A fixed dose combination for CVDs

1. AND SECONDARY
PREVENTIONS OF
CARDIOVASCULAR
MORBIDITY AND
MORTALITY
1
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd.
Presented at the IACS Conference 'Translational
Research in Cardiovascular Sciences”
Anand, Gujarat, February 5-6, 2016

2. CVDS: CURRENT GLOBAL
BURDEN
2

3. 3

4. CVD RISK FACTORS
 Cardiovascular risk factors
 Non-modifiable: Family history, ethnicity and age
 Modifiable: Hypertension, high cholesterol, obesity, physical
inactivity, diabetes, unhealthy diets, tobacco, and harmful use of alcohol
 Modifiable risk factors
 Hypertension – biggest risk factor for stroke; significant role in heart
attacks; preventable & treatable
 Physical inactivity & obesity increases heart disease and stroke risk
by 50%.
 Type2 diabetes doubles coronary heart disease and stroke risk
 A diet high in saturated fat increases the risk of heart disease and
stroke
 Chronically stressful life, social isolation, anxiety and depression
 Up to 1 or 2 alcohol drinks OK but above this will damage the heart
muscle
 Certain medicines e.g., contraceptive pill and hormone replacement
therapy (HRT).
 Left ventricular hypertrophy (LVH)
4

5. WHAT ARE CVDS?
 Cardiovascular diseases (CVDs) are a group of disorders of
the heart and blood vessels and they include:
 Coronary heart disease – disease of the blood vessels supplying
the heart muscle
 Cerebrovascular disease – disease of the blood vessels supplying
the brain
 Peripheral arterial disease – disease of blood vessels supplying
the arms and legs
 Rheumatic heart disease – damage to the heart muscle and heart
valves from rheumatic fever, caused by streptococcal bacteria;
 Congenital heart disease – malformations of heart structure
existing at birth
 Deep vein thrombosis and pulmonary embolism – blood clots in
the leg veins, which can dislodge and move to the heart and lungs
5

6. COMMON SYMPTOMS OF
CVDS
 Symptoms of heart attacks and strokes
 Pain or discomfort in the centre of the chest
 Pain or discomfort in the arms, the left shoulder, elbows, jaw, or back
 Difficulty or shortness of breath; feeling sick or vomiting; feeling light-
headed or faint; breaking into a cold sweat; and becoming pale
 Women are more likely to have the above
 Symptoms of stroke
 Sudden weakness of the face, arm, or leg, most often on one side of the
body
 Numbness of the face, arm, or leg, especially on one side of the body
 Confusion, difficulty speaking or understanding speech
 Difficulty seeing with one or both eyes
 Difficulty walking, dizziness, loss of balance or coordination
 Severe headache with no known cause
 Fainting or unconsciousness 6

7. PRIMARY PREVENTION OF
CVDS
 Population level primary prevention:
 Lowering the average risk factors like BP, LDL cholesterol,
smoking and obesity in the entire population
 Examples of population-wide interventions
 comprehensive tobacco control policies
 taxation to reduce the intake of foods that are high in fat, sugar
and salt
 building walking and cycle paths to increase physical activity
 strategies to reduce harmful use of alcohol
 providing healthy school meals to children.
 Individual level 1o
prevention:
 targeted those at high total cardiovascular risk or
 those with single risk factor levels above traditional thresholds,
e.g., hypertension and hypercholesterolemia 7

8. PRIMARY PREVENTION OF
CVDS
8
• Statin: simvastatin
• CCB: amlodipine
low dose
• ARB: losartan
low dose
• Thiazide:
hydrochlorothiazide
low dose
• No Aspirin
Wald NJ, Morris JK. Eur J Epidemiol 2014. DOI 10.1007/s10654-014-9932-1
Age of starting preventive treatment: 50
years
Among these, % who benefit: 33%
Their average benefit: 8 years
(Years of life gained without an IHD event or stroke.)

9. PRIMARY PREVENTION:
POLYPILL EFFICACY
9
Wald N. (2014). FDA Presentation

10. SECONDARY PREVENTION OF
CVDS
 For secondary prevention of CVDs in those with established disease,
including diabetes, treatment with the following medications are
necessary:
 Aspirin, beta-blockers, ACE inhibitors & statins
10
Yusuf S. (2002). THE LANCET , 360: 2-3

11. 5-COMPONENT POLYPILL
EFFICACY FOR SECONDARY
PREVENTION
11
Wald NJ, Law MR. (2003) BMJ 326:1419-24

12. THE CADILA POLYCAPTM
USED IN
TIPS1 & PK STUDY
 Hydrochlorothiazide (12.5mg)
 Atenolol (50mg)
 Ramipril (5mg)
 Simvastatin (20mg)
 Acetyl Salicylic Acid (ASA)
 (100mg, Enteric Coated)
 In a 00 hard gelatin capsule 12

