Discovery and Development of Semaglutide

Yumeng Duan

1,† a

and Ziyao Wan

2,† b

Jiangnan University, Wuxi, China

Nanjing Tech University, Nanjing, China

†

These authors contributed equally

Keywords: Diabetes, GLP-1 RAs, Semaglutide.

Abstract: Diabetes Mellitus is a universal disease around the world. There are many different types of drugs for

treatment, among which the glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have attached much

attention in recent years. Semaglutide, one of the GLP-1 RAs, is a long-acting diabetes drug developed by

Novo Nordisk. Compared with traditional diabetes drugs, semaglutide possesses a longer biological half-life,

which conduces to reduce the dosing frequency. And based on the general preparation of semaglutide, Novo

Nordisk made changes to the dosage form and made it into the oral drug. In 2019, FDA launched the new

drug, oral semaglutide. Oral semaglutide has been proved that it still maintains good effectiveness, and oral

semaglutide has better safety and can reduce the occurrence of hypoglycemia through pre-clinical and clinical

trials. This review introduces the mechanism, structure, pre-clinical and clinical trials of semaglutide and

discusses the entire process from the research and development background to the market.

1 INTRODUCTION

1.1 Diabetes

Diabetes is a metabolic disease characterized by high

blood sugar, and insulin secretion defects are the main

cause of diabetes.

Long-term diabetes can damage various tissues,

such as the eyes, heart, blood vessels, and kidneys.

Diabetes can also cause symptoms such as polydipsia,

polyuria, polyphagia, and weight loss.

Table 1 shows the comparison of some indexes

between healthy people and diabetic patients. The

highest fasting blood glucose (FBG) of healthy

people is only 6.1 mmol/L, while the free blood

glucose index of diabetic patients is at least 7 mmol/L.

The glycosylated hemoglobin (HbA1c) and body

mass index (BMI) of healthy people are also lower

than those of diabetic patients. The 2-hour

postprandial blood glucose of diabetic patients is even

about twice that of healthy people.

https://orcid.org/0000-0001-6760-5926

https://orcid.org/0000-0002-9507-7208

Table 1: Comparison between healthy and diabetes patients.

(American Diabetes Association 2010, World Health

Organization, Vijan 2010).

Indexes Healthy people Patients with diabetes

mellitus

FBG 4.4 – 6.1

mmol/L

≥7.0 mmol/L

HbA1c 4 % – 6 % ≥6.5 %

(OGTT)

2hPBG

4.6 – 7.8

mmol/L

≥11.1 mmol/L

BMI 18.50 – 24.99 Overweight: 25.00-29.99

Obese Class Ⅰ: 30.00-

34.99

Obese Class Ⅱ: 35.00-

39.99

Obese Class Ⅲ: ≥40.00

C-peptide

(Kong

2016)

0.8 – 4.2 ng/ml Extremely-low (T1D)

As shown in Table 2, diabetes can be divided into

type 1 diabetes and type 2 diabetes.

Type 1 diabetes is an autoimmune disease caused

by the effects of external environmental factors based

on genetic susceptibility, leading to the damage, even

destruction of pancreatic islet cells, and finally, the

Duan, Y. and Wan, Z.

Discovery and Development of Semaglutide.

DOI: 10.5220/0011378500003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 1119-1130

ISBN: 978-989-758-595-1

1119

failure of their function. Type 1 diabetes is mainly

caused by insulin deficiency, and its onset is sudden.

The patient's body is mainly thin or normal, and this

type of diabetes occurs mostly in children.

Type 2 diabetes is the most common one among

diabetes, which is due to insulin resistance. Insulin

resistance is the inability of cells to respond

adequately to normal levels of insulin. The onset of

Type 2 is gradual, and patients are usually obese. This

type of diabetes occurs mostly in adults.

Table 2: Comparison between type 1 and 2 diabetes.

(Williams textbook of endocrinology).

Feature Type 1 diabetes Type 2 diabetes

Cause Insulin deficiency Insulin resistance

Onse

Sudden Gradual

Age at onset Mostly in

children

Mostly in adults

Body shape Thin or normal Mostly obese

Ketoacidosis Common Rare

Autoantibodies Usually present Absen

Endogenous

insulin

Low or absent Normal,

decreased, or

increased

Concordance in

identical twins

50% 90%

Prevalence ~10% ~90%

1.2 Glucagon-like Peptide 1

Glucagon-like peptide 1 receptor agonist drugs are an

effective option for treatment for patients with type 2

diabetes, which is used as a single treatment or

supplement to other antihyperglycemic therapies to

reduce glycosylated hemoglobin and body weight.

