Chronic Kidney DiseaseDashboard Sample
Prepared October 2012
Custom IntelligenceCustom IntelligenceCustom IntelligenceCustom Intelligence
2
Topic Page
Table of Contents 2
Report Overview 5
Chronic Kidney Disease (CKD) Overview 6
CKD Landscape: Marketed Compounds 9
Marketed Compounds Overview 10
Kremezin® (Charcoal; AST-120) 11
Tanatril® (Imidapril) 16
Avapro® (Irbesartan) 19
Cozaar® (Losartan) 22
CKD Landscape: Registered & Phase III Compounds 25
Registered & Phase III Compounds Overview 26
Altace® (Ramipril) 27
Tekturna® (Aliskiren) 30
Lipitor® (Atorvastatin) 33
Beraprost
Bardoxolone Methyl
36
38
CKD Landscape: Phase II and I/II Compounds 42
Phase II and I/II Compounds Overview 43
Atrasentan
Baricitinib
46
49
Losartan-Thioctic Acid 51
CCX 140 53
BB 3 56
Table of Contents
Click the book
symbol on any
slide to return to
the table of
contents.
3
Topic Page
CKD Landscape: Phase II & I/II Compounds (cont.)
Pyridoxamine (Pyridorin™) 58
NOX-E36 61
CTP-499
LY-2382770
64
67
BCT197 69
Tabalumab 71
PF-48791 74
PHN031 76
Bindarit 78
FG3019
LY-2623091
80
83
DW1029M 85
NZ419 86
Renal Bio-Replacement Therapy™ 88
QPI-1002
CKD Landscape: Phase I Compounds
91
94
Phase II and I/II Compounds Overview 95
GKT-137831 96
PF-3882845 99
SAR407899 101
Low-dose Danazol (Vasaloc™ 104
Table of Contents (2)
4
Topic Page
CKD Landscape: Phase I Compounds (cont.)
TTPABC 105
CLP1004 106
CLP1002 107
CKD Landscape: Preclinical & Research Compounds 108
Pre-Clinical Compounds Overview 109
Active CKD Programs – Research Activity by Company 111
Bristol-Myers Squibb 112
Eli Lilly 114
GenKyoTex 116
Gentium 117
Kureha Corp. 118
Mitsubishi Tanabe Pharma 119
Novartis 120
Pfizer 121
Sanofi 123
Companies Involved in One Active Program 125
Abbreviations 131
Table of Contents (3)
5
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.
6
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.
7
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.
8
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.
9
Chronic Kidney Disease Competitive Landscape:
Marketed Compounds
10
Marketed Compounds Overview
Drug Company Mechanism Launched Development
Avapro®(irbesartan)
Sanofi-aventis (Bristol-
Myers Squibb, Shionogi)
Angiotensin type I
receptor antagonist
Diabetic nephropathies:
Canada, EU, USA†--
Cozaar®(losartan)
Bristol-Myers Squibb
(Merck & Co., Merck Sharp
& Dohme)
Angiotensin type I
receptor antagonist
Diabetic nephropathies:
Canada, Japan, UK,
USA††--
Kremezin®(charcoal)
Kureha Corp. (Daiichi
Sankyo Pharmaceutical,
Mitsubishi Tanabe
Pharma, Ocera
Therapeutics)
NF-kappa B inhibitorRenal failure: Japan,
South Korea
Argentina, Brazil, Canada, Czech
Republic, France, Germany,
Italy, Mexico, Poland, Puerto
Rico, Russia, Spain, Ukraine,
USA (all phase III)
Tanatril®(imidapril)
Tanabe Seiyaku
(Mitsubishi Tanabe
Pharma – owner)
ACE inhibitor
Diabetic nephropathies:
Japan† --
† Also launched for hypertension worldwide.
†† Also launched for hypertension and heart failure. Phase III trials for pediatric hypertension
ongoing globally.
11
Tanatril® (Imidapril) At A Glance
� 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.
