1. health and fitness
2. disease

Custom Intelligence
Chronic Kidney Disease
Dashboard Sample
Prepared October 2012
Table of Contents
Topic
Table of Contents
Report Overview
Chronic Kidney Disease (CKD) Overview
CKD Landscape: Marketed Compounds
Marketed Compounds Overview
Kremezin® (Charcoal; AST-120)
Tanatril® (Imidapril)
Avapro® (Irbesartan)
Cozaar® (Losartan)
CKD Landscape: Registered & Phase III Compounds
Registered & Phase III Compounds Overview
Altace® (Ramipril)
Tekturna® (Aliskiren)
Lipitor® (Atorvastatin)
Beraprost
Click the book
symbol on any
slide to return to
the table of
contents.
Bardoxolone Methyl
CKD Landscape: Phase II and I/II Compounds
Phase II and I/II Compounds Overview
Atrasentan
Baricitinib
Losartan-Thioctic Acid
CCX 140
BB 3
Page
2
5
6
9
10
11
16
19
22
25
26
27
30
33
36
38
42
43
46
49
51
53
56
2
Table of Contents (2)
Topic
CKD Landscape: Phase II & I/II Compounds (cont.)
Pyridoxamine (Pyridorin™)
NOX-E36
CTP-499
Page
58
61
64
LY-2382770
BCT197
Tabalumab
PF-48791
PHN031
Bindarit
FG3019
67
69
71
74
76
78
80
LY-2623091
DW1029M
NZ419
Renal Bio-Replacement Therapy™
QPI-1002
83
85
86
88
91
CKD Landscape: Phase I Compounds
Phase II and I/II Compounds Overview
GKT-137831
PF-3882845
SAR407899
Low-dose Danazol (Vasaloc™
94
95
96
99
101
104
3
Table of Contents (3)
Topic
CKD Landscape: Phase I Compounds (cont.)
TTPABC
CLP1004
CLP1002
CKD Landscape: Preclinical & Research Compounds
Pre-Clinical Compounds Overview
Active CKD Programs – Research Activity by Company
Bristol-Myers Squibb
Eli Lilly
GenKyoTex
Gentium
Kureha Corp.
Mitsubishi Tanabe Pharma
Novartis
Pfizer
Sanofi
Companies Involved in One Active Program
Abbreviations
Page
105
106
107
108
109
111
112
114
116
117
118
119
120
121
123
125
131
4
Report Overview
The purpose of this report is to accurately map the pharmaceutical landscape for CKD
(considered synonymous with diabetic nephropathies and renal failure), including existing
standards of care, recent market approvals, and novel treatments still undergoing
development. Highlights include:
Current trends in CKD R&D efforts e.g. mechanisms of action of interest
Major companies involved in the development of CKD therapies, and their therapeutic
strategies
The main body of the report will include an in-depth summary of each of the currently
marketed products for CKD*, those in late-stage development (phase II/III, III or at
submission), and those undergoing early stage development (phase I, I/II, II). Summary
tables of molecules or programmes undergoing preclinical development is also included.
A summary of company strategy will be provided for each company associated with a
marketed product, or any company with two or more products in development for
CKD
At the front of the presentation are summary tables briefly describing all those
marketed and clinical compounds, as well as a brief overview of the disease area and
CKD market
The Adis R&DI and CTI databases were used to source all information on individual drugs
(both marketed and in development).* The NIH clinical trials database clinicaltrials.gov was
used for additional clinical trial information, and information from individual company
websites was also used where appropriate.
* This report does not include compounds which are used off-label for CKD.
5
Chronic Kidney Disease Overview (1)
Chronic kidney disease (CKD) is defined by the presence of a marker of kidney damage (e.g.
proteinuria) or a decreased (<60 mL/min/1.73m2) glomerular filtration rate (GFR) for ≥3
months. Disease staging and severity is based on GFR.1
The major outcomes associated with the development of CKD include kidney failure,
complications due to reduced kidney function and the development of cardiovascular
disease (CVD). Subsequently, treatment goals include the prevention of disease progression
and complications.
CKD is a significant public health issue globally, affecting more than 50 million people
In the USA, the first large epidemiological study to look at CKD in the general
population found a prevalence of 11% in the US adult population2
A few years later, collection of data for the National Health and Nutrition Examination
Survey (NHANES) reported a prevalence (for stage 1-4 CKD) of 13.1% in the 1999-2004
survey.3
CKD is closely linked to diabetes and cardiovascular disease; it is both a risk factor for, and a
potential consequence of, CVD.
Diabetes is the singles biggest risk factor for CKD, and is the leading cause of the
problem in developed nations.
Other risk factors include older age, hypertension, family history of CKD and smoking.
1
National Kidney Foundation – Kidney Disease Outcome Quality Initiative Clinical Practice Guidelines for CKD: Evaluation, Classification, and
Stratification. 2 Coresh J, et al. Am J Kidney Dis 2003; 41: 1-12. 3 Coresh J, et al. J Am Med Assoc 2007; 298: 2038-2047.
