Rybelsus® Medical

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 Diabetes prevalence is increasing worldwide
Europe
(15% increase)
59 million
55 million 2019

48 million 2019
68 million
2019 2045

63 million Middle East and 108 million

163 million
2045 2045
North Africa
88 million Western
(96% increase) 2019

North America and 212 million

the Caribbean 19 million 2019 2045 Pacific
(33% increase) 32 million 2019
153 million (31% increase)
2019
47 million 2045

49 million Africa 2045 Southeast Asia

2045 (143% increase) (74% increase)
Central and
South America
(55% increase)

463 million 700 million

people with diabetes in the world (2019) people with diabetes in the world (2045)

IDF Diabetes Atlas (9th edition). International Diabetes Federation. 2019. https://diabetesatlas.org/en/resources/. Accessed 09 June 2020.

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Available Glucose-Lowering
Medication Classes for T2DM
• Aplha-glucosidase inhibitors (e.g., acarbose)
• Amylin analogue (pramlintide)
• Biguanide (metformin)
• Bile acid sequestrant (colesevelam)
• Dipetidyl peptidase-4 (DPP-4) inhibitos (e.g., Sitagliptin)
• Dopamine against (Bromocriptine mesylate)
• Glucagon-like peptide-1 (GLP-1) receptor against (e.g., liraglutide)
• Insulin (e.g., insulin glargine)
• Meglitinides (e.g., repaglinide)
• Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., canagliflozin)
• Sulfonylureas (e.g., glimepiride)
• Thiazolidinedionses (e.g., Pioglitazone)

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Drug/class Patients with CVD Patients with renal Older patients* Other
impairment
ASCVD: potential benefit Contraindications with
Low risk of hypoglycemia Use with caution in patients
HF: neutral eGFR <30 mL/min/1.73 m2 May cause gastrointestinal with impaired hepatic
due to risk of alactic acidosis side effects and reduced function because of the risk
Metformin Use with caution and appetite of lactic acidosis
reduce dose in patients Dose reduction or Treatment may be
with eGFR discontinuation may be discontinued during
<45 mL/min/1.73 m2 needed for patients hospitalization or if acute
ASCVD : neutral (exenatide potential befit with experiencing illness may compromise
gastrointestinal side effects renal or hepatic function
Potential for B12 deficiency

Low risk of hypoglycemia Boxed warming for tyroid

ER [32], lixisenatide, oral long-acting GLP-1RAs May not be preferred in C-cell tumors (exenatide
semaglutide [23]) No dose adjustment for older patients who are ER, dulagllutide, liraglutide,
GLP-1RAs ASCVD: benefit liraglutide, dulaglutide experiencing unexplained subcutaneous semaglutide
(dulaglutide [33], liraglutide subcutaneous semaglutide weight loss and oral semaglutide)
[34]. subcutaneous or oral semaglutide Potential increased risk of
semaglutide [35]) Exenatide ER acute pancreatitis
HF: neutral contrandicated in patients Side effects of nausea
with eGFR vomiting, and diarrhea
<45 mL/min/1.73 m2 Rental function should be
Exenatide contraindicated monitored in patients with
in patients with eGFR severe gastrointestinal side
<39 mL/min/1.73 m2 effects
ASCVD: benefit Reduction in worsening of
Low risk of hypoglycemi Increased risk of
SGLT2i (canagliflozin, CKD Low risk of hypoglycemia amputation and fractures
empagliflozin) Reduction in risk of ESRD Side effects such as volume (canagliflozin) Increased
HF: benefit (canagliflozin, Limited efficacy in patients depletion may be more risk of volume depletion
empagliflozin, dapagliflozin) with eGFR common among older and DKA (all agents)
Reduction in hospitalization <45 mL/min/1.73 m2 patients
for HF because of mechanism of Genitourinary infections
action Increased LDL cholesterol
Contraindicated in patients
with eGFR
<30 mL/min/1.73 m2 [36,37]
ASCVD: neutral Dose adjustment by renal
Low risk of hypoglycemia Joint pain
HF: possible increased function (not for linagliptin) Potential increased risk of
DPP-41
hospitalization for HF with acute pancreatitis
alogliptin and saxagliptin Possible angioedema and
ASCVD: potential benefit Not recommended in renal skin rashes [38]

Low risk of hypoglycemia Weight gain

Use with caution in patients
TZD with pioglitazone impairment due to the
HF: increased risk in potential for fluid retention with or at risk of CHF,
patients with HF osteoporosis, falls or
2nd ASCVD: neutral Glyburide: not fractures and/or macular
edema

Use with caution due to risk Weight gain

generation HF: neutral recommended of hypoglycemia

SU Glipizide and glimepiride: Glyburide: not
caution to avoid recommended
hypoglycemia
Insulin ASCVD: neutral Lower dose required with a

Risk of hypoglycemia Weight gain

HF: potential risk of CHF decrease in eGFR
Risk of hypoglycemia
Dose should be adjusted
according to clinical
response

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Key Characteristics of Currently Available Injectable GLP-1 Receptor Agonists

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GLP-1RAs: multifactorial effects beyond glycaemic control

CV, cardiovascular; GLP-1, glucagon-like peptide-1.

1. Campbell JE and Drucker DJ. Cell Metab. 2013;17:819–837; 2. Marso SP et al. N Engl J Med. 2016;375:311–322; 3. Ryan D and Acosta A Obesity. 2015;23:1119 –1129; 4. Hogan AE et al. Diabetologia.
2014;57:781–784; 5. Baggio LL and Drucker DJ. J Clin Invest. 2014;124:4223–4226; 6. Bagger JI et al. Clin Endocrinol Metab. 2015;100:4541–4552; 7. Flint A et al. J Clin Invest. 1998;101:515–520; 8. Blundell J
et al. Presented at the 76th Scientific Sessions of the American Diabetes Association June 10–14, 2016, New Orleans, Louisiana, USA: Oral Presentation 23-OR; 9. Tong J and D'Alessio D. Diabetes.
2014;63:407– 409; 10. Armstrong MJ et al. J Hepatol. 2016;64:399–408; 11. Armstrong MJ et al. Lancet. 2016;387:679–90.

