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Treating Diabetes: Designing the Once-Weekly and Oral GLP-1 Semaglutide
16www.acs.org/acswebinarsThis ACS Webinar is co-produced with the ACS Division of Medicinal Chemistry, American Association of Pharmaceutical Scientists, and ACS Publications
Puneet TyagiSenior Scientist,
AstraZeneca
Jesper LauVice President of Research Chemistry,
Novo Nordisk A/S
23/10/2019
9
Designing the Once-Weeklyand Oral GLP-1 Semaglutide
Jesper LauVice PresidentNovo Nordisk
17
What is Glucagon-like-peptide-1?
Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• A long acting artificial synthetic peptide
• A 32 amino acid natural peptide hormone
• A peptide released from the L-cells
• A peptide that increases appetite
18
* If your answer differs greatly from the choices above tell us in the chat!
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Native GLP-1 has limited clinical value because of its short half-life
PK data adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224
Type 2 diabetes (n=6)
Healthy individuals (n=6)
i.v. bolus GLP-1 (15 nmol/l)
In
tact
GLP
-1 (
pm
ol/
l)
Time (min)
–5 5 15 35 450
500
1000
25
t½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l)
Enzymatic cleavageHigh clearance (4–9 l/min)
19
Native GLP-1 must be administered continuously to realise full therapeutic potential k
Adapted from Larsen et al, Diabetes Care 2001;24:1416–1421. PBS, phosphate-buffered saline.
Day 0Blood glucose profiles: Day 7
Pla
sm
a g
lucose (
mm
ol/
l)
Intermittent (16 h/day) GLP-1 i.v. infusion
(8 ng/kg/min)(n=8)
PBSPBS
Time (h)
5
10
20
25
15
04 12 00 0408 16 20
GLP-1 infusion
Continuous (24 h/day) GLP-1 i.v. infusion
(8 ng/kg/min)(n=8)
GLP-1 infusion
Time (h)12 00 0408 16 2004
5
10
20
15
25
Pla
sm
a g
lucose (
mm
ol/
l)
20
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Bayliss and Starling proposed that intestinal mucosa contained a hormone which stimulated the exocrine secretion of the pancreas
1902
Discovery of the Insulinotropic Effect of GLP-1
Human proglucagongene was cloned Bell, Nature 1983;302:716-718
1983
GLP-1 receptor cloned Thorens, PNAS 992;89:8641-45
Early clinical potentialKreymann, Williams, Ghatei and Bloom, Lancet 1987;1300-1303Nathan, Schreiber, Fogel, Mojsov and Habener, Diabetes Care 1992;15(2):270-276Nauck, Kleine, Ørskov, Holst, Willms and Creutzfeldt, Diabetologia 1993;36:741-744
1989 20172005
First two GLP-1 RA approvals2005 and 2009
1987
GPCR class B structures
21
Key puzzle for successful GLP-1 engineering
Shelf-lifePhysical & chemical stability
PharmacokineticsEnzymatic stabilityRenal clearanceReceptor clearance
Pharmacodynamics Bioavailability
ConvenienceEasy to use
22
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Once weekly GLP-1:Parallel explorations of protraction enablers
• Sustained release: • Bydureon (BMS/AstraZeneca), Taspoglutide
(Roche/Ipsen)
• Fusion proteins: • Albiglutide (GSK)• Dulaglutide (GLP-1 Fc, LY2189265,Lilly)• GLP-1 transferrin (PF-4856883, Pfizer)
• Pegylation:• GLP-1 PEG (Lilly)
• Reversible albumin binding• Semaglutide (Novo Nordisk)
Several strategies have been explored by industry:
23
Human serum albumin
• Is a large (>60kDa) natural human protein
• Circulates in the blood in high concentrations (~40mg/ml)
• Has a long plasma T½ (3 weeks)
• Binds fatty acids reversibly (transport and solubility)
24
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Liraglutide obtains a once-daily profile by reversible binding to albumin
Adapted from Elbrønd et al. Diabetes Care 2002;25:1398–1404. n=72 (n=8 for each dose)
PK parameters
• Tmax: 9–12 h
• T½: 11–15 h
• Bioavailability: 55%
Type 2 diabetes (n=6)
Healthy individuals (n=6)
i.v. bolus GLP-1 (15 nmol/l)
Inta
ct G
LP-1
(pm
ol/l
)
Time (min)
–5 5 15 35 450
500
1000
25
H2N-HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-COOH
