Annexes to Chapter 6.4: Diabetes
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper for Review
Annexes
to
Diabetes
By Warren Kaplan
17 August 2004
Please send comments to:
Dr Warren Kaplan:
Dr Richard Laing: [email protected]
6.4-1
Annexes to Chapter 6.4: Diabetes
Table of Contents
Table 1:
Annex A:
Figure 1:
Figure 2:
Figure 3:
Table 2:
Table 3:
Endnotes
US Clinical Trials for Diabetes Pharmacological Interventions
(as of Q1 2004) ............................................................................................................. 3
Brief Summary of Diabetes Drugs in Development .............................................. 6
Funding Appropriations for Selected NIH Institutes ............................................ 7
Funding Appropriations for the National Institute of Diabetes
and Digestive and Kidney Diseases ......................................................................... 7
Expenditures of the Medical Research Council (UK) ............................................ 8
EU Awards and Grants for Diabetes-Related Research ........................................ 9
Fifth Framework 1998-2002: Quality of Life (RTD Activities)** ......................... 11
..................................................................................................................................... 12
6.4-2
Annexes to Chapter 6.4: Diabetes
Table 1: US Clinical Trials for Diabetes Pharmacological Interventions
(as of Q1 2004)
CONDITION SPONSOR
Phase
Treatment
NOTES
Synthetic
insulin
Type I
NIAID
1
IBC VS01 a
Type 1
GMP
Endotherapeutics
1
INGAP peptideb
Type 1
NIDDK
1
Islet transplantation
Type 1
NIDDK
1
AC2993
Type 2
Type 1
NCCAM
NIDDK
1
1
Type 2
NCRR
1
Ginko biloba
hOKT3g1
modified glucagon like
peptide (GLP-1)c
Type 1
NIDDK
2
Oral IFN alpha
Type 1
2
AVE0277
2
2
pramlintide acetate
Vedic medicines
Type 2
Type 1
Type 2
Type 2
Type 2
Aventis
Amylin
Pharmaceuticals
NCCAM
Amylin
Pharmaceuticals
Proctor & Gamble
Eli Lilly
Proctor & Gamble
NCCAM
2
2
2
2
2
Type 1
Type 1
Type 1
NIDDK
NCCAM
NIDDK
2
2
2
Type 1
NIDDK
2
AC2993
INGAP peptide b
unknown
INGAP peptide b
Vitamin C intraarterial
Islet transplant w/o
steroids
Soy protein
Islet cells
Islet cell + bone marrow
transplant
Type 2
Type 1
Type 1
Type 1
NIDDK
NCRR
Eli Lilly
NIAID
2
2
2
2
Quercetin
Ingested IFN alpha
Powdered insulin
Islet transplantation
Type 2
Hoffmann La Roche
2
Ro 205-2349
Type 2
Fujisawa Healthcare
2
FK614
Type I
Novo Nordisk
3
Aspart v. Lispro v.
Regular Insulin
Type I
Type 2
Massachusetts
US 4 sites
US 1 site
w/w/o
immunosupression US 1 site
effects
on
blood
glucose
US 1 site
US 1 site
US 1 site
US Texas, MN
and MD
synthetic
peptide?
d
e
6.4-3
Trial Sites
synthetic
exendin
US 5 sites
US
4
sitesbioavailability
US 1 site
US multiple sitesdose response
US multiple sites
US multiple sites
US multiple sites
US 1 site
US 1 site
US 1 site
US 1 site
US 1 site
natural
product
rIFN alpha
no steroids
S/E study
US 1 site
US I site
US multisite
US 1 site
US, Canada, and
overseas
US multiple sites
USbioequivalence
study
Annexes to Chapter 6.4: Diabetes
CONDITION SPONSOR
Type I
Type 2
Gestational
Diabetes
Phase
Treatment
NOTES
NIDDK and others
BMS
3
3
Insulin dosages
Metformin/glyburide
3
Insulin aspart
3
AC2993 + sulfonylurea
Type 1
Novo Nordisk
Amylin
Pharmaceuticals
Aventis
Pharmaceuticals
3
Insulin glulisine
Type 2
Amylin
3
AC2993
Type 1
Amylin
3
Type 2
US multiple sites
glucose
pumps
glucose
control
glycemic
control
Type 2
Aventis
3
Pramlintide acetate
glimepiride
metformin + TZD
Type 2
?