ADA Recommendations for Dual Antihyperglycemic-Therapy Selection

First Line:
Metformin + Comprehensive Lifestyle Intervention (Weight Management and Physical Activity)

Established ASCVD or CKD? If A1C remains above target proceed as outlined below:
NO

Patients Without Established ASCVD or CKD

HF or CKD Predominates:
ASCVD Predominates:
SGLT-2 inhibitor with evi-
-GLP-1 RA with proven
dence of HF and/or CKD Compelling Need to
CVD benefite OR Compelling Need to Costa Major Issue:
progression preferred, if Minimize Weight
SGLT-2 inhibitor with Minimize Hypoglycemia: 1. Sulfonylurea
eGFR adequate
proven CVD benefit, if DPP-4 inhibitor OR - Gain or Promote OR TZD
If SGLT-2 inhibitor not Weight Loss:
eGFR adequate GLP-1 RA OR
toler-ated or Liraglucido, dulaglutide semaguide
|- GLP-1 RA with good
-SGLT-2 inhibitor Empagliflozin > Canagliflozin
contraindicated, add GLP-1 efficacy for weight
OR TZD *Empugliflozin, Canagliflozin
RA with proven CVD benefit loss. OR and dapagliflozin
SGLT-2 inhibitor *Semagoide > liraglutide>
dulaglutide > exenatide
ADA: American Diabetes Association; AIC: glycated hemoglobin; ASCVD: atherosclerotic cardiovascular disease; CKD:
chronic kidney disease; CVD: cardiovascular disease; DPP-4: dipeptidyl peptidase-4; eGFR; estimated glomerular filtration
rate; GLP-1 RA: glucagon-like peptide-1 receptor agonist; HF: heart failure: SGLT-2: sodium-glucose cotransporter 2: TZD:
thiazolidinedione. Source: Adapted from Reference 13.

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 The challenges of oral protein delivery

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 Start patients on RYBELSUS® 3 mg and increase dose2

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 GLP-1 RA

Liver Pancreas Stomach

Suppresses Stimulates insulin Slows gastric

glucagon secretion secretion emptying

8 Amino Acid substitution at position 8

His Aib Glu Gly Thr Phe Thr Ser Asp

Val
COOH 26 Spacer and c-18 fatty diacid Ser
Spacer chain to lysine
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Phe Amino Acid substitution
34
at position 34
Ile
Ala Trp Leu Val Arg Gly Arg Gly

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This document is strictly for internal use only . Not for distribution or detailing.
Understanding the absorption of oral semaglutide/ SNAC

¦ SNAC¦ sodium N-(8-[2-hydroxybenzoyl] amino) caprylate

OH
O
H
N +
O Na
O

SNAC is an enhancer that facilitates absorption,

although the exact MoA remains unclear

SNAC increases the local pH around the tablet resulting in reduced pepsin activity &
thereby reduced metabolism of semaglutide in the stomach
SNAC interact with & incorporate in lipid membranes and, with increasing concentrations,
increases the fluidity and permeability of the membrane
SNAC led to an increase in the gastric epithelial and transcellular permeability, resulting in
better absorption of semaglutide

SNAC increased the intracellular accumulation of semaglutide indicating effect is mediated

via the transcellular route

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Rationale for Dosing of Rybelsus 3 mg;7mg;14 mg
A phase 2, randomized, parallel-group, dose finding trial
Semaglutide dose range (4-week escalation)

Key inclusion criteria: 2.5 mg oral once-daily (N=70) 2.5 mg

•
632 patients with T2D 5 mg oral once-daily (N=70) 2.5 mg 5
•
Age =18 years
10 mg oral once-daily (N=69) 5 mg 10
•
HbA1c 7.0–9.5%
• 2
BMI =25 kg/m and =40 kg/m
2 20 mg oral once-daily (N=70) 5 mg 10 20
•
Diet and exercise ± metformin 40 mg oral once-daily (N=71) 5 mg 10 20 40
for =30 days
Dose escalation (40 mg once-daily)
5-
Trial information
week
follo
w-u
p
• Phase 2, randomised, parallel-group, Slow (8-week) dose escalation (N=70) 5 mg 10 20 40
• dose-finding, multinational, multicentre Fast (2-week) dose escalation (N=70) 5 mg 10 20 40
Stratification according to Comparators (4-week escalation)
background metformin
Oral once-daily (N=71) Placebo
s.c. semaglutide once-weekly (N=69) 0.25 mg 1, open-label
0.5

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Trial objectives Week

• Primary: to assess the dose–response relationship on
glycaemic control of five doses of once-daily oral semaglutide
compared with placebo in a double-blind design Key endpoints
• Secondary: to assess the efficacy on glycaemic control of oral • Primary efficacy: change from baseline in HbA 1c at week 26
semaglutide in a Sodium N-(8-(2-hydroxybenzoyl) Amino) • Secondary efficacy: at week 26, proportion of patients achieving HbA 1c <7.0%,
Caprylate (SNAC) formulation with open-label, once-weekly change from baseline in fasting plasma glucose and body weight
s.c. semaglutide • Safety: number of TEAEs and hypoglycaemic episodes from baseline to week 31

BMI, body mass index; s.c., subcutaneous; SNAC, sodium N-(8-[2-hydroxybenzoyl]amino) caprylate; TEAE, treatment-emergent adverse event. Davies et al. JAMA. 2017.318;1460–1470.
This document is strictly for internal use only . Not for distribution or detailing.
 Significant HbA1c reduction in all oral
(%)
semaglutide groups at week 26
0.0
-1.0
-0.3
1c
to week 26 in HbA

-2.0
-0.7 -28

-3.0 -32
baseline

-4.0
-1.2 -36
from

* -1.5 -1.7
-40
Change

-5.0
* -1.9 -1.9
-6.0
*
-44
* *
Placebo Oral semaglutide 5 mg Oral semaglutide 20 mg s.c. semaglutide 1 mg
Oral semaglutide 2.5 mg Oral semaglutide 10 mg Oral semaglutide 40 mg

Significant dosage-dependent decreases

in body weight at week 26
Change
from
baseline to 0
week
weight26
body in
(kg)
-1
-1.2 -2.1
-2
-2.7

