Microsoft word - er_march_130318
PCSK9 mAbs or even vaccines – the new statins?
LONDON, UK----18th March 2013----ExpertREACT.
Novel PCSK9 (proprotein
convertases subtilisin/kexin type 9) inhibitors, such as Sanofi’s anti-PCSK9
monoclonal antibody SAR236553, have impressive LDL-C reducing efficacy. PCSK9 vaccines may represent an alternative strategy to the monoclonal antibody approach, taking a share of the multibillion-dollar PCSK9 market.
Cardiovascular disease (CVD), is the leading cause of death in high income countries1, and by 2030, around 40% of the US population are projected to have some form of CVD with direct medical costs of $818 billion2. Raised low-density lipoprotein cholesterol (LDL-C), smoking, and uncontrolled hypertension are major risk factors the development of CVD, and some 50% of US adults have at least one of these risk factors3.
Statins are the most effective drug class for reducing LDL-C, with the choice and dose of statin reflecting the degree of LDL-C reduction that is required to reach target LDL-C goals. LDL-C treatment goals are directly related to the level of CVD risk, with high-risk patients having the most demanding LDL-C targets. High-risk patients include those with acute coronary syndrome, non-coronary atherosclerosis (such as peripheral arterial disease and ischemic stroke), and heterozygous familial hypercholesterolemia (heFH), one of the most common hereditary metabolic disorders with a frequency in persons of European descent of ~1 in 500.
The joint European Society of Cardiology (ESC) and the European Atherosclerosis
Society (EAS) dyslipidemia guidelines4 recommend a target LDL-C goal of <1.8mmol/L
(<70mg/dL) in high-risk patients with CVD (a lower limit at which LDL-C reduction fails to
decrease CV risk has not been determined5). Based on current clinical practice,
however, only ~30-40% of CVD patients achieve this LDL-C goal6. It is likely that more
patients could reach the target LDL-C goal if they were prescribed the most potent
statins at the highest tolerable dose, or a second LDL-C lowering drug, such as Merck’s
Zetia (ezetimibe), was added. Even with optimal use of available LDL-C lowering drugs, VacZine Analytics
estimate that at least 50% of high-risk patients are unable to
achieve the recommended LDL-C goal. The LDL-C goal set by clinical practice
guidelines is beyond the limit of efficacy of currently approved therapies and novel
therapeutic strategies will be required to achieve target LDL-C levels in all high-risk
Several novel LDL-C lowering treatments are in clinical development: Pfizer, Sanofi, Amgen, Roche and Alnylam are all developing PCSK9 (proprotein convertases subtilisin/kexin type 9) inhibitors. Sanofi’s SAR236553, a twice-monthly subcutaneously administered anti-PCSK9 monoclonal antibody, is the most clinically advanced PCSK9 inhibitor (Sanofi licensed SAR236553 from Regeneron Pharmaceuticals). In a phase 2
trial, SAR236553 added to statin therapy further redu
represents a significant advance in LDL-C lowering efficacy, considering Zetia lowers LDL-C by an additional 15 to 20% when added to statin therapy.
ch of SAR236553 is expected in 2016. The FDA/EMEA are expected to
approve SAR236553 without data from the ongoing CV outcomes trial (which should repo
rt in 2018): other non-statin LDL-C lowering drugs, such as Zetia, received
regulatory approval based on a reduction in LDL-C as a surrogate outcome of CV risk redu
2013 VacZine Analytics. All rights reserved.
A key question is whether any safety signals arise with SAR236553, which could impact the regulatory risk/benefit analysis. If approved, SAR236553 would probably be used as an adjunct therapy in high-risk patients who fail to achieve the target LDL-C goal on a
statin plus a second LDL-C lowering treatment, or those who are statin intolerant.
PCSK9 vaccines could potentially induce functional PCSK9 antibodies to lower LDL-C.
No PCSK9 vaccines are in active clinical development, although Pfizer has claimed
patents for a PCSK9 vaccine and AFFiRiS AG (Austria) is developing a peptide-based
PCSK9 vaccine. Several questions remain about the PCSK9 vaccine approach, such as
the dosing required to achieve therapeutically-relevant levels of PCSK9-specific
antibodies, the possible variability of antibody response between patients and the
frequency of boosting required to prevent levels of circulating PCSK9 antibody falling
below the desired level. Assuming PCSK9 vaccination is feasible in humans, VacZine
research8 suggest vaccine players could attain a lucrative share of the
forecast multibillion-dollar market for novel PCSK9 therapies.
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*Top 5 companies:
GSK Biologicals, Sanofi Pasteur, Merck & Co, Pfizer (Wyeth) and
Novartis Vaccines and Diagnostics
References and Notes:
1. WHO Fact sheet No. 310. Available at:
http://www.who.int/mediacentre/factsheets/fs310/en/index.html. Accessed February 2013
2. Heidenreich PA et al. (2011) Forecasting the future of cardiovascular disease in the
United States: a policy statement from the American Heart Association. Circulation, 123(8):933-44.
3. Centers for Disease Control and Prevention (2011) Million hearts: strategies to reduce
the prevalence of leading cardiovascular disease risk factors--United States, 2011. MMWR, 60 (36): 1248-51.
4. European Association for Cardiovascular Prevention & Rehabilitation. ESC/EAS
Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011 Jul;32(14):1769-818.
5. Reddy G et al. LDL Lowering After Acute Coronary Syndrome: Is Lower Better? Curr
Treat Options Cardiovasc Med. 2013 Feb;15(1):33-40.
6. Karalis DG et al. Use of Lipid-Lowering Medications and the Likelihood of Achieving
Optimal LDL-Cholesterol Goals in Coronary Artery Disease Patients. Cholesterol. 2012;2012:861924.
7. McKenney JM et al. Safety and efficacy of a monoclonal antibody to proprotein
convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012 Jun 19;59(25):2344-53.
– Cholesterol (PCSK9) vaccines (CAT No: VAMV045),
A printable version of this article is available upon request.
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2013 VacZine Analytics. All rights reserved.
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