Therapy gaps identified and evidence generated through clinical research

1. Dr. Anil Pareek
President,
Medical Affairs and Clinical Research
Hydroxychloroquine Journey:
Safest DMARD to Anti-diabetic Drug
Clinical Research Initiatives and Innovation
Internist’s Experience in Pharma Industry
Dr. Anil Pareek
MD (Internal Medicine)
President - Medical Affairs & Clinical Research
Ipca Laboratories Ltd.

2. Clinical Research Initiatives at Ipca
• Therapy gap in safety of NSAIDs fulfilled by
Aceclofenac
• Renaissance of Chlorthalidone - An evidence based
diuretic in hypertension
• Diabetes - Inflammation link  Approval of first
anti-inflammatory drug – Hydroxychloroquine in
T2D
2

3. Background
• In November 2000, MSD published VIGOR study
• Compared clinically important upper GI events
between rofecoxib (selective COX-2 inh) and
naproxen (non-selective COX inh) in RA patients
• Rofecoxib associated with significantly fewer
clinically important upper GI events than naproxen
• However, the rate of MI was significantly higher in
the rofecoxib group vs. naproxen (0.4% vs. 0.1%)
3

4. Background
• In November 2000, MSD published VIGOR study
• Compared clinically important upper GI events
between rofecoxib (selective COX-2 inh) and
naproxen (non-selective COX inh) in RA patients
• Rofecoxib associated with significantly fewer
clinically important upper GI events than naproxen
• However, the rate of MI was significantly higher in
the rofecoxib group vs. naproxen (0.4% vs. 0.1%)
4Supplement to: Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. N Engl J Med
2006;DOI:10.1056/NEJMe068054.

5. Background
• Selective COX-2 inhibition is associated with
enhanced risk for CV events
• COX-2 inhibitors selectively reduce vascular
prostacyclin synthesis without disrupting COX-1-
derived thromboxane synthesis in platelets,
pre-disposing patients to thrombosis, hypertension,
and atherosclerosis
5

6. 6
Therapeutics and Clinical Risk Management 2007:3(2) 225–230
Anna Raber et al, University of Barcelona

7. GI Safety Proven in SOS Project
 28 studies involving 8.5 million new
NSAID users analyzed to study safety
of 13 NSAIDs
 All SOS data were communicated to
the European Medicines Agency

8. Least upper GI complications amongst NSAIDs
Drug Saf. 2012;35 (12):1127-46.

9. 9
BMJ. 2016 Sep 28;354:i4857.

10. 10
BMJ. 2016 Sep 28;354:i4857.

11. Aceclofenac – A Preferential COX -2 inhibitor
launched
• We identified need for balanced COX-1 and 2
inhibition
11

12. n = 591
21 centres

13. Aceclofenac in controlled release formulation
• First controlled released formulation of Aceclofenac
was developed at Ipca to allow once daily dosing
13

14. Aceclofenac in combination with Paracetamol
14

15. Aceclofenac in combination with Tizanidine
15
This study has been referred to in the guideline on Noninvasive
Treatments for Acute, Subacute, and Chronic Low Back Pain:
A Clinical Practice Guideline from the American College of
Physicians (ACP), Annals of Internal Medicine, Feb 2017

16. Aceclofenac in Combination with Drotaverine
16

17. Clinical Research Initiatives at Ipca
• Therapy gap in safety of NSAIDs fulfilled by
Aceclofenac
• Renaissance of Chlorthalidone - An evidence based
diuretic in hypertension
• Diabetes and Inflammation: A link, Approval of first
anti-inflammatory drug – Hydroxychloroquine in
T2DM
17

18. Background
18
• In the primary endpoint (fatal CHD and non-fatal MI), chlorthalidone (CTD) was
non-inferior to amlodipine and lisinopril
• 5-yr SBP was higher in amlodipine and lisinopril group compared to CTD
• 6 yr rate of HF was higher with amlodipine compared to CTD
• 6 yr rate of combined CVD was higher with lisinopril compared to CTD

19. CTD 6.25 mg in Hypertension
19
• CTD shown to be twice as potent as HCTZ
• HCTZ 12.5 mg dose is most commonly used; however,
corresponding dose of CTD was not available
• We conceived 6.25 mg dose of CTD and conducted series of
studies

20. First combination of Chlorthalidone with ARB
(Losartan)
20

21. Editorial on study of Losartan + CTD
Expert Opin. Pharmacother. (2009) 10(13):2037-39.

22. Chlorthalidone + Losartan Study
This study received New Investigator Travel award at Jackson
Cardiovascular Renal Meeting, University of Mississipi in 2008

23. Chlorthalidone + Metoprolol
23

24. Chlorthalidone ABPM Study
24
• We compared 24-h BP lowering efficacy of CTD 6.25 mg vs. HCTZ 12.5 mg
• Treatment with low-dose CTD 6.25 mg significantly reduced mean 24-h ABP and
nighttime BP, whereas no significant 24-h ABP reduction was seen with HCTZ
12.5 mg, which merely converted sustained hypertension into masked
hypertension
The 24-h ABP monitoring study of CTD vs. HCTZ has been referred in
Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk
assessment, Prevention, and Treatment of Hypertension in Adults,
Canadian Journal of Cardiology, March 2017

25. Editorial comment by Hillel Sternlicht and George Bakris on our
publication on low-dose chlorthalidone in Journal of the American
College of Cardiology
Chlorthalidone ABPM Study