-3 #
-4
-4.8
-5

-6 * -6.1
-6.4
-7
* -6.9
*
*
Placebo Oral semaglutide 5 mg Oral semaglutide 20 mg s.c. semaglutide 1 mg
Oral semaglutide 2.5 mg Oral semaglutide 10 mg Oral semaglutide 40 mg

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Rationale for Dosing of Rybelsus
3 mg;7mg;14 mg & dosing conditions

Proof of concept Market research for

Dose finding
studies (Phase I & II) Ideal dosing
study(Phase II)
conditions

Efficacy & safety Acceptable ideal

Various doses were Various SNAC tested with various conditions identified:
formulation were dosing conditions
tested: 2.5,5,10,20, Pre-dose fasting;
tested: and doses with
40 mg Post-dose fasting;
150,300,450,600 mg 300 mg of SNAC Water requirements

Bio-modelling for identifying

dose and dosing conditions
based on risk/benefits

Based on biomodelling of data, Over night fasting, 30 min post The 4-week escalation regimen
oral semaglutide 3, 7 and 14 mg dose fasting & 120 ml of water was also selected as
were selected for confirmatory selected based on market consideration between marked
testing in the phase 3 research & studies efficacy and acceptable
programme (PIONEER) to have gastrointestinal tolerability
the optimal benefits/risks profile

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Rybelsus® : Dosage & Administration
Take when you wake on an empty
stomach Then wait

Wake up and take your semaglutide tablet

Wait at least 30 minutes before eating, drinking
straight away with up to half a glass of water
or taking any other oral medication
(upto 120 mL/4 fl oz)
30 min

Schedule

3 mg (starting dose) 7 mg (treatment dose) 14 mg (treatment dose if further Glycemic control needed)

Start Month 1 Month 2

Dose escalation

Advise patients that if they miss a dose, they should skip the
missed dose and take the next dose as scheduled the next day

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 Oral semaglutide clinical trial programme
Clinical pharmacology 9,543
24
trials Subjects enrolled
Phase 2 trial
1
Subjects exposed to
10
Phase 3a trials oral semaglutide
~5,707

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An overview of PIONEER program
Diet and exercise OAD Insulin Users Japan
PIONEER 1 PIONEER 2 PIONEER 8 PIONEER 9

vs SGLT2i Add-on to insulin

(Met)
vs placebo (Insulin - Met) vs GLP-1RA/placebo
PIONEER 3
(Diet and exercise) (Diet and exercise)
vs DPP-4i Special Populations
(1–2 OADs: Met - SU)
PIONEER 4 PIONEER 5 PIONEER 10

vs GLP-1RA/placebo Renal impairment vs GLP-1RA

(1–2 OADs: Met - SGLT2i) (- Met, - SU, or - insulin)
PIONEER 7 (1 OAD: SU/TZD/
PIONEER 6 a-GI/SGLT2i)
Flexible dose adjustment CV safety
vs DPP-4i with extension
(1–2 OADs: Met, SU, (Standard of care)
TZD, SGLT2i)

India n = 1040 (Pioneer 6, 8 & SOUL)

Text in parentheses represents allowed background medications.
CV, cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; Met, metformin; OAD, oral anti-diabetes drug; PIONEER, peptide
innovation for early diabetes treatment; SGLT2i, sodium glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione.
1. Aroda VR et al. Diabetes Care 2019;42:1724–32; 2. Rodbard HW et al. Diabetes Care. 2019;42(12):2272–2281; 3. Rosenstock J et al. JAMA 2019;321:1466–80; 4. Pratley R et al.
Lancet 2019;394:39–50; 5. Mosenzon O et al. Lancet Diabetes Endocrinol 2019;7:515–27; 6. Husain M et al. N Engl J Med 2019. 381:841–51; 7. Pieber TR et al. Lancet Diabetes
Endocrinol 2019;7:528–39; 8. Zinman B et al. Diabetes Care. 2019;42(12):2262–2271; 9. Yamada et al. Lancet Diabetes Endocrinol 2020;8:377–91; 10. Yabe et al. Lancet Diabetes
Endocrinol 2020;8:392–6.

The PIONEER programme

1 Monotherapy Semaglutide 3 mg 5 Moderate renal impairment

Drug naive Semaglutide 7 mg ± Metformin ± SU ± Semaglutide 14 mg

26 weeks Semaglutide 14 mg Insulin 26 weeks Placebo

2 vs SGLT2i
Placebo
6 CVOT
50 years + CV disease or
60 years + CV risk Semaglutide 14 mg
Metformin Semaglutide 14 mg
OADs Insulin Soc Placebo + Soc
52 weeks Empagliflozin 25 mg  2122 MACE
3 Vs DPP-4i
7 Flexible dose adjustment
Semaglutide 3 mg 1-2 OADS
Metformin ± SU Metformin/TZD/SU/SGLT2i Semaglutide 3, 7, or 14
Senkglutide 7 mg
52 weeks
78 weeks Semaglutide 14 mg mg Sitagliptin 100 mg
Sitagliptin 100 mg 8 Insulin add-on
4 vs GLP-1 RA
Semaglutide 14 mg Any insulin ±Metformin
Semaglutide 3 mg
26 + 26 weeks Semaglutide 7 mg
Metformin SGLT2i Liraglutide 1.8 mg Semaglutide 14 mg
52 weeks Placebo Placebo
Japan OAD combination
Japan monotherapy Semaglutide 3 mg
1 OAD: Metformin,
Diet + exercise ± Semaglutide 7 mg Semaglutide 3 mg
1 OAD: Metformin, su, glinide, TZD,
Semaglutide 14 mg a-GI, or SGLT-2i Semaglutide 7 ms
SU, glinide, TZD,
a-GI, or SGLT-2i Placebo 52 weeks Semaglutide 14 mg
52 weeks Liraglutide 0.9 mg Dulaglutide 0.75 mg

*
Time to primary endpoint: 26 weeks for PIONEER 1, 2, 3, 4, 5, 8 and 9. CV, cardiovascular; CVOT, cardiovascular outcomes tria l; DPP-4i, dipeptidyl
peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; MACE, major adverse cardiovascular event;
OAD, oral anti-diabetes drug; PIONEER, peptide innovation for early diabetes treatment; SGLT2i, sodium glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione.
Aroda VR, et al. Diabetes Care 2019;42:1724–32; Rodbard HW et al. Diabetes Care. 2019;42(12):2272–2281; Rosenstock J, et al. JAMA 2019;321:1466–80; Pratley R, et al. Lancet 2019;394:39–50;
Mosenzon O, et al. Lancet Diabetes Endocrinol 2019;7:515–27; Husain M, et al. N Engl J Med 2019. 381:841–51; Pieber TR, et al. Lancet Diabetes Endocrinol 2019;7:528–39;
Zinman B et al. Diabetes Care. 2019;42(12):2262–2271.

