1.

Development

status of GLP-1 drugs

In the beginning of 20th century, scholars scientists observed that glucose administered orally
had a greater stimulation effect on insulin secretion than i.v. administration, suggesting
gastrointestinal signals might have regulated the hormone secretion of the pancreas. Owning to an
ability to cause a stronger glucose-induced insulin secretion, this intestinal hormone was called
incretin. The amount of insulin produced from an incretin approach contributes to one half of the
total amount of the after-meal insulin, showing an important influence of incretin on insulinassociatedinvolved reactions. Further studies demonstrated that incretin could also suppress the
secretion of glucagon, promote the proliferation of -cells (reduce the apoptosis), increase the
sensitivity of insulin, slow down the emptying of the stomach and enhance the feeling of satiation,
all of which could help with the regulation of the blood sugar level [1].
In the case of type 2 diabetes mellitus (T2DM), the significant suppression of incretin secretion
has lead to the malfunction of insulin. Experiments demonstrated that continuous intravenous
injection of Glucagon-like peptide-1 (GLP-1), a kind of incretin, could restore the fasting and the
postprandial blood glucose to normal. Unfortunately, since natural GLP-1 has a short half-life in
the circulation (about 2 minutes) and can be decomposed by dipeptidyl peptidase-4 (DPP-4) in the
blood in just a few minutes and thus can no longer promote the insulin secretion. Therefore, , it is
not practical for clinical use.

Fig. 2-1: Mechanism of the effect of GLP-1.

SourceJCI2005/12
GLP-1 is produced by the L-cells locatedsituated remotely in the ileum, which starts to secret
GLP-1 some minutes after food is taken and reflects the effect of the neural reflex. Later on, when

the L-cells are in direct contact with food, there is a subsequent secretion of GLP-1. Though the
level of GLP-1 is rather low in fasting status, it can rise up rapidly after taking a meal. GLP-1 can
stimulateencourage a glucose-induced insulin secretion, and the effect may retain even for a
patients with T2DM., this means iIt has a high potential to become a new therapeutic approach for
diabetes [2].
By acting on -cells, GLP-1 can stimulate the production and secretion of insulin through the
promotion of the transcription of insulin genes [3], meanwhile, by enhancing the proliferation and
differentiation and as well as by suppressing the apoptosis of -cells, it can also increase the
number of -cells and thus have a beneficial effect on these cells [4]. Moreover, GLP-1 can act on
-cells to suppress the release of glucagon significantly, and on -cells to promote the secretion of
somatostatin, which can act as a bypath hormone to take part in the suppression of glucagon
secretion.
In general, GLP-1 can bring down the blood glucose level in several ways [5]
1. Insulin stimulation: The main effect of insulin is to reduce the blood glucose level., When
therefore to raiseinsulin level increases, the level of insulin is to reduce the the level of blood
sugar will drop accordingly..
2. Glucagon suppression: Glucagon can cause the rise of blood glucose level.,When the level of
glucagom drops, the level of blood sugar will drop as well. which can be lowered once the
level of glucagon is dropped.
3. Gastric emptying suppression: This can leads to a smaller appetite, and then a reduced body
weight. This e feature distinguishesed GLP-1 largely from other diabetic drugs because the
latter usuallygenerally results in an increased body weight, which is quite a burden to diabetic
patients.
4. Islet cells regeneration: In T2DM, the reduced number of islet cells has lead led to a lesser
degree of insulin secretion and eventually a high level of blood glucose. If regeneration of islet
cells can be achieved, diabetic patients might have an opportunity to be cured fundamentally.
Currently, developed GLP-1 drugs come in two categories based on their effects:
1. long-acting DPP-4 decomposition -resistant long-acting GLP-1 analogs: Exenatide
(Byetta, Injection) and Liraglutide (Victoza, Injection) are two examples of this
category, which were approved for sale in 2005 and 2009, respectively. are two examples
of this category. Byetta is a synthesized product that simulatesmimic the saliva
ingredients of Gila Monster, a basilisk living in the desert of southwest America and
Mexico, whose saliva contains a protein that has the same effect as that of human GLP-1,
a kind of incretin which can stimulate the secretion of insulin.
2. DPP-4 inhibitor: This category of drugs can prolong the half-life period and effect of GLP-1
through its inhibition effect on DPP-4. The candidates , the representatives of which include
Sitagliptin (Januvia) of Merck & Co. and Vitagliptin (Galvus) of Novartis. In 2006 and
2007, the sale of Januvia was approved by FDA and EU, and in July, 2007, its marketing was
approved by the Department of Health in Taiwan. As for Galvus , EU had also granted

approval for its sale in September, 2007.

Table 1. GLP-1 related products already on sale.

Company

Product name

FDA approval
date

Eli Li

Byetta exe

2005/04/28

lly

&

Structure

Product picture

natide

Amylin

Novo

liraglutide

Nordisk

Victoza

2010/01/25

A/S

Merck &

Januvia

Co

2006/10/16

sitagliptin

phosphate
Novartis

Galvus
vildagliptin

Not sold in the

USA, but in
Europe and
other areas.

Note: Januvia has authorized the related production to Daewoong (South Korea), Almirall (Spain)
and Ono (Japan), while Galvushas authorized the production to Handok (South Korea).
Sourcewebsites of each company
Moreover, in April, 2007, FDA had approved another new drug, the sale of Janumet. As a
combination of Januvia and metformin, Janumet can be taken orally after each of the three meals
everyday. Merck & Co has specifically referred to the fact that this drug was the first and the
exclusive formula that combines Januvia with metformin.

Figure: Product picture of Janumet

Source: diaTribe website
Since approved by FDA In 2005, the year the use of Byetta was approved by FDA, the sales of
Byetta had reached $75 million in the US(limited to the USA market) and underwent a

considerable growth every year after 2006. In 2007 and 2008, it was increased by $220 million
and $100 million, with a growth rate of 51.1% and 15.6% respectively. And in 2009, its sales
reached had stricken on a figure of $800 million. With the influence of the sales in non-USA
market increasing, it is expected to grow continuously in the near future and its potential is not to
be overlooked.

Figure: Sales of Byetta in each year.

SourceEli Lilly Annual Report
() Million USD
As for Januvia and Janumet of Merck & Co, they came into market in 2006 and 2007
respectively, and according to the annual reports of the company, from October, 2006, the time
Januvia was first introduced into market, to the end of that year, the sales of Januvia had reached
$43 million. In the following year of 2007 and 2008, the sales went to about $670 million and
$1400 million, with the growth rate in 2008 alone achieving 109%. In 2009, the sales
reachedended on $2000 million, indicatingshowing a significant growth was realized. After
Janumet entered into market in April, 2007, its sales had reached $350 million by the end of
2008, and in 2009, with nearly a growth rate of 100%, it struck on a figure of $660 million. On the
whole, it seems that Januvia is quite a popular product to the public.

Figure: Sales of Januvia and Janumet.

SourceMerck & Co Annual Report
() Million USD
Currently, Galvus is sold mainly in Europe and is still being tested in the USA, though
according to Novartis, its new product Eucreas , a drug similar to Januvia in that it is also a
combination of Galvus and metformin, had already been approved to be used to treat T2DM in
Europe (in early 2008), making it the first single-tablet that combines DPP-4 inhibitor with
metformin in the area.
According to the annual reports of Novartis, in 2007, the year Galvus was first entered the
marketput on sale, the sales had reached $8 million. In 2008, with Eucreas being introduced into
market earlier that year, the sales of Galvus was promoted to $43 million, and in 2009, it even
raised up to $180 million, meanwhile the company was not prepared to apply for another FDA
test.

Figure: Sales of Galvus.

SourceNovartis Annual Report
() Million USD

(12 ):
1. Ou Hongyi (2008), New diabetes drug that strengthens blood glucose self-regulation DPP4Diabetes Care Foundation.
2. Huang Shufeng, Zhang Naiwen (05,2007), Incretins New target for diabetes treatment, Primary
Medical Care and Family Medicine, Issue 5, Vol. 22.
3. Drucker DNauck M2006The incretin system: glucagon-like peptide-1 receptor agonists and
dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet 2006, 368:1696.
4.
Giorgino FNatalicchio A Leonardini A et al.2007 Exploiting the pleiotropic actions of GLP-1
for the management of type 2 diabetes mellitus and its complications. Diab Res Clin Pract 2007, 78:
S59.
5. Fei Di (31,07,2008), New knowledge on diabetes drugs Getting to know DPP-4, Diabetic
Patients' Commune at: http://www.diacare.com.tw/html/modules/news/article.php?storyid=2955

2. Patent analysis on GLP-1 drugs

This program aims to develop novel small-molecules new to treat diabetes drugs based on
GLP-1 mechanism. From aA brief review oflooking at the current patent status sindicating that
hows there is a positive growth of GLP-1 related patents and patenteesassignees, and there is a
trend that more and more large international pharmaceutical companies, such as Pfizer Inc,
Bristol-Myers Squibb Co and Merck & Co, are engaging initiating R&D work on GLP-1 drugs,
resulting in a rapid increase of related patents every year. Since the R&D work is still in its callow
status, the companys do not no one knows which compound structure is the most effective and
different company each sets out with a different portfolio of strategies and core compounds.