6
Chronic Kidney Disease Overview (2)
Management of CKD depends on the form of disease and the presence/absence of certain
co-morbid conditions. The US National Kidney Foundation – Kidney Disease Outcomes
Quality Initiative (NKF-KDOQI) divides its recommendations into categories based on the
type of CKD and the presence of comorbid conditions
Table 1. Classification and management of comorbid conditions in CKD (NFK-KDOQI).
National Kidney Foundation – Kidney Disease Outcome Quality Initiative Clinical Practice Guidelines for
CKD: Evaluation, Classification, and Stratification.
7
Chronic Kidney Disease Overview (3)
Treatment of CKD generally includes some or all of the following depending on disease
severity:
Specific therapy based on diagnosis
Evaluation and management of comorbid conditions
Slowing loss of kidney function
Prevention and treatment of CVD and complications of decreased kidney function
Preparation for kidney failure and kidney replacement
Replacement of kidney function by dialysis and transplantation.
Many pharmacologic therapies for CKD are also indicated for CVD, including ACE inhibitors,
ARBs, beta-blockers, calcium channel blockers, direct renin inhibitors and diuretics.
Many patients also receive glucose-lowering medications for co-morbid diabetes and
statins for hyperlipidemia.
The pharmaceutical market for CKD is therefore, relatively crowded with drugs that are also
widely available in other indications, generally for hypertension or other forms of CVD
None of these medications have been demonstrated to be truly disease modifying;
they reduce the risk of CVD or slow the progression of kidney disease
There has been an increase in the number of studies of traditional antihypertensives
(such as ACEIs/ARBs) in patients with CKD, in order to increase their proportion of the
also crowded antihypertensive market
This relatively saturated market has led to interest in the development of novel
pharmaceuticals with direct effects on processes underlying CKD, and this is what we
see in the pipeline currently.
8
Chronic Kidney Disease Competitive Landscape:
Marketed Compounds
9
Marketed Compounds Overview
Drug
Company
Mechanism
Launched
Development
Avapro®
Sanofi-aventis (BristolMyers Squibb, Shionogi)
Angiotensin type I
receptor antagonist
Diabetic nephropathies:
Canada, EU, USA†
--
Bristol-Myers Squibb
(Merck & Co., Merck Sharp
& Dohme)
Angiotensin type I
receptor antagonist
Diabetic nephropathies:
Canada, Japan, UK,
USA††
(irbesartan)
Cozaar®
(losartan)
Kremezin®
(charcoal)
Tanatril®
(imidapril)
Kureha Corp. (Daiichi
Sankyo Pharmaceutical,
Mitsubishi Tanabe
Pharma, Ocera
Therapeutics)
NF-kappa B inhibitor
Tanabe Seiyaku
(Mitsubishi Tanabe
Pharma – owner)
ACE inhibitor
Renal failure: Japan,
South Korea
Diabetic nephropathies:
Japan†
--
Argentina, Brazil, Canada, Czech
Republic, France, Germany,
Italy, Mexico, Poland, Puerto
Rico, Russia, Spain, Ukraine,
USA (all phase III)
--
† Also launched for hypertension worldwide.
†† Also launched for hypertension and heart failure. Phase III trials for pediatric hypertension
ongoing globally.
10
Tanatril® (Imidapril) At A Glance
1993
Launched in
Japan for HTN
in 1993
1998
2000
Approved in
Phase III trials for
diabetic nephropathy in EU for HTN,
Dec 1998
Japan, Oct 1998
2002
Licensed to
aaiPharma in USA
and Canada,
Feb 2002
2003
Phase II trials
in HTN in USA,
Feb 2003
2004
2005
2006
Xanodyne acquires
pharmaceutical assets of
aaiPharma, Aug 2005
2007
2008
2009
Phase II trial for
autosomal polycystic
kidney disease in
Japan, Dec 2009
Tanatril® (imidapril, SH-6366, TA-6366) is a long-acting ACE inhibitor that is widely marketed
in Asia and Europe for the treatment of hypertension. It is also available in Japan as a
treatment for diabetic nephropathy.
The agent has orphan drug status in Japan for the treatment of diabetic nephropathy.
Tanatril® was originally developed by Tanabe Seiyaku (now Mitsubishi Tanabe Pharma). The
drug is marketed by Xanodyne Pharmaceuticals in the USA and Canada, Merck in the EU,
Trinity-Chiesi in the UK, Gerot in Austria and the Gerolymatos Group in Austria.
In Japan the drug is being investigated in a phase II trial as a second-line treatment for
hypertension in patients with autosomal dominant polycystic kidney disease (ADPKD), and in
Italy, a phase III trial is comparing the agent with ramipril in patients with T2DM,
hypertension and microalbuminuria.
