Download A Survey of Commercial Product Development

A Survey of Commercial Product Development
in T1DM: Reports from along the commercial roads to
treatments and cure
Randy L. Anderson, Ph.D., VP, Global Product Development (Metabolics)
Presentation at JDRF Research Summit, Washington, DC, 9 March 2013
JDRF Pedigree
1963
T1DM
Diagnosis
at age 6
1983–
1989
PhD,
Biostatistics;
diabetes
consulting
1979
Diabetes
management
independent
study
2
1994
Pharmaceuticals
development
1990
Began work
as diabetes
clinical
trialist
1999
2001
First local
JDRF Walk
to Cure
Diabetes
Firstborn
son T1DM
diagnosis;
first JDRF
work
2003–
2006
JDRF
Medical
Sci Review
Cmte;
>45 reviews
2001–
2007
NIH/JDRF
Immune
Tolerance
Network
via PPD
2006–
Now
JDRF ad hoc
proposals
reviewer;
>12 reviews
2004
First local
JDRF Hope
Gala
2003
Head
Metabolics
for PPD;
50-years
with T1DM
Technical or Biological Cure?
●
●
3
Technical innovations
−
Insulin pumps
−
Continuous glucose monitors
−
Artificial pancreas
Biological cure
−
Immune tolerance
−
Beta cell regeneration
Review: JDRF Triumvirate Cure Strategy
Immune
Tolerance
Induction
●
4
To stop
original causal
autoimmune
process
Beta Cell
Regeneration
●
To restore
functional beta
cell mass
Artificial
Pancreas
●
To bridge
gap between
treatment
initiation and
fully functional
beta cell mass
T1DM Products in Development
By Product Class
Count
Immunomodulator
Immunomodulator
Insulin analog,
analog, injected
injected
Insulin
Other or
or unspecified
unspecified
Other
Insulin analog,
analog, oral
oral
Insulin
cell regeneration
regeneration
ββ cell
SGLT1/SGLT2 inhibitor
inhibitor
SGLT1/SGLT2
cell, encapsulated
encapsulated
β βcells,
GLP-1 analog
analog
GLP-1
Total: 94
iInsulin analog,
analog, glucose
glucose responsive
responsive
iInsulin
Glucagon receptor
receptor agonist
agonist
Glucagon
Glucagon analog
analog
Glucagon
Insulin analog,
analog, inhaled
inhaled
Insulin
0
Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013
5
10
20
30
Immunomodulators (A Sampling)
6
Product/Sponsor
Ph
Status
Gevokizumab, Xoma052 (Xoma)
2
No improvement in BG, but big reduction
in CRP, LDL chol
α-1 antitrypsin (OmniBio,
Kamada)
2
Supresses beta cell apoptosis.
Ph 2 results 1H2013
beta cell-specific mTCRs fused
to cytokines IL-4 & IL-13
(Immunocore)
Pre
Clin
Naimit Consortium (natural
immunomodulators) partner; EU 7th
Framework Program funding
li key engenders antigen-specific
CD4+ T-helper cell stimulation
(Antigen Expr)
Pre
Clin
“robust, long lasting antigen-specific
immune response”
Diabetes vaccine
(Selecta Bioscience)
Pre
Clin
Targeted toleragenic antigen-specific
vaccine. JDRF industry partner
“
We have demonstrated in antea-diabetic mouse
model that lifelong recovery of β cells has a strong
correlation with normalization of the Treg cell population in
pancreatic lymph notes (PLNs). This finding offers new
opportunities for testing the immunomodulatory
regimens that promote accumulation of Treg cells in
PLNs as a therapeutic approach for type 1 diabetes (T1D).