Taking the development Based on the review of current patent development, to develop of
GLP-1 small-molecule drugs to treat diabetes based on the GLP-1 mechanism seems to be a as a
major trend.trend for future diabetes treatment, Iif the target drug of this program can be well
defined clearly based on a comprehensive analysis of the current patent status, it might give a
great help to the improvement of the market portfolio. Thus tThe following sections will attempt
to outline figure out the profile and developing trend of the program's GLP-1 target drug and the
related competitors patent applications through a reviewing and discussion of GLP-1 related
patents.
1) Global patent status
In the patent database of USPTO, EPO and WIPO (World Intellectual Property
Organization), within the rangesurvey of GLP-1 related patents claimed and published and granted
in the last 20 years, used diabetes related terms such as GLP-1, diabetic and blood sugar as
keywords to search the title, abstract and claims of the patent specifications, and then collected the
searched data to draw the following graph. In the graphFig. 4-1, it can be seentrend showed that it
was only after 2000 that GLP-1 technology had experienced a significant development, especially
in recent few years, suggesting a current interest is being focused on this technology and has led to
a considerable growth of related patents.
Fig. 4-1: Growth trend of GLP-1 drug patents claimed granted and published in USPTO, EPO and
WIPO.

SourceThomson Innovation, 2011/02

AnalysisFrom the region aspectrespectively, except in WIPO, related patents applied by US
and European patentees have a relative larger quantity, showing that the USA and Europe progress
faster than Asian countries in the development of GLP-1 drugs., wWhile in Asia, Mainland China,
South Korea and Japan take a descending order of related patent numbers. (See Fig. 4-2)

Fig. 4-2: Patent application numbers related to GLP-1 drugs by countries.

SourceThomson Innovation, 2011/02

A further examination reveals that Eli Lilly, Amylin Pharmaceuticals Inc. (co-developed) and
Novo Nordisk As each has put one GLP-1 protein drug on sale, neverthelessthough their shares in
GLP-1 small-molecule drug patents are also considerably high. This shows that these leading
players do not stay on Exenatide, the already popular protein drug, but progress to develop small
molecule drugs, the promising GLP-1 new generation drugs. Along with the patent portfolio of
those large international pharmaceutical companies, such as Bristol- Myers Squibb and Bayer, a
development focus on GLP-1 drugs is quite obvious.
Fig. 4-2: Leading fifteen patentees of GLP-1 drugs.

SourceThomson Innovation

2) Analysis on GLP-1 small-molecule drug related patents

With a purpose to develop GLP-1 small-molecule drug to promote the signaling activity in
GLP-1 downstream signal transductioninformation transmission, this program set out to analyze
patents related to GLP-1 agonists or GLP-1 signal stimulatorsenhancers that were collected from
claimed patents. The objective of the analysis is to find out the development status of the
competitors, so that further breakthrough could be achieved and repetitive R&D work be avoided
and ultimately the GLP-1 technology greatly be improved.
After the searching and analysis on GLP-1 small molecule drug related patents, Pfizer Inc,
Bristol-Myers Squibb Co. and Merck & Co Inc stood out in companies who owned an outstanding
patent portfolio, to which the following section will give a brief introduction respectively:
(i) Pfizer Inc:
With 13 patents related to GLP-1 small molecule drugs, Pfizer's patent portfolio is most
striking. Analysis shows that Cannabinoid (CB) receptor antagonist is the focus of Pfizer's R&D
work. This antagonist takes Pyrazolo as its primary structure, and been modifiedmodifies it to
have a CB1 (central cannabinoid) inhibition effect. It is expected to curtail appetite as well as to
promote fat decomposition and glucose metabolism. It can activate GLP-1 and restore the
abnormal blood lipid level, thus is a promising for T2DM prevention. Another patent of this
company is -3-Adrenergic receptor inhibitor, but with only one related patent, it is not supposed
to be the main R&D direction of the company. The company's patent information is provided in
the following table:

Table: Pfizer, GLP-1 patents.

Pub.
Numbe
r

Title

Appl. Date

Pub. Date

Description

Stucture

Structure classics

US7176
210B2

Cannabinoid receptor ligands and

uses thereof

2004/01/21

2007/02/13

Cannabinoid (CB) receptor

antagonist

Pyrazolo[1,5-a]pyrimidine
compounds

US2004
0092520
A1

Purine compounds and uses thereof

2003/10/20

2004/05/13

Cannabinoid (CB) receptor

antagonist

Purine derivatives

US2004
0235926
A1

Cannabinoid receptor ligands and

uses thereof

2004/05/03

2004/11/25

Cannabinoid (CB) receptor

antagonist

Substituted pyrazole compounds

US7230
024B2

Cannabinoid receptor ligands and

uses thereof

2006/05/12

2007/06/12

Cannabinoid (CB) receptor

antagonist

Bicyclic
pyrazolyl
imidazolyl compounds

US7232
823B2

Cannabinoid receptor ligands and

uses thereof

2004/05/25

2007/06/19

Cannabinoid (CB) receptor

antagonist

Pyrazolo[3,4-d]pyridazine
compounds

and

Pub.
Numbe
r

Title

Appl. Date

Pub. Date

Description

Stucture

Structure classics

US7268
133B2

Cannabinoid receptor ligands and

uses thereof

2004/04/12

2007/09/11

Cannabinoid (CB) receptor

antagonist

Pyrazolo[4,3-d]pyrimidine and
pyrazolo[3,4-c]pyridine
compounds

US2007
0027133
A1

Bicyclic pyrazolyl and imidazolyl

compounds and uses thereof

2006/09/07

2007/02/01

Cannabinoid (CB) receptor

antagonist

A pharmaceutical composition
(C1)
comprises
bicyclic
pyrazolyl
and
imidazolyl
compounds

US2004
0259887
A1

Cannabinoid receptor ligands and

uses thereof

2004/05/13

2004/12/23

Cannabinoid (CB) receptor

antagonist

Pyrimidine-2-carboxylic amide
derivatives

US2004
0122074
A1

Cannabinoid receptor ligands and

uses thereof

2003/11/04

2004/06/24

Cannabinoid (CB) receptor

antagonist

Pyrazole
derivatives

US2006
0241100
A1

Acylaminobicyclic heteroaromatic
compounds and uses thereof

2006/04/20

2006/10/26

Cannabinoid (CB) receptor

antagonist

An acylaminobicyclic compound

EP9208
64A1

Combination therapy including a

specific beta-3 agonist and an
anorectic agent

1998/11/12

1999/06/09

Cannabinoid (CB) receptor

antagonist

Composition
compound

and

imidazole

comprises

Pub.
Numbe
r

Title

Appl. Date

Pub. Date

Description

WO200
3072572
A1

Beta | agonistes du recepteur

$g(b)3-adrenergique

2003/02/17

2003/09/04

-3-Adrenergic
agonist

Stucture

receptor

Structure classics

2(R)-hydroxy-ethyl
phenyl compounds

Source Thomson Innovation

(ii) Bristol-Myers Squibb Co:
There are 10 patents applied by Bristol-Myers Squibb Co., besides the patent that describes a similar mechanism to Pfizer's Cannabinoid (CB) receptor
antagonist, BMS'sthe company's strategies on GLP-1 drug development regulation is much diversified, including DPP-IV inhibitor, PPAR agonist, GPR119 Gprotein coupled receptor agonist and aP2 inhibitors, . aAmong which patent WO2003020737A1, EP1506211B1and EP1268502B1 are all about taking SGLT2
inhibitor as a main therapeutic approach. SGLT2 is an important transporter protein in glucose reabsorption in the kidney., iInhibition of SGLT2 is thought to have a
curative effect on high blood glucose. From the following table, it can be inferred that BMSthe company is currently concentrating on the development SGLT2 in
the territory area of GLP-1 small molecule drugs, other patents of the company are also listed:
Table: Bristol-Myers Squibb Co, GLP-1 patents.

amino

Pub.
Numbe
r

Title

Appl. Date

Pub. Date

Description

Stucture

US2003
015823
2A1

Substituted azole acid derivatives

useful as antidiabetic and
antiobesity agents and method

2002/11/14

2003/08/21

PPAR agonist

Substituted
derivatives

US6670
380B2

Pyridone inhibitors of fatty acid

binding protein and method

2001/11/20

2003/12/30

Adipocyte fatty binding

protein (aP2) inhibitors

Pyridone derivatives

US7279
485B2

Substituted
heterocyclic
derivatives useful as antidiabetic
and antiobesity agents and method

2003/07/08

2007/10/09

Blood
glucose
modulator.

Substituted
derivative

WO200
503719
9A2

Pyrazole
derivatives
as
cannabinoid receptor modulators

2004/10/06

2005/04/28

Cannabinoid (CB) receptor

antagonist

level

Structure classics

azole

acid

heterocyclic

5-(hetero)aryl-1H-pyrazole
derivatives

Pub.
Numbe
r

Title

Appl. Date

Pub. Date

Description

Stucture

US2007
009991
3A1

Pyrrolidinyl beta-amino amidebased inhibitors of dipeptidyl

peptidase iv and methods

2006/10/30

2007/05/03

Dipeptidyl peptidase
(DPP-IV) inhibitor.