Glucagon-like peptide 1 (GLP-1) works by

binding to GLP-1 related receptors. GLP-1 receptors

are distributed in various tissues throughout the body,

including the pancreas, lungs, kidneys, and

cardiovascular system (Andersen 2018). GLP-1

regulates blood sugar in many ways, including

increasing blood sugar and suppressing the source of

blood sugar. The effects of GLP-1 on the pancreas

include regulating the secretion of insulin by lifetime

control on β-cells, inhibiting the secretion of

glucagon from α-cells, acting on δ-cells, and

promoting somatostatin synthesis (Smits 2016).

It is currently believed that the cAMP/Epac2/PKA

pathway is a classic activation pathway for the

regulation of insulin secretion by GLP-1 (Shigeto

2017). The protective effect of GLP-1 on β-cells is

reflected in the reduction of the damage caused by

endoplasmic reticulum stress to β-cells through

TUM1-Ex4 (Son 2018). The regulation of glucagon

may be achieved indirectly through δ cells to promote

the synthesis of somatostatin. Studies suggest that

GLP-1 can directly act on α-cells to inhibit the

secretion of glucagon (Davis 2020). The control of

GLP-1 on blood sugar is also affected by the basic

condition of patients and the type of medication. For

diabetic patients, the ones with a lower BMI can

achieve better results than those with a higher BMI

(Meier 2015).

In general, the regulation of blood sugar by GLP-

1 is a complex process, which is affected by blood

sugar levels, GLP-1 levels, receptor distribution, and

diversity (Wang 2020).

1.3 GLP-1RAs

Intravenous injection of exogenous GLP-1 to patients

with type 2 diabetes can reduce the blood glucose

concentration to the normal fasting range. However,

the short half-life and fast degradation speed limit the

further therapeutic application of GLP-1 (Gupta

2013). To overcome this problem, the development of

glucagon-like peptide 1 receptor agonists (GLP-

1RAs) was proposed.

GLP-1RAs are a class of anti-diabetic drugs with

unique characteristics. Although there are intra-class

differences in clinical efficacy due to different

biochemical structures and pharmacokinetic

characteristics, a significant hypoglycemic effect was

shown in all members of the GLP1-RA class, such as

liraglutide, abiglutide, exenatide, and semaglutide. In

addition, the safety of these drugs is generally

satisfactory (Christina 2019). Table 3 is the

comparison between liraglutide, exenatide and

semaglutide.

Table 3: Comparison of liraglutide, exenatide and

semaglutide.

Liraglutide Exenatide Semaglutide

Chemical

Structure

H-His-

Ala-Glu-

Gly-Thr-

Phe-Thr-

Ser-Asp-

Val-Ser-

Ser-Tyr-

Leu-Glu-

Gly-Gln-

Ala-Ala-

Lys (Pal-ν-

Glu)-Glu-

Phe-Ile-

Ala-Trp-

Leu-Val-

Arg-Gly-

H-His-

Gly-Glu-

Gly-Thr-

Phe-Thr-

Ser-Asp-

Leu-Ser-

Lys-Gln-

Met-Glu-

Glu-Glu-

Ala-Val-

Arg-Leu-

Phe-Ile-

Glu-Trp-

Leu-Lys-

Asn-Gly-

Gly-Pro-

H-His-Aib-Glu-

Gly-Thr-Phe-Thr-

Ser-Asp-Val-Ser-

Ser-Tyr-Leu-Glu-

Gly-Gln-Ala-Ala-

Lys (AEEAc-

AEEAc-γ-Glu-17-

carboxyheptadeca

noyl)-Glu-Phe-

Ile-Ala-Trp-Leu-

Val-Arg-Gly-Arg-

Gly-OH

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Liraglutide Exenatide Semaglutide

Arg-Gly-

Ser-Ser-

Gly-Ala-

Pro-Pro-

Pro-Ser-

NH2

acetate salt

Pancreatic

β-cell

Improve

pancreatic

β-cell

function

Protect

pancreatic

β-cells

Protect pancreatic

β-cells

DPP-IV Antagoniz

e the

degration

of DPP-IV

Antagoniz

e the

degration

of DPP-IV

Cover the

hydrolysis site of

DPP-IV encyme

Half-life Long half-

life

Long half-

life

Long half-life

Cardiovasc

ular system

Improve

cardiovasc

ular risk

factors

Protect the

cardiovasc

ular

system

Protect the

cardiovascular

system

1.3.1 Liraglutide

As shown in Figure 1, liraglutide is a GLP-1 analogue

formed by adding a 16-carbon acyl chain to the 26th

lysine residue of GLP-1 and substituting arginine for

the 34th lysine of GLP-1. The plasma forms a non-

covalent binding with albumin and releases slowly,

antagonizing the degradation of DPP-IV (Bock 2003).