3
rosiglitazone
Type 2
?
3
"Avandamet"
Type 2
Eli Lilly
4
Type 1
Aventis
4
Lispro v. comparator
Insulin glargine v.
humulins,Lispro
Trial Sites
DPT-1 Trial US
and Canada
US multiple sites
US 1 site- safety
and efficacy
France 1 site
US multisite
US multisite
+
US 1 site
w/w/o
insulin
US multsite
w/w/o
France, Germany,
insulin
Italy, Spain, UK
twice v. once
a day
US mulicenter
US
Notes:
a. Chemical structure unknown
b. Researchers have cloned a gene that appears to treat the underlying causes of both type 1
(juvenile onset) and type 2 (adult onset) diabetes. The gene codes for a pancreatic protein called
INGAP, for islet neogenesis associated protein. INGAP is a protein that's responsible for the
formation of new insulin-producing beta-cells and holds great promise for the regulation of
glucose levels in diabetics. The treatment under development involves the injection of a small
fragment of native INGAP, called INGAP peptide. Procter & Gamble is commercializing this
product.
c. Glucagon like peptide (GLP-I) has a number of actions that make it unusually attractive as a
therapeutic agent in the treatment of Type 2 diabetes: It potentiates glucose-induced insulin
secretion, but has no effect on unstimulated insulin secretion, which means that, unlike for
example sulphonylureas, it cannot cause hypoglycaemia; It stimulates all steps of insulin
biosynthesis; and it decreases hepatic glucose production 1, 2 The main problem in trying to turn
GLP-I into a clinically useful therapeutic agent is its rapid breakdown In humans as well as in
experimental animals since the peptide is immediately attacked by an enzyme which inactivates
it. 3 Several companies are working on GLP-1 agonists to improve the biological activity of
natural GLP-1.
6.4-4
Annexes to Chapter 6.4: Diabetes
d. SYMLIN® is Amylin’s pramlintide acetate. In late 2003, Amylin we received a second
approvable letter from the FDA indicating that SYMLIN is approvable for marketing in the
United States as an adjunctive therapy with insulin, provided that Amylin prove to the FDA
that they can identify a patient population and method of use where the side effects of SYMLIN
(hypoglycemia) are counterbalanced by added drug benefit.
e. Exendin-4 is a peptide isolated from reptile venom and it is 53% homologous to GLP-I. A
single amino acid substitution results in almost complete resistance to enzymatic degradation. 102
Exendin-4 has effects on blood glucose and glycated haemoglobin levels as well as on body
weight 4. Amylin and Eli Lilly are developing a synthetic exendin-4 called Exenatide tm.
Amylin Pharmaceuticals and Alkermes, Inc. a developing an injectable sustained release
formulation of Exenatide.
6.4-5
Annexes to Chapter 6.4: Diabetes
Annex A: Brief Summary of Diabetes Drugs in Development
Metabolex: This company has a lead clinical compound, MBX-102, which is an oral, smallmolecule insulin sensitizer. It is a re-worked form of a compound, Halofenate, tested clinically as a
lipid-lowering agent in the 1970's, but never commercialized. Halofenate is comprised of two
components that are mirror images (enantiomers or isomers) of each other. MBX-102 is a
proprietary, isomerically pure version of Halofenate.
Peptor, Ltd. Israeli scientists at the Weizmann Institute are injecting mice with a small peptide
fragment of a larger antigenic protein. This fragment preventing the progression of Type I
diabetes in animal models. Peptor Ltd. Is an Israeli based company that purchased the rights
from Weizmann and has turned the fragment into a drug called DiaPep277. Peptor is planning
to present a New Drug Application to the US Food and Drug Administration in 2004. Phase II
trials are finished and Phase III trials are to begin in various centers around the world next year.