11
Tanatril® Efficacy & Safety Summary
In 76 patients with essential hypertension, Tanatril® 5-20 mg/day, alone or in combination
with other antihypertensives (n=47), significantly reduced BP from baseline after 8 weeks.
A total of 48/62 patients with mild-to-moderate hypertension responded (BP<150/90 mmHg)
to 12 weeks of treatment with Tanatril® 2.5-20 mg/day (in combination with a fixed-dose
thiazide diuretic).
A multicentre, randomised, double-blind study compared the efficacy and tolerability of
Tanatril® and enalapril in 223 patients with mild-to-moderate essential hypertension. Both
agents showed similar antihypertensive efficacy; however Tanatril® was associated with a
lower incidence of adverse events.
In a randomised, double-blind, parallel study in 161 patients with essential hypertension,
once-daily Tanatril® 5-20 mg/day for 8 weeks reduced mean sitting diastolic BP (DBP). DBP
was reduced to ≤90mmHg in 52/106 Tanatril® recipients and 18/55 placebo recipients.
In a multicentre (196), crossover study in 489 patients with mild-to-severe hypertension, 12weeks’ treatment with enalapril 5-10 mg/day induced cough in 39% of patients, compared
with 15% of patients after the same doses of Tanatril®. A total of 21% of patients who did not
experience cough while receiving Tanatril®, developed cough after switching to enalapril.
Conversely, cough developed in 0.9% of patients who, having no cough on enalapril, crossed
over to Tanatril®.
In a randomised, double-blind, parallel study in 161 patients with essential hypertension,
adverse effects reported by placebo and Tanatril® recipients, respectively, included: tiredness
(2% and 5%), dizziness (2% and 6%), headache (9% and 6%) and vertigo (5% and 1%).
12
Tanatril® Key Clinical Trials
Phase II Study for the Second-Line Treatment of
Hypertension in Patients With Autosomal Dominant
Polycystic Kidney Disease; ACEI vs. CCB.
Randomized, Controlled, PROBE Trial, Evaluating the
Antiproteinuric Effect of Imidapril Versus Ramipril in
Type 2 Diabetic Patients and Mild to Moderate
Hypertension With Microalbuminuria.
Effect of Imidapril or Amlodipine on the Progression
of Diabetic Nephropathy in Japanese Patients with
Type 2 Diabetes Mellitus: a Randomized Controlled
Study.
USER NOTE: Click on
magnifying glass to see
full trial summary
n=160
July
2009
November
2012
n=206
October
2010
July
2011
September
2001
April
2004
n=100
13
Tanatril Revenue Forecast 2013 – 2020
100
90
91
89
83
80
77
72
70
70
66
$US M
60
64
Japan
50
ROW
40
Worldwide
30
20
10
0
2013
2014
2015
2016
2017
2018
2019
2020
* Forecasts made by Credit Suisse
14
Chronic Kidney Disease Competitive Landscape:
Registered and Phase III
Developmental Compounds
15
Registered/Phase III Compounds Overview
Drug
Company
Class
Mechanism
Altace®
sanofi-aventis
Heterocyclic bicyclo
compound; Small
molecule
ACE inhibitor
Diabetic nephropathies: UK
(Registered) †
Diabetic nephropathies:
Australia, Austria, Belgium,
Canada, Czech Republic, France,
Germany, Israel, Italy, Mexico,
Puerto Rico, Spain, Sweden, UK,
USA (all phase III); Japan (Phase
II)
(ramipril)
Phase of Development
Bardoxolone
methyl
Eli Lilly
Small molecule;
Triterpene
NF-kappa B inhibitor,
Nitric oxide synthase
type II inhibitor, STAT3
transcription factor
inhibitors
Beraprost
Toray (Astellas Pharma)
Benzofuran;
Prostaglandin; Small
molecule
Prostacyclin agonist
Renal failure: Asia, Japan (Phase
III) ††
Lipitor®
Pfizer
Fatty acid; Heptanoic
acid; Pyrrole
HMG-CoA reductase
inhibitor
Prevention of diabetic
retinopathies: UK (Phase III) *
Renin inhibitor
Diabetic nephropathies:
Canada, China, EU, India, Japan,
Latin America, Norway, South
Africa, South Korea,
Switzerland, Taiwan, Thailand,
Turkey, USA (all phase III)**
(atorvastatin)
Tekturna®
(aliskiren)
Novartis
Amide, Fumarate,
Small molecule
† Marketed for CV disorders and heart failure.
†† Marketed for arterial occlusive disorders and peripheral vascular disorders in Japan and South Korea.
* Marketed for CV disorders, heart failure and hypercholesterolaemia.