The hypoglycemic effect of liraglutide is glucose

concentration-dependent, so the incidence of

hypoglycemia with long-term use of liraglutide is

very low. Liraglutide can also reduce patient weight,

improve cardiovascular risk factors, and at the same

time improve pancreatic β-cell function (Astrup

2012).

1.3.2 Exenatide

As shown in Figure 1, Exenatide is a GLP-1 analog

isolated from the salivary glands of the blunt-tailed

lizard distributed in the southwestern United States

and northern Mexico. It consists of 39 amino acid

residues and has a molecular mass of 4186.6, which

has 53% homology to GLP-1., And GLP-1 acts on G-

protein coupled receptors with higher affinity. The

second-to-last amino acid at the N-terminal of

exenatide is glycine (His-Gly-Glu), which is different

from the N-terminal sequence of GLP-1 (His-Ala-

Glu) and is not decomposed by DPP-IV, so it has a

longer half-life, can be more effective (HANSEN

1999, Zhou 2010). Dramatical reduction of blood

sugar and body weight was found by dosing twice a

day and protecting pancreatic β-cells and the

cardiovascular system (Bunck 2009). The main

adverse reaction of Exenatide is mild to moderate

nausea, which mostly occurs in the early stage of

medication, and its severity decreases with the

passage of time (Yoo 2006).

1.3.3 Semaglutide

As shown in Figure 1, Semaglutide is a long-acting

dosage developed from the structure of liraglutide

(Lau 2015). A1a at position 8 on the GLP-1 (7-37)

chain is replaced with Aib, and Lys at position 34 is

replaced with Arg. The Lys at position 26 is

connected to the fatty acid chain of octadecanoic acid.

Compared with Liraglutide, semaglutide has a longer

aliphatic chain with higher hydrophobicity. However,

semaglutide has been modified with a short chain of

PEG to greatly increase its hydrophilicity. The

modified semaglutide can bind tightly to albumin,

cover up the DPP-4 enzymatic hydrolysis site, and

reduce renal excretion, prolong the biological half-

life, and achieve the effect of long circulation

(Kapitza 2012).

(a)

(b)

Discovery and Development of Semaglutide

1121

(c)

Figure 1: Structure of liraglutide (a), exenatide (b) and

semaglutide (c).

2 DEVELOPMENT OF ORAL

SEMAGLUTIDE

Their main disadvantage is that the subcutaneous

route of administration can cause malabsorption.

Therefore, the development of oral GLP1-RA

preparations will further consolidate its beneficial

effects in clinical practice. Oral semaglutide is a

modified form of semaglutide with the addition of a

carrier sodium N-(8-[2-hydroxybenzoyl] amino)

caprylate.

2.1 The Mode of Action of Oral

Semaglutide

Figure 2 shows the mode of action of oral semaglutide.

Oral semaglutide is limited to extensive degradation

by proteolytic enzymes in the gastrointestinal tract

and poor absorption across the gastrointestinal

epithelium (Mahato 2003). To achieve adequate

bioavailability of semaglutide after oral

administration, oral semaglutide has been co-

formulated with a 300 mg concentration of the

absorption enhancer called SNAC (Rasmussen 2020).

One disadvantage of using SNAC is the fast

absorption rate. Because of its low potency as a type

of permeation enhancer, it is difficult to maintain a

threshold concentration in the intestinal wall for a

long enough time. Therefore, semaglutide tablets

must use a 300 mg concentration of SNAC. SNAC

protects semaglutide against enzymatic degradation

via a local pH buffering effect (Rasmussen 2020). As

the oral semaglutide tablet rapidly erodes, SNAC

causes a local increase in pH, leading to the higher

solubility of semaglutide and protection from

proteolytic degradation (Rasmussen 2020). SNAC

also promotes the absorption of semaglutide across

the gastric epithelium in a concentration-dependent

manner by effects on transcellular pathways, which

are transient and fully reversible (Rasmussen 2020).

This absorption of semaglutide is highly localized and

depends on the spatial proximity of semaglutide and

SNAC (Buckley 2018).

Figure 2: Mode of action of oral semaglutide. SNAC,

sodium N-(8-hydroxybenzoyl] amino) caprylate.

2.2 Dosing and Medical Condition

Now researchers face another question, which is the

appropriate dosing condition.

Clinically, they found out food intake can have a

negative impact on the absorption of oral semaglutide,

so when oral semaglutide is taken in a fasting sate,

sufficient exposure can be reached. After the dosage

condition was figured out, the clinical pharmacology

of oral semaglutide becomes the focal point of the

research. Through several studies, researchers get

deep insight into how the exposure of semaglutide

following oral administration is influenced by

comorbidities or medication and how oral

semaglutide might impact the exposure of

concomitant medications (Rasmussen 2020).