1993 1998 2000 2002 2003 2004 2005 2006 2007 2008 2009
Phase III trials for
diabetic nephropathy in
Japan, Oct 1998
Phase II trial for
autosomal polycystic
kidney disease in
Japan, Dec 2009
Licensed to
aaiPharma in USA
and Canada,
Feb 2002
Launched in
Japan for HTN
in 1993
Approved in
EU for HTN,
Dec 1998
Xanodyne acquires
pharmaceutical assets of
aaiPharma, Aug 2005
Phase II trials
in HTN in USA,
Feb 2003
12
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, 12-
weeks’ 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%).
13
Tanatril® Key Clinical Trials
USER NOTE: Click on
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full trial summary
Effect of Imidapril or Amlodipine on the Progression of Diabetic Nephropathy in Japanese Patients with Type 2 Diabetes Mellitus: a Randomized Controlled Study.
n=100September
2001
April
2004
Randomized, Controlled, PROBE Trial, Evaluating the Antiproteinuric Effect of Imidapril Versus Ramipril in Type 2 Diabetic Patients and Mild to Moderate Hypertension With Microalbuminuria.
n=206October
2010
July
2011
Phase II Study for the Second-Line Treatment of Hypertension in Patients With Autosomal Dominant Polycystic Kidney Disease; ACEI vs. CCB.
n=160
July
2009
November
2012
14
91 89
83
7772 70
66 64
0
10
20
30
40
50
60
70
80
90
100
2013 2014 2015 2016 2017 2018 2019 2020
$U
S M
Japan
ROW
Worldwide
Tanatril Revenue Forecast 2013 – 2020
* Forecasts made by Credit Suisse
15
Chronic Kidney Disease Competitive Landscape:
Registered and Phase III Developmental Compounds
16
Registered/Phase III Compounds Overview
Drug Company Class Mechanism Phase of Development
Altace®(ramipril)
sanofi-aventis
Heterocyclic bicyclo
compound; Small
molecule
ACE inhibitorDiabetic nephropathies: UK
(Registered) †
Bardoxolone
methylEli Lilly
Small molecule;
Triterpene
NF-kappa B inhibitor,
Nitric oxide synthase
type II inhibitor, STAT3
transcription factor
inhibitors
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)
Beraprost Toray (Astellas Pharma)
Benzofuran;
Prostaglandin; Small
molecule
Prostacyclin agonistRenal failure: Asia, Japan (Phase
III) ††
Lipitor® (atorvastatin)
Pfizer Fatty acid; Heptanoic
acid; Pyrrole
HMG-CoA reductase
inhibitor
Prevention of diabetic
retinopathies: UK (Phase III) *
Tekturna®(aliskiren)
NovartisAmide, Fumarate,
Small moleculeRenin inhibitor
Diabetic nephropathies:
Canada, China, EU, India, Japan,
Latin America, Norway, South
Africa, South Korea,
Switzerland, Taiwan, Thailand,
Turkey, USA (all phase III)**
† 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.
17
Bardoxolone methyl At A Glance
� 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.
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Licensed to Reata
worldwide, Nov 2004
Phase II trials for
CKD initiated in the
US, Apr 2008
Sub-licensed to Kyowa
Hakko Kirin and Abbott
Jan and Sept 2010
Results expected
from the phase III
BEACON trial
Phase III BEACON trial
initiated worldwide,
June 2011
First clinical trial
initiated in the US
for Cancer,
Feb 2006
18
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.
19
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.
20
Bardoxolone Methyl Key Clinical Trials
An Open-Label, Randomized, Dose-ranging Phase IIaTrial to Determine the Effects of RTA 402 (Bardoxolone Methyl) on Renal Function in Patients With Diabetic Nephropathy.
n=80April
2008
May
2009
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.
n=227April
2009
December
2010
BEACON. Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON).