7 10 15 20 25 30 35
N
O
NH
O OO
LgGluC16
25
Four key hurdles to engineering a superior once -weekly GLP-1
Lau, J. et al J. Med. Chem; 2015, 58, 7370-7380
H2N-HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-COOH
7 10 15 20 25 30 35
N
O
NH
O OO
3. DPP-IV stability
1. Albumin binding (limiting renal elimination)
2. Access to the right target tissues
4. Maintain high receptor affinity
26
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Linker exploration of GLP-1
gGlu:
2xOEG:
gGlu-3xOEG:
gGlu-2xOEG:
Lau, J. et al J. Med. Chem; 2015, 58, 7370-7380
0,170,12
0,32
0,160,19
0,03
0
0.1
0.2
0.3
0.4
GLP-1R binding
RATIO2%/0% HSA
0,5 42 2,3 21 20 8,0
2% HSAIC50 nM
0% HSAIC50 nM
0,08
5,05
0,75
3,4 3,78
0,22
01234567
X = Aib
linker
27
Linker exploration of GLP-1
gGlu:
2xOEG:
gGlu-3xOEG:
gGlu-2xOEG:
Lau, J. et al J. Med. Chem; 2015, 58, 7370-7380
X = Aib
linker
28
6,2
19,2
11,1
14,7
2,74,3
0
5
10
15
20
25
GLP-1R potency (EC50 pM)
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Prolonging the half-life from once-daily to once-weekly by fatty acid exploration
RelativeAlbuminbinding
20 0,9 3,3 22 940 85 116
C12 diacid
C14 diacid
C16 diacid
C18 diacid
C20 diacid
C22 diacid
2,7
42,6
15,7
8,66,2
11,5
24,4
-10
0
10
20
30
40
50
GLP-1R potency (EC50 pM)
C16 acid
sem
aglu
tide
X = Aib
Fatty acid
29
Lau, J. et al J. Med. Chem; 2015, 58, 7370-7380
Systemic half-life increases - with increasing length of di-acid
i.v. dosing to rats
Semaglutide
30
Lau, J. et al J. Med. Chem; 2015, 58, 7370-7380
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7 Days duration of action of semaglutide- in mini pigs, hyperglycaemic clamp
B a s e lin e D a y 1 D a y 3 D a y 7
0
1 0 0 0 0
2 0 0 0 0
3 0 0 0 0
4 0 0 0 0
5 0 0 0 0
* * *
*
*
Insu
lin (
pm
ol/l
*min
)
Day -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9Day -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9
NNC0113-0217 (nmol/kg)
0.5 2 2 2
NNC0113-0217 (nmol/kg)
0.5 2 2 2
protocol:
= clamp study (n=6)
semaglutide
unpublished
31
• Effect on appetite in LYD pigs:
• Dose dependent effect on appetite
• 7 days duration of action
0 1 2 3 4 5 6 7 80
1
2
3
Vehicle (n=6)
semaglutide
*** *** ** *
Day number
24h-
food
inta
ke (
Kg)
P K s im u la t io n o f
s e m a g lu t id e , s .c . in p ig s
0 3 6 9 1 2 1 5
0
5 0 0 0
1 0 0 0 0
1 5 0 0 0
2 0 0 0 0
2 5 0 0 0
3 0 0 0 0
3 5 0 0 0
D a y s
Pla
sm
a c
on
ce
ntr
ati
on
(pM
)
Efficacy and duration of action of semaglutide- in LYD pigs
Day -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9Day -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9
Semaglutide (nmol/kg)
10 4.5 5 5
Semaglutide (nmol/kg)
10 4.5 5 5
24-hour food intakeprotocol
unpublished
32
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GLP-1 Once-daily vs Once-Weekly - Minor Structural differences
H2N-HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-COOH
7 10 15 20 25 30 35
H2N-HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-COOH
7 10 15 20 25 30 35
Liraglutide
Semaglutide
N
O
NH
O OO
O
OO
O
NH
O
OO
O NH
LgGlu bis-aminodiethoxyacetylC18diacid
X = Aib
NH2
O
OH
N
O
NH
O OO
LgGluC16
33
Semaglutide was selected as once weekly lead- based on animal data
Liraglutide Semaglutide
Mini pig s.c. availability 66% 94%
MRT minipig (s.c. dosing) 23hrs 64hrs
In vivo potency (db/db mice) 6.9 nmol/kg 0.3 nmol/kg
T½ humans (s.c. dosing) 13hrs ?Expected Human dose <2mg/day <2mg/week
34
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Semaglutide has an optimal pharmacokinetic profile for once weekly dosing…
GLP-1 peptide with 2 substituted amino acids• protect against
enzymatic degradation by DPP-4
C-18 fatty di-acid• Strong albumin binding
creates a circulating depot of active compound
Semaglutide
Liraglutide
Exenatide
Endogenous GLP-1
Simulation of pharmacokinetic profile
35
