Transcript L-224715: Background and Rationale

Background and Initial Evaluation
of the DPP-IV Inhibitor, MK-431, for
Type 2 Diabetes
Slide 1
Overview
• The beta cell in type 2 diabetes: an important target
of therapy
• The incretin axis: potential therapeutic role
• DPP-IV inhibition and GLP-1 as therapeutic strategies
GLP-1=glucagon-like peptide 1; DPP-IV=dipeptidyl peptidase IV
Adapted from UKPDS Group Diabetes 1995;44:1249–1258; Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Vilsbøll T, Holst JJ
Diabetologia 2004;47:357–366.
The Beta Cell in Type 2 Diabetes:
An Important Target of Therapy
Pathophysiology of Hyperglycemia
in Type 2 Diabetes
Pancreas
Impaired
Insulin
insulin = deficiency
secretion
 Hepatic glucose
production
Liver
Diabetes =
Hyperglycemia
 Glucose
uptake
=
Insulin
resistance
Muscle
Adapted from Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.
Pathogenesis of Hyperglycemia in Type 2 Diabetes:
Progressive Deterioration of Glucose Tolerance
Normal
glucose
tolerance
Obesity
and increased
insulin
resistance
30.6% of
US adults
Impaired
glucose
tolerance (IGT)
or impaired
fasting glucose
(IFG)
and beta-cell
loss
Diabetes
8.3% of
US adults
6.1% of
US adults
Incidence rates based on US adults 20 years of age during 1999–2000
Adapted from Weyer C et al Diabetes Care 2001;24:89–94; Hedley AA et al JAMA 2004;291:2847–2850; CDC MMWR
2003;52:833–837.
Abnormal Beta-Cell Function in Type 2 Diabetes
• A range of functional
Mixed meal
abnormalities is present
*p<0.05 between groups
Adapted from Vilsbøll T et al Diabetes 2001;50:609–613.
500
Normal subjects
Type 2 diabetics
*
Insulin (pmol/L)
– Abnormal oscillatory
insulin release
– Increased proinsulin levels
– Loss of 1st-phase insulin
release
– Abnormal 2nd-phase
insulin release
– Progressive loss of
beta-cell functional mass
* *
400
300
200
100
0
0
60
120
Time (minutes)
180
Proinsulin as a Predictor of Type 2 Diabetes
20
Relative risk* for
progression to diabetes
17.6
15
10
4.4
5
5.2
0
Fasting glucose
(mmol/L)
Fasting insulin
(pmol/L)
n=937
*Unadjusted relative risk between top and bottom quartiles
Adapted from Wareham NJ et al Diabetes Care 1999;22:262–270.
Fasting intact
proinsulin
(pmol/L)
Blood Glucose and Serum Insulin Responses
to a Meal in Type 2 Diabetes
Blood glucose
Diabetic (n=8)
Normal (n=9)
Serum insulin
60
14
40
10
8
p<0.001
mU/L
mmol/L
12
p<0.05
20
6
4
0
0
60
120
180
Minutes
Adapted from Bruce DG et al Diabetes 1988;37:736–744.
0
60
120
Minutes
180
M-Low
(mg/kg EMBS/min)
Transition to Diabetes: Insulin Secretion
AIR
*
200
**
1.5
1.0
Overall time
effect
p<0.001
0.5
NGT
IGT
DIA
EGO
100
Overall time
effect
p<0.0001
50
0
2.0
0.0
150
NGT
IGT
DIA
EGO
(mg/kg EMBS/min)
AIR (µU/ml)
250
Glucose disposal (M-Low)
2.5
2.5
Suppressible
Nonsuppressible
**
2.0
1.5
1.0
Overall time
effect
p<0.05
0.5
0.0
NGT
IGT
DIA
AIR=acute insulin response; NGT=normal glucose tolerance; IGT=impaired glucose tolerance; DIA=diabetes; M=insulin-stimulated
glucose disposal; EMBS=estimated metabolic body size; EGO=endogenous glucose output
Asterisks denote significant differences among the three stages within each group: *p<0.05, **p<0.01
Adapted from Weyer C et al J Clin Invest 1999;104:787–794.