US2009
001805
5A1

[6,5]-bicyclic gpr119 g proteincoupled receptor agonists

2008/04/30

2009/01/15

GPR119 G-protein coupled

receptor agonist

US2008
000953
3A1

Substituted acid derivatives useful

as anti-atherosclerotic, antidyslipidemic, anti-diabetic and
anti-obesity agents and method

2007/07/05

2008/01/10

PPAR agonist

WO200
302073
7A1

O-pyrazole glucoside SGLT2

inhibitors and method of use

2002/09/05

2003/03/13

SGLT2 inhibitor

O-Pyrazole
derivatives

IV

Structure classics

Substituted
pyrrolidine
containing -amino amides

Aryl
and
compound

heterocyclyl

glucoside

Pub.
Numbe
r

Title

Appl. Date

Pub. Date

Description

Stucture

Structure classics

EP1506
211B

C-aryl
glucoside
inhibitors and method

SGLT2

2003/05/15

2007/02/07

SGLT2 inhibitor

1-Deoxy-1-(3-(4ethoxybenzyl)-4-chlorophenyl)--Dglucopyranoside

EP1268
502B1

O-aryl
glucoside
inhibitors and method

SGLT2

2001/03/29

2006/02/01

SGLT2 inhibitor

O-aryl glucoside derivatives

Source Thomson Innovation

(iii) Merck & Co Inc:
Since 2007, Merck & Co Inc has applied two patents related to GPR119 agnosit agonist, suggesting the company may step into the GLP-1 small molecule drug
market with two GPR-119 drugs in the future. In humankind and murine animals, GPR119 is expressed in the pancreas and intestines, when activated, it can act
oncould interact with the receptors in the brain and promote the secretion of GLP-1, therefore regulate the level of blood sugar can be regulated.
Table: Merck & Co, GLP-1 patents.
Pub.
Number

Title

Appl. Date

Pub. Date

Description

US200401
33011A1

Triazole derivatives as inhibitors

of
11-beta-hydroxysteroid
dehydrogenase-1

2003/12/18

2004/07/08

11-Hydroxysteroid
dehydrogenase-1 inhibitor.

Stucture

Structure classics
Bicyclo[2.2.2]-oct-1-yl1,2,4-triazole derivatives

Pub.
Number

Title

Appl. Date

Pub. Date

Description

Stucture

Structure classics

WO20080
85316A1

Bipiperidinyl
compounds,
compositions containing such
compounds and methods of
treatment

2007/12/14

2008/07/17

GPR119
G-protein
coupled receptor agonist

A bipiperidinyl compound

WO20091
29036A1

Substituted
cyclopropyl
compounds,
compositions
containing such compounds and
methods of treatment

2009/03/26

2009/10/22

GPR119
G-protein
coupled receptor agonist

Substituted
compounds

cyclopropyl

Source Thomson Innovation, 2011/02

(iv) Kalypsys Inc:
TGR5 is one type of G-protein coupled receptor. TGR5 is highly expressed in the gall bladder and intestines, when activated, it can promotinge the GLP-1
secretion with bile acid and thus realize the regulation on blood glucose concentration. The patent applied by Kalypsys Inc is about in regard to the development of
GLP-1 small molecule drugs, how to manage GLP-1 secretion through the stimulation of TGR5 secretion in intestines.

Table: KALYPSYS INC, GLP-1 patents.

Pub.
Numbe
r

Title

Appl. Date

Pub. Date

Description

Stucture

Structure classics

WO201
001473
9A2

Heterocyclic modulators of
tgr5

2009/07/29

2010/02/04

G protein-coupled bile acid

receptor
1
(TGR5)
modulator

Fused
compounds

pyrimidine

WO201
001684
6A1

Heterocyclic modulators of
tgr5 for treatment of disease

2008/08/08

2010/02/11

G protein-coupled bile acid

receptor
1
(TGR5)
modulator

TGR5
compounds

modulator

Source Thomson Innovation

(v) Other GLP-1 small molecule drug patents:
Glycemia or diabetes can also be cured controlled through the regulation of GLP-1 level with Glucokinase activator., GPR119 G-protein coupled receptor
agonist, -3-Adrenergic receptor agonist and PPAR agonist. In addition, Transtech Pharma Inc has established a screening platform for GLP-1 agonist, which can
be used to select GLP-1 related small molecule drugs on a large scale.
Table: Other GLP-1 small molecule drug patents.

P
u
b
.
N
O

Title

Assignee

Appl. Date

Pub. Date

Description

W
O
2
0
0
9
0
4
7
7
9
8
A
2

Acetamide derivatives as
glucokinase activators, their
process
and
medicinal
applications

Advinus
Therapeutics
Private Ltd

2008/10/07

2009/04/16

Glucokinase activator

Stucture

Structure classics

Acetamide derivative

P
u
b
.
N
O

Title

Assignee

Appl. Date

Pub. Date

Description

W
O
2
0
0
8
1
4
9
3
8
2
A
1

Pyrrole-2-carboxamide
derivatives as glucokinase
activators, their process and
pharmaceutical application

Advinus
Therapeutics
Private Ltd

2008/06/05

2008/12/11

Glucokinase activator

Stucture

Structure classics

Pyrrole-2-carboxamide
derivatives

P
u
b
.
N
O
W
O
2
0
0
9
0
4
8
5
2
7
A
1

Title

Substituted biphenyl
modulators

Assignee

gpr40

Amgen Inc

Appl. Date

Pub. Date

2008/10/03

2009/04/16

Description

GPR119
coupled
agonist

G-protein
receptor

Stucture

Structure classics

Substituted biphenyl derivative

P
u
b
.
N
O

Title

W
O
2
0
0
2
0
3
2
8
9
7
A
1

Alpha-aryl ethanolamines and

their use as beta-3 adrenergic
receptor agonists

Assignee

Day R F

Appl. Date

Pub. Date

2001/10/04

2002/04/25

Description

-3-Adrenergic
receptor agonist

Stucture

Structure classics

Alpha-aryl
ethanolamines
compound derivatives

P
u
b
.
N
O

Title

W
O
2
0
0
9
1
1
4
1
7
3
A
1

Azabicyclo [3. 2. i] octyl

derivatives as 11 beta-hsdl
modulators

Assignee

Appl. Date

Pub. Date

Description

Exelixis Inc

2009/03/13

2009/09/17

11 Hydroxysteroid
dehydrogenase-1

Stucture

Structure classics

Azabicyclo[3.2.1]octyl
derivatives

P
u
b
.
N
O

Title

W
O
2
0
1
0
0
9
3
8
4
5
A
1

Triazole
and
imidazole
derivatives for use as tgr5
agonists in the treatment of
diabetes and obesity

Assignee

Appl. Date

Pub. Date

Description

Exelixis Inc

2010/02/12

2010/08/19

G protein-coupled bile
acid
receptor
1
(TGR5) modulator

Stucture

Structure classics

Triazole
and
compounds

imidazole

P
u
b
.
N
O

Title

E
P
1
9
5
1
6
9
2
B
1

Oxazole and thiazole ppar

modulator

Assignee

Irm Llc

Appl. Date

Pub. Date

2006/11/07

2010/08/18

Description

PPAR agonist

Stucture

Structure classics

Oxazole or thiazole derivatives

P
u
b
.
N
O

Title

W
O
2
0
0
7
0
8
9
5
5
7
A
2

Compounds and compositions

as ppar modulators

Assignee

Irm Llc

Appl. Date

Pub. Date

2007/01/25

2007/08/09

Description

PPAR agonist

Stucture

Structure classics

Isoquinoline derivatives

P
u
b
.
N
O

Title

Assignee

Appl. Date

Pub. Date

Description

U
S
2
0
0
8
0
1
3
9
4
8
4
A
1

1(beta-d-glycopyranosyl)-3substituted
nitrogenous
heterocyclic
compound,
medicinal
composition
containing the same, and
medicinal use thereof

Kissei Pharm
Co Ltd

2007/03/28

2008/06/12

SGLT2 inhibitor

Stucture

Structure classics

1-()-D-Glycopyranosyl)-3substituted
nitrogenous
heterocyclic compounds

P
u
b
.
N
O

Title

Assignee

Appl. Date

Pub. Date

Description

U
S
2
0
0
8
0
1
8
8
4
2
6
A
1

Nitrogenous
fused-ring
derivatives,
medicinal
compositions containing the
derivatives, and use thereof as
drugs

Kissei Pharm
Co Ltd

2008/02/15

2008/08/07

SGLT2 inhibitor

Stucture

Structure classics

Nitrogenous
derivatives

fused

ring

P
u
b
.
N
O

Title

W
O
2
0
0
9
1
2
6
7
0
9
A
1

Ligands for the glp-1 receptor

and methods for discovery
thereof

Assignee

Appl. Date

Pub. Date

Description

Transtech
Pharma Inc

2009/04/08

2009/10/15

GLP-1R Modulator.