** Marketed for hypertension.
16
Bardoxolone methyl At A Glance
2002
2003
2004
Licensed to Reata
worldwide, Nov 2004
2005
2006
First clinical trial
initiated in the US
for Cancer,
Feb 2006
2007
2008
Phase II trials for
CKD initiated in the
US, Apr 2008
2009
2010
Sub-licensed to Kyowa
Hakko Kirin and Abbott
Jan and Sept 2010
2011
2012
Phase III BEACON trial
initiated worldwide,
June 2011
2013
Results expected
from the phase III
BEACON trial
Reata Pharmaceuticals, Abbott and Kyowa Hakko Kirin are developing bardoxolone methyl,
an orally available antioxidant inflammation modulator (AIM) that inhibits NF-κB and STAT3,
for the treatment of CKD associated with diabetes. The compound directly inhibits activation
of NF-κB by binding to IKKβ, the kinase that regulates NF-κB activation. Bardoxolone methyl
increases the estimated glomerular filtration rate (eGFR) of the kidneys.
The agent is primarily being investigated for its efficacy in improving kidney function and/or
delaying worsening of kidney function in patients with diabetic nephropathies. Phase III
development of the agent, in patients with stage IV CKD associated with T2DM, was ongoing
worldwide in the BEACON trial, however the trial was discontinued in October 2012 due to
safety concerns.
Bardoxolone methyl is an analogue of RTA 401, which was first synthesised by investigators at
Dartmouth College and developed in co-operation with the University of Texas M.D.
Anderson Cancer Centre. Reata subsequently licensed the agent to Kyowa Hakko Kirin in
Japan, China, Taiwan, Korea and South-East Asia in January 2010; and to Abbott Laboratories
for all markets outside of the US and certain Asian countries in September that same year.
17
Bardoxolone Methyl Efficacy & Safety Summary (1)
In the open-label, randomised, phase II BEAM study, bardoxolone methyl sustained
improvement in estimated glomerular filtration rate (eGFR) over 52 weeks in patients with
moderate-to-severe CKD and T2DM. eGFR was significantly improved by up to 10.5
mL/min/1.73m2 in patients receiving 75mg bardoxolone methyl (p<0.001). Increases were
5.8 and 9.3 mL/min/1.73m2 for the 25mg and 150mg bardoxolone methyl groups,
respectively, relative to placebo (p=0.002, 25mg; p<0.001, 150mg). Nineteen percent of
patients who received placebo had a decline in eGFR of more than 25% over 52 weeks,
compared with 9% of bardoxolone methyl-treated patients (p=0.058). Uric acid levels were
significantly reduced in all bardoxolone methyl groups. Levels of blood urea nitrogen were
also improved.
Approximately 60% of patients receiving bardoxolone methyl showed a reduction in their
classification of the severity of the disease after 24 weeks of treatment, compared with 17%
of patients in the placebo group. Only 4% of patients in the bardoxolone methyl group had
their disease worsened compared with 13% of placebo recipients. These were data from a
randomised, double-blind phase IIb trial in 227 patients with T2DM and stage 3b (moderate)
to severe (stage 4) CKD who received once daily bardoxolone methyl 25, 75 or 150mg or
placebo. Approximately 3/4 of patients receiving bardoxolone methyl experienced an
improvement in eGFR of ≥10%, including 1/4 of patients with an improvement of ≥50%
compared with ≤2% in the placebo group (p<0.001). Patients in the bardoxolone methyl
group demonstrated a mean increase in estimated GFR of 10 mL/min/1.72m2 compared with
no change in the placebo group.
18
Bardoxolone Methyl Efficacy & Safety Summary (2)
In the open-label, randomised, phase II BEAM study, the most common adverse event
experienced with bardoxolone methyl was muscle spasm, over 52 weeks in patients (n=227)
with moderate-to-severe CKD and T2DM. The incidence of muscle spasm was 42%, 61% and
59% in the 25, 75 and 150mg groups, respectively, compared with 18% in the placebo group.
Transient elevations in liver enzymes, nausea, decreased appetite and hypomagnesaemia
were also observed.
19
Bardoxolone Methyl Key Clinical Trials
BEACON. Bardoxolone Methyl Evaluation in Patients
With Chronic Kidney Disease and Type 2 Diabetes:
the Occurrence of Renal Events (BEACON).
BEAM. A 52-Week, Multi-center, Double-blind,
Randomized, Placebo-controlled Phase IIb Trial to
Determine the Effects of Bardoxolone Methyl (RTA
402) on eGFR in Patients With Type 2 Diabetes and
Chronic Kidney Disease With an eGFR of 20 - 45
mL/Min/1.73m2.
An Open-Label, Randomized, Dose-ranging Phase IIa
Trial to Determine the Effects of RTA 402
(Bardoxolone Methyl) on Renal Function in Patients
With Diabetic Nephropathy.