13. Reduction in
Heart Rate
Polycap -7.0
Other Atenolol
arms
-7.0
Non Atenolol arms 0.0
1)
POLYCAP: MEAN CHANGES IN BP, HEART
RATE
Lancet. 2009 Apr 18;373(9672):1341-51
Polycap reduces BP and Heart Rate similar to
component drugs
13

14. • Both groups showed
reduction in LDL levels
• Similar reduction in 11-
dehydrothromboxane B2
• Polycap conserved the LDL
reduction and Antiplatelet
activity
TIPS1: MEAN CHANGES IN LDL &
PLATELET FUNCTION WITH POLYCAPTM
Polycap reduces Lipids and platelet activity similar
to component drugs
14
LDL11-dehydrothromboxaneB2
14

15.  518 patients with previous vascular
disease or DM
 Assigned to a single (regular dose) or
to 2 capsules of the Polycap (full dose)
 Full dose showed superior reduction in
 BP
 LDL, compared to regular dose
 Similar tolerability profile in both
arms
THE INDIAN POLYCAP STUDY 2
(TIPS 2) POLYCAPTM
: MEAN
CHANGES IN BP
Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):463-71
Polycap can be titrated from regular to full dose for
better control
LipidloweringBPlowering
15

16.  Potential reduction in CVD
attacks
 An apt therapeutic option for
 High risk CVD patients
 Secondary prevention
 Easy Dosing
 Once daily dosing improves
patient compliance
 Easy to titrate
 Start with 1 cap OD, move to 2
caps/day if needed
THE EVIDENCE OF POLYCAP’S
EFFECTIVENESS
Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):463-71
TIPS 1 and TIPS 2: Result Summary
TIPS 1
(Regular
Polycap)
TIPS 2
(Full dose
Polycap)
16

17. ARE THE EFFECTS INDEPENDENT
IN REDUCING RISK?
 YES
 Evidence
 the mechanisms are different
 cohort studies
 randomised trials
 e.g. Heart Protection Study, 2002; EUROPA trial, 2002; TIPS (2009)
 So, when used together in appropriate patients, up to
80% future CV events can be prevented
 Potential benefits of quitting smoking, diabetes control
and exercise can virtually eliminate the entire CVD risk
in in high-risk individuals
17

18. THE PHARMACOKINETIC (PK)
ISSUES WITH POLYCAP
 While the efficacy of giving multiple proven drugs in a
single pill or capsule has been proven, the questions are:
 Is such a combination of several active drugs safe and
tolerable?
 Is there any drug-drug and drug-metabolite interaction?
 Such interactions can lead to toxic or suboptimal levels of one
or more ingredients (and metabolites), which may lead to
increased adverse effects or alternatively decreased efficacy
 Is the bioavailability of some or all its components
preserved or getting altered?
 While TIPS1 and TIPS2 studied the efficacy of risk factor
reductions and clinical safety, we also studied the PK and
drug-drug interaction of Polycap 18
Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103

19. A five arm
randomized,
single-dose,
two-period,
two-treatment,
two-sequence,
crossover trial
in a total of
195 healthy
humans
19
Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103

20. Ramipril
Ramiprilat
Aspirin
Atenolol
Hydrochlorthiazide
Simvastatin20
PatelA.,ShahT.,….ChakrabortyB.S.(2010).AmJCardiovascDrugs,10:95-103

21. CONCLUSIONS OF THE
POLYCAPTM
PK STUDY
 Aspirin, ramipril, atenolol, and hydrochlorothiazide
from Polycap were absorbed with a comparable rate
and extent with those of single ingredient formulations
 Preservation of bioavailabilty
 There was no kinetic drug-drug interaction in vivo
 For simvastatin, there was a loss of bioavailability
(~20%) but >equal increase in bioavailability of
simvastatin acid
 The PK study of Polycap establishes the required
bioavailability for all its component drugs, thus
explaining its reported efficacy kinetically 21
Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103

22. FINAL REMARKS
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 Polycap provides potential primary reduction in CVD
attacks
 An apt therapeutic option for
 High risk CVD patients
 Secondary prevention
 Once daily dosing improves patient compliance
 Easy to titrate
 Start with 1 cap OD, move to 2 caps/day if needed
 No loss of bioavailability of individual components
when formulated as Polycap
 No drug-drug or drug-metabolite interaction
 Affordable in low income countries

23. THANK YOU VERY
MUCH
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