7
”
Curative Hematopoietic Stem Cell Transplant
NOD mouse develops autoimmune diabetes spontaneously
●
NOD mouse undergoes immune system ablation
Experiment
●
Transplanted hematopoietic stem cells from NORMAL mouse
●
Transplanted islets placed under kidney capsule
temporarily to maintain normoglycemia
Results
●
New Tregs appear in pancreatic lymph nodes
3 Weeks
Later
●
New pancreatic islets appear spontaneously in recipient
mouse pancreas
●
NOD mouse has normal, permanent, functioning
autologous pancreatic islets
●
NOD mouse has NO islet autoimmunity
16 Weeks
Later
8
Immunomodulators
T1DM Viability Assessment
●
Essential for cure
−
Immune system complexity
lowers prospects
−
Near certain need for
combination therapies
−
●
Safety: Selective immune
tolerance is critical
Timing
Timing
Safety
Safety
Prevent
Prevent
Need to verify low cancer
risk, low infection risk
Treat
Treat
Best cure prospect appears
to be some stem cell
transplant
Cure
Cure
−
●
Long follow-up times
Potential
0
9
50
100
T1DM Products in Development
By Product Class
Count
Immunomodulator
Immunomodulator
Insulin analog,
analog, injected
injected
Insulin
Other or
or unspecified
unspecified
Other
Insulin analog,
analog, oral
oral
Insulin
β cell
cell
regeneration
ββ
cell
regeneration
regeneration
SGLT1/SGLT2 inhibitor
inhibitor
SGLT1/SGLT2
cell, encapsulated
encapsulated
β βcells,
GLP-1 analog
analog
GLP-1
Total: 94
iInsulin analog,
analog, glucose
glucose responsive
responsive
iInsulin
Glucagon receptor
receptor agonist
agonist
Glucagon
Glucagon analog
analog
Glucagon
Insulin analog,
analog, inhaled
inhaled
Insulin
0
Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013
10
10
20
30
Beta Cell Regeneration
11
Product/Sponsor
Ph
Status
Human proislet peptide
(CureDM/Sanofi)
1
Stabilized form of human proislet peptide
(analogous to INGAP). Ph 1 study
completed Nov2012
FT-201 (Fate Therapeutics)
Pre Clin
Rh protein stimulate islet neogenesis
EVT-770 (Evotec/AZ)
Pre Clin
β cell growth factor
NGM-282 (NGM Biopharm/
Daiichi Sankyo)
1
β cell regeneration modulators. JDRF
industry partner. SAD/MAD design on
clinicaltrials.gov 1Feb2013
Beta Cell Regeneration
T1DM Viability Assessment
●
●
●
Efficacy: Essential for cure
Potential
−
Immune tolerance
prerequsite
Timing
Timing
−
Concept verified in animal
and human T2DM implies
high likelihood of efficacy,
AFTER immune tolerance
Safety
Safety
Safety: Need to verify
low cancer risk
Timing: Moderate
regulatory hurdles
Prevent
Prevent
Treat
Treat
Cure
Cure
0
12
50
100
Roche Accu-Chec® Diaport
New York, 16 August 2011
“
...JDRF will provide funding to test two new devices
aimed at providing mechanical means to achieve faster
insulin action. The first will support Dr. Howard Zisser at the
University of California, Santa Barbara's Sansum Diabetes
Research Institute testing Roche Diabetes Care's Accu-Chek®
DiaPort system. The Accu-Chek DiaPort is a percutaneous
port system, connected with an external pump, that
delivers insulin directly to the liver, the primary site
of insulin action....
”
13
Technical or Biological Cure?
14
●
Dietary carbohydates absorbed
as glucose from small intestine
●
Pancreas circulation includes
glucose-enriched circulation
from small intestine
●
Pancreas releases insulin in
response to glucose-enriched
circulation
●
Pancreatic insulin and glucose
enriched blood flows to liver
through hepatic portal vein
●
Insulin release inhibits glucagon
release from α cells, which stops
liver release of stored glucose and
initiates liver storage of excess
glucose from gut
●
Both liver actions are critical
to stabilizing blood glucose
Optimizing Insulin Action:
Intraperitoneal Infusion vs. Subcutaneous Injection
Schade DS, et.al. Diabetologia, 1980; 19(1): 35-39
15
Roche Accu-Chec® Diaport
16
Roche Accu-Chec® Diaport®
Diaport provides more
appropriate timing of insulin,
delivered more
directly to liver
17
●
Stabilize blood glucose against
large post-meal spikes
●
Increase liver storage of
glucose (as glycogen)
●
Increased liver glycogen
storage reduces
hypoglycemia risk
Current Accu-Check Diaport® Studies
Phase
Protocol Title
Completion Date
Sample Size
2
Evaluation of Accu-Chek DiaPort,
a Port System for Continuous
Intraperitoneal Insulin Infusion,
in Patients With Type I Diabetes
Feb 2013
12
2
Closed Loop Artificial Pancreas
Using Intraperitoneal (IP) Insulin
Via DiaPort®
Dec 2013
10
Source: Clinicaltrials.gov, 5Mar2013
18
T1DM Products in Development
By Product Class
Count
Immunomodulator
Immunomodulator
Insulin analog,
analog, injected
injected
Insulin
Other or
or unspecified
unspecified
Other
Insulinanalog,
analog, oral
oral
Insulin
Insulin
analog,
oral
cell regeneration
regeneration
ββ cell
SGLT1/SGLT2 inhibitor
inhibitor
SGLT1/SGLT2
cell, encapsulated
encapsulated
β βcells,
GLP-1 analog
analog
GLP-1
Total: 94
iInsulin analog,
analog, glucose
glucose responsive
responsive
iInsulin
Glucagon receptor
receptor agonist
agonist
Glucagon
Glucagon analog
analog
Glucagon
Insulin analog,
analog, inhaled
inhaled
Insulin
0
Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013
19
10
20
30
Oral Insulins
20
Product/Sponsor
Ph
Status
Oshadi Drug Admin (Israel)
1-2
Methods/use patent granted 2012; trial
start Feb2013
Oramed (Israel)
2
IND filed 12Dec2012; trial start pending
IND approval
Capsulin, Diabetology (UK)
2
No activity in clinicaltrials.gov
Novo Nordisk (Denmark)
1
Oral basal insulin
Tamarisk (USA)
1
Nano-encapsulation preclinical white paper
Feb 2012
Ora-lyn®, Generex (Canada)
3
Registration trials results
expected Mar 2013
TrabiOral, Transgene
Biotech (India)
Preclin
Ongoing preclinical development
Potential of Oral Insulins
Positives
●
●
●
21
Suppresses postprandial
glucagon from pancreatic
alpha cells
Adequately insulinizes
liver for postprandial
glucose storage
–
Great protection against
post-meal highs
–
Much less susceptibility
to lows
No injection!