USER NOTE: Click on
magnifying glass to see
full trial summary
n=2000
June
2011
June
2013
n=227
April
2009
December
2010
April
2008
May
2009
n=80
20
Chronic Kidney Disease Competitive Landscape:
Phase II and I/II Compounds
21
Phase II and I/II Compounds Overview
Drug
Company
Class
Mechanism
Phase of Development
Atrasentan
Abbott Laboratories
Pyrrolidine
Endothelin A receptor
antagonist
Diabetic nephropathies: Japan,
Puerto Rico, USA (Phase II)
Baricitinib
Eli Lilly
Small molecule
Janus kinase 1 and 2
inhibitor
Diabetic nephropathies: USA,
Puerto Rico (Phase II)
BB3
Angion Biomedica
Small molecule
Hepatocyte growth
factor stimulant
Renal failure: Netherlands, USA
(Phase II)
BCT197
Novartis
--
Unknown
Renal failure: USA (Phase II)
Bindarit
Angelini Group
Analgesic, Indazole,
Propionate, Small
molecule
Chemokine CCL2
inhibitor
Diabetic nephropathies: Italy,
Slovenia (Phase II) †
CCX140
ChemoCentryx
Small molecule
CCR2 receptor
antagonist
Diabetic nephropathies:
Belgium, Hungary, Netherlands,
Poland, UK (Phase II)
CTP-499
Concert Pharmaceuticals
--
Antioxidant
Diabetic nephropathies: USA
(Phase II)
DA9801
Dong-A Pharmaceutical
--
Unknown
Diabetic nephropathies: South
Korea (Phase II) †
DW-1029M
Dong Wha Pharmaceutical
--
Unknown
Diabetic nephropathies: South
Korea (Phase II)
† Available for licensing.
22
Phase II and I/II Compounds Overview (2)
Drug
Company
Class
Mechanism
FG-3019
FibroGen
Monoclonal antibody
Connective tissue growth
factor inhibitor
Diabetic nephropathies: USA
(Phase II)
InVasc Therapeutics
Biphenyl compound,
Imidazole, Tetrazole
Angiotensin type 1
receptor antagonist;
Antioxidant; Free radical
scavenger
Diabetic nephropathies: USA
(Phase II)
Monoclonal antibody
Transforming growth
factor-beta inhibitor
Diabetic nephropathies:
Australia, Czech Republic,
France, Hungary, Israel, Puerto
Rico, USA (all phase II); Japan
(Phase I)
Chronic kidney disease:
Bulgaria, Macedonia, South
Africa (Phase II)
Losartan/thioctic acid
(INV-144)
LY-2382770
Eli Lilly
Phase of Development
LY-2623091
Eli Lilly
--
Mineralocorticoid
receptor antagonist
NOX-E36
NOXXON Pharma
Nucleotide aptamer
CCR2 receptor
antagonist
Diabetic nephropathies:
Germany (Phase II) †
NZ419
Nippon Zoki
Hydantoin; Small
molecule
Antioxidant
Renal failure: Japan (Phase II)
Type 5 cyclic nucleotide
phosphodiesterase
inhibitor
Diabetic nephropathies:
Canada, EU, Hong Kong,
Malaysia, Mexico, South Africa,
South Korea, USA (Phase II)
PF-489791
Pfizer
Small molecule
Renal failure: USA (Phase II)
† Planning to seek a development partner.
23
Phase II and I/II Compounds Overview (3)
Drug
Company
Class
Mechanism
PHN031
PhytoHealth (BioKey)
Small molecule
Unknown
Diabetic nephropathies: Taiwan
(Phase II) †
Pyridoxamine
BioStratum
(NephroGenex)
Picoline; Small
molecule
Advanced glycosylation
end product inhibitor
Diabetic nephroapthies:
Australia, Israel, USA (Phase II) †
Renal Bioreplacement
Therapy™
RenaMed Biologics
--
Cell replacements
Renal failure: USA (Phase II)
Tabalumab
Eli Lilly
Monoclonal antibody
B-cell activating factor
inhibitor
Renal failure (end-stage renal
disease): USA (Phase II)
Small interfering RNA
RNA interference;
Tumour suppressor
protein p53 inhibitor
Prevention of renal failure:
Israel, Switzerland, USA (Phase
I/II)
QPI-1002
Quark Pharmaceuticals
Phase of Development
† Available for licensing.
24
Atrasentan At A Glance
1998
First USbased
clinical trials
initiated,
Apr1999
2000
2002
2004
2005
Preclinical development in kidney
disorders initiated in US, July 2000
Phase III trials in prostate cancer in
USA, June 2001
Phase II trials in renal cancer in
USA, Sep 2003
2006
2007
ODAC of the US FDA does
not recommend approval
for prostate cancer,
Sep 2005
2008
2009
2010
Phase II trials in diabetic
nephropathies initiated in
the USA and Puerto Rico,
July 2009
2011
2012
Phase II trials in diabetic
nephropathies initiated
in Japan, Aug 2011
Atrasentan (ABT 627), the active enantiomer of A 127722, is a selective endothelin A
receptor antagonist that is being developed by Abbott Laboratories as an orally administered
treatment for diabetic nephropathies. Atrasentan has been shown to reduce albuminuria in
patients with diabetic nephropathies, and phase II development is underway in this
indication in the US, Canada, Japan, Taiwan and Puerto Rico.