Progressive Decline in Insulin Secretion:
Type 2 Diabetes
Insulin response to OGTT
(mU/ml·min)
80,000
60,000
40,000
Nondiabetics
Diabetics
20,000
0
–20,000
100
200
300
Two-hour glucose (mg/dl)
OGTT=oral glucose tolerance test
Adapted from Bruce DG et al Diabetes 1988;37:736–744.
400
500
Lessons from UKPDS: Progressive Loss
of Glycemic Control Associated with Progressive
Impairment in Beta-Cell Function
100
HbA1c
9
8
7
6
Diet/conv Tx (n=297)
Metformin (n=251)
SU/intensive (n=695)
5
Beta-cell function (%)
10
75
50
25
Diet/conv Tx (n=376)
Metformin (n=159)
SU/intensive (n=511)
0
0
1
2
3
4
5
6
0
Years
1
2
3
Years
UKPDS=United Kingdom Prospective Diabetes Study; conv Tx=conventional therapy; SU=sulfonylurea
Adapted from UK Prospective Diabetes Study Group Diabetes 1995;44:1249–1258.
4
5
6
Theoretical Implications for Therapy during
Progressive Beta-Cell Loss in Type 2 Diabetes
Diabetes
diagnosed
Beta-cell function (%)
100
Monotherapy
failure
Requiring
insulin
80
Monotherapy
60
40
Dual drug Multidrug
comb
regimens
+/–
insulin
Insulinbased
regimens
20
IGT
0
0
10
Approximate time (years)
15–25
The Incretin Axis:
Potential Therapeutic Role
Incretins
• Incretins
– Insulinotropic hormones from the intestinal mucosa
– Released in response to ingestion of a meal;
enhance insulin secretion
• Two major incretins
– Glucose-dependent insulinotropic polypeptide (GIP):
released from upper small intestine
– Glucagon-like peptide-1 (GLP-1): released from lower
small intestine
• Actions
– Stimulation of insulin secretion
– Suppression of glucagon secretion and
hepatic neoglucogenesis
– Delayed gastric emptying
Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659.
Physiologic Explanation of the Incretin Response
Plasma insulin
Incretins
• GLP-1
• GIP
• ? Other incretins
With oral glucose load
With IV glucose load
Time
IV=intravenous
Adapted from Vilsbøll T, Holst JJ Diabetologia 2004;47:357–366; Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659.
Characteristics of GLP-1
• Member of the glucagon gene peptide family
• 30 amino acid peptide produced primarily in distal
•
•
•
•
•
small intestine L cells by cleavage from proglucagon
Potentiates glucose-dependent secretion of insulin
from pancreatic beta cells
Stimulates insulin gene transcription
Promotes beta-cell formation
Inhibits apoptosis in beta cells
Inhibits
– Glucagon secretion
– Gastrointestinal secretion and motility
– Appetite and food intake
Adapted from Ahrén B Curr Diab Rep 2003;3:365–372; Holst JJ Diabetes Metab Res Rev 2002;18:430–441; Vilsbøll T, Holst JJ
et al Diabetologia 2004;47:357–366.
Regulation and Actions of GLP-1
Meal bolus
GI tract
GLP-1 produced by L cells in
the distal small intestine
Delayed
gastric
emptying
Skeletal muscle
Neural
innervation
GLP-1
 Glucose
uptake
Insulin (beta cell)
Pancreatic islet
 Glucagon (alpha cell)
CNS
 Food intake/body weight
GI=gastrointestinal; CNS=central nervous system
 Hepatic glucose
production
GLP-1: Potential Effects on Beta Cells
GLP-1
(produced
by L cells in
the small
intestine)
Glucose dependent: no stimulation
of insulin release when hypoglycemia
induced
Increased insulin synthesis
Functional improvements in beta cell
Beta cell
? in
humans
Beta-cell neogenesis
Long-term improvements
in glycemic control?