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TABLE 2 provides a summary of key information from PIONEER 1-8.27-34

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 Treatment Trial product
policy
Estimand
estimand

Real-world perspective Ideal situation

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This document is strictly for internal use only . Not for distribution or detailing.
 PIONEER 1,2,3,4,5,7 and 8
Change in body weight - trial product estimand - end of treatment
PIONEER 1 PIONEER 2 PIONEER 3 PIONEER 4 PIONEER 5 PIONEER 7 PIONEER 8
Monotherapy vs empagliflozin vs sitagliptin vs liraglutide Renal Flex With insulin
26 weeks 52 weeks 78 weeks 52 weeks 26 weeks 52 weeks 52 weeks
8.0 8.1 8.3 8.0 8.0 8.3 8.2
SemaSemaSema Pbo SemaEmpa SemaSemaSema Sita Sema Lira Pbo Sema Pbo Sema Sita SemaSemaSema Pbo
0.5 3 mg 7 mg 14 mg 14 mg 25 mg 3 mg 7 mg 14 mg 100 mg 14 mg 1.8 mg 14 mg Flex 100 mg 3 mg 7 mg 14 mg

0.0 0.2

-0.1 -0.1 0.0

-0.3
-0.5
-0.4 -0.5
-0.7 *
-1.0 -0.8 -0.8 -0*.7 -0.9 -0.8
* *
-1.5 -1.3 -1.3 -1*.1 -1.2 -1*.1 -1.2
* -1.4 *
*
-1.5 * vs Lira
* & Pbo *
-2.0

PIONEER 1,2,3,4,5,7 and 8

Change in body weight - trial product estimand - end of treatment
PIONEER 1 PIONEER 2 PIONEER 3 PIONEER 4 PIONEER 5 PIONEER 7 PIONEER 8
Monotherapy vs empagliflozin vs sitagliptin vs liraglutide Renal Flex With insulin
26 weeks 52 weeks 78 weeks 52 weeks 26 weeks 52 weeks 52 weeks
7 mg 7 mg 7 mg 7 mg 7 mg 7 mg 7 mg
SemaSemaSema Pbo SemaEmpa SemaSemaSema Sita Sema Lira Pbo Sema Pbo Sema Sita SemaSemaSema Pbo
1.0 3 mg 7 mg 14 mg 14 mg 25 mg 3 mg 7 mg 14 mg 100 mg 14 mg 1.8 mg 14 mg Flex 100 mg 3 mg 7 mg 14 mg
6.0
0.0
Change in body weight, kg

-1.0 -1.1 -1.1 -0.8

-1*.0

-2.0 -1.7
-1.2
-1.5

-2.5 -1*.9
-3.0 -2.7
* -2.9 -2.9
* -3.1
-4.0 -3.5 -3.7 * *
-4.1 -3.8 *
*
-5.0 * -4.7 -4*.3
* -5.0
* Mean baseline body weight, kg (lbs)
vs Lira & Pbo

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 PIONEER 1,2,3,4,5,7 and 8
HbA1c < 7.0 % - trial product estimand - end of treatment
PIONEER 1 PIONEER 2 PIONEER 3 PIONEER 4 PIONEER 5 PIONEER 7 PIONEER 8
Monotherapy vs empagliflozin vs sitagliptin vs liraglutide Renal Flex With insulin
26 weeks 52 weeks 78 weeks 52 weeks 26 weeks 52 weeks 52 weeks
8.0 8.1 8.3 8.0 8.0 8.3 8.2
SemaSemaSema Pbo SemaEmpa SemaSemaSema Sita Sema Lira Pbo Sema Pbo Sema Sita SemaSemaSema Pbo
3 mg 7 mg 14 mg 14 mg 25 mg 3 mg 7 mg 14 mg 100 mg 14 mg 1.8 mg 14 mg Flex 100 mg 3 mg 7 mg 14 mg
50
* vs Pbo Mean baseline HbA1c

* 80 *
*
Proportion of subjects (%)

40 * * *
72 72 69
* * 63 64 63 64
30 59 * *
47 50 52
39 * 47
20 34 33 28 36

18 21
10
10

Change in HbA1c from baseline > 9%

With Oral Semaglutide 14 mg
Estimated means

PIONEER 1 PIONEER 2 PIONEER 3 PIONEER 4 PIONEER 5 PIONEER 7 PIONEER 8

Sema 14 Placebo Sema 14 Empa Sema 14 Sita Sema 14 Lira Placebo Sema 14 Placebo Flex Sita Sema 14 Placebo
of 9%

Oral sema 14 mg Placebo Empa 30 mg Sita 100 mg Lira 1.8 mg

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PIONEER 1,2,3,4,5,7 and 8
Proportion of patients with nausea
50

40

30 23.2

19.6 20.9
20 16.0 19.8 15.1 18.0 19.0 16.6

13.4 11.4
10 8.0 5.6 7.3 6.9 7.5 7.1
5.1 2.4 3.5 2.4
0
SemaSemaSema Pbo SemaEmpa SemaSemaSema Sita Sema Lira Pbo Sema Pbo Sema Sita SemaSemaSema Pbo
3 mg 7 mg 14 mg 14 mg 25 mg 3 mg 7 mg 14 mg 100 mg 14 mg 1.8 mg 14 mg Flex 100 mg 3 mg 7 mg 14 mg
PIONEER 1 PIONEER 2 PIONEER 3 PIONEER 4 PIONEER 5 PIONEER 7 PIONEER 8
Monotherapy vs empagliflozin vs sitagliptin vs liraglutide Renal Flex With insulin
26 weeks 52 weeks 78 weeks 52 weeks 26 weeks 52 weeks 52 weeks

