HDL Therapeutics in the Wake of Torcetrapibknowledgebase.definedhealth.net/wp-content/uploads/... · Dr. John LaMattina , Senior Vice President, Pfizer Inc. and President, Pfizer

HDL Therapeutics in the Wake of Torcetrapib

Michael C. RiceSenior Consultant, Defined Health

Cardiovascular Insight BriefingBasking Ridge, NJJanuary, 2007

© Defined Health, 2007

CVD Insight BriefingDefined Health, January 2007- Pg. 2



Defined Health’s 2006 – 2007 Insight Series

HDL Therapeutics in the Wake of Torcetrapib

The information in this report has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change.




Agenda

• Introduction• What do we know about torcetrapib?• What are we waiting to find out?• What is at stake?• The drive to make HDL a druggable target• Hitting the wall in cardioprevention?• The HDL therapeutic pipeline beyond CETP• Discussion



December 2 nd Headline Says:

Why is There Such Interest in This Drug?



Why is There Such Interest in this Drug, and Why are We Here Tonight?

• Torcetrapib was the most expensive drug development project in history.

• It was intended to open a new category in cardiopre vention, but met an untimely demise.

• At this point, we don’t know why, but torcetrapib i ncreased mortality.

– Mortality increase could be limited to torcetrapib or a CETP class effect.

– Trial data may raise questions about the validity o f HDL-C and imaging as surrogate markers.

• If CETP inhibitors go down as a class, we may have run up against the wall in cardioprevention.

• Commercially, we may have nowhere to go, since near ly the entire cardioprevention market will be genericized by 2011.



Agenda

• Introduction

• What do we know about torcetrapib?

• What are we waiting to find out?

• What is at stake?

• The drive to make HDL a druggable target

• Hitting the wall in cardioprevention?

• The HDL therapeutic pipeline beyond CETP

• Discussion



Key Torcetrapib Milestones

Pfizer begins torcetrapib productionat a $90 million plant in Ireland

Begin enrollmentof ILLUMINATE outcomes trial

$800 million prospective Phase III trials beginto test efficacy

Larger-scale, Phase II trials further test safety and efficacy

Pfizer gives first dose of torcetrapib to humans

Pfizer demonstrates activity in preclinical models

Pfizer improves CP-529, 414, now known as torcetrapib

CETP first described as a therapeutic target

20052004200320001999199519941990

Dodges a Left Hook in the 2nd Round… … and Throws in the Towel in the 3rd

The DSMB monitoring ILLUMINATE recommends terminati ng ILLUMINATE due to mortality and CV events.

ILLUMINATE enrolled 15,003 pts. There were 82 death s in the T/A arm compared to 51 deaths in the atorvastatin ar m. The event rate seen in the atorvastatin arm was cons istent with the rate seen in other trials.

Jeffrey Kindler hails torcetrapib as “..the most important new development in cardiovascular medicine in years.”

Pfizer states that the net benefits of the drug’s HDL elevation and LDL lowering vs. the small elevation in BP will greatly benefit patients with CV risk.

Although a Phase 3 study in patients with HeFH shows a 56% ↑in HDL and a 27% ↓ in LDL, concerns of a 3-4 mmMgincrease in systolic BP rise.

December 2, 2006November 30, 2006October 31, 2006

Comes on Strong from the Bell…

The Wall Street Journal; Pfizer Company Press Releases












20052004200320001999199519941990


What We Know About Torcetrapib

CETP firstdescribed as atherapeutic target

1990

The Wall Street Journal; Pfizer company press releases.



First, Let’s Talk About Cholesterol Metabolism, RCT and CETP

Lipidsonline.org



The Golden Boy and The Ugly Stepchild

Lipidsonline.org



LiverLiver CECE

FCFC

BileBile

SRSR--BIBI

Role of Cholesteryl E ster T ransfer P rotein (CETP)

LDLRLDLR

CETPCETP

Sterol Sterol ExcretionExcretion

Recycled to systemic Recycled to systemic CirculationCirculation

• CETP is a member of the lipid transfer/lipopolysaccharide binding protein gene family.

– CETP transfers neutral lipids from high-density lipoprotein (HDL) to very low-density lipoprotein (VLDL).

– Helps regulate the size and age of cholesterol particles.

• A number of mutations are known in the CETP gene (chromosome locus 16q21).

– Some mutations result in CETP deficiency, increased levels of HDL and unusually large cholesterol particles.

– Some forms of CETP deficiency may be antiatherogenic, conferring unusual longevity, while others may lead to increased CHD risk.

Lipidsonline.org




CETPCETP

X

torcetrapib










20052004200320001999199519941990


Pfizer improvesCP-529, 414,now known astorcetrapib

1994




Torcetrapib/Atorvastatin: PhRMA’s Proverbial $800 Million Development Program

POW!!!!POW!!!! Pfizer’s 1-2 Punch Against Cholesterol!