Besides, some special medical conditions, such as

hepatic or renal impairment, might have a strong

impact on the pharmacokinetics of oral semaglutide.

To assess this, researchers clinically assessed how

oral semaglutide changes in its efficacy or absorption

under those medical conditions. From the results,

there is no apparent effect observed on the

pharmacokinetics or tolerability of oral semaglutide,

which indicates the dose redesign is not necessary at

this point.

Last but not the least, they investigated the effect

of oral semaglutide on exposure to various

medications normally taken by T2D patients. Based

on their results, when co-administered, oral

semaglutide had no clinically relevant effect on the

exposure of lisinopril, warfarin, and digoxin in

healthy subjects (Rasmussen 2020). When co-

administrated with metforminm furosemide, and

rosuvastatin, it only resulted in small change of oral

semaglutide. Similarly, they observed that there was

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

1122

an increase in thyroxine exposure when co-

administered with levothyroxine. Until now, they still

keep doing studies about drug-drug interaction for

oral semaglutide. When enough information is

gathered, it will be more lucid and straightforward for

researchers to give more useful suggestions when oral

semaglutide is co-administered with other

medications by T2D patients.

3 PRE-CLINICAL TRAILS OF

SEMAGLUTIDE

3.1 AME Test

Semaglutide is an analogue of human glucagon-like

peptide 1 and is in clinical development to treat type

2 diabetes. In Lene Jensen’s study, the radioactivity

in blood, plasma, urine, and feces was measured in

rats and monkeys; the radioactivity in exhaled air was

measured in rats. The researchers quantified

metabolites in plasma, urine, and feces after analysis

and radiological testing. The blood-to-plasma ratio

and pharmacokinetics of both radiolabelled

semaglutide-related materials were assessed (Lene

2017).

This trial studied 0.5 mg of Semaglutide,

providing sufficient exposure to estimate the relevant

PK endpoint. Semaglutide was radiolabelled in the

octadecanedioic acid moiety in the side chain of

lysine 26 to characterise the metabolism of the most

modified part of the molecule (Lene 2017).

3.1.1 Blood-to-Plasma Ratio

The researchers collected blood and plasma samples

for 24 hours in rats to assess the ratio of blood to

plasma. The average blood-to-plasma ratio of the rats

was found to be 0.44-0.46 (Lene 2017). For monkeys,

in the absence of a small amount of tritium water, the

average blood-to-plasma ratio of samples collected

48 hours after dosing is in the range of 0.54-0.60

(Lene 2017).

3.1.2 Excretion of

[

H]-semaglutide-related Material

Table 4 shows the excretion of radioactivity in rats

and monkeys. In rats, the recovery of total excretion

of [

H]-semaglutide related substances after 168

hours showed that urine and feces are important

excretion pathways (Table 4). Radioactivity was still

detectable in urine 168h after dose administration,

and 22.4% was recovered in the carcasses. Less than

0.5% of the radioactivity was detected in expired air

(Lene 2017).

For monkeys, the total recovery of [

H]-

semaglutide-related material after 336 h showed that

similar to rats, urine and faeces were important routes

of excretion. When the collection is stopped, the

recovery of urine and feces is not complete. This can

be seen from the slightly positive slope of the

cumulative excretion versus the time curve. Unlike

mice, the radioactivity in the carcass has not been

determined. The total recovery rates of intact and dry

urine and stool samples were 12.6% and 7.0%,

respectively (Lene 2017).

Table 4: Excretion of radioactivity. (Lene 2017).

Species Rat

(% of dose [%

coefficient of

variation])

n=3

Monkey

(% of dose [%

coefficient of

variation])

n=3

Dose 0.3 mg/kg

10 MBq/kg

0.03 mg/kg

14 MBq/kg

Time 0-1week 0-2weeks

Gender Male Male

Urine 35.6 (27.7) 30.3 (25.3)

Faeces 32.6 (9.7) 20.7 (3.0)

Expired air <0.2 Not applicable

Carcass 22.4 (27.0) Not applicable

Cage wash and

debris

3.7 (22.2) 7.2 (28.4)

Total excretion 72.1 (8.8) 58.3 (10.2)

Total recovery 94.5 (0.5) 58.2

3.1.3 Metabolite Profiling

(1) Plasma

As shown in Figure 3, twelve components were

detected in the plasma of rats. At all time points of the

analysis, [

H]-semaglutide is the main component in

plasma, and the retention time of [

H]-semaglutide

reference substance is similar to the main peak in

plasma chromatogram. [

H]-semaglutide accounts for

69% of the total semaglutide related substances. As

shown in Table 5, another 10 metabolites were

detected in the plasma, each accounting for <1-7% of

the total AUC

0-last

(Lene 2017).