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PIONEER 1: Trial Design
703 Enrolled
26 Weeks
3 mg Oral semaglutide
175
7 mg Oral semaglutide
175
14 mg Oral semaglutide
175
Placebo STOP
178
Primary
Key insclusion Criteria evaluation &
1 Age : 18 year* 2 HbA1c 7.0-9.5% (53-91 mmol/mol) End of trial

3 Diabetes duration 30 days 4 Stable metformin doses ± SGLT2i for 30 days

Change in HbA1c
Mean baseline HbA1c: 8.0%
Week 26
0.0
-0.1
(%)

-0.5
-0.8

-1.0

* -1.3
-1.5
-1.5
*
-2.0 *
Oral sema 3 mg Oral sema 7 mg Oral sema 14 mg Placebo

*p<0.05 in favour of oral semaglutide. sema, semaglutide. Aroda VR, et al. Diabetes Care 2019;42:1724–32.

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 Change in body weight
Mean baseline body weight: 88.1 kg (194.2 lbs)
Week 26
0.0
Change in body weight (kg)

-1.0

-2.0
-1.5
-1.7

-3.0 -2.5
*
-4.0

-4.1
-5.0
*

-6.0
Oral sema 3 mg Oral sema 7 mg Oral sema 14 mg Placebo

*p<0.05 in favour of oral semaglutide. sema, semaglutide.Aroda VR, et al. Diabetes Care 2019;42:1724–32.

Subjects achieving HbA1c <7.0%

Mean baseline HbA1c: 8.0%

100 *
* [VALUE]
Proportion of subjects (%)

80
* [VALUE]
60 [VALUE]
40 33.8

20

Week 26
Oral sema 3 mg Oral sema 7 mg Oral sema 14 mg Placebo

*p<0.05 for odds of achieving HbA1c <7.0% with oral semaglutide vs placebo. sema, semaglutide.Aroda VR, et al. Diabetes Care 2019;42:1724–32.

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PIONEER 2 : Trial Design
82 Enrolled
26 52
14 mg oral semaglutide
412
25 mg empagliflozin STOP
410
Primary evaluation End of trial

Key insclusion Criteria

1 Age 18 year 2 HbA1c 7.0-10.5% (53-91mmol/mol)

3 Diabetes duration 90 days 4

Stable doses of metformin ± SGLT2i for 90 days*

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 Change in HbA1c
Mean baseline HbA1c: 8.1%
Week 26 Week 52
0.0
(%)

-0.5

-1.0 -0.8
-0.9
-1.5 -1.4 -1.3
*
*
-2.0
Oral sema 14 mg Empa 25 mg

*p<0.05 in favour of oral semaglutide. sema, semaglutide; Empa, empagliflozin. Rodbard HW, et al. Diabetes Care 2019;42:2272–2281.

Subjects achieving HbA1c <7.0%

Mean baseline HbA1c: 8.1%
100 * *
(%)

80 70.3 71.6
of subjects

60

47.5
40 40.7
Proportion

20
Week 26 Week 52

Oral sema 14 mg Empa 25 mg

*p<0.05 for odds of achieving HbA1c <7.0% with oral semaglutide vs empagliflozin. sema, semaglutide; Empa, empagliflozin. Rodbard HW, et al. Diabetes Care 2019;42:2272–2281.

Change in body weight

Mean baseline body weight: 91.6 kg (201.9 lbs)
Week 26 Week 52
0.0
Change in body weight (kg)

-1.0

-2.0

-3.0

-4.0
-3.8 -3.8
-4.2 -4.7
-5.0

*
-6.0
Oral sema 14 mg Empa 25 mg

*p<0.05 in favour of oral semaglutide. sema, semaglutide; Empa, empagliflozin. Rodbard HW, et al. Diabetes Care 2019;42:2272–2281.

This document is strictly for internal use only . Not for distribution or detailing.
 Body weightreduction > 5 % & 10%
At week 26 and 52

Subject achieving weight loss >5% Subject achieving weight loss >10%
Mean baseline body weight :91.2 kg:91.6 kg Mean baseline body weight :91.2 kg:91.6 kg
(%)

60 1.4X more 1.3X more 20

2.5X more

subjects of (%)
40
2X more
ofProportio

Proportio
n

n
subjects

20

0 0

Week 26 Week 52 Week 26 Week 52

Oral sema 14 mg Empa 25 mg

Proportions of patients achieving > 5% or > 10 % weight loss were higher with oral
semaglutide 14 mg compared to Empagliflozin 25 mg

Composite endpoint
HbA1c < 7 % without hypoclycemia and no weight gain HbA1c Reduction ³1% and body weight loss ³3%

Week 26 Week 52 Week 26 Week 52

Oral Empagliflozin Oral Empagliflozin Oral Empagliflozin Oral Empagliflozin

semaglutide semaglutide semaglutide semaglutide

14 mg 25 mg 14 mg 25 mg 14 mg 25 mg 14 mg 25 mg

Patients, N 411 410 411 410 Patients, N 411 410 411 410
Patients 222 139 (36.8) 191 (63.0) 139 (44.0) Patients 172 (49.6) 110 (29.1) 148 (48.8) 91 (28.8)
reaching
reaching
endpoint, n (%) endpoint, n (%)

64% vs 36.8% 63% vs 44% 49.6% vs 29.1% 48.8% vs 28.8%

Significant a greater number of patient achieved composite endpoints with oral

semaglutide compared to empagliflozin

This document is strictly for internal use only . Not for distribution or detailing.
This document is strictly for internal use only . Not for distribution or detailing.
Trial Design
1864 Enrolled
26 Weeks 52 Weeks

Oral semaglutide 3 mg
466
466 Oral semaglutide 7 mg

465 Oral semaglutide 14 mg

467 Sitagliptin 100 mg STOP

End of trial
Primary evaluation

Key insclusion Criteria

1 Age : 18 year* 2 HbA1c 7.0-10.5% (53-91 mmol/mol)

3 Diabetes duration 90 days 4

Stable metformin doses ± SGLT2i for 90 days

Rosenstock J, et al. JAMA 2019;321:1466–80.