The agent was previously being developed as a treatment for a variety of cancers; however,
development in this indication appears to have been discontinued.
Abbot is currently conducting three phase IIb trials of atrasenan, as a once-daily, adjunctive
treatment for patients with diabetic nephropathy. Results from an earlier phase II trial of the
drug in patients with T2DM and related diabetic nephropathy were published in the Journal
of the American Society of Nephrology in March 2011.
25
Atrasentan Efficacy & Safety Summary
Atrasentan 0.75mg and 1.75mg significantly reduced urine albumin-to-creatinine ratio
(UACR) compared with placebo in a phase II dose-ranging trial in patients with diabetic
nephropathy. In this randomised, double-blind, placebo-controlled trial, 89 subjects with
received atrasentan 0.25mg, 0.75mg, 1.75mg or placebo for 8 weeks in combination with
renin-angiotensin system (RAS) inhibitors. Patients in the 0.25, 0.75 and 1.75mg atrasentan
groups had final UACR reductions from baseline of 21%, 42% and 35%, respectively,
compared with 11% in the placebo group. Furthermore, a significantly greater proportion of
patients in the 0.75mg group achieved a >40% reduction in UACR from baseline versus
placebo (50% and 17%, respectively).
Atrasentan 0.25mg, 0.75mg and 1.75 was associated with peripheral oedema (primarily
mild) in this same phase II trial in 89 subjects with diabetic nephropathy. Oedema was
observed in 14%, 18% and 46% of patients in the respective atrasentan cohorts, and 9% of
patients in the placebo group.
26
Atrasentan Key Clinical Trials
A Phase 2b, Prospective, Double-Blind, PlaceboControlled, Multicenter Study to Evaluate Efficacy
and Safety of Atrasentan, Including Thoracic
Bioimpedance, in Type 2 Diabetic Subjects With
Nephropathy.
RADAR. Reducing Residual Albuminuria in Subjects
With Diabetes and Nephropathy With AtRasentan A Phase 2b, Prospective, Randomized, Double-Blind,
Placebo-Controlled Trial to Evaluate Safety and
Efficacy.
Reducing Residual Albuminuria in Subjects With
Diabetes & Nephropathy With Atrasentan - A Phase
2b, Prospective, Randomized, Double-Blind, PlaceboControlled Trial to Evaluate Safety & Efficacy in
Japanese Subjects.
USER NOTE: Click on
magnifying glass to see
full trial summary
n=45
August September
2011
2012
n=150
April
2011
August
2012
August
2011
July
2012
n=54
27
Chronic Kidney Disease Competitive Landscape:
Phase I Compounds
28
Phase I Compounds Overview
Drug
Company
Class
Mechanism
Phase of Development
CLP1002
Sorbent Therapeutics
Polymer
Unknown
Renal failure: USA (Phase I)
CLP1004
Sorbent Therapeutics
Polymer
Potassium channel
modulator
Renal failure (CKD & end-stage
renal disease): USA (Phase I)
Low-dose danazol
Ampio Pharmaceuticals
Oxazole; Small
molecule
Unknown
Diabetic nephropathies: Canada
(Phase I) †
Diabetic nephropathies:
Switzerland (Phase I)
GKT-137831
GenKyoTex
Small molecule
NADPH oxidase inhibitor;
NOX1 and NOX4 protein
inhibitor
PF-3882845
Pfizer
Indazole
Unknown
Diabetic nephropathies: USA,
Singapore (Phase I)
SAR407899
sanofi-aventis
Analgesic; Small
molecule
Rho-associated kinase
inhibitor
Diabetic nephropathies: France
(Phase I)
TTPABC
TransTech Pharma
--
Unknown
Diabetic nephropathies: USA
(Phase I)
† Available for licensing.
†† Intends to seek development partner aŌer establishing proof-of-concept.
29
PF-3882845 At A Glance
2008
First clinical trials for diabetic
nephropathies initiated in the
USA, Sep 2008
2009
2010
2011
Phase I trial for
T2DM initiated in
Belgium, Feb 2011
Phase I trial for diabetic
nephropathies initiated
in Singapore, Aug 2011
2012
2013
Phase I development for
diabetic nephropathies
ongoing in the USA as of
Sep 2012
Pfizer is developing PF-3882845, an orally available compound for the treatment of diabetic
nephropathies. Phase I development of PF-3882845 is underway in the US, Belgium and
Singapore. The agent is also being investigated as a treatment for T2DM.
A total of six clinical trials of PF-3882845 appear to have been initiated to date; five of these
have been completed and investigated the safety, tolerability, pharmacokinetics (PK) and
pharmacodynamics (PD) of the agent in healthy volunteers.