GlaxoSmithKline: GlaxoSmithKline is extending the Avandia tm product line by launching a
fixed-dose combination treatment called Avandaryl which is a combination of Avandia tm and
Aventis’ Amaryl, a market leading sulphonylurea. i
Merck. The company is studying a glucose-lowering compound for the treatment of Type II
diabetes. Merck plans to enter Phase III clinical trials with this investigational compound in the
second quarter of 2004 and expects to submit an NDA to the FDA in 2006.
Novo Nordisk: Insulin detemir (Levemir™) is a soluble basal insulin analogue with a duration
of at least 20h. In the fourth quarter of 2003 Novo Nordisk received an Approvable Letter from
the US Food and Drug Administration. Novo Nordisk expects an approval of insulin detemir by
mid-2005 in the US. The European regulatory process for Levemir™ (insulin detemir) is
proceeding.
Pfizer Advanced-stage clinical studies are continuing for Exubera tm, an inhalable form of
insulin for Type 1 and Type 2 diabetes under co-development, co-manufacture, and comarketing with Aventis Pharma (Aventis), with the participation of Nektar Therapeutics.
As an aside, this is another example of fixed dose combinations being created in which two companies agree to
combine their intellectual property. Such collaborations should not be lost on those who believe the IP barriers to
creating fixed dose combinations of patented antiretrovirals are more apparent than real.
i
6.4-6
Annexes to Chapter 6.4: Diabetes
Figure 1: Funding Appropriations for Selected NIH Institutes
Figure 2: Funding Appropriations for the National Institute of Diabetes
and Digestive and Kidney Diseases
1,400,000
1,200,000
NIDDK
Appropriations
($)
Appropriations
per Capita ($)
4.5
4.0
3.5
3.0
1,000,000
2.5
800,000
2.0
600,000
1.5
400,000
1.0
200,000
0.5
0
0.0
1 5 9 13 17 21 25 29 33 37 41 45 49
Year (1= 1948)
6.4-7
Per capita appropriation ($)
Appropriation (Thousands $)
1,600,000
Annexes to Chapter 6.4: Diabetes
Figure 3: Expenditures of the Medical Research Council (UK)
9.0
Expenditures (M$)
8.0
2500
7.0
2000
6.0
5.0
1500
4.0
1000
500
3.0
MRC Expenditures
2.0
(million $)
Per capita ($)
1.0
0
0.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Year (1=1986)
6.4-8
Expenditures per capita
($)
3000
Annexes to Chapter 6.4: Diabetes
Table 2: EU Awards and Grants for Diabetes-Related Research
Award(s)
Funding
EFSD/MSD
Travel
Fellowships for Young Up to € 6,000 (approximately £3,600)
Scientists
Duration
< 6 months
EFSD/Servier Type 2 Three grants, each of €100,000 (approx
Single
Grants on Vascular £60,000), payable in one year in one
Payment
Complications
instalment.
Closing
Date
Apply
Anytime
01
February
2005
Up to€ 2.1 million (£1.45 million) will be
Nordisk
made available over three years:
Support
2004 - 7 grants each of €100,000 (approx Single
for
£69,000)
Payment
Diabetes
2005 - up to 7 grants, each of €100,000
2006 - up to 7 grants, each of €100,000
01
December
2004
Up to €900,000 will be made available, over
three years, for Focused Research Grants.
Research will be performed in Europe and
EFSD/Lilly
European its associated countries. The grants will be Single
Diabetes Research Fund distributed as follows: 2003 - 3 grants, each Payment
of
€100,000
(approx
£69,000)
2004 - 3 grants, each of €100,000
2005 - 3 grants, each of €100,000
15
September
2004
EFSD / Pfizer Resource
Awards for European € 200,000 (approx £140,000).
Diabetes Research
03
2004
EFSD/Novo
Continuing
Programme
European
Research
Unspecified
Up to €2.25 million will be made available,
over three years, for Focused Research
Grants. Research will be performed in
EFSD/JDRF/Novo
Europe and its associated countries. The
Nordisk
European
Single
grants will be distributed as follows:
Programme in Type 1
Payment
2004 - Up to 8 grants, each of €100,000
Diabetes
(approx
£69,000)
2005 - Up to 8 grants, each of €100,000
2006 - Up to 8 grants, each of €100,000.