n=2000
June
2011
June
2013
USER NOTE: Click on
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21
Chronic Kidney Disease Competitive Landscape:
Phase II and I/II Compounds
22
Phase II and I/II Compounds Overview
Drug Company Class Mechanism Phase of Development
Atrasentan Abbott Laboratories PyrrolidineEndothelin A receptor
antagonist
Diabetic nephropathies: Japan,
Puerto Rico, USA (Phase II)
Baricitinib Eli Lilly Small moleculeJanus kinase 1 and 2
inhibitor
Diabetic nephropathies: USA,
Puerto Rico (Phase II)
BB3 Angion Biomedica Small moleculeHepatocyte 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 moleculeCCR2 receptor
antagonist
Diabetic nephropathies:
Belgium, Hungary, Netherlands,
Poland, UK (Phase II)
CTP-499 Concert Pharmaceuticals -- AntioxidantDiabetic nephropathies: USA
(Phase II)
DA9801 Dong-A Pharmaceutical -- UnknownDiabetic nephropathies: South
Korea (Phase II) †
DW-1029M Dong Wha Pharmaceutical -- UnknownDiabetic nephropathies: South
Korea (Phase II)
† Available for licensing.
23
Phase II and I/II Compounds Overview (2)
Drug Company Class Mechanism Phase of Development
FG-3019 FibroGen Monoclonal antibodyConnective tissue growth
factor inhibitor
Diabetic nephropathies: USA
(Phase II)
Losartan/thioctic acid
(INV-144)InVasc Therapeutics
Biphenyl compound,
Imidazole, Tetrazole
Angiotensin type 1
receptor antagonist;
Antioxidant; Free radical
scavenger
Diabetic nephropathies: USA
(Phase II)
LY-2382770 Eli Lilly Monoclonal antibodyTransforming growth
factor-beta inhibitor
Diabetic nephropathies:
Australia, Czech Republic,
France, Hungary, Israel, Puerto
Rico, USA (all phase II); Japan
(Phase I)
LY-2623091 Eli Lilly --Mineralocorticoid
receptor antagonist
Chronic kidney disease:
Bulgaria, Macedonia, South
Africa (Phase II)
NOX-E36 NOXXON Pharma Nucleotide aptamerCCR2 receptor
antagonist
Diabetic nephropathies:
Germany (Phase II) †
NZ419 Nippon ZokiHydantoin; Small
moleculeAntioxidant Renal failure: Japan (Phase II)
PF-489791 Pfizer Small molecule
Type 5 cyclic nucleotide
phosphodiesterase
inhibitor
Diabetic nephropathies:
Canada, EU, Hong Kong,
Malaysia, Mexico, South Africa,
South Korea, USA (Phase II)
Renal failure: USA (Phase II)
† Planning to seek a development partner.
24
Phase II and I/II Compounds Overview (3)
Drug Company Class Mechanism Phase of Development
PHN031 PhytoHealth (BioKey) Small molecule UnknownDiabetic nephropathies: Taiwan
(Phase II) †
PyridoxamineBioStratum
(NephroGenex)
Picoline; Small
molecule
Advanced glycosylation
end product inhibitor
Diabetic nephroapthies:
Australia, Israel, USA (Phase II) †
Renal Bio-
replacement
Therapy™
RenaMed Biologics -- Cell replacements Renal failure: USA (Phase II)
Tabalumab Eli Lilly Monoclonal antibodyB-cell activating factor
inhibitor
Renal failure (end-stage renal
disease): USA (Phase II)
QPI-1002 Quark Pharmaceuticals Small interfering RNA
RNA interference;
Tumour suppressor
protein p53 inhibitor
Prevention of renal failure:
Israel, Switzerland, USA (Phase
I/II)
† Available for licensing.
25
Atrasentan At A Glance
� 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.
1998 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012
First US-
based
clinical trials
initiated,
Apr1999
Phase II trials in diabetic
nephropathies initiated in
the USA and Puerto Rico,
July 2009
Phase II trials in diabetic
nephropathies initiated
in Japan, Aug 2011
Preclinical development in kidney
disorders initiated in US, July 2000Phase III trials in prostate cancer in
USA, June 2001
Phase II trials in renal cancer in
USA, Sep 2003
ODAC of the US FDA does
not recommend approval
for prostate cancer,
Sep 2005
26
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.