One trial is currently being conducted in the US and Belgium (NCT01488877). This phase Ib,
randomized, double-blind study is investigating the safety, tolerability, PK and PD of PF3882845 (plus one dose of spironolactone) in patients with type 2 diabetic nephropathy.
30
PF-3882845 Key Clinical Trials
A 2-week, Phase 1b, Randomized, Double-Blind,
Placebo- Controlled, Multi-Dose, Dose-Escalating
Study With PF-03882845 And One Dose Of
Spironolactone To Evaluate Safety, Tolerability,
Pharmacokinetics And Pharmacodynamics In
Subjects With Type 2 Diabetes Mellitus And
Albuminuria.
A Phase 1, Double-Blind (Sponsor-Open), PlaceboAnd Active-Controlled, Single Dose, Crossover Study
To Assess Antimineralocorticoid Activity Of Oral Pf03882845 In Healthy Subjects.
A Phase 1, Double-Blind (Sponsor Open),
Randomized, Placebo- Controlled, Parallel Group,
Oral Multiple-Dose Trial to Evaluate The Safety,
Tolerability, Pharmacokinetics, and
Pharmacodynamics of PF-03882845 in Healthy
Volunteers.
USER NOTE: Click on
magnifying glass to see
full trial summary
n=64
January
2012
June
2013
n=12
March
2011
June
2011
September
2009
February
2010
n=50
31
Chronic Kidney Disease Competitive Landscape:
Preclinical & Research Compounds
32
Pre-Clinical Compounds Overview
Drug
Company
Class
Mechanism
Phase of Development
GCS-100
La Jolla Pharmaceutical
Company
Polysaccharides
Galectin-3 inhibitor,
angiogenesis inhibitor,
apoptosis stimulant,
cell adhesion molecule
inhibitor
Preclinical - Renal failure
(USA)
Fimasartan
Boryung
Pyrimidinones, small
molecules
Angiotensin type-1
receptor antagonist
Preclinical - Diabetic
nephropathies
(South Korea)†
Recombinant alkaline
phosphatase
AM Pharma Holding
Phosphoric monoester
hydrolases
Endotoxin inhibitor
Preclinical – Acute renal
failure (EU)
Defibrotide
Gentium (Medison
Pharma, Sigma-Tau
Pharmaceuticals, Swedish
Orphan Biovitrum,
PharmaSwiss, Gen Ilac)
Nucleotide aptamers,
polydeoxyribonucleotides
Angiogenesis inhibitor,
cytokine modulator,
heparanase inhibitor,
signal transduction
pathway inhibitor
Preclinical – Diabetic
nephropathies (Italy)††
PB1603
Panacor Bioscience
--
--
Preclinical – Prevention of
renal failure due to CKD
(Taiwan)
IG-MD-020
Indigene Pharmaceuticals
--
--
Preclinical – Diabetic
nephropathies (India)
K-21299
Kowa
--
Angiotensin receptor
antagonist, peroxisome
proliferator-activator
receptor gamma
agonist
Preclinical – Diabetic
nephropathies (Japan)
† Marketed for hypertension in South Korea
†† Regulatory filings have been submitted in EU for veno-occlusive disorders
33
Pre-Clinical Compounds Overview (2)
Drug
Company
Class
Mechanism
Phase of
Development
THG21329
Theratechnologies
Peptides
--
Preclinical - Acute renal
failure (Canada)
DT23552
University of Virginia
(DiaKine Therapeutics)
--
Interluekin-12 inhibitor,
immunomodulator
Preclinical – Diabetic
nephropathies (USA)
HL033
HanAll Biopharma
Erythropoietins
Erythropoiesis stimulant
Preclinical – Renal failure
(South Korea)†
Research programme: NADPH
oxidase inhibitors GenKyoTex
GenKyoTex
Small molecules
CYBB protein inhibitor,
NADPH oxidase inhibitor,
NOX1&4 protein inhibitor
Research – Diabetic
nephropathies
(Switzerland)
Research programme:
embryonic tissue
xenotransplants – Tissera
Weizmann Institute of
Science (Tissera)
Cell therapies
Tissue replacements
Preclinical – Renal failure
(Israel)
Research programme: Gprotein coupled receptor
antagonists - Proximagen
Proximagen
Small molecules
G-protein coupled
receptor antagonist
Preclinical – Diabetic
nephropathies (UK)
Research programme:
midkine therapeutics – Cell
Signals
Cell Signals
--
Apoptosis inhibitor,
cytokine inhibitor
Preclinical – Renal failure
(Japan)
Research programme: singlestranded oligonucleotide
based therapeutics – Gentium
Gentium
Oligonucleotides
Cell membrane
modulator, heparanase
inhibitor
Preclinical – Diabetic
nephropathies (Italy)
Research programme:
therapeutics against diabetesassociated complications Vascular Pharmaceuticals
Vascular Pharmaceuticals
Monoclonalantibodies
Insulin-like growth
factor-I receptor
antagonists, Integrin
alphaVbeta3 modulators
Preclinical – Diabetic
Nephropathies & Diabetic
Complications (USA)
34
† Available for licensing
Active Chronic Kidney Disease Programs
Research Activity By Company
35
Bristol-Myers Squibb (1)
Bristol-Myers Squibb is involved in the development of
two products that are widely available as treatments for
diabetic nephropathy – Cozaar® and Avapro®. It does
not appear to be developing any compounds at earlier
stages of development in this area.