Source Thomson Innovation

Stucture

Structure classics

3. Market analysis
(1) Global distribution of diabetic patients
According to the statistics provided by of International Diabetes Federation (IDF),
worldwide, every ten seconds there is one patient dying from diabetes and two persons diagnosed
as new diabetic patients every ten seconds. In 2007, the number of global diabetic patients
reachedwas 246 million, 46% of which are working population with ages between 40-59. In
addition, according to the data provided by WHO, 1.10 million people died from from diabetes in
2005, 80% of whichwhom are in countries with low to middle incomes, and within the death
population, half 50% of the dead which were under 70 years old. Among the daed, 55% and the
proportion of thewas female deceased is 55%. The global diabetic deaths contribute to 5% of the
world's total death total. It was found that, and most of the diabetic patients are not the persons in
elderly group (65+) but rather in the middle-aged group (45-64). It is estimated that in the next 10
years, the diabetic death rate population would increase rapidly at a rate with an over 50% growth
rate,, suggesting iIt is a serious chronic disease for whichrequiring particular attention [6].is
needed in order to take preventive measures [6].
In 2007, the globalworld's diabetic population was estimated to reached 171 million, and in
2030, it is expected to increase by 100% to reach 366 million. If viewed Ffrom a regional
propective aspect, the growth of diabetic population in Eastern Mediterranean Region is most
impressive, and is expected to grow by 180% in 2030. African Region and South-East Asia
Region follow in the sequence, with an expected growth rate of 160% and 155% respectively.
Meanwhile, the growth is slowest in European Region, with an expected growth rate of 44%.
Other regions, like Region of the Americas and Western Pacific Region, the growth rate of which
are expected to be 102% and 99% respectively.

() Growth Rate

() Thousand population

FigGlobal prevalence of diabetes: estimates in 2000 and 2030

SourceWHO website
And in the following table, prevalence of diabetes by countries is listed:

Table Prevalence of diabetes worldwide

,000
Country
2000

2030

Country

2000

2030

Country

2000

2030

Algeria

426

1,203

Antigua and

Albania

86

188

Barbuda
Angola

51

140

Argentina

1,426

2,457

Andora

18

Benin

87

266

Bahamas

12

26

Armenia

120

206

Botswana

25

45

Barbados

11

22

Austria

239

366

Burkina Faso

124

388

Belize

15

Azerbaijan

337

733

Burundi

26

72

Bolivia

207

562

Belarus

735

922

Cameroon

70

171

Brazil

4,553

11,305

Belgium

317

461

Cape Verde

24

Canada

2,006

3,543

Bosnia and

111

180

Herzegovina
Central African

18

38

Chile

495

1,047

Bulgaria

472

458

Chad

97

269

Colombia

883

2,425

Croatia

155

180

Comoros

15

Costa Rica

76

237

Czech Rep.

336

441

Congo

14

39

Cuba

480

855

Denmark

157

232

Cte d'Ivoire

264

636

Dominica

Estonia

46

43

Democratic

291

910

Dominican

245

594

Finland

157

239

Republic

Republic of the

Republic

Congo
Equatorial

21

Ecuador

341

921

France

1,710

2,645

Eritrea

47

142

El Salvador

103

320

Georgia

200

223

Ethiopia

796

1,820

Grenada

Germany

2,627

3,771

Gabon

14

Guatemala

139

447

Greece

853

1,077

Gambia

22

61

Guyana

19

36

Hungary

333

376

Ghana

302

851

Haiti

161

401

Iceland

12

Guinea

34

89

Honduras

81

269

Ireland

86

157

Guinea-Bissau

17

44

Jamaica

81

189

Israel

257

500

Kenya

183

498

Mexico

2,179

6,130

Italy

4,252

5,374

Lesotho

31

42

Nicaragua

68

246

Kazakstan

452

668

Liberia

40

154

Panama

59

155

Kyrgyzstan

98

222

Madagascar

100

301

Paraguay

102

324

Latvia

82

90

Malawi

55

118

Peru

754

1,961

Lithuania

114

146

Mali

140

405

Saint Kitts and

Luxembourg

12

21

11

Malta

39

57

Guinea

Nevis
Mauritania

34

103

Saint Lucia

Mauritius

111

233

W Saint Vincent

and the

Grenadines

Mozambique
A

Namibia

133
25

273
60

f
r

Niger

108

382

Suriname
R Trinidad and
e
Tobago
g

United States

of America

4,835

Uruguay

77

Nigeria
Rwanda

1,707
30

Venezuela

9
60

20
125

Total

Netherlands

426

720

Norway

130

207

Poland

1,134

1,541

u
17,702

30,312

r
o

154
583

224

Portugal

662

882

1,606

Republic of

171

243

Moldova

Romania

1,092

1,395

Russian

4,576

5,320

n
Sao Tome-

Monaco

33,016

66,812

Principe

o
A

m
e
r
i
c
a
s
Senegal

143

421

Australia

941

1,673

Federation
Seychelles

19

Brunei

18

49

San Marino

Darussalam
65

178

Cambodia

110

317

Slovakia

153

220

South Africa

814

1,286

China

20,757

42,321

Slovenia

66

87

Swaziland

13

21

Cook Islands

Spain

2,717

3,752

Togo

64

184

Fiji

37

72

Sweden

292

404

Uganda

98

328

Japan

6,765

8,914

Switzerland

219

336

United

201

605

Kiribati

Tajikistan

93

246

70

186

Lao People's

46

128

The Former

54

96

2,920

6,422

Republic of
Tanzania
Zambia

Zimbabwe

108

265

WHO Western Pacific Region

Sierra Leone

Dem. Rep.

Yugoslav
Republic of
Macedonia

Malaysia

942

2,479

Turkey

Total

7,020

18,234

Marshall

Turkmenistan

80

222

13

Ukraine

1,629

1,642

34

81

United

1,765

2,668

Islands
Afghanistan

468

1,403

Federated
States of
Micronesia

Bahrain

37

99

Mongolia

Kingdom of
Great Britain
and Northern
Ireland
Cyprus

50

87

Nauru

Uzbekistan

430

1,165

Djibouti

New Zealand

179

307

Yugoslavia

324

393

Egypt

2,623

6,726

Niue

<100

<100

Total

33,332

47,973

Islamic

2,103

6,421

Palau

Bangladesh

3,196

11,140

668

2,009

Papua New

152

392

Bhutan

35

109

2,770

7,798

Dem. People's

367

635

India

31,705

79,441

Indonesia

8,426

21,257

Maldives

25

Myanmar

543

1,330

Republic of
Iran
Guinea
Jordan
Kuwait

195
104

680
319

Philippines
Republic of

1,859

3,378

Korea
Lebanon

146

378

Samoa

Libyan Arab

88

245

Singapore

328

695

427

1,138

Solomon

13

41

Jamahiriya
Morocco

WHO South-East Asia Region

WHO Eastern Mediterranean Region

Iraq

Rep. of Korea

Islands
Oman

113

343

Tonga

Nepal

436

1,328

Pakistan

5,217

13,853

Tuvalu

Sri Lanka

653

1,537

Qatar

38

88

Vanuatu

17

Thailand

1,536

2,739

Saudi Arabia

890

2,523

Viet Nam

792

2,343

Total

46,903

119,541

Somalia

97

331

Total

35,771

71,050

Sudan

447

1,277

Syrian Arab

627

2,313

Tunisia

166

388

United Arab

350

684

Yemen

327

1,286

Total

15,188

42,600

Republic

Emirates

SourceWHO website

The table clearly shows that the developing countries have more diabetic patients than those
of developed countries. In the developed countries, diabetic patients were more concentrated in
45-64 as well as in 65+ age group in 2000, but in 2030, patients older than 65 are expected to
increase significantly, with the concentration be shifted to 65+ age group. As for the developing
countries, the patients were concentrated in middle-aged group in 2000, though patients older than
65 are not few, and in 2030, this pattern of distribution might become more distinct. Also in
developing countries, there were more patients in 20-44 age group than in developed countries,
reflecting the fact that more attention should be paid to young adults' diabetes in developing
countries.

FigGlobal prevalence of diabetes: estimates in Developed and Developing

countries
SourceWHO website
Among all of the countries, India, Mainland China and the USA are have the countries
having three largest diabetic populations. In 2000, the estimated numbers of diabetic patients in
these three countries were 31.7 million, 20.8 million and 17.7 million, respectively, and in 2030,
with an expected growth rate of 150%, 103% and 71%, the numbers are supposed to reach 79.4
million, 42.30 million and 30.30 million.

FigGlobal prevalence of diabetes: estimates for the year 2000 and projections for
2030
SourceWHO website
As for the death toll by regions, in 2000, Asia and Australia had the largest number of
diabetic death, 60% of which were patients with ages between 35-65. Following in the sequence
were Europe, the Americas, Africa and Middle East, each had a diabetic death population of 0.61
million, 0.49 million, 0.32 million and 0.15 million, and the proportion of patients in middle-aged
group dying from diabetes was 43%, 47%, 64% and 61%.

FigThe Burden of Mortality Attributable to Diabetes: Realistic estimates for the

year 2000.
SourceWHO website
(2) An overview of the global diabetes drug market
According to the reports of Business Insight report, in 2008, with a gross sales of $12,900
million, the US market isremained to be the largest diabetes drug market in the world with and its
about 47.6% share in world market was about 47.6%. However, if viewed from the year-on-year
growth rate, markets in several countries with emerging economies, such as United Arab Emirates
(UAE), Israel and the BRIC Countries, had a larger growing potential with their growth rates
achieving 59.7%. 54% and 26%, respectively. Specifically, each of the four BRIC Countries, that
is, the Brazil, Russia, India and Mainland China, had a growth rate of 35.7%, 15.3%, 0.5% and
38.3% for their diabetes drug markets. On the other hand, the UK and Canada were the two
countries among the main countries whose markets reduced by 8.6% and 0.6% in 2000.