Inactivation of GLP-1
DPP-IV cleavage
GLP-1 of N-terminal amino acids
Inactive
GLP-1
Adapted from Ahrén B Curr Diabetes Rep 2003;3:365–372; Deacon CF et al J Clin Endocrinol Metab 1995;80:952–957;
Weber AE J Med Chem 2004;47:4135–4141.
GLP-1 Release in Response to a Mixed Meal
Is Abnormal in Type 2 Diabetes
*
500
Normal
Insulin (pmol/L)
GLP-1 (pmol/L)
20
10
*
*
Diabetic
0
*
*
400
300
Diabetic
200
100
Normal
0
50
100
150
0
0
Time (minutes)
120
Time (minutes)
15
Glucose
(mmol/L)
60
10
Diabetic
5
Normal
0
0
*p<0.05 between groups
Adapted from Vilsbøll T et al Diabetes 2001;50:609–613.
50
100
150
Time (minutes)
180
Incretin Axis: Potential Therapeutic Intervention
Meal
GLP-1 or
GLP-1 analog
Incretin factors
• GLP-1
• GIP
• ? Other incretins
Active GLP-1
Meal
Inhibition of DPP-IV:
MK-431
X DPP-IV
Inactive GLP-1
Inactive GIP
GLP-1 activity
15
DPP-IV inhibitor
10
5
Placebo
0
Time
Adapted from Weber A J Med Chem 2004;47:4135–4141; Ahrén B Curr Diabetes Rep 2003;3:365–372; Drucker DJ Diabetes
Care 2003;26:2929–2940; Holz GG, Chepurny OG Curr Med Chem 2003;10:2471–2483; Deacon CF et al J Clin Endocrinol
Metab 1995;80:952–957; Drucker DJ Curr Pharm Des 2001;7:1399–1412.
Incretin Axis: Therapeutic Intervention
Meal
Continuous infusion
of GLP-1 or
GLP-1 analog
administration
Incretin factors
• GLP-1 (7–36)
• GIP
• ? Other incretins
Active GLP-1
Meal
Inhibition of DPP-IV:
MK-431
X DPP-IV
Inactive GLP-1
Inactive GIP
GLP-1 activity
15
DPP-IV inhibitor
10
5
Placebo
Incretin and
other metabolic
effects
• CNS
• Gastric
• Other hormonal
0
Time
Adapted from Weber A J Med Chem 2004;47:4135–4141; Ahrén B Curr Diabetes Rep 2003;3:365–372; Drucker DJ Diabetes
Care 2003;26:2929–2940; Holz GG, Chepurny OG Curr Med Chem 2003;10:2471–2483; Deacon CF et al J Clin Endocrinol
Metab 1995;80:952–957; Drucker DJ Curr Pharm Des 2001;7:1399–1412.
Potential of GLP-1 Therapy to Preserve Islet
Cell and Reverse the Typical Course of
Type 2 Diabetes
100
Beta-cell function (%)
Diabetes diagnosis
80
?GLP-1–directed therapy
60
40
20
0
0
10
15–25
Approximate time (years)
Adapted from UKPDS Group Diabetes 1995;44:1249–1258; Porte D Jr, Kahn SE Diabetes 2001;50(suppl 1):S160–S163; Brubaker PL,
Drucker DJ Endocrinology 2004;145(6):2653–2659.