Figure 3 shows that 6 components were detected

in plasma of monkeys. Semaglutide was the primary

component in plasma at all time-point analysed. As

shown in Table 5, in the other peak areas, 4

metabolites are eluting close to semaglutide, each

accounting for <1-9% of the total AUC

0-last

(Lene

2017).

Discovery and Development of Semaglutide

1123

The retention time for the first eluting peak was

characteristic of tritiated water for both rats and

monkeys, and this was confirmed by data from

freeze-dried samples (Lene 2017).

Table 5: Exposure of semaglutide and metabolites in plasma across species. (Lene 2017).

AUC

total

Timepoint of samples profiled % semaglutide Total number of metabolites % metabolites

Rat 2-72 hours 69 10 <1-7

Monkey 0.5-168 hours 71 5 <1-9

Figure 3: HPLC analysis of metabolite profile in plasma

from rat, monkey, and human (Lene 2017).

(2) Urine and feces

For rats, the radioactive content in urine

accounted for about 89% of the total excreted

radioactivity (0-168 hours) from 0-120 hours after

administration, and a total of six components were

detected. The total amount of radioactivity in the

feces accounted for 89% of the total excreted

radioactivity (0-168 hours) from 0-120 hours after the

dose, and 14 ingredients were detected (Lene 2017).

In monkeys, the total amount of radioactivity in

urine from 0-216 hours after administration

accounted for 63% of the total excreted radioactivity

(0-336 hours). A total of 9 components were detected;

none of them had a retention time similar to [

H]-

semaglutide. The total amount of radioactivity in the

feces from 0-216 hours after the dose accounts for

74% of the total excreted radioactivity (0-336 hours),

and 15 ingredients were detected in monkeys (Lene

2017).

For both rats and monkeys, the retention time for

the first eluting peak was characteristic of tritiated

water (Lene 2017).

3.2 Nonclinical Toxicology

Carcinogenesis, mutagenesis, impairment of fertility.

In a 2-year carcinogenicity study in CD-1 mice,

subcutaneous doses of 0.3, 1, and 3 mg/kg/day of

semaglutide were administered to the males, and 0.1,

0.3, and 1 mg/kg/day were administered to the

females. A statistically significant increase in thyroid

C-cell adenomas and a numerical increase in C-cell

carcinomas were observed in males and females at all

dose levels (

http://www.novonordisk-

us.com/products/product-patents.html.)

In a 2-year carcinogenicity study in Sprague

Dawley rats, subcutaneous doses of 0.0025, 0.01,

0.025, and 0.1 mg/kg/day of semaglutide were

administered. A statistically significant increase in

thyroid C-cell adenomas was observed in males and

females at all dose levels, and a statistically

significant increase in thyroid C-cell carcinomas was

observed in males at ≥0.01 mg/kg/day, at clinically

relevant exposures (http://www.novonordisk-

us.com/products/product-patents.html.).

In a combined fertility and embryo-fetal

development study in rats, subcutaneous doses of 0.01,

0.03, and 0.09 mg/kg/day of semaglutide were

administered to male and female rats. Males were

dosed for 4 weeks before mating, and females were

dosed for 2 weeks prior to mating and throughout

organogenesis until Gestation Day 17. No effects were

observed on male fertility. In females, an increase in

estrus cycle length was observed at all dose levels,

together with a small reduction in numbers of corpora

lutea at ≥0.03 mg/kg/day. These effects were likely an

adaptive response secondary to the pharmacological

effect of semaglutide on food consumption and body

weight (http://www.novonordisk-us.com/products/

product-patents.html.).

3.2.1 Animal Toxicology and Pharmacology

An increase in lactate levels and decreased glucose

levels in the plasma and cerebrospinal fluid (CSF)

were observed in mechanistic studies with SNAC in

rats. Small but statistically significant increases in

lactate levels were observed in a few animals at

approximately the clinical exposure. These findings

were associated with moderate to marked adverse

clinical signs (lethargy, abnormal respiration, ataxia,

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

1124

reduced activity, body tone, and reflexes) and marked

decreases in plasma and CSF glucose levels at higher

exposures. These findings are consistent with

inhibition of cellular respiration and lead to mortality

at SNAC concentrations >100-times the clinical

Cmax (http://www.novonordisk-us.com/products/

product-patents.html.).

4 CLINICAL TRAILS

4.1 Overview of Clinical Development

of Semaglutide

The clinical trial is a carefully designed study that

tests the benefits and risks of a specific medical

treatment or intervention in humans. It is to determine

the efficacy and safety of the trial drug. It consists of

four phases, phase I, phase Ⅱ, phase Ⅲ, and phase IV

(after the drug marketed).

