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Role of Evogliptin
INCRETINS
Incretin effect
Insulin concentration
0 10 20 30 40 50 60 70 80 90
minutes
Normal Glucose Homeostasis: Role of Incretins
In response to meals, incretin Fat Increased
1 hormones (GIP and GLP-1)
are increasingly released from Glucose
the small intestine Uptake
Insulin Secretion
DPP-4
Enzymes
Glucagon Secretion
Pancreatic cells
Incretins (GIP/GLP-1)
2 respond to high
levels of incretins
β Pancreatic beta cell
Liver
α DPP-4 enzymes Decreased
Pancreatic alpha cell
3 break down incretins Glucose
Production
Glucagon Secretion
Incretin action on
Incretins (GIP/GLP-1) 2 pancreatic cells is
reduced
β Pancreatic beta cell
Liver
α Pancreatic alpha cell Increased
Glucose
Production
15 *
10
0
0 60 120 180 240
Time (min)
Insulin
T2DM
Incretin
Further impaired
response Hyperglycemia
islet function
Glucose diminished
Glucagon
DPP-4 inhibitor
Insulin
Incretin
Improved islet Improved
activity
function glycemic control
Glucose prolonged
Glucagon
Meal
Intestinal
GLP-1 GLP-1 t½=1–2 min
release
Active
GLP-1
DPP-4
GLP-1
inactive
(>80% of pool)
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1
Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.
15
DPP4-I
AACE
DPP4-I: Current Status
Gliptins: What we already know?
The relative risk for adverse CV events during follow-up was 52%
lower for DPP4 inhibitors compared to other therapies
Pooled safety studies for other individual DPP4 inhibitors have shown
decreases in risk for major adverse CV events, 57% with saxagliptin,
66% with linagliptin, and 48% with alogliptin
https://www.boehringer-ingelheim.com/press-release/CARMELINA-high-level
Evogliptin
(DPP-4 Inhibitor)
Evogliptin
• Evogliptin (DA-1229) is a piperazine derivative
• Selective, potent and reversible inhibitor of DPP-4a
• Extensively studied in-vitro & in-vivo animal models for its efficacy and
safetya
• Evogliptin has been studied in a RCTs Phase II study and two Phase III
studies in South Korean patient with Type 2 DMb
• Drug has low potential for interaction with other co-administered drugsb
• Evogliptin is approved in South Korea (Dong-A) in 2nd October 2015 & also
in Azerbaijan as Monotherapy and in combination with metformin
• Approved by DCGI to manufacture and market the drug on 28.08.2018.
(a) Wu D, et al. Diabetes Obes Metab. 2014 Jan;16(1):30-7. (b) McCormack PL. Drugs. 2015 Nov;75(17):2045-9.
Evolving DPP4 Inhibitors
EVOGLIPTIN
Are all DPP4I Equal?
DPP4 Enzyme
Vildagliptin,
Saxagliptin
DPP4 Enzyme
Alogliptin, linagliptin
DPP4 Enzyme
Sitagliptin, Teneligliptin,
Evogliptin
DPP4 Enzyme
• Evogliptin
• Binds S1, S2, and S2 extensive binding sites
• Noncovalent binding
• 6,000 times higher potency compared to human DPP-VIII and DPP-IX
• 20,000 times greater potency compared to human DPP-I,II
2.5, 5, 10 mg/ day dose levels were selected for Phase 2 study
Clin Ther. 2012 Sep;34(9):1986-98.
30
IC 50
Drug Design, Development and Therapy 2014:8 1709–1721
Evogliptin: Favourable Pharmacokinetics
European Journal of Medicinal Chemistry 74 (2014) 1-32, Endocr J. 2015;62(1):13-20; Metabolic Syndrome and Obesity: Targets and Therapy 2013:6
187–195
Phase II study
• Study Title:
–A randomized, double-blind, placebo-
controlled, therapeutic exploratory clinical trial
to investigate the efficacy and safety of DA-
1229 after oral administration in patients with
type 2 diabetes who have inadequate
glycaemic control on diet and
exercise
• Objective:
– To evaluate efficacy and safety of DA-1229
and determine the optimal dose.
• Study design:
– Randomized, double-blind, placebo-controlled,
parallel-group, fixed-dose, multi-center, dose
finding design, setting 3 dose groups of DA-
1229 (2.5mg, 5mg and 10mg).
– Patients randomized 158
Diabetes Metab Res Rev 2015; 31: 295–306.