Note: bubble size represents sales growth for 200708 period.

BRIC Brazil, Russia, India, China (and Hong Kong); Middle East: Kuwait, Jordan, Israel,
Lebanon, the UAE, Saudi Arabia, Egypt (Turkey data not available).

Fig Global market sizes in 2008

SourceBusiness Insight Report
From the aspect of drug category of drugs, it can be told from the reports fromof Business
Insight indicated that in 2008, the sales of insulin drugs wasere $12,200 million, which took a
share of 45% in the overall diabetes drug market. When viewed from mechanism of drugs, the
reports shows that insulin sensitinizer (Glitazone) was the most commonly used drug and nearly
had a 22.8%one quarter market share, that is,. 22.8%. As for GLP-1 drugs, the sales of which was
$700 million in 2008, increasing by 20% on the basis of 2007 and having a meager share of 2.9%
in the whole diabetes drug market.

TableDistribution of the global diabetes market by drug class, 200708

Sales

Sales Growth 2007-

Market share

2008$m

2008%

2008%

12,278

19.7

44.9

16

4.7

0.1

12,294

19.7

45.0

Glitazone

6,217

-7.9

22.8

Sulfonylureas

2,001

2.7

7.3

Insulin Market
Human insulins
Animal insulins
TotalInsulins
Drugs targeting underlying causes

Biguanides

1,954

5.9

7.2

DPPIV inhibitors

1,725

145.5

6.3

1,057

11.9

3.9

GLP-1

700

19.8

2.6

Glinide

812

12.7

2.9

14,465

7.2

53.0

Other anti-diabetics

395

16.6

1.5

Insulin devices

140

19.2

0.5

27,294

12.7

100.0

Alpha-

glucosidase

inhibitors

AGIs

TotalDrugs targeting underlying causes

Grand Totaldiabetes market

SourceBusiness Insight Report

However, if viewed from the market potential, the compound annual growth rate (CAGR) of
GLP-1 drugs is estimated to become as high as 46.6% in the next few years, and in 2014, the sales
of GLP-1 drugs is expected to reach $7,000 million, which will take a share a 15.7% in the whole
market. Compared to a market share of 2.9% in 2008, the difference is significant, suggesting a
large market potential is to be expected for this new approach.
TableDiabetes market sales forecast by drug classes
Salesf$M
2009

2010

2011

2012

CAGR
2013

2014

20082014%

Insulin

13,898

14,327

15,989

17,597

18,324

19,673

8.2

Glitazone

4,735

3,215

2,335

2,220

2,155

1,389

-22.1

Sulfonylureas

2,023

2,031

2,005

1,770

1,560

945

-11.8

Biguanides

2,031

2,093

2,154

2,208

2,274

2,315

2.9

DPPIV inhibitors

2,151

2,209

2,287

2,491

2,973

3,892

14.5

1,050

1,040

1,037

1,030

985

960

-1.6

Glinide

910

880

865

855

845

793

-0.4

GLP-1

995

1,065

2,295

3,735

5,245

6,960

46.6

27,793

26,860

28,967

31,906

34,361

36,927

16.9

3,026

6,292

7,107

6,427

6,870

7,549

55.4

30,819

33,152

36,074

38,333

41,231

44,476

8.5

Drugs targeting underlying causes

Alpha-

glucosidase

inhibitors

AGIs

TotalDrugs targeting underlying

causes
Others
Grand Totaldiabetes market

SourceBusiness Insight Report

(3) An overview of the R&D drug development competition

On the basis of ThomsonPharma database, when viewed from the mechanism of Glucagonlike-peptide-1- receptor- modulator and if indications of the drugs are not considered, the majority
of the current development actions on GLP-1 related drugs with their latest status are still in the
period ahead of phase II clinical trails, with nearly half of the drugs still being studied and only 3
drugs having entered into the process of phase III clinical trials.
50

NO.

50

45

NO.

40

43.1

45
40

35

35

30

30

25
20
15
10
5

11
2

3.9

0
Launched

22

23.5

21.6

20
15

12

10
5.9

2.0
Preregistration

25 %

0
Phase III

Phase II

Phase I

Discovery

Figure: Observation on the development status of GLP-1 related drugs.

Source: ThomsonPharma Database
When viewed from the progress along the different phases of clinical trials, it is found that
Amylin Pharmaceuticals Inc and Eli Lilly & Co are most active in their R&D work, with Novo
Nordisk A/S following behind them. Further examination reveals that Asian countries, such as
India, Japan, South Korea and Mainland China are all engaging in the development of certain
GLP-1 drugs (see the following table), suggesting the technology is promising and worth paying
more attention. For example, the Uni-Bio Science Group Limited in Mainland China has already
put a drug into clinical trials (Phase II clinical trials in Mainland China), according to the
information provided by the company's website, the UNI-rE-4 drug can prolong the duration of
Exendin-4 in the blood, and based on the preclinical data analysis, the drug is supposed to be
absorbed by the body and lead to a significant drop of blood glucose level [7]. However, the drug's
protein structure distinguishes itself from the targeted small molecule drugs of this program.

Table: Companies with drugs acting as GLP-1 modulators being developed in different clinical

stages.
Launched

Pre-Registration

Amylin

Amylin

Pharmaceuticals Inc /

Pharmaceuticals

Eli Lilly & Co

Inc / Eli Lilly & Co

Novo Nordisk A/S

Phase III
GlaxoSmithKline plc

Sanofi-Aventis2

Phase II
CellMed

Phase I

AG

CovX

AstraZeneca plc

Pharmaceuticals Inc

Intarcia Therapeutics

Amylin

Inc

Pharmaceuticals Inc

CellMed AG / Eisai

Amylin

Co Ltd

Pharmaceuticals
Inc/Eli Lilly & Co

Hanmi

Dong-A

Pharmaceutical

Co

Pharmaceutical

Co

Ltd

Ltd

PhaseBio

Emisphere

Pharmaceuticals Inc

Technologies Inc

(OSI) Prosidion

Marcadia Biotech Inc

Rose Pharma A/S

MannKind Corp

Novo Nordisk A/S

Novo

Nordisk

A/S2
Chugai

Oramed

Pharmaceutical

Co

Pharmaceuticals

Ltd /

Inc

Teijin Ltd

TransTech

Pharma

Inc

TransPharma
Medical Ltd

Uni-Bio

Science

Group Limited

Zydus-Cadila
Group

() Japan () South Korea () Israel () India

Note: The number in the parentheses indicates the company has more than one drug being
developed in that specific stage. Symbol / represents co-development due to license
granting or transferring. An underline stands for a company not based in the USA or
Europe, and usually it is a company headquartered in Asia.
Source: ThomsonPharma Database; rearranged by Technology Transfer Team, 02/2011.
In addition, as for drugs based on taking Glucagon-like peptide 1 receptor as their action
targets and drugs employing a small molecule therapeutic strategy, their data is further compared
and GLP-1 small molecule drugs being developed in different clinical stages (with the latest

development status being considered) are sorted out. Drugs which are not GLP-1 small molecule
drugs are excluded from the discussion here.
I. Phase II clinical trials
(1) PSB-821
Developed by OSI Pharmaceutical, PSN-821 is composed mainly by of GPCR agonists.
According to the data provided by the company, the drug is a new candidate in GPR119 Project
which can act on GPCR and has a significant effect on the gall bladder and islet cells [8]. The
patent application and the related publications are rearranged as the following:

Patent

Table: Patent and publications related to the PSN-821 drug of OSI Pharmaceutical.
Pub. No.

WO/2007/003962

International Appl. No:

PCT/GB2006/050178

2007/01/11

International Filing Date:

2006/06/29

Publication Date
Title
Abstract

GPCR AGONISTS
Compounds of formula (I): or pharmaceutically acceptable salts thereof, are GPCR agonists and are
useful as for the treatment of obesity and diabetes.

Reference

Main Structure

Source
Title

Cell Metabolism 3, 167-175 2006.

Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery
of small-molecule hypophagic agents

Summary

The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a
peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This
paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G
protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and
gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food
intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the
recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by
PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose
tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore
represents a novel and attractive potential target for the therapy of obesity and related metabolic
disorders.

Fig.

Source: Rearranged by Technology Transfer Team, 02/2011.

(2) TTP-054
TTP-054 (developed by Transtech Pharma) is another drug that has entered into the Phase II
clinical trials. According to the data on the website of the company, TTP-054 is a non-peptide
agonist, the isolated product of which can be used as an oral drug [9]. The name of TTP-054 given in
the patent specification is Non-Peptide GLP-1 Agonists, with a patent number of
WO/2000/042026, the relevant entries are listed as the following:
Table: Content of the WO/2000/042026 patent.
Pub. No.

