822
Dr. Reddy’s Laboratories
Small molecule
Phase II
JTT‑302
Japan Tobacco Inc.
Small molecule
Phase II
PRC‑4016
BASF AG
Small molecule
Phase II
PCSK9 inhibitors
CETP inhibitors
PCSK9, proprotein convertase subtilisin kexin type 9; CETP, cholesteryl ester transfer protein; EU, European Union.
NATURE REVIEWS | DRUG DISCOVERY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S FROM THE ANALYST’S COUCH ▶
Inhibition of PCSK9 prevents the lyososomal degradation of LDL receptors within hepatocytes. This facilitates the recycling of LDL receptors to the surface of hepatocytes and leads to increased clearance of plasma LDL‑C. PCSK9 inhibitors in late-stage development include the monoclonal antibodies evolocumab (Amgen), alirocumab (Sanofi/Regeneron), and bococizumab (Pfizer). A number of RNA interference approaches and adnectins (engineered proteins) that target PCSK9 are also in early-stage or preclinical development. Both evolocumab and alirocumab have demonstrated strong reductions in LDL‑C alongside promising safety data in Phase III trials. Both are expected to launch in the second half of 2015. Regulatory filings for evolocumab were submitted in Q3 2014 in the United States and in the European Union (EU), and regulatory filings for alirocumab are anticipated to be submitted by the end of 2014. The regulatory approval of alirocumab in the United States is expected to be expedited with a priority review voucher. Uptake of both therapies is anticipated to be initially restricted to patients with familial hypercholesterolaemia, as well as to statin-intolerant patients. Uptake of PCSK9 inhibitors in the larger secondary-prevention population of patients (who already have coronary heart disease and are at a much higher risk of having another myocardial infarction, stroke or thromboembolism) is expected to be based on data from CVD outcome trials. These data will be crucial given the repeated failure of statin add‑on therapies to clearly demonstrate a beneficial impact on CVD events. The FOURIER trial of evolocumab is expected to complete in February 2018, the ODYSSEY trial of a 2014 $0.97
$0.83 $0.02
$0.32
Market indicators The dyslipidaemia market — and in particular, the statin class — is facing increasing generic competition. As a result of the widespread launch of generic equivalents, atorvastatin sales fell from US$9.6 billion in 2011 to $3.9 billion in 2012. Rosuvastatin is expected to face generic competition in the United States from May 2016. Owing to the widespread availability of cheap and efficacious statins, the class is expected to continue to dominate the treatment of
b 2021 $5.89
$11.47
$2.57
alirocumab, in January 2018, and the SPIRE‑1 and SPIRE‑2 trials of bococizumab, in August 2018. The two CETP inhibitors in Phase III development are the orally available small-molecule drugs evacetrapib (Eli Lilly) and anacetrapib (Merck), which have both demonstrated clear reductions in LDL‑C and increases in HDL‑C in Phase II and Phase III trials, respectively. However, questions over the mechanism of action of CETP inhibitors and their ultimate impact on CVD outcomes remain. So far, the development of eight CETP inhibitors has been suspended, with the two highest-profile suspensions involving torcetrapib (Pfizer) and dalcetrapib (Roche). Torcetrapib had off-target effects on blood pressure, whereas dalcetrapib was a weak inhibitor of CETP and failed to demonstrate sufficient efficacy. Although serious uncertainty surrounds the class, anacetrapib and evacetrapib have so far shown better efficacy and safety than have dalcetrapib or torcetrapib. Moreover, the adverse impact of torcetrapib on blood pressure is believed to be molecule-specific rather than representing a class effect. Nevertheless, demonstrating a clear benefit on CVD outcomes will be crucial for the CETP inhibitors still in development.