As shown in Figure 4, a comprehensive global

clinical development program was conducted for

semaglutide. At the time of cut-off for the NDA, 25

trials with semaglutide s.c. once-weekly had been

completed: 16 phases 1 clinical pharmacology trials,

one phase 2 dose-finding trial, and 8 phase 3a trials

(including a 2-year cardiovascular outcomes trial

[CVOT]). A total of 9,384 individuals were included

in the clinical development program, of whom 5,710

were exposed to semaglutide and 3,674 to

comparators, including placebo. Approximately 1/3

of the total population was recruited from sites in the

US. (https://www.fda.gov/media/108291/download).

Figure 4: Semaglutide development program: Overview of completed clinical trials.

4.2 Phase 1

4.2.1 Trail Design

The purpose of phase 1 clinical trial is to investigate

the first safety, pharmacokinetic and

pharmacodynamic data for oral semaglutide in

healthy subjects and subjects with T2D.

In the first-in-human experiment, there are two

kinds of trials, single-dose trial, and multiple-dose

trial. The single-dose trial is tested in healthy subjects,

and the multiple-dose trial is tested between the

healthy subjects and the subjects with T2D. Both

trials were randomized, placebo-controlled, double-

blind trials, each conducted at single sites (Parexel

International, Harrow, UK, and Parexel International

GmbH, Berlin, Germany, respectively). (Granhall

2019)

4.2.2 Selection Condition of Subjects

Table 6 shows the selection conditions of subjects. In

the single-dose trial, eligible subjects are healthy men

aged 18-50, weighing 65.0-95.0 kg, and having a

Completed Trials

Phase 1

Clinical pharmacology trials

Phase 2 trial

1821-Dose finding

Phase 3a trials

SUSTAIN 1(3623) sema vs placebo

(Mono)

SUSTAIN 2(3626) sema vs sita

(OADs)

SUSTAIN 3(3624) sema vs exe ER

(OADs)

SUSTAIN 4(3625) sema vs IGlar

(OADs)

SUSTAIN 5(3627) sema vs placebo

(Insulin)

SUSTAIN JP Mono (4092) sema vs

sita (Mono), JP

SUSTAIN JP OADs (4091) sema vs

OAD (OAD), JP

Healthy subjects

1820-First human dose

3697-Equivalence-product strength

3687-Equivalence/bioavailability

4010-Bioequivalence-

manufacturing process

3633-Multiple dose-Caucasian/JP

3634-Pk/Pd-Caucasian/JP

3789-Metabolism

3652-QTc

Special populations

3616-Renal impairment

3651-Hepatic impairment

Drug-drug interaction

3817-DDI-metformin and warfarin

3818-DDI atorvastatin and digoxin

3819-DDI-oral contraceptives

Phase 3b trial

Long-term outcomes trial

SUSTAIN 6 COVT (3744) sema vs

placebo (SoC)

Pharmacodynamics

3635-Beta-cell function

3684-Hypoglycaemia

3685-Ener

intake

Discovery and Development of Semaglutide

1125

body mass index (BMI) of 18.5-27.5 kg/m

. In the

multi-dose trial, eligible subjects are healthy men

aged 18-64 with a BMI of 20.0-29.9kg/m

and men

who have been diagnosed with T2D after diet,

exercise, and/or metformin treatment within the last

10 years, aged 18-64 years old, with a BMI of 20.0-

37.0 kg/m

, glycosylated hemoglobin (HbA1c) of

6.5-9.0%.

If the subject has a clinically significant

concomitant disease or disorder, clinically significant

outliers in laboratory screening tests, any history of

gastrointestinal surgery (except for simple surgical

procedures such as appendectomy and hernia

surgery), or if they smoked more than five cigarettes

or the equivalent per day. (Granhall 2019).

Table 6: The selection conditions of subjects.

Single-dose

trial

Multiple-dose trial

Healthy males Healthy males Males with T2D

(Within the last

10 years, treated

with diet and

exercise and/or

metformin

)

 18~50

years old

 65.0~95.0

 BMI

18.5~27.5

kg/m

 18~64

years old

 BMI

20.0~29.9

kg/m

 18~64

years old

 BMI

20.0~37.0

kg/m

 HbA1c

6.5~9.0%

4.2.3 Trail Methods

Figure 5 shows the details of the trail design. The

single-dose trial is to investigate the best dose of oral

semaglutide. It is divided into 3 parts, part 1a, part 1b,

and part 2.

In part 1a, four ascending dose groups are tested

in a sequential design. When the first dose level is

proved safe, test the next dose level until it reached

the specified maximum dose. In part 1b, there are

three additional dose groups in a parallel design. This

process is to confirm which dose level of the

semaglutide with SNAC has a better curative effect.