WO/2000/042026

International Appl. No:

PCT/DK2000/000014

2000/07/20

International Filing Date:

2000/01/14

Publication Date
Title

NON-PEPTIDE GLP-1 AGONISTS

Abstract

Novel non-peptide GLP-1 agonists, pharmaceutical compositions comprising them, use of the
non-peptide GLP-1 agonists for the preparation of pharmaceutical compositions and methods
for the treatment and/or prevention of disorders and diseases wherein an activation of the
human GLP-1 receptor is beneficial, especially metabolic disorders such as IGT, Type 1
diabetes, Type 2 diabetes and obesity.

Main Structure

Source: Rearranged by Technology Transfer Team, 02/2011.

II. Phase I clinical trials
(1) MKC-253

As for drugs that have entered into Phase I clinical trials, MKC-253 developed by Mannkind
takes the form of Technosphere particles and is a GLP-1 drug that can be administered using
Mannkind's proprietary inhaler (see the following pictures).

Figure: Mannkind's proprietary inhaler.

Source: Mannkind's website; rearranged by Technology Transfer Team.
In addition, according to the data from the clinicaltrials.gov website, MKC-253 started to
startedenter into Phase I clinical trials in 2007 and the trials were completed in 2008, but though
no information was availablehas referred to any subsequent trials. The drug's patent application is
summarized in the following table. In the specification of this WO2010080964 patent, it is
suggested that the inhaled powder contains GLP-1 molecules and diketopiperazine. The structure
of diketopiperazine, including its derivatives and analogs, is depicted as the following picture:

Figure: Scope of the general Formula of diketopiperazine

Source: WO2010080964 patent; rearranged by Technology Transfer Team, 02/2011.
The content of MKC-253 related patent is summarized as the following:
Table: MKC-253 related patent.
Pub. No.
Publication Date

WO/2007/033316

International Appl. No:

PCT/US2006/035822

2007/03/22

International Filing Date:

2006/09/14

Title

METHOD OF DRUG FORMULATION BASED ON INCREASING THE AFFINITY OF

ACTIVE AGENTS FOR CRYSTALLINE MICROPARTICLE SURFACES

Abstract

Methods are provided for promoting the adsorption of an active agent to microparticles by
modifying the structural properties of the active agent in order to facilitate favorable
association to the microparticle.

Pub. No.
Publication Date

WO/2010/080964

International Appl. No:

PCT/US2010/020448

2010/07/15

International Filing Date:

2010/01/08

Title

METHOD FOR TREATING HYPERGLYCEMIA WITH GLP-1

Abstract

A method for treating hyperglycemia and/or diabetes in a subject is provided. In particular, the
method is directed for the treatment of patients with type 2 diabetes mellitus who have a fasting
blood glucose concentration greater than about 8 mM, wherein the patient is administered a
formulation comprising a GLP-1 molecule and a diketopiperazine by pulmonary inhalation
with a dry powder inhalation system.
Source: Rearranged by Technology Transfer Team, 02/2011.

(2) ORMD-0901
To give a brief introduction of tThe ORMD-0901 drug was developed by Oramed
Pharmaceuticals Inc, it represents an effort of the company to modify focused one the
improvement of the GLP-1 drug already on marketsale,, that is, the Byetta drug, to a formulation
that can be taken orally and be absorbed in the intestines.
Table: Content of WO2009/136392 patent.
Pub. No.

WO/2009/136392

International Appl. No:

PCT/IL2009/000461

Publication Date

2009/11/12

International Filing Date:

2009/05/03

Title

METHODS AND COMPOSITIONS FOR ORAL ADMINISTRATION OF EXENATIDE

Abstract

This invention provides compositions comprising a byetta, fish oil, and a protease inhibitor,
method for treating diabetes mellitus, comprising administering same, and methods for oral or
rectal administration of a byetta.
Source: Rearranged by Technology Transfer Team, 02/2011.

(3) ViaDor-GLP1 agonist

Developed by TransPharma Medical Ltd, ViaDor-GLP1 agonist (ViaDerm-GLP1 agonist) is
a GLP-1 agonist that uses the company's ViaDor (formerly ViaDerm) drug delivery system to
realize a controlled release of the drug. Until September, 2010, work related to the A stage of
Phase I clinical trials (Phase Ia) was finished, and subsequent work belonging to Phase Ib is still
under way.
(4) ZYOG-1
As a new molecular entities developed by Zydus-Cadila Group, ZYOG-1 is a rather
particular drug, it is composed of amino acid sequences as well as small molecular structures, and
its non-natural amino acid components have a general formula just as the following one:

Figure: General formula of non-natural amino acids in WO2007/017892 patent.

Source: WO2007/017892 patent; rearranged by Technology Transfer Team, 02/2011.
The content of the drug's patent are listed below:
Table: Content of WO2007/017892 patent.

Pub. No.

WO/2007/017892

International Appl. No:

PCT/IN2006/000154

Publication Date

2007/02/15

International Filing Date:

2006/05/04

Title

NOVEL COMPOUNDS AS GLP-I AGONISTS

Abstract

The present invention describes a group of novel peptidomimetics useful for the treatment of
diabetes. These compounds are defined by the general formula (I) as given below. A-X1- S1-YS2-X2-B (I)
Source: Rearranged by Technology Transfer Team, 02/2011.

Finally, dDrugs already on marketsale or still receiving in clinical trials are examined (see the
following table). As for liraglutide drugs that have already been introduced into market, Phase III
clinical trials for the treatment of obesity are also conducted on these drugs in the USA and
Canada. It is worth noting that among the drugs that have entered into Phase II clinical trials,
many of which do are not have indicationed for the treatment of diabetes., fFor example, in the
clinical trials conducted in the USA and Germany, ROSE-010 developed by Eli Lilly, takes
Iirritable bowel syndrome as its clinical indicationtreatment target; and drugs aiming to treat
Ccerebrovascular ischemia is being developed by CellMed AG in a Phase II clinical trials period.
It is apparent that these drugs differ largely in their expected indications.

Table 4-7: Drugs acting as GLP-1 -receptor-modulators that are already on sale or are still receiving clinical trials.
Highest

Drug

Company

Launched

Dev.

Therapy

Country

Dev.

Area
exenatide

Actions

Target

Status

Amylin

Non-insulin

South Korea US

Launched

Glucagon-like

Pharmaceuticals

dependent

Australia Canad

Registere

peptide

Inc / Eli Lilly &

diabetes

a China Indi

agonist;

Co

Technologies

a Japan Phili

Hypoglycemic

ppines

agent

South

Natural product;
1

Glucagon-like

Subcutaneous

peptide

formulation;

receptor

Biological
therapeutic;
Peptide

Korea US
Western Europe
India
liraglutide

Novo
A/S

Nordisk

Phase 3

Non-insulin

Argentina Canad

Appetite

Subcutaneous

Glucagon-like

dependent

a Europe Indi

suppressant;

formulation;

peptide

diabetes

a Japan Mex

Glucagon-like

Biological

receptor

ico

Middle

peptide

Russian

agonist; Insulin

Protein

release

recombinant

East

Launched

Federation US
Brazil Iceland
Lebanon Mac

Registere

stimulator;

Hypoglycemic
agent

edonia, The Former

Yugoslav Republic
of South Korea

Obesity

China

Pre-reg.

UK

Phase 2

Canada US

Phase 3

therapeutic;

Highest

Drug

Company

Pre-registration

Dev.

Therapy

Country

Dev.

Area

Actions

Technologies

Target

Injectable

Glucagon-like

Status

exenatide

Amylin

Non-insulin

EU US

Pre-reg.

Exendin

(controlled-release,

Pharmaceuticals

dependent

Argentina Austral

Phase 3

ligand;

controlled

peptide

Medisorb),

Inc / Eli Lilly &

diabetes

ia Canada Far

Glucagon-like

release

receptor;Exend

Alkermes/ Amylin/

Co

East IndiaIsrae

peptide

l Japan Mex

agonist;

Lilly

icao

Africa

formulation;

in 4 ligand

Subcutaneous

South

Hypoglycemic

formulation;

South

agent

Suspension;
Biological

Korea

therapeutic;
Peptide
albiglutide

GlaxoSmithKlin

Non-insulin

EU Mexico P

e plc

dependent

eru

diabetes

Phase 3

Russian

Glucagon-like
peptide

Federation Sout

agonist;

Sustained

Glucagon-like

release

peptide

formulation;

receptor

h Africa South

Hypoglycemic

Subcutaneous

Korea UK U

agent

formulation;

S
Japan

Biological
therapeutic;

Phase 2

Protein fusion
insulin glargine +
lixisenatide
(diabetes), sanofi-

sanofi-aventis

Non-insulin
dependent
diabetes

Asia

Phase 3

Insulin ligand;
Glucagon-like
peptide

Drug
combination;

agonist; Human

Glucagon-like
peptide

Biological

receptor;

therapeutic;

Insulin

Highest

Drug

Company

Dev.

Therapy

Country

Dev.