$16.63
$29.54
$10.80
$8.89
$1.12
$0.73 $0.13 $1.25 $0.91 $0.25 $0.015
Statins Fibrates Ion-exchange resins Other Anti-atheroma of natural origins Fixed-dose combinations Cross-disease-area FDCs CETP inhibitors PCSK9 inhibitors
Figure 1 | Shifting composition of the dyslipidaemia market. Data are for the United States, Japan, and five major European Union markets (namely, France, Germany, Italy, Spain and the United Nature Reviews | Drug Discovery Kingdom). The dyslipidaemia market is forecast to grow from US$16.6 billion in 2014 to $29.5 billion in 2021. ‘Other’ refers to the compounds in Merck & Co.’s ezetimibe franchise: Zetia, Vytorin, and Liptruzet, as well as to the niacin class. All values are in US$ billions. CETP, cholesteryl ester transport protein; FDC, fixed-dose combination; PCSK9, proprotein convertase subtilisin kexin type 9. 2 | ADVANCE ONLINE PUBLICATION
dyslipidaemia at first line. Moreover, statins are increasingly being used as monotherapy owing to the failure of a number of add-on therapies to demonstrate a beneficial impact. The increasing importance of CVD outcome data is affecting the ezetimibe franchise in particular. The IMPROVE‑IT study of Vytorin should help to determine the franchise’s ultimate future value. The trial results will also help to answer the questions surrounding the use of biomarkers as a proxy for CVD outcomes. The results are anticipated to be released in early 2015. Despite the shift towards statin monotherapy regimens, there is still a sizeable opportunity for pipeline candidates. This is owing to the overall size of the dyslipidaemic patient population which, in the United States alone, is forecast to comprise 94 million patients by 2021 (REF. 2). If the PCSK9 inhibitors and CETP inhibitors can demonstrate clear benefits in reducing CVD, the dyslipidaemia market in the United States, Japan and five major EU markets is forecast to grow from $16.6 billion in 2014 to $29.5 billion in 2021 (FIG. 1), reversing the current trend of declining sales. If approved, the PCSK9 inhibitors are forecast to achieve combined annual sales in the United States, Japan and five major EU markets of $11.5 billion by 2021. As injectable biologics, the class is very different to the currently available therapies. However, patients are not expected to struggle with using an injectable, owing to the high prevalence of type 2 diabetes amongst the dyslipidaemia population. The biggest challenge will be the justification of the higher prices of biologic therapies. If approved, the CETP inhibitor class is expected to achieve combined sales of $8.9 billion by 2021. The advantage of orally administered small molecules will help to facilitate uptake. However, owing to the earlier failures of torcetrapib and dalcetrapib, if other CETP inhibitors are unable to demonstrate a clear benefit on CVD outcomes, or if any serious off‑target effects are shown, then the class will not reach the market. Victoria Hudson is at Datamonitor Healthcare, Christchurch Court, 10–15 Newgate Street, London EC1A 7AZ, United Kingdom. e-mail: [email protected] doi:10.1038/nrd4475 Published online 17 October 2014 The author declares no competing financial interests. 1. World Health Organization. Cardiovascular diseases (CVDs) Factsheet No 316. [online], http://www.who.int/ mediacentre/factsheets/fs317/en/ (2013). 2. Datamonitor Healthcare. Epidemiology: Dyslipidemia (December 2013).