26. Chlorthalidone ABPM Study
CARE 2016 Finalists
26

27. Chlorthalidone ABPM Study
CARE 2016 Winner

28. Chlorthalidone ABPM Study in Textbook
28
Our study has been referred to in two chapters in the latest
(11th) edition of Braunwald’s Heart Disease - A Textbook of
Cardiovascular Medicine

29. Chlorthalidone ABPM Study in Textbook
29
Our study has been referred to in two chapters in the latest
(11th) edition of Braunwald’s Heart Disease - A Textbook of
Cardiovascular Medicine

30. Comment on PREVER Study 2016
30

31. Comment in Hypertension Journal 2017
31

32. Comment in Journal of Clinical Investigation 2017
32

34. Clinical Research Initiatives at Ipca
• Therapy gap in safety of NSAIDs fulfilled by
Aceclofenac
• Renaissance of Chlorthalidone - An evidence based
diuretic in hypertension
• Diabetes and Inflammation: A link, Approval of first
anti-inflammatory drug – Hydroxychloroquine in
T2DM
34

35. Background
35
Use of HCQ >4 years was associated with 77% lower risk of
developing diabetes

36. Hydroxychloroquine in T2D
36
• We conducted a Phase III RCT to compare HCQ 400 mg with
pioglitazone in T2D patients uncontrolled on sulfonylurea and
metformin combination
• After 24 weeks of therapy, significant reduction in A1C, FPG, and
PPG was observed in both the groups. This change from baseline
was not significantly different between HCQ and pioglitazone
• Change in TC and LDL-C was significantly in favor of HCQ
(p<0.05)

37. Hydroxychloroquine gets approval in Diabetes
37

38. Pareek A et al. Curr Med Res Opin. 2015 Nov;31(11):2105-17.
HCQ in Dyslipidemia

39. Outcome
Pre-diabetic Diabetic
ATV + HCQ
(N = 47)
ATV
(N = 48)
P value
ATV + HCQ
(N = 54)
ATV
(N =48)
P
value
Baseline* 5.97 ± 0.22 5.97 ± 0.21 0.925 7.36 ± 0.87 7.44 ± 0.72 0.613
Week 24* 5.89 ± 0.35 6.13 ± 0.51 0.010 7.08 ± 1.17 7.76 ± 1.52 0.012
Change †
-0.08
(-0.19 to 0.04)
0.16
(0.04 to 0.27)
0.005
-0.30
(-0.65 to 0.05)
0.34
(-0.03 to 0.70)
0.014
P-value‡ 0.089 0.023 0.077 0.149
*- Values presented as mean ± SD, and compared using two sample t test;
†-Least square mean change from baseline (95% CI) adjusted to its baseline value,
‡-indicates comparison with baseline and paired t test used for comparison,
Modified intention to treat population comprised of patients who completed at-least 12 weeks of study without
any protocol violation.
HCQ in Dyslipidemia

40. HCQ in Dyslipidemia
Pareek A et al. Curr Med Res Opin. 2015 Nov;31(11):2105-17.
Change in HbA1c in prediabetics & diabetics at week 24

41. 41

42. 42

43. HCQ’s Anti-platelet Action
Achuthan S, et al. J Cardiovasc Pharmacol Ther 2014
First human pharmacodynamic study demonstrating
antiplatelet activity of HCQ

44. Comment on OXI Trial
44
Based on the potential benefits of hydroxychloroquine on CHF, we recommended
authors of the OXI trial to include CHF as one of the outcome measures
Authors accepted suggestion and modified the protocol
incorporating evaluation of CHF during visits

45. Comment on CANTOS Study
45

46. HCQ in RSSDI 2017 Guidelines
46

47. HCQ in ICMR 2018 Guidelines for Management of
T2D
47

48. Core pathophysiologic defects in Indian phenotype
as compared to the Caucasians – ICMR 2018
48HCQ favorably affects core pathophysiologic defects

49. HCQ Safety and Efficacy Study
Abstract presented at AACE
49
Abstract titled
PHASE 4 STUDY OF SAFETY AND EFFICACY OF THE FIRST ANTI-
INFLAMMATORY DRUG APPROVED IN INDIA IN TYPE 2 DIABETES
MELLITUS (HYDROXYCHLOROQUINE) - A PRELIMINARY
EVALUATION
Presented at the AACE 27th Annual Scientific & Clinical Congress in
Boston, MA, May 16-20, 2018.

50. Received formulation Patent for Pharmaceutical Compositions for the
treatment of Diabetes Mellitus along with 2 API family patent
(2 US and 2 Indian)
This was the 6th consecutive year of Ipca receiving patent award from IDMA
Best Formulation Patent Award 2014-15

51. HCQ + Anti-diabetic Agent: Ipca’s Patent
51

52. HCQ + Anti-diabetic Agent: Ipca’s Patent
52

53. HCQ and DPP-IV Inhibitor: Ipca’s Patent
53

54. HCQ and Statin: Ipca’s Patent
54

55. HCQ in Prophylaxis and Treatment of Statin
induced Diabetes
55

56. HCQ in NAFLD: Ipca’s Patent
56

57. Preclinical studies: HCQ in Diabetic Nephropathy
57

58. 58
Acknowledgement
This work is result of efforts of the Clinical Research Team
and support of Ipca Management.
I dedicate this work to my teachers at Topiwala National
Medical College & BYL Nair Hospital, Mumbai:
Late Dr A L Dsouza Dr. S D Mehtalia Dr S L Soneji
Late Dr A J Desai Late Dr P J Mehta
Dr V R Joshi Dr V S Ajgaonkar