In part 2, three of the doses from part 1 were selected

to be repeated in a parallel design in another three

groups. At the same time, intravenous and

subcutaneous semaglutide are also tested to

investigate absolute and relative biotechnology.

The multiple dose trial is to reveal the therapeutic

potential in the treatment of T2D. As the subjects are

divided into healthy males and males with T2D, their

tests are also different. This trial is to identify if the

semaglutide gets the therapeutic potential in the

treatment of T2D. Healthy males receive oral

semaglutide maintenance doses of 20 and 40 mg, and

also compared them with receiving placebo and

placebo with SNAC. But the subjects with T2D only

receive an oral semaglutide dose of 40 mg. In the

multiple-dose trial, subjects are randomized to once-

daily treatment for 10 weeks with different tablets.

(Granhall 2019)

Figure 5: Trail design.

4.2.4 Results

Overview two trials, it confirmed that there are no

safety concerns identified and the pharmacokinetic

properties of oral semaglutide are comparable in

healthy subjects and subjects with T2D.

About the single-dose trial, it concluded that

semaglutide with 300mg SNAC gets the best

pharmacokinetics. Through comparing different dose

levels, 300mg compared with 150 or 600mg is the

optimal amount of SNAC to enhance absorption of

oral semaglutide. Next, at a fixed amount of 300 mg

SNAC, both the proportion of subjects with

measurable semaglutide in plasma and the

semaglutide exposure appeared to increase with

increasing dose of oral semaglutide from 2 to 10 mg,

as shown in Figure 6. And in healthy subjects of the

multiple-dose trial, semaglutide plasma exposure was

about twofold higher with oral semaglutide 40 mg

compared with 20 mg, as shown in Figure 7.

Furthermore, semaglutide plasma exposure did not

differ between healthy subjects receiving 40 mg and

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1126

subjects with T2D receiving 40 mg, as shown in

Figure 8 and 9.

(Granhall 2019)

Comparison of a AUC

0–24 h, semaglutide, SS(steady state)

and b C

max, semaglutide, SS

between 20 and 40 mg doses of

oral semaglutide in healthy males and between

healthy males and males with T2D receiving 40 mg

oral semaglutide (multiple-dose trial)

Figure 6: Arithmetic mean semaglutide plasma

concentration-time pro-files after a single dose of oral

semaglutide with varying amounts of SNAC in healthy

male subjects in single-dose trial.

(Granhall 2019)

Figure 7: Arithmetic means semaglutide plasma

concentration-time profiles after ascending single doses of

oral semaglutide with 300 mg SNAC in healthy male

subjects in single-dose trial. (Granhall 2019)

Figure 8: Geometric mean semaglutide plasma

concentration-time pro-files at steady state in multiple-dose

trial. Profiles represent geometric means of the last 3 days

of once-daily oral semaglutide treatment for 10 weeks. T2D

type 2 diabetes.

(Granhall 2019).

Figure 9. Comparison of a AUC0–24 h, semaglutide, SS and b Cmax, semaglutide, SS between 20 and 40 mg doses of oral

semaglutide in healthy males and between healthy males and males with T2D receiving 40 mg oral semaglutide in multiple-

dose trial. (Granhall 2019).

4.3 Phase 2

4.3.1 Trail Design

Phase 2 compares the effects of oral semaglutide with

placebo (primary) and open-label subcutaneous

semaglutide (secondary) on glycemic control in

patients with type 2 diabetes.

From December 2013 to December 2014, a 2-

week randomized, parallel grouping, the dose-

determined 26-week trial was conducted in 100

locations (hospital clinics, general practice, and

clinical research centers) in 14 countries/regions. 5-

week follow-up. Among the 1106 participants

evaluated, 632 patients with type 2 diabetes and

insufficient blood glucose control only through diet

Discovery and Development of Semaglutide

1127

and exercise or a stable dose of metformin were

randomly assigned. Randomization was stratified by

metformin use. (Davies 2017)

4.3.2 Trail Methods

Subjects took orally semaglutide 2.5 mg (n=70), 5 mg

(n=70), 10 mg (n=70), 20 mg (n=70), 40 mg orally

once a day in 4 weekly dose escalations (standard

Escalation; n=71), 40 mg 8-week dose escalation

(slow escalation; n=70), 40 mg 2-week dose

escalation (rapid escalation, n=70), oral placebo

(n=71; double-blind) or every Semaglutide 1.0 mg

(n=70) was injected subcutaneously once a week for

26 weeks. (Davies 2017)