GLP-1 Administration
and DPP-IV Inhibition
as Therapeutic Strategies
Marked and Rapid Improvement in Glycemic
Control Occurs with GLP-1 Infusion
20
8-hour glucose profile
15
Week 0
10
HbA1c
9.5
Week 6
p=0.4
9.1
5
9
Saline infusion
0
20
15
Week 0
Percent
Plasma glucose (mmol/L)
Study design: 20 patients with inadequately controlled type 2 diabetes treated
with subcutaneous infusion of saline (n=10) or GLP-1 (n=10) for 6 weeks
Week 0
Week 6
p=0.003
9.2
8.9
8.5
14%
7.9
8
10
Week 6
5
7.5
GLP-1 infusion
0
7
0
2
4
6
8
Hours
Adapted from Zander M et al Lancet 2002;359:824–830.
Saline
GLP-1
Reduction in Appetite and Body Weight
Study design: 20 patients with inadequately controlled type 2 diabetes treated
with subcutaneous infusion of saline (n=10) or GLP-1 (n=10) for 6 weeks
Change in indices of appetite—GLP-1 infusion
400
Week 0
Week 6
VAS score*
250
200
p=0.008
106
399
104
412
347
350
300
p=0.013
308
p=0.02
p=0.007
102
313
100
247
217
182
150
Kilograms
450
p=NS
Change in body weight
Week 0
Week 6
104.8
102.9
98
96
94
p=NS
93.3
92.6
92
100
90
50
88
0
86
Hunger
Satiety
(n=10)
(n=10)
Fullness Food intake
(n=10)
(n=10)
VAS=visual analog scale
Adapted from Zander M et al Lancet 2002;359:824–830.
*Mean area under the curve for VAS score (mm) vs. time (hours).
Saline
GLP-1
(n=9)
(n=10)
DPP-IV Inhibition as a Therapeutic Strategy
• Membrane-bound serine protease belonging to prolyl
oligopeptidase family
• Found in kidney, liver, intestinal epithelium, prostate,
placenta, pancreas, and plasma
• Mediator of immune function and regulation of
inflammatory, nervous, and endocrine functions
• Substrates of DPP-IV include
– Incretins (GIP, GLP-1, GLP-2)
– CNS peptides (substance P, neuropeptide Y)
– Endocrine system peptides (growth-hormone–releasing
factor)
• Potential role in treatment of type 2 diabetes through
enzymatic activity on incretins
Adapted from Drucker DJ Curr Pharm Des 2001;7:1399–1412; Drucker DJ Expert Opin Investig Drugs 2003;12:87–100;
Evans DM IDrugs 2002;5:577–585.
Experimental Models and Preclinical Data
Demonstrating Potential Physiological/
Pharmacological Impact of DPP-IV Inhibition
• Knockout (KO) mouse model
• DPP-IV inhibitors in preclinical and clinical use
Oral Glucose Tolerance in Knockout Female Mice
Lacking GIP and/or GLP-1 Receptors
30
1200
AUC (mM/min)
25
Blood glucose (mM)
1400
WT (n=11)
GLP-1R–/– (n=6)
GIP-R–/– (n=9)
Double KO (n=11)
20
15
10
–30
1000
400
0
0
60
90
c,d
a,b
600
200
30
e
800
5
0
WT (n=11)
GLP-1R–/– (n=6)
GIP-R–/– (n=9)
Double KO (n=11)
120
Time (minutes)
WT=wild type; AUC=area under the curve
ap<0.05
vs. WT controls; bp<0.01 vs. double KO; cp<0.01 vs. WT controls; dp<0.05 vs. double KO; ep<0.005 vs. WT controls
Adapted from Preitner F et al J Clin Invest 2004;113:635–645.
Insulin Response to Oral Glucose Challenge in
Knockout Mice Lacking GIP and/or GLP-1 Receptors
Plasma insulin (ng/ml)
1.6
1.4
1.2
WT (n=11)
GLP-1R–/– (n=6)
GIP-R–/– (n=9)
Double KO (n=11)
1.0
**,***
*
0.8
*
0.6
0.4
0.2
**
*
*
0
0
15
Time (minutes)
*p<0.005 and **p<0.05 vs. WT controls; ***p<0.05 vs. double KO
Adapted from Preitner F et al J Clin Invest 2004;113:635–645.