This document is strictly for internal use only . Not for distribution or detailing.
Change in HbA1c
Mean baseline HbA1c: 8.3%
Week 26 Week 78
0.0
(%)

-0.5 -0.5 -0.3 -0.4

-0.7
-1.0
-0.8
-1.1 † *
-1.1
-1.5 * -1.4 *
*
-2.0 Oral sema 3 mg Oral sema 7 mg Oral sema 14 mg Sitagliptin 100 mg

*p<0.05 in favour of oral semaglutide. †p<0.05 in favour of sitagliptin vs oral semaglutide 3 mg. sema, semaglutide. Rosenstock J, et al. JAMA 2019;321:1466–80.

This document is strictly for internal use only . Not for distribution or detailing.
 Change in body weight
Mean baseline body weight: 91.2 kg

Week 26 Week 78
0
Body weight change from baseline (kg)

-1 -1.2 -0.7 -1.1

-2 * -1.9
-2.2 *
-3 * -2.7
-3.3 * -3.5
-4
* *
Oral sema 3 mg Oral sema 7 mg Oral sema 14 mg Sitagliptin 100 mg
-5

-6

*p<0.05 in favour of oral semaglutide. sema, semaglutide. Rosenstock J, et al. JAMA 2019;321:1466–80.

Subjects achieving HbA1c <7.0%

Mean baseline HbA1c: 8.3%

100
* * *
Proportion of subjects (%)

80

59.0
60 * 49.8 51.8
46.2 † 39.0
40 33.4 32.9
27.9
20

0
Week 26 Week 78

Oral sema 3 mg Oral sema 7 mg Oral sema 14 mg Sitagliptin 100 mg

*p<0.05 for odds of achieving HbA1c <7.0% with oral semaglutide vs sitagliptin. †p<0.05 for odds of achieving HbA1c <7.0% with sitagliptin vs oral semaglutide 3 mg. sema, semaglutide. R
osenstock J, et al. SAT-139. Presented at ENDO 2019, March 23 2019.

This document is strictly for internal use only . Not for distribution or detailing.
 Subjects achieving weightloss > 5 %

100

Mean baseline Body weight : 91.2 %

80
Proportion of subjects (%)

60
35
40
31

28
19 22
20
14
12 11
0

Week 26 Week 78
Oral sema 3 mg Oral sema 7 mg Oral sema 14 mg sitagliptin 100 mg

HbA1c < 7.0% without hypoglycaemic

episodes and body weight gain
Proportion of subjects (%)

*
*
* 47.7 *
35.4 32.1 35.5

20.0 20.2 20.2 19.1

Week 26 Week 78

This document is strictly for internal use only . Not for distribution or detailing.
Trial Design
711 Enrolled
26 52
14 mg oral semaglutide
285
1.8 mg liraglutide
284
Placebo STOP
142
Primary evaluation End of trial

Key insclusion Criteria

1 Age 18 year* 2 HbA1c 7.0-9.5% (53-80 mmol/mol)

3 Diabetes duration 90 days 4

Stable doses of metformin ± SGLT2i for 90 days

Pratley R, et al. Lancet 2019;394:39–50.

This document is strictly for internal use only . Not for distribution or detailing.
 Change in HbA1c
Mean baseline HbA1c: 8.0%
Week 26 Week 52
0.2
(%)

0.0

-0.1
-0.5

-1.0
-0.9
-1.1 -1.2
-1.5 -1.3
*,†
*,†
-2.0
Oral sema 14 mg Liraglutide 1.8 mg Placebo

*p<0.05 in favour of oral semaglutide vs placebo. †p<0.05 in favour of oral semaglutide vs liraglutide 1.8 mg.sema, semaglutide. Pratley R, et al. Lancet 2019;394:39–50.

Subjects achieving HbA1c <7.0%

Mean baseline HbA1c: 8.0%
100 * *
Proportion of subjects (%)

80 72.3 68.8
65.3 62.6
60

40

16.1 18.3
20

0
Week 26 Week 52
Oral sema 14 mg Liraglutide 1.8 mg Placebo

*p<0.05 for odds of achieving HbA1c <7.0% compared with placebo. sema, semaglutide. Pratley R, et al. Lancet 2019;394:39–50.

This document is strictly for internal use only . Not for distribution or detailing.
 Change in body weight
Mean baseline body weight: 94.0 kg
Week 26Week 52
0.0
Body weight change from baseline (kg)

-1.0
-0.7
-1.2
-2.0

-3.0

-3.1
-3.2
-4.0

-5.0
-4.7 -5.0
*,†
-6.0 *,†
Oral sema 14 mg Liraglutide 1.8 mg Placebo

*p<0.05 in favour of oral semaglutide vs placebo. †p<0.05 in favour of oral semaglutide vs liraglutide 1.8 mg.sema, semaglutide. Pratley R, et al. Lancet 2019;394:39–50.

This document is strictly for internal use only . Not for distribution or detailing.
This document is strictly for internal use only . Not for distribution or detailing.
Subject population
Parameters
Diagnosed with T2D Age 50 years & clinical evidence of CV disease or moderate CKD
1 2 Age 60 years and CV risk factors only
Patient breakdown

~66 years 14.9 years 90.9 years 8.2 % ~68.4 %

3183 average age Diabetes average HbA1c male

duration body weight
Patient with T2D

This document is strictly for internal use only . Not for distribution or detailing.
First MACE – primary endpoint
with anevent (%)

6 HR: 0.79 [0.57; 1.11] 76 events

%
5 p-value for non-inferiority: <0.0001 Rate: 3.7 events per
p-value for superiority: 0.1749 100 patient–years
4 61 events
Rate: 2.9 events per
w 100 patient–years
subjects

3
of

1
Proportion

0 9 18 27 36 45 54 63 72 83

0
Time from randomisation (weeks)
Oral sema 14 mg Placebo
All events confirmed by EAC. Cumulative incidence estimate plot for first EAC-confirmed CV death, non-fatal MI and non-fatal stroke using ‘in-trial’ data from subjects in the full analysis set. Time
from randomisation to first EAC-confirmed CV death, non-fatal MI and non-fatal stroke was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified
by evidence of CV disease at screening. Subjects were censored at the end of their in-trial observation period. CV, cardiovascular; EAC, event adjudication committee; HR, hazard ratio; MI,
myocardial infarction; MACE, major adverse cardiovascular event; sema, semaglutide.Husain M, et al. N Engl J Med 2019;381:841–51.