www.nature.com/reviews/drugdisc © 2014 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S
FROM THE ANALYST’S COUCH
The dyslipidaemia market Victoria Hudson It is estimated that the annual global number of deaths that are attributable to cardiovascular diseases (CVDs) will rise to 23.3 million by 2030 (REF. 1). Dyslipidaemia, which refers to any deviations in lipid levels from defined normal parameters, is a major modifiable risk factor for CVDs. The most common deviations include elevated low-density lipoprotein (LDL) cholesterol (LDL‑C; also known as ‘bad’ cholesterol), elevated triglycerides, and reduced high-density lipoprotein (HDL) cholesterol (HDL‑C; also known as ‘good’ cholesterol). Excessively elevated LDL‑C levels can lead to atherosclerosis when cholesterol is deposited in plaques in arterial walls. These plaques can rupture, leading to myocardial infarctions or ischaemic strokes. Although the underlying biological association between the other biomarkers (elevated triglycerides and low HDL‑C levels) and CVDs is less clear, there are strong epidemiological correlations that justify the treatment of those deviations. Current therapeutic options The efficacious statin class dominates the treatment of dyslipidaemia. Statins inhibit 3‑hydroxy‑3‑methylglutaryl-coenzyme‑A (HMG‑CoA) reductase, a rate-limiting enzyme involved in the hepatic synthesis of cholesterol. By reducing cholesterol synthesis, LDL receptors are upregulated, leading to increased LDL‑C endocytosis. Accordingly, the statin class has been shown to lower LDL‑C by 30–50%. A large body of randomized clinical trials demonstrate the efficacy of statins in reducing CVD outcomes (defined as death from coronary heart disease, myocardial infarction, unstable angina or stroke). The key statins are atorvastatin (Lipitor; Pfizer) and rosuvastatin (Crestor; AstraZeneca), either of which can lower LDL‑C by 50% or more. Other statin therapies commonly prescribed include simvastatin and pravastatin, which have been shown to lower LDL‑C levels by 30–50%. A number of drug classes that target non‑LDL‑C biomarkers are used as add‑on therapies with statins. Different formulations of niacin (also known as vitamin B3), anti-atheroma preparations of natural origin (for instance, from fish oils), and ezetimibe (Zetia; Merck & Co.) all demonstrate a
Yellow sofa, image from iStock.
beneficial impact on their respective target lipids, but they have been unable to demonstrate a clear impact on CVD outcomes. Niacin preparations target HDL‑C, whereas the fish-oil-derived products target triglycerides. Ezetimibe, an inhibitor of the transmembrane Niemann–Pick C1‑like protein 1 (NPC1L1), increases clearance of LDL‑C from the blood. It is positioned as an add-on therapy to statins or as an alternative treatment for statin-intolerant patients. However, the post-marketing ENHANCE trial did not show a slower progression of atherosclerosis in individuals with heterozygous familial hypercholesterol aemia, questioning its impact on CVDs despite its efficacy in reducing LDL‑C. A fixed-dose combination (FDC) of ezetimibe and simvastatin (Vytorin; Merck & Co.) is currently being investigated in the IMPROVE‑IT Phase IV study. Another FDC, which comprises ezetimibe and atorvastatin (Liptruzet; Merck & Co.), is also available, but its uptake has been limited given the uncertainty of ezetimibe’s impact on CVD outcomes. Other drugs that are used to treat dyslipidaemia include fibrates and ion-exchange resins; several FDCs of marketed antidyslipidaemic drugs; and cross-disease-area FDCs that involve antidyslipidaemic and antihypertensive therapies.
Fibrates increase HDL‑C levels as well as lowering triglycerides, and are mostly used in individuals with hypertriglycerid aemia or mixed dyslipidaemia. They activate peroxisome proliferator-activated receptors (PPARs), which are transcription factors for various genes encoding proteins that facilitate lipid metabolism. Ion-exchange resins tend to be used in statin-intolerant patients, but gastrointestinal side effects limit their uptake. These therapies disrupt the enterohepatic circulation of bile acids, leading to an upregulation of hepatic bile acids, which are produced from cholesterol. This in turn leads to increased clearance of LDL‑C from the plasma. Pipeline analysis The key late-stage pipeline therapies target statin-intolerant patients (approximately 10–15% of patients); patients with serious genetic causes of hypercholesterolaemia, (known as familial hypercholesterolaemia) in whom LDL‑C levels remain elevated in spite of high‑dose statin therapy; and other patients who remain at an elevated risk of having a CVD event. There are two main pipeline classes vying for these subpopulations: the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and the cholesteryl ester transport protein (CETP) inhibitors ▶ (TABLE 1).