GLP-1 Enhanced Early Insulin Secretion
Plasma insulin (ng/ml)
1.4
1.2
WT (n=11)
GLP-1R–/– (n=6)
GIP-R–/– (n=9)
Double KO (n=11)
1.0
0.8
**
0.6
**
0.4
*
*
*
0.2
0
0
2
Time (minutes)
*p<0.005 and **p<0.05 vs. WT controls
Adapted from Preitner F et al J Clin Invest 2004;113:635–645.
30
Restoration of Pancreatic Islet Beta Cells with an
Analogue of MK-431 in Mice
Diabetic mice
Diabetic mice +
MK-431 analogue
Lean control mice
Green: Insulin-producing beta cell
Red: Glucagon-producing alpha cell
Adapted from Zhang BB et al. Poster presentation at the 64th Scientific Session of the ADA, Orlando, Florida, USA, June 2004.
Effects of DPP-IV Inhibitors in Rodent Models
of Diabetes
DPP-IV inhibitor P32/98 in Vancouver diabetic fatty fa/fa rats for 12 weeks
Fasting blood glucose
Peak blood glucose
24
Peak blood glucose
(mmol/L)
Fasting blood
glucose (mmol/L)
10
8
*
6
4
20
*
16
*
12
8
0
4
8
12
0
4
8
12
Week
*p<0.05 vs. control group
Adapted from Pospisilik JA et al Diabetes 2002;51:943–950.
Control
Treated
0
4
8
12
0
Week
4
8
12
Potential Effects of Modulating DPP-IV on
Substrates Associated with Endocrine Function
Effect of modulation
by DPP-IV
Substrate
Growth hormone
releasing factor
Degradation
Glucagon-like peptide 1, glucagon-like
peptide 2, and gastric inhibitory peptide
Degradation
Procolipase
Partial activation
Fibrinogen alpha chain
Hydrolysis
Kentsin
Degradation
Enterostatin
Degradation and inactivation
Human chorionic gonadotropin
Degradation
N-procalcitonin
Potent bone-cell mitogen
Trypsinogen
Degradation
Adapted from Hildebrandt M et al Clin Sci 2000;99:93–104.
Potential Effects of Modulating DPP-IV on Substrates
Associated with Immune System Function
Substrate
SDF-1-alpha
Lymphotoxin, IL-2 fragments,
murine IL-6, IL-1
Eotaxin
TNF-alpha
IP-10
Monocyte chemotactic protein
RANTES
Effect of modulation
by DPP-IV
Degradation to
SDF-1-alpha (3–68)
Degradation
Inactivation
Degradation
Inactivation
Degradation, inactivation
Altered receptor specificity: RANTES-(3–68)
does not bind to CCR1, but still binds to CCR5;
no increase in cytosolic Ca2+ in monocytes
SDF-1-alpha=stromal-cell–derived factor-1-alpha; CXCR-4=C-X-C chemokine receptor type 4; IL=interleukin; TNF-alpha=tumor necrosis
factor-alpha; IP-10=interferon-inducible protein 10; RANTES=regulated on activation, normal T-cell expressed and secreted; CCR=C-C
chemokine receptor; Th2=T-helper cell 2
Adapted from Hildebrandt M et al Clin Sci 2000;99:93–104.
Potential Effects of Modulating DPP-IV
on Peptide Substrates
Substrate
Endomorphin-1
Beta-casomorphin
Kentsin
Peptide YY, NPY
(analogue of peptide Y)
Substrate P
NP=neuropeptide
Adapted from Hildebrandt M et al Clin Sci 2000;99:93–104.