4.3.3 Results

The baseline characteristics of each treatment group

are comparable. Among 632 randomized patients, 583

(92%) completed the test. From baseline to week 26,

the average change in HbA1c levels decreased with

oral semaglutide (dose-dependent range, -0.7% to -

1.9%) and subcutaneous semaglutide (-1.9%) and

placebo (-0.3%); Compared with placebo, the

reduction in oral semaglutide was significant

compared to the dose (the dose-dependent) estimated

treatment difference between oral semaglutide and

placebo [ETD] ranged from –0.4% to –1.6%; for 2.5

mg, P = 0.01, for all other doses, <0.01). Oral

simaglutide (dose-dependent range, -2.1 kg to -6.9 kg)

and subcutaneous simaglutide (-6.4 kg) have greater

weight loss than placebo (-1.2 kg), and oral

simaglutide doses Significantly compared to placebo

at 10 mg or higher (dose-dependent ETD range –0.9

to –5.7 kg; P<0.01). The reported incidence of adverse

events was 63% to 86% in the oral semaglutide group

(371 of 490 patients), 81% of the subcutaneous

semaglutide group (56 of 69 patients), and placebo

group 68% (48 of 71 patients); mild to moderate

gastrointestinal events are the most common. Within

26 weeks, oral semaglutide can control blood sugar

better than a placebo and is effective for patients with

type 2 diabetes. (Davies 2017)

4.4 Phase 3

4.4.1 Trail Design

Phase 3 is a series of PIONEER programs. The

PIONEER program includes 10 trials, including a

pre-approval cardiovascular outcome trial, which

aims to evaluate the efficacy and safety of oral

semagluide in a wide range of patients with type 2

diabetes. The program includes eight global trials,

including Japanese patients, and two trials conducted

only in Japan. All trials started in 2016, and the main

treatment period ended in 2018. (Rasmussen 2020)

4.4.2 Results

The PIONEER clinical trial plan includes several

studies that recruit Japanese patients.

Throughout the plan, oral semaglutide 14 mg

reduced HbA1c significantly more than placebo,

empagliflozin, and sitagliptin, and was not inferior to

liraglutide. In the PIONEER trial in Japan, the

reduction in HbA1c of 14 mg of oral semaglutide was

significantly higher than that of liraglutide 0.9 mg or

dulaglutide 0.75 mg, and the reduction of HbA1c at a

7 mg dose was similar to that of dulaglutide 0.75 mg.

Compared with oral placebo, sitagliptin, and

liraglutide, oral sitagutide 14 mg can also

significantly reduce body weight. And the weight loss

was similar to ipaglifozin. Oral semaglutide also has

more beneficial effects in achieving blood sugar

control and weight loss than sitagliptin, even when

flexible dosage adjustments are made, which reflect

the actual dosage setting.

Whether it is based on the estimated value of the

treatment strategy (regardless of whether the trial

product is discontinued or the use of emergency drugs)

or the estimated value of the trial product (the patient

continues to use the experimental drug and does not

use emergency drugs), the results are usually

consistent.

In all PIONEER trials, oral semaglutide was well

tolerated, and its adverse events were consistent with

other GLP-1RA administered subcutaneously. There

were no unexpected safety risks in individual trials.

For patients with moderate renal insufficiency, the

safety of oral semaglutide seems to be acceptable. In

Japanese patients, oral semaglutide is also well

tolerated. The incidence of adverse events of oral

semaglutide is similar to that of dulaglutide, and its

safety is consistent with that of injectable GLP-1RA.

In the PIONEER 6 trial, oral glucosamine showed

good cardiovascular safety compared with

conventional care and compared with placebo,

cardiovascular death and all-cause mortality were

significantly reduced. (Rasmussen 2020)

5 CONCLUSIONS

Oral semaglutide is a novel tablet containing the

human glucagon-like peptide-1 (GLP-1) analogue

semaglutide, co-formulated with the absorption

enhancer SNAC. It has three major effects of

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lowering blood glucose, weight loss, and reducing

cardiovascular risk. For non-clinical species, intact

semaglutide is a major component circulating in

plasma and is metabolized prior to excretion.

Additionally, it has been found to affect the thyroid's

fertility and C cell adenomas in preclinical studies. In

the single-dose experiment of clinical trials, it was

found that semaglutide with 300mg SNAC will exert

the maximum effect. Multi-dose experiments have

proved that semaglutide has the therapeutic properties

of T2D. In phase 2 trials, semaglutide has better

potency and effects than other therapeutic drugs

already on the market. Phase 3 trial further proved

that semaglutide has the function of reducing HbA1c

and body weight. In conclusion, the successful design

of the oral formulation of Semaglutide paves the way

for the subsequent development of oral forms of

GLP-1RAs.

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