PCSK-9 inhibitors: The next blockbuster?
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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?
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PCSK-9 inhibitors: The next blockbuster?
- 1. PCSK-9 Inhibitors The next big thing…? 12/4/2015Pharma Reading: Group No. 6 1
- 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. 12/4/2015Pharma Reading: Group No. 6 2
- 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 12/4/2015Pharma Reading: Group No. 6 3
- 4. 12/4/2015Pharma Reading: Group No. 6 4
- 5. Emerging Therapies RNAi Therapeutics 1. Genetic targets 12/4/2015Pharma Reading: Group No. 6 5
- 6. 12/4/2015Pharma Reading: Group No. 6 6
- 7. 12/4/2015Pharma Reading: Group No. 6 7
- 8. 12/4/2015Pharma Reading: Group No. 6 8
- 9. Summary 12/4/2015Pharma Reading: Group No. 6 9
- 10. Future Prospects…What’s in store? Current Approvals 12/4/2015Pharma Reading: Group No. 6 10 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) 12/4/2015Pharma Reading: Group No. 6 11
- 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 12/4/2015Pharma Reading: Group No. 6 13
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.