Bristol-Myers Squibb is the owner of Cozaar ® (losartan), an orally
administered, angiotensin type-II receptor blocker or ARB, which is widely
available throughout the world as a treatment for hypertension. The agent
was originally jointly developed by DuPont Pharmaceuticals (who were
merged into Bristol-Myers Squibb in 2001 and Merck).
Cozaar® is also available in Canada, Japan, the UK and the USA as a
treatment for diabetic nephropathy, and a phase III trial in pediatric
patients with hypertension is ongoing worldwide.
Generic versions of Cozaar® are available for hypertension in Canada and
the USA.
36
Bristol-Myers Squibb (2)
Bristol-Myers Squibb also entered into a development and licensing agreement with
Sanofi for Avapro® (irbesartan), an angiotensin type-II receptor blocker (ARB). The
company co-developed Avapro® for both the treatment of hypertension and the
treatment of diabetic nephropathy.
Bristol-Myers Squibb markets Avapro® for hypertension and diabetic
nephropathies in the USA. The agent is available worldwide for hypertension,
and in the US, Canada and the EU for diabetic nephropathy.
37
Eli Lilly (1)
Eli Lilly is involved in the development of three separate
clinical-stage products in the CKD space, including the
monoclonal antibody product LY-2382770, as well as
baricitinib and LY-2623091. Another of their compounds,
tabalumab, is also being investigated in an exploratory
trial in patients with ESRD.
Eli Lilly is developing the small molecule, janus kinase (JAK) 1 and 2 inhibitor,
baricitinib, under an exclusive license from Incyte Corporation.
A phase II trial of the agent is underway in patients with diabetic kidney
disease at sites in the US, Puerto Rico and Japan. Approximately 250
patients are expected to be enrolled.
Baricitinib is also in phase II trials for the treatment of rheumatoid arthritis
and psoriasis.
38
Eli Lilly (2)
Eli Lilly is also developing LY-238770, a monoclonal antibody product against
transforming growth factor-beta (TGFβ) kinase, for the treament of diabetic kidney
disease (diabetic nephropathies).
A global phase II trial is underway at sites throughout the US, Australia, Europe,
Israel and Puerto Rico, which is evaluating the ability of the antibody to protect
kidney function in patients with diabetic nephropathies. Approximately 400
patients will be enrolled in total.
LY-2623091, a mineralocorticoid receptor antagonist, is also in phase II trials with the
company as a treatment for CKD; and Eli Lilly’s phase III rheumatoid arthritis
candidate tabalumab (an anti-BAFF monoclonal antibody) is also being investigated
in an exploratory trial in patients with ESRD.
The exploratory phase II trial will investigate tabalumab in HLA-presensitized
patients with ESRD who are awaiting kidney transplantation. The primary
outcome measure will investigate single antigen reactivity and panel reactive
antibodies.
39
Companies Involved in One Active Program
Developer
Role
Drug
Indication
Phase (Country)
Licensee
(Country)
Licensing
availability
Abbott
Laboratories
Originator
Atrasentan
Diabetic
nephropathies
II (Japan, Puerto Rico,
USA)
--
NA
AM-Pharma
Holding
Originator
Recombinant
alkaline
phosphatase
Renal failure
Preclinical (EU)
--
NA
Ampion
Pharmaceuticals
Originator
Low-dose
danazol
Diabetic
nephropathies
I (Canada)
--
In partnering
discussions
Angion
Biomedica
Originator
BB-3
Acute renal
failure
II (Netherlands, USA)
--
NA
Angelini Group
Originator
Bindarit
Diabetic
nephropathies
II (Italy, Slovenia)
--
Yes, as of 22
June 2012
Bio3 Research
Originator
BIOCYSCAN™
Renal failure
Preclinical (Italy)
Daxley Group
(Latin America)
NA
40
Abbreviations
ACEI(s)
AE(s)
ARBs
BP
CKD
COPD
CV
CVD
EU
ESRD
FDC
GFR
HCTZ
HTN
MI
angiotensin converting enzyme inhibitor(s)
adverse event(s)
angiotensin type II receptor blockers(s)
blood pressure
chronic kidney disease
chronic obstructive pulmonary disease
cardiovascular
CV disease
European Union
end-stage renal disease
fixed-dose combination
glomerular filtration rate
hydrochlorothiazide
hypertension
myocardial infarction
41