May
05
April
2004
Up to €60,000 (approximately £36,000) per
annum for salary (according to local salary
scale). A research allowance of €20,000
(approximately £12,000) will be made
Albert Renold Career
1 year - 3 February available to the host laboratory to cover
Development Award
years
2005
costs of supplies. In addition, travel
expenses
not
to
exceed
€3,000
(approximately £1,800) will be provided for
the candidate and his/her family.
One fellowship will be awarded annually
EFSD/Eli Lilly Research
in the sum of $50,000 (approx £34,000), the Single
Fellowship in Diabetes
money awarded will be paid into the Payment
and Metabolism
account of the host institution.
February 2005
EFSD/Eli Lilly Research One fellowship will be annually in the sum Single
February -
6.4-9
Annexes to Chapter 6.4: Diabetes
Award(s)
Funding
Duration
Fellowship in Diabetes of €50,000 (approx £34,000). The money will Payment
Microvascular
be paid into the account of the host
Complications
institution.
Research will be supported through the
award of fixed sum grants, each of €100,000
(approx £69,000). The duration of each
EFSD/Johnson
& award may be one year or longer, Single
Johnson Type 2 Grants depending upon the needs of the project Payment
and as justified in the application, so long
as the total budget does not exceed the
fixed sum of € 100,000.
6.4-10
Closing
Date
2005
February 2005
Annexes to Chapter 6.4: Diabetes
Table 3: Fifth Framework 1998-2002: Quality of Life (RTD Activities)**
SUBJECT
Proposed Outcome
Blood monocyte as biomarker New tools to predict Type 1 diabetes to
for Type 1
serve as a basis for potential therapies
Phenotypes and genes linked
to insulin resistance and risk Identify Type 2 specific gene markers
for Type 2 diabetes
and function
Genes involved in pancreas
development
New diagnostic tools or new therapies
Genetics of multifactorial
conditions using Type 2
Improving genomic approaches to
diabetes as a model
“complex traits”
Identification of genes
involved in diabetes
complications
Novel therapies and targets
Molecular biology of secretion General strategies to grow beta cells
in pancreatic beta cells
and influence their function
Molecular biology of AMPactivated protein kinase
New therapeutic regimes to modulate
system in cells
the key cellular “metabolic switch”
Heat shock protein as a
Mechanisms of immune response in
therapeutic target
diabetes
Biology of vascular adhesion
protein-1 as an amine oxidase Novel therapeutics and diagnostics
enzyme
based on novel enzymes
Optical methods for
Optimize novel non-invasive optical
monitoring diseases
methods for clinical use
Insulin sensitivity and CVD
risk
Prevention and treatment strategies
Epidemiology and biology of
LADA in Europe
Therapy using heat shock
protein DiaPep277
Clinical trials
Creating a healthcare
organization for diabetic foot
care
"Best evidence" practice
Total funding per year
Average funding per year
** Research and Technological
Development Activities of a
Generic Nature
6.4-11
Years
Euros/Year Funding
289140
3
773986
4
539284
4
1082730
3
613534
3
432538
3
603491
3
433297
3
388495
4
365247
3
544072
4
566054
3
138297
6770165
520782
4
Annexes to Chapter 6.4: Diabetes
Endnotes
Fehmann HC, Habener JF. 1992. Insulinotropic hormone glucagon-like peptide-I(7–37) stimulation
of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells.
Endocrinology 130: 159–66.
1
Hvidberg A, Nielsen MT, Hilsted J et al. 1994. Effect of glucagon-like peptide-1 (proglucagon 78–
107amide) on hepatic glucose production in healthy man. Metabolism 43: 104–8.
2
Xu G, Stoffers DA, Habener JF, Bonner-Weir S. 1999. Exendin-4 stimulates both ß-cell replication
and neogenesis, resulting in increased ß-cell mass and improved glucose tolerance in diabetic rats.
Diabetes 48: 2270–6.
3
Agersø H, Jensen LB, Elbrønd B, Rolan P, Zdravkovic M., 2002. The pharmacokinetics,
pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy
men. Diabetologia, 45: 192-202.
4
6.4-12