Baseline characteristics of study participants
according to treatment groups
– Combination therapy
• No of patients: 222
• Design: Sitagliptin controlled with
background metformin therapy
• Treatment duration: 24weeks
Phase III study: Evogliptin Monotherapy in
Patients with T2DM
group)
• Treatment-emergent AEs were reported by 33.3% of the patients in the evogliptin group and 35.0% of
the patients in the placebo group
• Four adverse drug reactions (constipation, diarrhoea, hypersensitivity and hyperglycaemia) were
suspected to be related to evogliptin.
• No serious AEs occurred with evogliptin, and one serious AE (tendon rupture) was reported in one
placebo recipient.
Pancreatitis was not reported in this study. Diabetes Obes Metab. 2017;19:1681–1687
Conclusion
• The results from the present study suggest that patients with T2D with
modest hyperglycaemia may be good candidates for evogliptin
monotherapy.
Those participants, who completed the 24-week treatment period, gave their
consent to receive another extended 28 weeks of open label treatment with 5
mg evogliptin qd. In the extended study, patients visited the site every 7 weeks
(at weeks 31, 38, 45 and 52).
Evogliptin and sitagliptin decreased the HbA1c level after treatment during 24
weeks (−0.59% ± 0.61% and −0.65% ± 0.61%, respectively; all P < 0.0001)
58
Subject Disposition
Screened
(N=411)
Screen
Failure(N=227 )
Randomize
d (N=184)
Completed Completed
(N=82) (N=82)
Visit 6/ wk 12
7.96 ± 1.24 8.03 ± 1.23
(Mean change from 0.751
(-0.37) (-0.32)
baseline)
Visit 9/ Week 24
7.78 ± 1.22 7.86 ± 1.15
(Mean change from 0.654
(-0.55) (-0.48)
baseline)
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
Week 12 - Visit 6 Week 24 - Visit 9
Evogliptin -0.37 -0.55
Sitagliptin -0.32 -0.48
63
50
Proportion of patients
45
40
35
30 26.7
25 20
20
15
10
5
0
Week 24 - Visit 9
Evogliptin 26.7
Sitagliptin 20
64
-10
-20
-30
-40
-50
-60
Week 12 - Visit 6 Week 24 - Visit 9
Evogliptin -19.08 -22.96
Sitagliptin -24.74 -33.58
66
-10
-20
-30
-40
-50
-60
Week 12 - Visit 6 Week 24 - Visit 9
Evogliptin -21.45 -25.4
Sitagliptin -28.12 -19.35
67
Evogliptin Sitagliptin
Screen
75 • 66.23 ± 12.26 Scree • 69.10 ±
ing ning • 13.77
69.06±
Visit 2 • 66.17 ± 12.19 Visit 2
70 13.78
•68.67
69.12 ±
Visit69.13 • 66.2569.12
69.06
± 12.0969.03 68.92
Visit68.823 68.78 68.7
13.70
•65.78
Mean Weight
66.23
65Visit 4
66.17 66.25
• 66.31 ± 12.15
66.31 66.02 66.02 69.03 ±
65.77 65.88
Visit 4
Visit 5 • 66.02 ± 12.17 • 13.41
68.92 ±
Visit 5
60
• 66.02 ± 11.98 • 13.36
68.82±
Visit 6 Visit 6
55
Visit 9 • 65.90 ± 11.91 Visit 9
• 13.55
68.71 ±
13.51
50 No Significant weight change noted across both the
Screening( Week 0 - Week 2 -
* Values represent Mean± SD groups
Week 4 - Week 8 - Week 12 - Week 16 - Week 20 - Week 24 -
Visit 1) Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9
Safety
• Two hypoglycemia events were reported during the study; 1 event
each in evogliptin and sitagliptin groups. Both events were mild and
unlikely to be related to the study drug.
• AE was dyslipidaemia (evogliptin: 6 events in 6 [6.5%] patients;
sitagliptin: 5 events in 5 [5.4%] patients), and most of these events
were reported to be unrelated to the study drug.
69
https://clinicaltrials.gov/ct2/results?cond=evogliptin&term=&cntry=&state=&city=&dist=
76
Abstract Presented
Hypoglycemic events, mostly mild, were reported in 1.98% of patients with evogliptin and 4.76% of patients with linagliptin for 12weeks.
Salient features of Evogliptin
Highly Selective for DPP-4 (More than 1,000-fold selective against total 170 off-target
enzymes and receptors)
Weight neutral
Decreased hepatic steatosis & normalized liver enzymes, Potential benefits in NAFLD
and NASH#