Table 1 | Overview of the key compounds in development for dyslipidaemia Drug
Developer
Drug type
Status
Evolocumab
Amgen
Biologic
Filed (USA, EU)
Alirocumab
Sanofi/Regeneron
Biologic
Phase III
Bococizumab
Pfizer
Biologic
Phase III
LY3015014
Eli Lilly
Biologic
Phase II
Anacetrapib
Merck & Co.
Small molecule
Phase III
Evacetrapib
Eli Lilly
Small molecule
Phase III
DRL 17822
Dr. Reddy’s Laboratories
Small molecule
Phase II
JTT‑302
Japan Tobacco Inc.
Small molecule
Phase II
PRC‑4016
BASF AG
Small molecule
Phase II
PCSK9 inhibitors
CETP inhibitors
PCSK9, proprotein convertase subtilisin kexin type 9; CETP, cholesteryl ester transfer protein; EU, European Union.
NATURE REVIEWS | DRUG DISCOVERY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S FROM THE ANALYST’S COUCH ▶
Inhibition of PCSK9 prevents the lyososomal degradation of LDL receptors within hepatocytes. This facilitates the recycling of LDL receptors to the surface of hepatocytes and leads to increased clearance of plasma LDL‑C. PCSK9 inhibitors in late-stage development include the monoclonal antibodies evolocumab (Amgen), alirocumab (Sanofi/Regeneron), and bococizumab (Pfizer). A number of RNA interference approaches and adnectins (engineered proteins) that target PCSK9 are also in early-stage or preclinical development. Both evolocumab and alirocumab have demonstrated strong reductions in LDL‑C alongside promising safety data in Phase III trials. Both are expected to launch in the second half of 2015. Regulatory filings for evolocumab were submitted in Q3 2014 in the United States and in the European Union (EU), and regulatory filings for alirocumab are anticipated to be submitted by the end of 2014. The regulatory approval of alirocumab in the United States is expected to be expedited with a priority review voucher. Uptake of both therapies is anticipated to be initially restricted to patients with familial hypercholesterolaemia, as well as to statin-intolerant patients. Uptake of PCSK9 inhibitors in the larger secondary-prevention population of patients (who already have coronary heart disease and are at a much higher risk of having another myocardial infarction, stroke or thromboembolism) is expected to be based on data from CVD outcome trials. These data will be crucial given the repeated failure of statin add‑on therapies to clearly demonstrate a beneficial impact on CVD events. The FOURIER trial of evolocumab is expected to complete in February 2018, the ODYSSEY trial of a 2014 $0.97
$0.83 $0.02
$0.32
Market indicators The dyslipidaemia market — and in particular, the statin class — is facing increasing generic competition. As a result of the widespread launch of generic equivalents, atorvastatin sales fell from US$9.6 billion in 2011 to $3.9 billion in 2012. Rosuvastatin is expected to face generic competition in the United States from May 2016. Owing to the widespread availability of cheap and efficacious statins, the class is expected to continue to dominate the treatment of
b 2021 $5.89
$11.47
$2.57
alirocumab, in January 2018, and the SPIRE‑1 and SPIRE‑2 trials of bococizumab, in August 2018. The two CETP inhibitors in Phase III development are the orally available small-molecule drugs evacetrapib (Eli Lilly) and anacetrapib (Merck), which have both demonstrated clear reductions in LDL‑C and increases in HDL‑C in Phase II and Phase III trials, respectively. However, questions over the mechanism of action of CETP inhibitors and their ultimate impact on CVD outcomes remain. So far, the development of eight CETP inhibitors has been suspended, with the two highest-profile suspensions involving torcetrapib (Pfizer) and dalcetrapib (Roche). Torcetrapib had off-target effects on blood pressure, whereas dalcetrapib was a weak inhibitor of CETP and failed to demonstrate sufficient efficacy. Although serious uncertainty surrounds the class, anacetrapib and evacetrapib have so far shown better efficacy and safety than have dalcetrapib or torcetrapib. Moreover, the adverse impact of torcetrapib on blood pressure is believed to be molecule-specific rather than representing a class effect. Nevertheless, demonstrating a clear benefit on CVD outcomes will be crucial for the CETP inhibitors still in development.
