An introduction to PCSK-9 inhibitors: a new therapeutic class of drugs approved by US FDA in July 2015 to treat Heterozygous familial hypercholesterolemia (HeFH) and its superiority over gold standard statins in treatment. Does it have potential to become a blockbuster and emulate Lipitor's success?
2. Hypercholesterolemia
Type IIa of Hyperlipidemia/Hyperlipoproteinemia
Familial (genetic/hereditary): Homozygous (HoFH) (rare,
1 in million) and Heterozygous (HeFH) (1 in 500). Genetic
disorder with high levels of LDL and cholesterol
Non-familial (rare)
Treatment:
HeFH: Statins, bile acid sequestrants, etc. Genetic
counselling more prevalent these days.
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3. Limitations of current therapies
Efficiency of statins: Doubling the dose of the statin
decreases the LDL level further by only 6%
Side effects: Rhabdomyolosis, intolerance to dosage, risk
of Type II diabetes, liver damage, etc.
Functional limitations of statins as a therapeutic class:
Target level specified by NCEP-ATP guidelines for LDL-C is
not met consistently
Poor adherence to long term regime of dosing
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10. Future Prospects…What’s in store?
Current Approvals
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Sr.
No.
Molecule Brand Company Approved
1 Alirocumab Praluent Sanofi-
Aventis
July 24, 2015
2 Evolocumab Repatha Amgen August 27,
2015
3 Bococizumab - Pfizer Phase II trials
11. Future Prospects…What’s in store?
Vaccines: ALN-PCS02 PCSK-9 synthesis inhibitor from
Alnylam in Phase I
Small molecules: Adnectin (BMS), K-132 (CETP inhibitor).
Oral therapy with similar dosing would be a dream come
true, but strategies to protect the formulation from GI
tract is tricky
Gene therapy
Outcomes vs Biomarkers, Initial bubble (to pop or not to
pop)
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12. Bibliography
1. Cholesterol busting drugs. The Pharmaceutical Journal, April 2015.
http://www.pharmaceutical-journal.com/news-and-analysis/features/pcsk9-
inhibitors-the-next-cholesterol-lowering-blockbusters/20068181.article
2. Reuters Health Jan 13 2015. Pfizer developing PCSK9 pill, vaccine to lower
cholesterol http://www.reuters.com/article/2015/01/13/us-healthcare-
pfizer-cholesterol-idUSKBN0KM27A20150113#GVz6WtY2XWWt9Hu9.97
3. MedPage Today | PCSK9 Inhibitors: What's Coming Down the Pipeline. Could
oral agents or vaccines be next? July 21, 2015
http://www.medpagetoday.com/Cardiology/Atherosclerosis/52703
4. Healthline | High Cholesterol | Home | Cholesterol Control: PCSK9 inhibitors
vs. Statins. http://www.healthline.com/health/high-cholesterol/pcsk9-
inhibitors-vs-statins#TheTakeaway5
12/4/2015Pharma Reading: Group No. 6 12
13. Bibliography
5. Bitzur, R. et al. 'Intolerance To Statins: Mechanisms And Management'.
Diabetes Care 36.Supplement_2 (2013): S325-S330. Web. 3 Dec. 2015.
6. Fda.gov,. 'FDA Approves Praluent To Treat Certain Patients With High
Cholesterol'. N.p., 2015. Web. 3 Dec. 2015.
7. Fda.gov,. 'FDA Approves Repatha To Treat Certain Patients With High
Cholesterol'. N.p., 2015. Web. 3 Dec. 2015.
8. Joshi SR, et al. 'Prevalence Of Dyslipidemia In Urban And Rural India: The
ICMR-INDIAB Study. - Pubmed - NCBI'. Ncbi.nlm.nih.gov. N.p., 2015. Web. 3
Dec. 2015.
9. Medpagetoday.com,. 'PCSK9 Inhibitors: Now That We Have Them, What Do
We Do?'. N.p., 2015. Web. 3 Dec. 2015.
10. Alnylam Therapeutics www.alnylam.com
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Editor's Notes
Proprotein convertase subtilisin kexin-9
HeFH: Heterozygous Familial Hypercholesterolemia
LDL: Low density lipoprotein
Increasing the dosage of statins due to lack of efficiency/progression of disease may not result in proportionate decrease in cholesterol level.
Rhabdomyolosis: Muscle breakdown and degradation, pain in muscles, myopathy
Intolerance: Gastrointestinal disturbances, immune reactions, etc.
NCEP-ATP: National Cholesterol Education Program – Adult Treatment Panel
CVD: Cardiovascular Disease
GOF: Gain-of-function mutation, activating certain genes abnormally as a result of mutation
CHD: Coronary Heart Disease
LOF: Loss-of-function mutation, deactivating certain genes
Indian population with Hypercholesterolemia: 13.9% in four representative regions of India both rural and urban
Comparison with Statins: Statins act on the HMG-CoA reductase enzyme interrupting the chain synthesis of cholesterol.
Enzymatic inhibition of Statin vs Genetic modulation and receptor modulation of PCSK-9 inhibitors Mabs
Diffused target (Statins) vs Specific, well defined and differentiated genetic target (PCSK-9)
SAE: Short term Adverse Events
LP: Lipoprotein a
Currently, lack of safety and efficacy data in large populations has limited the use of the drugs to combinations with statins only when statins alone are inefficient/intolerant
Bi-annual dosing and quarterly monitoring of blood levels of cholesterol and LDL means better adherence and patient compliance in a chronic disease treatment
Huge potential in terms of clinical superiority so far, enabling commercial opportunity for being a blockbuster drug
Target 70mg/dl
Average costs $14000-15000 a year
Amgen has introduced co-pay cards of $5 each covering upto $4200/year in copay costs
An estimated 15% of patients will be on PCSK-9 inhibitors by next year: Cardiologists
No delay in Rx or cautious start by physicians leading to a long term benefits of discovering potential side effects faster and modifying quicker.
First is not the best always… Lovastatin vs Atorvastatin (Lipitor)
Analysts forecasts about $2 billion annual sales at peak. Chronic therapy, life term of disease, strict entry barriers for generic players surrounding biologics, etc.