Effect of modulation
by DPP-IV
Degradation and inactivation
Degradation and inactivation
Degradation
Modulation of receptor specificity/loss
of Y1-receptor– mediated functions
Degradation to a more potent
heptapeptide
Human Crossover Study: Description
• Patients (41 males, 15 females; mean age, 50.1 years) with type 2
diabetes: non–drug treated, HbA1c 6.5%–11.7% (mean, 8.3%)
• Single-dose, randomized, three-period crossover study:
MK-431 25 mg or 200 mg or placebo
• Procedures
•
– OGTT at 2 hours (Tmax) and 24 hours
 To assess pharmacokinetics and DPP-IV inhibition and
measure glucose, insulin, glucagon
Endpoints
– Primary: Post-OGTT incremental glucose AUC
– Plasma DPP-IV activity, active and total GLP-1
– Insulin, C-peptide, glucagon
Adapted from Herman GA et al. Oral presentation at the ADA, Orlando, Florida, USA, June 2004.
Crossover Study in Patients with Type 2 Diabetes:
Impact of MK-431 on Inhibition of Plasma DPP-IV
Activity
Inhibition* from baseline (%)
OGTT
MK-431 200 mg (n=56)
MK-431 25 mg (n=56)
Placebo (n=56)
100
90
80
70
60
50
40
30
20
10
0
–10
Trough DPP-IV
inhibition
~80%
~50%
0 1 2
4
6
*Back-transformed from the log scale
8
10
12
14
16
18
20
22
24
Hour
Adapted from Herman GA et al. Oral presentation at the ADA, Orlando, Florida, USA, June 2004.
Plasma glucose (mg/dl)
Effect of Different Doses of MK-431 on Post-OGTT
Glucose Lowering: 25 mg and 200 mg Doses
MK-431 200 mg* (n=56)
MK-431 25 mg* (n=56)
Placebo (n=56)
OGTT
310
290
270
250
230
210
190
170
150
0
1
2
3
4
Hour
*p<0.001 vs. placebo
Adapted from Herman GA et al. Oral presentation at the ADA, Orlando, Florida, USA, June 2004.
5
6
MK-431 Stimulated Insulin Release and
Suppressed Glucagon Post OGTT
MK-431 200 mg* (n=56)
MK-431 25 mg** (n=56)
Placebo (n=56)
8
Plasma C-peptide (ng/ml)
Plasma glucagon (pg/ml)
80
MK-431 200 mg* (n=56)
MK-431 25 mg* (n=56)
Placebo (n=56)
OGTT
70
60
50
7
OGTT
6
5
4
3
2
0
1
2
3
4
5
0
1
2
Hour
*p<0.001 vs. placebo; **p<0.015 vs. placebo
Adapted from Herman GA et al. Oral presentation at the ADA, Orlando, Florida, USA, June 2004.
3
Hour
4
5
Potential Therapeutic Profile of DPP-IV Inhibitors
• Oral
• Once-daily dosage
• Improved glucose homeostasis after meals
– Unlikely to cause hypoglycemia
• May decrease appetite and food intake; weight gain unlikely
• May preserve beta-cell function
Adapted from Weber AE J Med Chem 2004;47:4135–4141; Drucker DJ Expert Opin Investig Drugs 2003;12:87–100; Vilsbøll T,
Holst JJ Diabetologia 2004;47:357–366.
Conclusions
• New therapy is needed, especially if beta-cell numbers
and function are to be preserved
• DPP-IV inhibitors are a promising new class of therapy
undergoing clinical study for type 2 diabetes mellitus
Adapted from Drucker DJ Expert Opin Investig Drugs 2003;12:87–100; Evans MD IDrugs 2002;5:577–585.
References
See note page.
References (continued)
See note page.
References (continued)
See note page.
Background and Initial Evaluation of the DPP-IV
Inhibitor, MK-431, for Type 2 Diabetes
Before prescribing, please consult
the manufacturers’ prescribing information.
Merck does not recommend the use of any product
in any different manner than as described
in the prescribing information.
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
1-06 MK431 2004-W-7024-SS
Printed in USA
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