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PCSK-9 InhibitorsThe next big thing…?

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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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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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Emerging Therapies

RNAi Therapeutics1. Genetic targets

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Summary

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Future Prospects…What’s in store? Current Approvals

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

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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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Bibliography1. 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

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Bibliography5. 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