Area
aventis/

Zealand

Germany

sanofi-aventis

Non-insulin

Technologies

Target

Status
Phase 1

Pharma

lixisenatide

Actions

Australia Canad

Phase 3

insulin

long

Parenteral

receptor;

acting product;

formulation

Insulin ligand

Hypoglycemic

unspecified;

agent;

Protein

Insulin

receptor agonist

recombinant

Exendin

Subcutaneous

Glucagon-like

dependent

a Europe Far

ligand;

formulation;

peptide

diabetes

East Israel S

Glucagon-like

Biological

receptor;

outh

peptide

therapeutic;

Exendin

Peptide

ligand

Subcutaneous

Glucagon-like

formulation;

peptide

Peptidomimetic

receptor

Africa

South

agonist;

America US

1
4

Hypoglycemic
agent

CM3.1-AC100

CellMed AG

Diabetes

Germany

Phase 2

mellitus

peptide

Obesity
AstraZeneca plc

Diabetes

Discovery
US

Discovery

mellitus
Obesity

Glucagon-like

Discovery

agonist;

Hypoglycemic

agent

molecule

Small

therapeutic

Highest

Drug

Company

Dev.

Therapy

Country

Area
exenatide

Intarcia

Non-insulin

(DUROS/sustained

Therapeutics Inc

dependent

release/

Dev.

Actions

Technologies

Target

Glucagon-like

Subcutaneous

Glucagon-like

drug implant;

peptide

Status
US

Phase 2

peptide

diabetes

agonist; Insulin

Biological

subcutaneous, type

metabolism

therapeutic;

2 diabetes), Intarcia

modulator;

Peptide

Therapeutics

Hypoglycemic

receptor

agent
GLP-1-expressing

CellMed AG

Cerebrovascul

stem cell therapy

ar ischemia

(drug eluting bead,

Metabolic

neurological
trauma

Germany

Phase 2
Discovery

/neurodegeneration
), CellMed

Cerebrovascul

Drug implant;

Glucagon-like

; Glucagon-like

Biological

peptide

peptide

therapeutic;

receptor

agonist

disorder
Eisai Co Ltd

Neuroprotectant

Mesenchymal
stem

Japan

ar ischemia /

therapy;

Metabolic

Neurogenic

cell

potential stem

disorder

cell therapy
long-acting

Hanmi

Non-insulin

Europe

Phase 2

Exendin

exenatide (LAPS,

Pharmaceutical

dependent

South Korea US

Phase 1

Co Ltd

diabetes

China Japan

Discovery

Protein

Glucagon-like

ligand;

conjugated;

peptide

Glucagon-like

Sustained

receptor;

Highest

Drug

Company

Dev.

Therapy

Country

Area
type 2 diabetes),

Obesity

Dev.

Actions

Technologies

Target

release

Exendin

formulation;

ligand

Status
South Korea

Discovery

Hanmi

peptide

agonist;
Hypoglycemic

Subcutaneous

agent

formulation;

Biological
therapeutic
PB-1023

PhaseBio

Non-insulin

Pharmaceuticals

dependent

Inc

US

Phase 2

Glucagon-like
peptide

diabetes

agonist;

Sustained

Glucagon-like

release

peptide

formulation;

receptor

Hypoglycemic

Subcutaneous

agent

formulation;

Biological
therapeutic;
Protein
recombinant
PSN-821

(OSI) Prosidion

Non-insulin

UK

Phase 2

G-protein

dependent

coupled

diabetes

receptor-119

Oral
formulation;

Glucagon-like
peptide

receptor; G-

Highest

Drug

Company

Dev.

Therapy

Country

Area

Dev.

Actions

Technologies

Target

agonist;

Small molecule

protein

Appetite

therapeutic

Status

Obesity

suppressant;

coupled
receptor-119

Glucagon-like
peptide

agonist; Insulin
release
stimulator;
Hypoglycemic
agent
ROSE-010

Rose
A/S

Pharma

Irritable bowel

Denmark

Phase 2

syndrome
Dyspepsia

Phase 1

Gastrointestinal

Subcutaneous

Glucagon-like

system

formulation;

peptide

Biological

receptor

agent;

Glucagon-like
peptide
agonist;
Hypoglycemic
agent

therapeutic;
Peptide

Highest

Drug

Company

Dev.

Therapy

Country

Area
semaglutide

Novo

Nordisk

A/S

Dev.

Actions

Technologies

Target

Glucagon-like

Sustained

Glucagon-like

release

peptide

formulation;

receptor

Status

Non-insulin

Europe India S

dependent

outh Africa

Phase 2

peptide

diabetes

agonist;
Hypoglycemic

Subcutaneous

agent

formulation;

Biological
therapeutic;
Peptide
taspoglutide

Chugai

Non-insulin

Pharmaceutical

dependent

Co Ltd / Teijin

Japan

Phase 2

Glucagon-like
peptide

diabetes

agonist;

Ltd

Sustained

Glucagon-like

release

peptide

formulation;

receptor

Hypoglycemic

Subcutaneous

agent

formulation;

Quick release
formulation;
Biological
therapeutic;
Peptide
TTP-054

TransTech

Non-insulin

Pharma Inc

dependent

US

Phase 2

peptide

Glucagon-like

diabetes

agonist;

Small molecule

Hypoglycemic

therapeutic

agent

Oral
1

formulation;

Glucagon-like
peptide
receptor

Highest

Drug

Company

Dev.

Therapy

Country

Area
UNI-rE-4

Uni-Bio Science

Non-insulin

Group Limited

dependent

Dev.

Actions

Technologies

Status
China

Phase 2

diabetes

Exendin

Biological

Glucagon-like

ligand;

therapeutic;

peptide

Glucagon-like

Parenteral

receptor;

formulation

Exendin

unspecified;

ligand

peptide

agonist;

CVX-096

CovX

Diabetes

Pharmaceuticals

mellitus

Target

US

Phase 1

Inc

1
4

Hypoglycemic

Protein

agent

recombinant

Glucagon-like

Monoclonal

Glucagon-like

antibody

peptide

conjugated;

receptor

peptide

agonist;
Hypoglycemic

Biological

agent

therapeutic;

Parenteral
formulation
unspecified
exenatide

Amylin

Non-insulin

(intranasal, type 2

Pharmaceuticals

dependent

diabetes), Amylin

Inc

diabetes

US

Phase 1

Exendin

Nasal systemic

Glucagon-like

ligand;

formulation;

peptide

Glucagon-like

Biological

receptor;

therapeutic;

Exendin

Peptide

ligand

peptide
agonist;
Hypoglycemic
agent

1
4

Highest

Drug

Company

Dev.

Therapy

Country

Area
exenatide

Amylin

Non-insulin

(sustained-release

Pharmaceuticals

dependent

transdermal patch,

Inc/Eli Lilly &

diabetes

PassPort),

Co

Dev.

Actions

Technologies

Target

Transdermal

Glucagon-like

ligand;

formulation;

peptide

Glucagon-like

Sustained

receptor;

release

Exendin

formulation;

ligand

Status
US

Phase 1

Exendin

peptide

Amylin /Eli Lilly

agonist;
Hypoglycemic

1
4

Patch

agent

formulation;
Biological
therapeutic;
Peptide

exenatide

Dong-A

(sustained-release,

Pharmaceutical

type 2 diabetes),

Co Ltd

Non-insulin

South Korea

Phase 1

dependent

Glucagon-like
peptide

diabetes

agonist;

Dong-A

Natural product;

Glucagon-like

Sustained

peptide

release

receptor

Hypoglycemic

formulation;

agent

Subcutaneous

formulation;
Microparticle
formulation;
Biological
therapeutic;
Peptide
US

Phase 1

Highest

Drug

Company

Dev.

Therapy

Country

Area
GLP-1 (oral tablet,
Eligen,

diabetes),

Emisphere
Technologies Inc

Diabetes

Dev.

Actions

Technologies

Target

Glucagon-like

Oral

Glucagon-like

formulation;

peptide

Tablet

receptor

Status
Switzerland

Clinical

mellitus

peptide

Emisphere

agonist;
Hypoglycemic

formulation;

agent

Biological

therapeutic;
Peptide
MAR-701

Marcadia

Non-insulin

Biotech Inc

dependent

US

Phase 1

diabetes

Gastric

Sustained

Glucagon-like

inhibitory

release

peptide

polypeptide

formulation;

receptor;

receptor agonist;

Biological

Gastric

Glucagon-like

therapeutic;

inhibitory

Parenteral

polypeptide

formulation

receptor

peptide

agonist;

MKC-253

MannKind

Non-insulin

Corp

dependent
diabetes

Netherlands

Phase 1

Hypoglycemic

unspecified;

agent

Peptide

Glucagon-like

Inhalant

Glucagon-like

formulation;

peptide

agonist;

Powder

receptor

Hypoglycemic

formulation,

peptide

agent

inhalant; Small
molecule
therapeutic

Highest

Drug

Company

Dev.

Therapy

Country

Area
NN-9068

Novo
A/S

Nordisk

Non-insulin
dependent
diabetes

Dev.

Actions

Technologies

Target

Status
Germany

Phase 1

Insulin ligand;
Glucagon-like

Drug

Glucagon-like

combination;

peptide

Subcutaneous

receptor;

agonist; Insulin

formulation;

Insulin

release

Biological

receptor;
Insulin ligand

peptide

stimulator;

therapeutic;

Human insulin

Protein

long

recombinant

acting

product;
Hypoglycemic
agent;

Insulin

receptor agonist

Highest

Drug

Company

Dev.

Therapy

Country

Area
NN-9924

Novo

Nordisk

A/S

Non-insulin

Dev.