Semaglutide is the result of a few smart modifications to the human GLP-1 molecule
H2N-HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-COOH
7 10 15 20 25 30 35
N
O
NH
O OO
O
OO
O
NH
O
OO
O NH
LgGlu
X = Aib
NH2
O
OH
OEG linker for peptide flexibility and optimised binding to receptor
Fatty acid optimisation for strong albumin binding.NN protein chemical engineering
Peptide chain based on liraglutidediscovery (human GLP-1):NN protein chemical engineering and alanine scan
Aib is an unnatural amino acid for preventing peptidase degradation
36
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Once-weekly semaglutide provides unprecedented glucose regulation…
-1.5-1.6
0.0
-1.3
-1.6
-0.5
-1.5
-0.9
-1.2
-1.6
-0.8
-1.5
-1.8
-0.1
-1.1
-1.4
-0.4 -0.4
-1.5
-1.8
-1.1
-1.4
-2.0
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Change in H
bA
1c
(%)
SUSTAIN 130 weeks
Baseline: 8.1%
SUSTAIN 256 weeks
Baseline: 8.1%
SUSTAIN 356 weeks
Baseline: 8.4%
SUSTAIN 430 weeks
Baseline: 8.2%
SUSTAIN 530 weeks
Baseline: 8.4%
SUSTAIN 6104 weeks
Baseline: 8.7%
SUSTAIN 740 weeks
Baseline: 8.2%
Sema0.5mg
Sema1.0mg
PBO Sema0.5mg
Sema1.0 mg
Sita100mg
Sema1.0mg
Exe2.0 mg
Sema0.5mg
Sema1.0mg
IGlar29U
Sema0.5mg
Sema1.0mg
PBO Sema0.5mg
Sema1.0mg
PBO0.5mg
PBO1.0mg
Sema0.5mg
Sema1.0mg
Dula0.75mg
Dula1.5mg
Dula: Dulaglutide (Trulicity®); Exe: exenatide (Bydureon®); IGlar: insulin glargine (Lantus®); PBO: placebo; Sita: sitagliptin
37
… and unprecedented weight loss
SUSTAIN 130 weeks
Baseline: 91.9 kg
SUSTAIN 256 weeks
Baseline: 89.5 kg
SUSTAIN 356 weeks
Baseline: 95.8 kg
SUSTAIN 430 weeks
Baseline: 93.5 kg
SUSTAIN 530 weeks
Baseline: 91.7 kg
SUSTAIN 6104 weeks
Baseline: 92.1 kg
SUSTAIN 740 weeks
Baseline: 95.2 kg
-3.7
-4.5
-1.0
-4.3
-6.1
-1.9
-5.6
-1.9
-3.5
-5.2
1.2
-3.7
-6.4
-1.4
-3.6
-4.9
-0.7-0.5
-4.6
-6.5
-2.3
-3.0
-7
-6
-5
-4
-3
-2
-1
0
1
2
Change in b
ody w
eig
ht
(kg)
Dula: Dulaglutide (Trulicity®); Exe: exenatide (Bydureon®); IGlar: insulin glargine (Lantus®); PBO: placebo; Sita: sitagliptin
Sema0.5mg
Sema1.0mg
PBO Sema0.5mg
Sema1.0 mg
Sita100mg
Sema1.0mg
Exe2.0 mg
Sema0.5mg
Sema1.0mg
IGlar29U
Sema0.5mg
Sema1.0mg
PBO Sema0.5mg
Sema1.0mg
PBO0.5mg
PBO1.0mg
Sema0.5mg
Sema1.0mg
Dula0.75mg
Dula1.5mg
38
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ECD
Binding site defined primarily by ECD, ECL1, TM1, TM2 and TM7
ECL1
TM2TM1
TM7
GLP-1 almost entirely a-helical in the receptor-bound state
TM1
TM7
ECD
…and a highly selective binding to the human GLP-1 receptor
39
lira
glu
tide
sem
aglu
tide
Why is semaglutide different?Continuous plasma exposure with little fluctuation and higher concentration in specific area of the appetite centre
Chronic administrationSimulated pharmacokinetic profiles
semaglutide once weekly
lixisenatide once daily
liraglutide once daily
PK modelling
Sources: Watson E, et al., J. Clin. Pharm 2010; 50: 886–894 (liraglutide), meta-analysis ClinPharm trials (semaglutide – data on file) and Frank T (2013) J Pharm Drug Deliv Res. 2013; 2:1 (lixisenatide)
40
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21
Semaglutide
• is an analogue of human GLP-1
• has a once weekly profile through binding to albumin
• has a high potency and long duration of action in animals which translate to an excellent profile in humans
• holds great opportunity for oral administration
Semaglutide - a convenient once-weekly GLP-1 with superior blood glucose regulation
41
42
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Which statement is wrong? Oral GLP-1 peptide delivery is a challenge due to:
Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• Enzymatic degradation in the intestinal tract
• The intestinal uptake due to the size of the peptide
• The clinical trials are very difficult
• An absorption enhancer may be required
43
* If your answer differs greatly from the choices above tell us in the chat!