$16.63
$29.54
$10.80
$8.89
$1.12
$0.73 $0.13 $1.25 $0.91 $0.25 $0.015
Statins Fibrates Ion-exchange resins Other Anti-atheroma of natural origins Fixed-dose combinations Cross-disease-area FDCs CETP inhibitors PCSK9 inhibitors
Figure 1 | Shifting composition of the dyslipidaemia market. Data are for the United States, Japan, and five major European Union markets (namely, France, Germany, Italy, Spain and the United Nature Reviews | Drug Discovery Kingdom). The dyslipidaemia market is forecast to grow from US$16.6 billion in 2014 to $29.5 billion in 2021. ‘Other’ refers to the compounds in Merck & Co.’s ezetimibe franchise: Zetia, Vytorin, and Liptruzet, as well as to the niacin class. All values are in US$ billions. CETP, cholesteryl ester transport protein; FDC, fixed-dose combination; PCSK9, proprotein convertase subtilisin kexin type 9. 2 | ADVANCE ONLINE PUBLICATION
dyslipidaemia at first line. Moreover, statins are increasingly being used as monotherapy owing to the failure of a number of add-on therapies to demonstrate a beneficial impact. The increasing importance of CVD outcome data is affecting the ezetimibe franchise in particular. The IMPROVE‑IT study of Vytorin should help to determine the franchise’s ultimate future value. The trial results will also help to answer the questions surrounding the use of biomarkers as a proxy for CVD outcomes. The results are anticipated to be released in early 2015. Despite the shift towards statin monotherapy regimens, there is still a sizeable opportunity for pipeline candidates. This is owing to the overall size of the dyslipidaemic patient population which, in the United States alone, is forecast to comprise 94 million patients by 2021 (REF. 2). If the PCSK9 inhibitors and CETP inhibitors can demonstrate clear benefits in reducing CVD, the dyslipidaemia market in the United States, Japan and five major EU markets is forecast to grow from $16.6 billion in 2014 to $29.5 billion in 2021 (FIG. 1), reversing the current trend of declining sales. If approved, the PCSK9 inhibitors are forecast to achieve combined annual sales in the United States, Japan and five major EU markets of $11.5 billion by 2021. As injectable biologics, the class is very different to the currently available therapies. However, patients are not expected to struggle with using an injectable, owing to the high prevalence of type 2 diabetes amongst the dyslipidaemia population. The biggest challenge will be the justification of the higher prices of biologic therapies. If approved, the CETP inhibitor class is expected to achieve combined sales of $8.9 billion by 2021. The advantage of orally administered small molecules will help to facilitate uptake. However, owing to the earlier failures of torcetrapib and dalcetrapib, if other CETP inhibitors are unable to demonstrate a clear benefit on CVD outcomes, or if any serious off‑target effects are shown, then the class will not reach the market. Victoria Hudson is at Datamonitor Healthcare, Christchurch Court, 10–15 Newgate Street, London EC1A 7AZ, United Kingdom. e-mail: [email protected] doi:10.1038/nrd4475 Published online 17 October 2014 The author declares no competing financial interests. 1. World Health Organization. Cardiovascular diseases (CVDs) Factsheet No 316. [online], http://www.who.int/ mediacentre/factsheets/fs317/en/ (2013). 2. Datamonitor Healthcare. Epidemiology: Dyslipidemia (December 2013).
www.nature.com/reviews/drugdisc © 2014 Macmillan Publishers Limited. All rights reserved
