Custom Intelligence - Springer · experience cough while receiving Tanatril®, developed cough...

Chronic Kidney DiseaseDashboard Sample

Prepared October 2012

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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

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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


� 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


� 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


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


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

magnifying glass to see

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


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


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


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


full trial summary

21


Phase II and I/II Compounds

22

Phase II and I/II Compounds Overview


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


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)


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


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


Germany (Phase II) †

NZ419 Nippon ZokiHydantoin; Small

moleculeAntioxidant Renal failure: Japan (Phase II)

PF-489791 Pfizer Small molecule

Type 5 cyclic nucleotide

phosphodiesterase

inhibitor


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)


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)


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


full trial summary

28


Phase I Compounds

29

Phase I Compounds Overview


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


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)


†† 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


full trial summary

32


Preclinical & Research Compounds

3333

Pre-Clinical Compounds Overview


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


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


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


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


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


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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