pcsk-9 inhibitors: the next blockbuster?

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PCSK-9 Inhibitors The next big thing…? 06/24/2022 Pharma Reading: Group No. 6 1

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PCSK9 Inhibitors The next big thing

PCSK-9 InhibitorsThe next big thing?

04-Dec-15Pharma Reading: Group No. 61

Proprotein convertase subtilisin kexin-91

HypercholesterolemiaType IIa of Hyperlipidemia/HyperlipoproteinemiaFamilial (genetic/hereditary): Homozygous (HoFH) (rare, 1 in million) and Heterozygous (HeFH) (1 in 500). Genetic disorder with high levels of LDL and cholesterolNon-familial (rare)

Treatment:HeFH: Statins, bile acid sequestrants, etc. Genetic counselling more prevalent these days.04-Dec-15Pharma Reading: Group No. 62

HeFH: Heterozygous Familial HypercholesterolemiaLDL: Low density lipoprotein2

Limitations of current therapiesEfficiency 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 consistentlyPoor adherence to long term regime of dosing04-Dec-15Pharma Reading: Group No. 63

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, myopathyIntolerance: Gastrointestinal disturbances, immune reactions, etc.NCEP-ATP: National Cholesterol Education Program Adult Treatment Panel3

04-Dec-15Pharma Reading: Group No. 64

Emerging TherapiesRNAi TherapeuticsGenetic targets04-Dec-15Pharma Reading: Group No. 65

CVD: Cardiovascular DiseaseGOF: Gain-of-function mutation, activating certain genes abnormally as a result of mutationCHD: Coronary Heart DiseaseLOF: Loss-of-function mutation, deactivating certain genesIndian population with Hypercholesterolemia: 13.9% in four representative regions of India both rural and urban5

04-Dec-15Pharma Reading: Group No. 66

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 MabsDiffused target (Statins) vs Specific, well defined and differentiated genetic target (PCSK-9)6

04-Dec-15Pharma Reading: Group No. 67

04-Dec-15Pharma Reading: Group No. 68

Summary

04-Dec-15Pharma Reading: Group No. 69

SAE: Short term Adverse EventsLP: Lipoprotein aCurrently, 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/intolerantBi-annual dosing and quarterly monitoring of blood levels of cholesterol and LDL means better adherence and patient compliance in a chronic disease treatmentHuge potential in terms of clinical superiority so far, enabling commercial opportunity for being a blockbuster drug9

Future ProspectsWhats in store?Current Approvals04-Dec-15Pharma Reading: Group No. 610Sr. No.MoleculeBrandCompanyApproved1AlirocumabPraluentSanofi-AventisJuly 24, 20152EvolocumabRepathaAmgenAugust 27, 20153Bococizumab-PfizerPhase II trials

Target 70mg/dlAverage costs $14000-15000 a yearAmgen has introduced co-pay cards of $5 each covering upto $4200/year in copay costsAn estimated 15% of patients will be on PCSK-9 inhibitors by next year: CardiologistsNo 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)10

Future ProspectsWhats 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 trickyGene therapyOutcomes vs Biomarkers, Initial bubble (to pop or not to pop)04-Dec-15Pharma Reading: Group No. 611

Analysts forecasts about $2 billion annual sales at peak. Chronic therapy, life term of disease, strict entry barriers for generic players surrounding biologics, etc.11

BibliographyCholesterol busting drugs. The Pharmaceutical Journal, April 2015. http://www.pharmaceutical-journal.com/news-and-analysis/features/pcsk9-inhibitors-the-next-cholesterol-lowering-blockbusters/20068181.articleReuters 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#GVz6WtY2XWWt9Hu9.97MedPage 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/52703Healthline | High Cholesterol | Home | Cholesterol Control: PCSK9 inhibitors vs. Statins. http://www.healthline.com/health/high-cholesterol/pcsk9-inhibitors-vs-statins#TheTakeaway504-Dec-15Pharma Reading: Group No. 612

BibliographyBitzur, R. et al. 'Intolerance To Statins: Mechanisms And Management'. Diabetes Care 36.Supplement_2 (2013): S325-S330. Web. 3 Dec. 2015.Fda.gov,. 'FDA Approves Praluent To Treat Certain Patients With High Cholesterol'. N.p., 2015. Web. 3 Dec. 2015.Fda.gov,. 'FDA Approves Repatha To Treat Certain Patients With High Cholesterol'. N.p., 2015. Web. 3 Dec. 2015.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.Medpagetoday.com,. 'PCSK9 Inhibitors: Now That We Have Them, What Do We Do?'. N.p., 2015. Web. 3 Dec. 2015.Alnylam Therapeutics www.alnylam.com

04-Dec-15Pharma Reading: Group No. 613