Components of primary endpoint

6
Cardiovascular death 6
First non-fatal MI
of subjects (%)

of subjects (%)

5 5
4 HR: 0.49 [0.27; 0.92] 4 HR: 1.18 [0.73; 1.90]
3 3 37 events

2 30 events 2 31 events
Proportion

Proportion

1 15 events 1

0 0 9 18 27 36 45 54 63 72 83

0 9 18 27 36 45 54 63 72 83 0
Time from randomisation (weeks) Time from randomisation (weeks)
6
5
First non-fatal stroke
(%)
subjects

Oral sema 14 mg 3 HR: 0.74 [0.35; 1.57]

4
of

Placebo
0
Proportion

2
1 16 events
12 events
0 9 18 27 36 45 54 63 72 83

Time from randomisation (weeks)

All events confirmed by EAC. Cumulative incidence estimate plot for EAC-confirmed events using ‘in-trial’ data from subjects in the full analysis set. Time from randomisation to first event was
analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of CV disease at screening. Subjects were censored at the end of their in-
trial observation period. CV, cardiovascular; EAC, event adjudication committee; HR, hazard ratio; MI, myocardial infarction; sema, semaglutide.Husain M, et al. N Engl J Med 2019;381:841–51.

This document is strictly for internal use only . Not for distribution or detailing.
All-cause death
6
(%)

4 HR: 0.51 [0.31; 0.84]

Proportion of patients

45 events 30 CV death
3
15 non-CV death
2

23 events 15 CV death

1 8 non-CV death
0 9 18 27 36 45 54 63 72 83

0
Time from randomisation (weeks)

Oral sema 14 mg Placebo

All events confirmed by EAC. Cumulative incidence estimate plot for EAC-confirmed all-cause death using ‘in-trial’ data from subjects in the full analysis set. Time from randomisation to EAC-
confirmed all-cause death was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of CV disease at screening. Subjects were
censored at the end of their in-trial observation period. EAC, event adjudication committee. CV, cardiovascular; HR, hazard ratio; sema, semaglutide.Husain M, et al. N Engl J Med 2019;381:841–51.

PIONEER-6 efficacy endpoint HbA1c

Secondary efficacy endpoint

Observed means Oral sema 14 mg Placebo

Mean baseline HbA1c: 8.2%

0.0
HbA 1c - change from baseline (%)

–0.3% (SEM: ± 0.033)

-0.5

-1.0 –1.0% (SEM: ± 0.037)

-1.5

-2.0
0 8 14 26 38 50 62 EOT

Time since randomisation (weeks)

Error bars are +/– standard error of the mean (SEM). EOT, end of treatment; N, number of subjects contributing to the means; sema, semaglutide.Husain M, et al. N Engl J Med 2019;381:841–51.

This document is strictly for internal use only . Not for distribution or detailing.
Fewer major cardiovascular events with semaglutide
compared with standard of care
Oral semaglutide (PIONEER 6)1 Subcutaneous semaglutide (SUSTAIN 6)2
10 Event rates: 3.2 vs 4.4 events/100 patient-years SoC

10 Event rates: 2.9 vs 3.7 events/100 patient-years

9 9
(%)

HR 0.79 (95% Cl: 0.57, 1.11)

with event (%)

HR 0.74 (95% Cl: 0.58, 0.95)
8 p<0.001 for noninferiority 8 p<0.001 for noninferiority

p=0.17 for superiority

event

7 7 p=0.02 for superiority

SoC
6 6
with

5 5 Subcutaneous

4 Oral semaglutide 4 semaglutide

+ SoC

Patients
3
Patients

3
+ SoC
2 2

1 1

0 0
8 16 24 32 40 48 56 64 72
80 88 96 104 109
0
0 9 18 27 36 45 54 63 72 83
No. at risk Weeks since randomisation
No. at risk Weeks since randomisation
Semaglutide 1,648 1,619 1,601 1,584 1,568 1,543 1,524
Oral semaglutide 1,591 1,583 1,575 1,564 1,557 1,547 1,512 1,062 735 16
Placebo 1,649 1,616 1,586 1,567 1,534 1,508 1,479
Placebo 1,592 1,577 1,565 1,551 1,538 1,528 1,489 1,032 713 11
First major cardiovascular event Patients with events/

HR (95% CI) analysed semaglutide + SoC; SoC

0.76 (0.62, 0.92) 169/3,239; 222/3,241
Semaglutide pooled 3
Oral semaglutide1 0.79 (0.57, 1.11) 61/1,591; 76/1,592
0.74 (0.58, 0.95) 108/1,648; 146/1,649
Subcutaneous semaglutide2

0.25 0.5 1 2

Major cardiovascular events were cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. Cardiovascular death includes undetermined cause of death. Estimated HRs and
corresponding CIs are from separate Cox proportional hazards models with treatment as fixed factor and stratified by trial and stratification factors. CI, confidence interval; HR, hazard ratio; SoC,
standard of care
1. Husain M et al. N Engl J Med 2019;381:841–851; 2. Marso SP et al. N Engl J Med 2016;375:1834–1844; 3. Husain M et al. Diabetes Obes Metab 2020;22:442–451

This document is strictly for internal use only . Not for distribution or detailing.
Oral semaglutide was well tolerated in subjects with
varying degrees of hepatic impairment

• No apparent effect of hepatic

impairment, regardless of
severity, on PK or tolerability
of oral semaglutide
• Results of this study suggest
dose adjustment of oral
semaglutide is not necessary
in subjects with
hepatic impairment

PK, pharmacokinetic.Baekdal TA, et al. J Clin Pharmacol. 2018;58:1314-1323.

This document is strictly for internal use only . Not for distribution or detailing.
Oral semaglutide was well tolerated in subjects with
varying degrees of renal impairment

• Renal impairment did not

appear to impact PK
properties of oral semaglutide
following 10 consecutive
once-daily doses
• Results of this study suggest
dose adjustment of oral
semaglutide is not necessary
in subjects with
renal impairment

PK, pharmacokinetic.Granhall C, et al. Clin Pharmacokinet. 2018;57:1571-1580.