Negatives
●
●
Must prevent insulin
(protein) digestion
before absorption
Requires predictable insulin
activity after absorption
–
Uniformity of absorption?
–
Dosing accuracy?
Oral Insulins
T1DM Viability Assessment
●
●
●
Promising preclinical data
Need evidence of liver
insulinization
−
Moderated BG excursions
−
Lowered hypoglycemia risk
Potential
Timing
Timing
Safety
Safety
Moderate regulatory hurdles
Prevent
Prevent
Treat
Treat
Cure
Cure
0
22
50
100
T1DM Products in Development
By Product Class
Count
Immunomodulator
Immunomodulator
Insulin analog,
analog, injected
injected
Insulin
Other or
or unspecified
unspecified
Other
Insulin analog,
analog, oral
oral
Insulin
cell regeneration
regeneration
ββ cell
SGLT1/SGLT2inhibitor
inhibitor
SGLT1/SGLT2
SGLT1/SGLT2
inhibitor
cell, encapsulated
encapsulated
β βcells,
GLP-1 analog
analog
GLP-1
Total: 94
iInsulin analog,
analog, glucose
glucose responsive
responsive
iInsulin
Glucagon receptor
receptor agonist
agonist
Glucagon
Glucagon analog
analog
Glucagon
Insulin analog,
analog, inhaled
inhaled
Insulin
0
Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013
23
10
20
30
Sodium Glucose Cotransporter
(1&2) Inhibitors
●
SGLT1 predominant gut
glucose transporter
−
●
SGLT2 predominant kidney
glucose transporter
−
24
Inhibition reduces
postprandial BG spikes
Inhibition stops glucose
reabsorption from kidney
filtrate, leaving excess
in urine
SGLT1-2 Inhibitors
25
Product/Sponsor
Ph
Status
Canagliflozin (J&J)
3
(SGLT2 only) In T2DM, concerns about
increased CV risk; increased LDL
cholesterol, UTIs, fungal infections,
hypotension, hypoglycemia
Dapagliflozin (BMS/AZ)
3
(SGLT2 only) In T2DM, concerns about
bladder cancer; increased UTIs, fungal
infections, hypotension
Empagliflozin (BI/Lilly)
3
(SGLT2 only) In T2DM, increased UTIs,
fungal infections
LX4211 (Lexicon)
2
(Both) In T2DM, better HbA1c, lower
infection rates, better weight loss
Luseogliflozin (Taisho/Novartis)
2
(Both) In T2DM, better HbA1c, lower
infection rates, better weight loss
SGLTx Inhibitors
T1DM Viability Assessment
●
●
●
Efficacy: High likelihood in
T1DM based on Phase 3
studies in T2DM
Safety:
−
Need PK activity limited
to daytime hours
−
Need to verify
no hypoglycemia
exacerbation in T1DM
Timing: Low regulatory
hurdles implies short
development time
Potential
Timing
Timing
Safety
Safety
Prevent
Prevent
Treat
Treat
Cure
Cure
0
26
50
100
T1DM Perspectives 1923-2013
1923–1963
Glass syringe,
SS 16g needle,
beef/pork insulin,
Ames Clinitest®
tablets for urine
BG testing
1965
1970, 1971
JDRF founded;
Ames
photoreflectance
glucometer
BD plastic
disposable
syringes, 23g
needle; Ames
Dextrostix®
colorimetric BG
strips
27
1995, 1996
DPT-1 Study;
Lilly Humalog R
receives FDA
approval
1983
Lilly human insulin
of recombinant
DNA origin;
Minimed 502
insulin pump
2003, 2004
NIH/JDRF Trialnet
starts; <12
products in
development
2000, 2001
FDA approves
Novo Novolog R,
Aventis Lantus;
NIH/JDRF Immune
Tolerance Network
starts
2004, 1971
>94 drugs/
biologics in
development;
Highly accurate BG
meters; Medtronic
Veo pump/CGM;
Dexcom G4 CGM;
5 major pumps;
>3 artificial
pancreas devices
in development
2006
NIH/JDRF TEDDY
study starts;
Medtronic
pump/CGM
Randy’s Top Prospects 2013-Forward
Treat
28
●
SGLT1/2 inhibitors
for BG control
●
Oral insulin for
“natural” insulin
action in liver
Cure
Prevent
●
Vaccine to
maintain beta
cell-specific Tregs
in pancreatic
lymph nodes
●
Hematopoietic
stem cell
transplant to
reconfigure
immune system
against
autoimmunity
JDRF works for me;
so I work for JDRF!
29