27
Atrasentan Key Clinical Trials
Reducing Residual Albuminuria in Subjects With Diabetes & Nephropathy With Atrasentan - A Phase 2b, Prospective, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety & Efficacy in Japanese Subjects.
n=54August
2011
July
2012
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.
n=150April
2011
August
2012
A Phase 2b, Prospective, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate Efficacy and Safety of Atrasentan, Including Thoracic Bioimpedance, in Type 2 Diabetic Subjects With Nephropathy.
n=45
August
2011
September
2012
USER NOTE: Click on
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28
Chronic Kidney Disease Competitive Landscape:
Phase I Compounds
29
Phase I Compounds Overview
Drug Company Class Mechanism Phase of Development
CLP1002 Sorbent Therapeutics Polymer Unknown Renal failure: USA (Phase I)
CLP1004 Sorbent Therapeutics PolymerPotassium channel
modulator
Renal failure (CKD & end-stage
renal disease): USA (Phase I)
Low-dose danazol Ampio PharmaceuticalsOxazole; Small
moleculeUnknown
Diabetic nephropathies: Canada
(Phase I) †
GKT-137831 GenKyoTex Small molecule
NADPH oxidase inhibitor;
NOX1 and NOX4 protein
inhibitor
Diabetic nephropathies:
Switzerland (Phase I)
PF-3882845 Pfizer Indazole UnknownDiabetic nephropathies: USA,
Singapore (Phase I)
SAR407899 sanofi-aventisAnalgesic; Small
molecule
Rho-associated kinase
inhibitor
Diabetic nephropathies: France
(Phase I)
TTPABC TransTech Pharma -- UnknownDiabetic nephropathies: USA
(Phase I)
† Available for licensing.
†† Intends to seek development partner aWer establishing proof-of-concept.
30
PF-3882845 At A Glance
� 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 PF-
3882845 (plus one dose of spironolactone) in patients with type 2 diabetic nephropathy.
2008 2009 2010 2011 2012 2013
First clinical trials for diabetic
nephropathies initiated in the
USA, Sep 2008
Phase I trial for
T2DM initiated in
Belgium, Feb 2011
Phase I trial for diabetic
nephropathies initiated
in Singapore, Aug 2011
Phase I development for
diabetic nephropathies
ongoing in the USA as of
Sep 2012
31
PF-3882845 Key Clinical Trials
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.
n=50September
2009
February
2010
A Phase 1, Double-Blind (Sponsor-Open), Placebo-And Active-Controlled, Single Dose, Crossover Study To Assess Antimineralocorticoid Activity Of Oral Pf-03882845 In Healthy Subjects.
n=12March
2011
June
2011
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.
n=64
January
2012
June
2013
USER NOTE: Click on
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full trial summary
32
Chronic Kidney Disease Competitive Landscape:
Preclinical & Research Compounds
3333
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
3434
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: G-
protein 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: single-
stranded oligonucleotide
based therapeutics – Gentium
Gentium Oligonucleotides Cell membrane
modulator, heparanase
inhibitor
Preclinical – Diabetic
nephropathies (Italy)
Research programme:
therapeutics against diabetes-
associated complications -
Vascular Pharmaceuticals
Vascular Pharmaceuticals Monoclonal-
antibodies
Insulin-like growth
factor-I receptor
antagonists, Integrin
alphaVbeta3 modulators
Preclinical – Diabetic
Nephropathies & Diabetic
Complications (USA)
† Available for licensing
35
Active Chronic Kidney Disease Programs
Research Activity By Company
36
Bristol-Myers Squibb (1)
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.
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.
37
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.
38
Eli Lilly (1)
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.
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.
39
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.
40
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
41
Abbreviations
ACEI(s) angiotensin converting enzyme inhibitor(s)AE(s) adverse event(s)ARBs angiotensin type II receptor blockers(s)BP blood pressureCKD chronic kidney diseaseCOPD chronic obstructive pulmonary diseaseCV cardiovascularCVD CV diseaseEU European UnionESRD end-stage renal diseaseFDC fixed-dose combinationGFR glomerular filtration rateHCTZ hydrochlorothiazideHTN hypertensionMI myocardial infarction
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