This document is strictly for internal use only . Not for distribution or detailing.
Effect of oral semaglutide on the
PK of co-administered drugs
Lisinopril AUC 1.07 (0.99, 1.15)
0–8
C
max 0.96 (0.88, 1.06)
AUC
S-warfarin 0–8
1.08 (1.04, 1.12)
C
max 0.88 (0.83, 0.94)
Digoxin AUC 1.03 (0.96, 1.11)
0–8
C
max 0.98 (0.89, 1.09)
AUC
Metformin 0–12h
1.32 (1.23, 1.43)
C
max 0.98 (0.90, 1.06)
Furosemide AUC0–8 1.28 (1.16, 1.42)
C
max 0.66 (0.53, 0.82)
AUC
Rosuvastatin 0–8
1.41 (1.24, 1.60)
C
max 1.10 (0.94, 1.28)
Ethinylestradiol AUC 1.06 (1.01, 1.10)
0–24h
C
max 0.97 (0.90, 1.05)
AUC
Levonorgestrel 0–24h
1.06 (0.97, 1.17)
C
max 0.95 (0.87, 1.05)
AUC
Levothyroxine bc 0–48h
1.33 (1.25, 1.42)
C 0.88 (0.81, 0.94)
bc max
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.25 1.45 1.65
Estimated ratio, 90% CI
AUC, area under the curve; bc, baseline-correlated; CI, confidence interval; Cmax, maximum concentration; PK, pharmacokinetics. Baekdal TA, et al. Clin Pharmacokinet. 2019;58(9):1193-1203;
Baekdal TA et al. Poster 714. EASD 54th Annual Meeting. 1–5 October, 2018; Hauge C et al. Poster SAT-140. ENDO 101st Annual Meeting and Expo. 23–26 March, 2019; Jordy AB et al. Poster
713. EASD 54th Annual Meeting. 1–5 October, 2018.

This document is strictly for internal use only . Not for distribution or detailing.
 * No studies have investigated bedtime dosing of
levothyroxine in patients also treated with oral semaglutide

Effect of oral semaglutide

PK co-administered drugs: PPI (Omeprazole)
semaglutide,Day1

450 1.13 [0.88;1.45] 1.16 [0.90; 1.49]

 400
0(nmoI/L)
350
300 20

Plasma
25 15 oral semaglutide
200
250

150 20
100 + omeprzole
24h

50 15

(nmoI/L)
10

(nmoI/L
0
AUC0 -

oral oral oral oral 10 oral semaglutide

semaglutide semaglutide semaglutide semaglutide

Semaglutide,
alone + alone + 5 5
omeprzole omeprzole
0

Day10Cmax,se
maglutide,
Exposure of semaglutide appeared to be slightly 0 6 12 24
increased, though not satistically significant, when 01234
administered with omeprazole
Time since dosing (hours)

Oral semaglutide was well tolerated when administered

alone and in combination with omeprazole

No dose adjustment is required if Oral semaglutide

administere with omeprazole

Effect of oral semaglutide

PK co-administered drugs: Levothyroxine
levothyroxine to be administered as a single daily dose,
preferably on an empty stomach, 7-1 hr before BF &
administerzed at least 4 hrs before or after drugs known
Estimated treatment ratio (90% CI) for levothyroxine co- to interfere with its absorption

administered with steady-state oral semaglutide vs

levathyroxine alone* American Thyroid Association's guideline for the treatment of
hypothyroidism dosing of levothyroxine is recommended
either 60 minutes before BF or at bedtime (3 or more hours
Total T4 after the evening meal) for optimal, consistent absorption
bCAUC 11.33 (1.25, 1.42)

bc Cmax Bedtime dosing of levothyroxine has been investigated in

10.88 (0.81, 0.94)
clinical studies* as a possible alternative to morning
0.8 0.9 1.0 1.1 1.25 dosing and demonstrated similar exposure

Levothyroxine co-administered with steady-state oral Always advise compliance with the dosing conditions for
semaglutide resulted in a 33% increase in total levothyroxine oral semaglutide, along with monitoring of thyroid
bcAUCO-48h. No effect on baseline- corrected maximum total parameters and treating hypothyroidism according to
levothyroxine concentrations (bcc-max) was observed local guidelines

Oral semaglutide should be taken in a fasting state and at least 30 minutes before the first food, beverage or any other oral medication for the day, including levothyroxine

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This document is strictly for internal use only . Not for distribution or detailing.
Dosing instructions for oral semaglutide

Wake up fasting and take

2 Wait at least 30 minutes before 3 Have your first meal and
1 your semaglutide tablet with up eating, drinking or taking any drink of the day and take any
to half a glass of water
other oral medication other medications you need
(approximately 120 mL/4 fl oz)

30 min

3 7
3 mg Initiation dose 4 Weeks 7 mg maintenance dose 4 weeks 14 14 mg Optimization dose

Advise patients that if they miss a dose, they should skip the missed
dose and take the next dose ad scheduled the next day

Used in Phase 2 and Phase 3a (PIONEER) programme. PIONEER, peptide innovation for early diabetes treatment.

This document is strictly for internal use only . Not for distribution or detailing.
This document is strictly for internal use only . Not for distribution or detailing.
This document is strictly for internal use only . Not for distribution or detailing.
This document is strictly for internal use only . Not for distribution or detailing.
Keep tablet in the blister pack in a dry place, away from moisture, until ready to take
it

Push tablet out of blister. Do not cut from the packaging

Swallow tablet whole. Do not split, crush, or chew

Take RYBELSUS® upon waking: Patients must take RYBELSUS®

on an empty stomach

Take with no more than 120 ml of water: Patients should take RYBELSUS® with a
sip of plain water

Wait 30 minutes before the first food, beverage, or other oral medications:
Waiting less than 30 minutes or taking with food, beverages (other than plain water), or
other oral medications will lessen the effect of RYBELSUS®. Waiting more than 30
minutes to eat may increase the absorption of RYBELSUS®

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This document is strictly for internal use only . Not for distribution or detailing.
This document is strictly for internal use only . Not for distribution or detailing.
This document is strictly for internal use only . Not for distribution or detailing.