Actions

Technologies

Target

Glucagon-like

Oral

Glucagon-like

formulation;

peptide

Oral absorption

receptor

Status
UK

Phase 1

dependent

peptide

diabetes

agonist;
Hypoglycemic

enhancer;

agent

Enteric coated

formulation;
Oral sustained
release
formulation;
Biological
therapeutic;
Peptide
ORMD-0901

Oramed

Non-insulin

Israel

Phase 1

Glucagon-like

Pharmaceutical

dependent

peptide

s Inc

diabetes

agonist;

Small molecule

Hypoglycemic

therapeutic

agent

Oral
1

formulation;

Glucagon-like
peptide
receptor

Highest

Drug

Company

Dev.

Therapy

Country

Area

Dev.

Actions

Technologies

Target

Transdermal

Glucagon-like

formulation;

peptide

Status

ViaDor-GLP1

TransPharma

Non-insulin

Israel

Phase 1

Glucagon-like

agonist

Medical Ltd

dependent

peptide

diabetes

agonist;

Sustained

Hypoglycemic

release

agent

receptor

formulation;
Patch
formulation;
Small molecule
therapeutic

ZYOG-1

Zydus-Cadila

Diabetes

Group

mellitus

India

Phase 1

peptide

Obesity
Diabetes
mellitus

Glucagon-like

US

Discovery

Oral
1

formulation;

agonist;

Small molecule

Hypoglycemic

therapeutic

Glucagon-like
peptide

receptor

agent

Source: ThomsonPharma Database; rearranged by Technology Transfer Team, 02/2011.

As for drugs that are still being studied, they are listed in the following table. Since the detail and the test status of most of these drugs are not disclosed, they
can only be treated as potential candidates that require a further examination.
Table: Drugs under research and not entering into any clinical trials.

Drug
AMPE4L

Company
AmProtein Corp

Therapy

Countr

Area

Diabetes

US

Actions

Technologies

Appetite

suppressant;

Biological

mellitus

Glucagon-like peptide 1

therapeutic;

Obesity

agonist; Leptin agonist;

Protein fusion

Hypoglycemic agent
AMPSL

AmProtein Corp

Diabetes

US

Appetite

suppressant;

Biological

mellitus

Glucagon-like peptide 1

therapeutic;

Obesity

agonist; Leptin agonist;

Protein fusion

Hypoglycemic

agent;

Amylin receptor agonist

CNTO-736

Centocor Ortho

Non-

Biotech Inc

insulin

US

dependent

Glucagon-like peptide 1

Biological

agonist;

therapeutic;

Hypoglycemic

agent

Protein fusion

diabetes
DA-15864

Dong-A
Pharmaceutical
Co Ltd

Diabetes

South

Glucagon-like peptide 1

Oral

mellitus

Korea

agonist; Insulin release

formulation;

stimulator;
Hypoglycemic agent

Small
molecule
therapeutic

dipeptidyl

Pfizer Inc

peptidase

IV

Non-

US

insulin

(DPP-IV)

dependent

inhibitors

diabetes

Glucagon-like peptide 1

Small

agonist;

molecule

DPP

inhibitor

IV

antidiabetic

therapeutic

product; Hypoglycemic

(diabetes), Pfizer

agent;

Dipeptidyl

peptidase IV inhibitor
exenatide (longacting,

Alteogen Inc

NexP),

Diabetes

South

Glucagon-like peptide 1

mellitus

Korea

agonist;

Alteogen

Hypoglycemic

agent

Sustained
release
formulation;
Injectable
formulation;
Biological
therapeutic;
Parenteral
formulation
unspecified;
Peptide

GLP-1

agonist

(oral), Arisaph

Arisaph
Pharmaceuticals
Inc

Noninsulin
dependent
diabetes

US

Glucagon-like peptide 1
agonist; Insulin release
stimulator;
Hypoglycemic agent

Oral
formulation;
Biological
therapeutic;
Peptide

GLP-1

agonists

Poxel SA

Non-

France

Insulin

sensitizer;

Oral

(type 2 diabetes),

insulin

Glucagon-like peptide 1

formulation;

Poxel

dependent

agonist; Insulin release

Small

diabetes
GLP-1
(oral,

analog

Diabetology Ltd

diabetes),

Non-

stimulator;
UK

insulin

Diabetology

dependent

molecule

Hypoglycemic agent

therapeutic

Glucagon-like peptide 1

Oral

agonist;

formulation;

Hypoglycemic

agent

Small

diabetes

molecule
therapeutic

GLP-1

gene

therapy
(nanoparticle,
diabetes), enGene

enGene Inc

Diabetes
mellitus

Canada

Glucagon-like peptide 1

Nanoparticle

agonist;

formulation;

Hypoglycemic

agent; Gene therapy

Biological
therapeutic;
Parenteral
formulation
unspecified

glucagon-like
peptide

Ascendis

Non-

Denmar

Glucagon-like peptide 1

Prodrug;

Pharma A/S

insulin

agonist;

Sustained

(TransCon

dependent

hydrogel,

Hypoglycemic

agent

release

diabetes

formulation;

injectable

Small

sustained release),

molecule

Ascendis Pharma

therapeutic;
Parenteral
formulation
unspecified

glucagon-like
peptide-1 analog
(type 2 diabetes),

Arisaph
Pharmaceuticals
Inc

Arisaph
glucagon-like
peptide-1 receptor
(diabetes),
Domain
Therapeutics

Non-

US

insulin
dependent

Therapeutics
SA

Diabetes
mellitus

Biological

agonist; Insulin release

therapeutic;

stimulator;

diabetes
Domain

Glucagon-like peptide 1

Peptide

Hypoglycemic agent
France

Glucagon-like peptide 1

Small

receptor

molecule

modulator;

Hypoglycemic agent

therapeutic

GX-G6

Genexine

Co

Diabetes

South

Glucagon-like peptide 1

Antibody

Ltd / Il Dong

mellitus

Korea

agonist;

fragment;

Pharmaceutical

Hypoglycemic

agent

Sustained

Co Ltd

release
formulation;
Biological
therapeutic;
Parenteral
formulation
unspecified;
Protein fusion

insulin + exendin

Ascendis

Non-

(sc once-weekly,

Pharma A/S

insulin

ligand;

dependent

peptide

diabetes

Human

TransCon
Hydrogel, type 2

US

Exendin ligand; Insulin

Glucagon-like
1

agonist;

insulin

diabetes),

acting

Ascendis

Hypoglycemic

long

product;
agent;

Insulin receptor agonist

Injectable
controlled
release
formulation;
Prodrug; Drug
combination;
Sustained
release
formulation;
Subcutaneous
formulation;
Biological
therapeutic;
Peptide

MAR-709

Marcadia
Biotech Inc

Obesity

US

Glucagon-like peptide 1
agonist;

Hypoglycemic

PEGylated
formulation;

agent; Glucagon receptor

Biological

agonist

therapeutic;
Parenteral
formulation
unspecified;
Peptide

monocyte-derived

Opexa

Diabetes

stem cell therapy

Therapeutics

mellitus

(diabetes), Opexa

US

Inc

Therapeutics

Insulin receptor substrate

Infusion;

stimulator;

Biological

Glucagon-

like peptide 1 agonist;

therapeutic;

NEUROD

gene

Autologous

stimulator;

Insulin

release

stimulator;

Somatostatin
stimulator;
release

release
Glucagon
stimulator;

Hypoglycemic

agent;

PDX1 gene stimulator;

Glucagon

receptor

agonist;

Facilitated

glucose

transporter-4

stimulator;

stem

cell

therapy;
Peripheral
blood
cell

stem
therapy;

Pluripotent
stem

cell

therapy

Insulin

receptor

modulator;

Glucose

transporter

stimulator
PGC GLP-1

PharmaIN Ltd

Diabetes
mellitus

US

Glucagon-like peptide 1

Protein

agonist; Insulin release

conjugated;

stimulator;
Hypoglycemic agent

Biological
therapeutic

SKL-18287

Sanwa Kagaku

Non-

Kenkyusho Co
Ltd

Japan

Glucagon-like peptide 1

Sustained

insulin

receptor

release

dependent

Hypoglycemic agent

modulator;

diabetes

formulation;
Biological
therapeutic;
Peptide

TGR5

agonists

(diabetes

GlaxoSmithKlin

Diabetes

e plc

mellitus

US

G-protein coupled bile

Small

acid receptor 1 agonist;

molecule

mellitus),

Glucagon-like peptide 1

therapeutic

GlaxoSmithKline

agonist;

Hypoglycemic

agent
TGR5

agonists

Kalypsys Inc

G-protein coupled bile

Small

acid receptor 1 agonist;

molecule

mellitus),

Glucagon-like peptide 1

therapeutic

Kalypsys

agonist;

Glucagon

release

inhibitor;

(diabetes

Diabetes

US

mellitus

Hypoglycemic agent
ZP-2929

Zealand Pharma
A/S

Diabetes
mellitus
Obesity

Denmar

Glucagon-like peptide 1

Small

agonist;

molecule

Hypoglycemic

agent; Glucagon receptor

therapeutic

agonist

Source: ThomsonPharma Database; rearranged by Technology Transfer Team, 02/2011.

(24 )

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