There are many barriers to oral protein delivery
Avoiding degradation
The gastro-intestinal tract is designed to degrade proteins by enzymes and low pH
Reaching epithelial cells
Absorption to blood
Proteins are lipophobic: no passive transport through the intestinal wall
44
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23
Oral delivery platforms
Eligen®
SNAC
GIPET®
45
Understanding the absorption of oral semaglutide/SNAC tablets
Stomach
Semaglutide SNAC
Gastric mucosa
OOH
O
NH
O Na+
│SNAC│Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate
SNAC is an enhancer that facilitates absorption
The available data for semaglutide co-formulated with SNAC support that absorption takes place in the stomach in a localised buffered environment
The effect is strictly time- and size-dependent and occurs primarily via trans-cellular route
23/10/2019
24
Stomach is the predominant site of absorptionHighest concentration of semaglutide observed in vena linealis in dogs
0
50
100
150
200
0 10 20 30
Sem
aglu
tide p
lasm
a
Concentr
ation (
nm
ol/
L)
Time since administration (minutes)
Splenic vein
Portal vein
Semaglutide levels were higher in the splenic vein over the first 30 min after dosing (AUC0-30min splenic/portal: 1.9)
Plasma concentration of semaglutideafter 10 mg oral dose in dogs
15 min after dosing20 min after dosing83 min after dosing100 min after dosing120 min after dosing
• Mean time to complete tablet erosion was 85 minutes (95% CI: [62;118])
Complete tablet erosion of oral semaglutide occurs in the stomachScintigraphic imaging of an indium-111 labelled tablet
23/10/2019
25
SNAC carrier facilitates semaglutide absorption
Stomach
Intercellular space
Microvilli
Columnar epithelial cell
semaglutideSNAC
SNAC: Sodium N-[8-(2-hydroxybenzoyl) Amino] Caprylate
49
Oral semaglutide dose dependently reduced HbA1c
and body weight in phase 2 trial
Data on graph are estimated mean +/- standard error of the mean
SC: subcutaneous; Sema: semaglutideMain inclusion criteria: Type 2 diabetes; 7.0% ≤ HbA1c ≤ 9.5%; Treatment with diet and exercise
+/-metformin Source: Trial NN9924-3790
HbA1c reduction from a mean baseline of 7.9%
5.5
6.0
6.5
7.0
7.5
8.0
0 4 8 12 16 20 24 28
-8.0
-6.0
-4.0
-2.0
0.0
0 4 8 12 16 20 24 28
Weight loss from a mean base line of 92 kg
Placebo sema 2.5 mg sema 5 mg sema 10 mg sema 20 mg sema 1 mg SCsema 40 mg
HbA1c (%) Weight loss (kg)
0.0
Time (weeks) Time (weeks)
50
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26
Conclusion
Semaglutide:
• Is a once weekly GLP-1 analog that binds to albumin
• Is an analog of human GLP-1
• Was selected as once weekly candidate based on long duration of action in pigs
• Once weekly profile was confirmed in humans
• Has now shown great opportunity for both once weekly dosing and oral treatment
51
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Presentation slides are available now! Recordings are an exclusive ACS member benefit.
Treating Diabetes: Designing the Once-Weekly and Oral GLP-1 Semaglutide
53www.acs.org/acswebinarsThis ACS Webinar is co-produced with the ACS Division of Medicinal Chemistry, American Association of Pharmaceutical Scientists, and ACS Publications
Puneet TyagiSenior Scientist,
AstraZeneca
Jesper LauVice President of Research Chemistry,
Novo Nordisk A/S
Celebrating 5 years & 50 Drug Discovery Webinars!http://bit.ly/acsDrugDiscoveryArchive
54
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