Atorvastatin: The Jab to Lower LDL-C

“Bad” Cholesterol

Torcetrapib: The Upper Cut to HDL-C

“Good” CholesterolAdis R&D Insight












20052004200320001999199519941990






200019991995




Comes on Strong From the Opening Bell…










20052004200320001999199519941990


Pfizer beginstorcetrapib productionat a $90 million plant in Ireland

Begin enrollment of ILLUMINATE outcomes trial

$800 million prospective Phase III trials begin to test efficacy

200520042003




Proving Ground for Surrogates of Outcomes

"Do we really have to wait that long for this drug? I am optimistic that we can convince the FDA to approve new drugs on the basis of a reduction in plaque burden, especially now that IVUS has been validated by the REVERSAL and PROVE-IT studies.”

Dr. Steve Nissen, 2004

HDL cholesterol: The next target in the battle against heart disease 2004, HeartWire.







Pfizer states that the net benefits of the drug’s HDL elevation and LDL lowering vs. the small elevation in BP will greatly benefit patients with CV risk.”



Pfizer Updates Preliminary Results of Torcetrapib/Atorvastatin Clinical Trials as Abstract for Phase 3 Study is Released; Oct 31, 2006 Pfizer press release; The Wall Street Journal..

Although a Phase 3 study in patients

With HeFH shows a 56% ↑in HDL and

a 27% ↓ in LDL, concerns of a

3-4 mmMg increase in systolic BPwere confirmed.

October 31, 2006

Dodges a Left Hook in the 2 nd Round…



“… T/A raises HDL and lowers LDL. We believe that the net benefits of the drug -- characterized by significant HDL elevation and LDL lowering vs. the small elevation in blood pressure -- will greatly benefit patients with CV risk.”

Dr. John LaMattina , Senior Vice President, Pfizer Inc. and President, Pfizer Global R&D

Dodges a Left Hook in the 2nd Round...

Pfizer Presents Robust and Diversified Product Pipeline Across 11 Therapeutic Areas Nov 30, 2006 Pfizer press release.










Dodges a Left Hook in the 2 nd Round…

Pfizer Presents Robust and Diversified Product Pipeline Across 11 Therapeutic Areas Nov 30, 2006 Pfizer press release; The Wall Street Journal.

Jeffrey Kindler hails torcetrapib as “..the mostimportant new development in cardiovascular medicin ein years.”

Pfizer states that the net benefits of the drug’s H DLelevation and LDL lowering vs. the small elevation inBP will greatly benefit patients with CV risk.

November 30, 2006



… and Throws in The Towel in the 3 rd








The DSMB monitoring ILLUMINATE recommendsterminating ILLUMINATE due to increased mortality a nd CV events(p=.007).

ILLUMINATE enrolled 15,003 pts. There were 82 death s in theT/A arm compared to 51 deaths in the atorvastatin ar m. The eventrate seen in the atorvastatin arm was consistent wit h the rateseen in other trials.

December 2, 2006

The Wall Street Journal; Pfizer Company press releases.



… and Throws in The Towel in the 3 rd








The DSMB monitoring ILLUMINATE recommendsterminating ILLUMINATE due to increased mortality a nd CV events(p=.007).

ILLUMINATE enrolled 15,003 pts. There were 82 death s in theT/A arm compared to 51 deaths in the atorvastatin ar m. The eventrate seen in the atorvastatin arm was consistent wit h the rateseen in other trials.

December 2, 2006

The Wall Street Journal; Pfizer Company press releases.

“The bigger they are, the harder they fall!”

$21 B



Surprise of an Early Demise

“I am surprised, but there was always the possibility that the drug might not work," Nissentold HeartWire. "I didn't think it would be harmful , and I didn't think we would know before the end of the trial. To know this early in a major morbidity and mortality trial is pretty surprising. ”

Torcetrapib Torpedoed: Increased Risk of Mortality, Cardiovascular Events Ends Development, Dec 4, 2006, HeartWire.



Agenda




What Are We Waiting To Find Out?

• Is it the molecule and limited to torcetrapib?– Blood Pressure?

• When rats, which lack CETP, were given torcetrapib, BP increased, indicating a molecular characteristic .

• Torcetrapib effectively raised HDL-C in early clini cal studies, but also slightly raised systolic blood pressure.

– Some other other unknown “off target” effect?

Missing pieces of the puzzle: It is not known at this time why there was an excess of deaths in the patients treated wit h torcetrapib.




• Is it the molecule and limited to torcetrapib?– Blood Pressure?

• When rats, which lack CETP, were given torcetrapib, BP increased, indicating a molecular characteristic .

• Torcetrapib effectively raised HDL-C in early clini cal studies, but also slightly raised systolic blood pressure.

– Some other other unknown “off target” effect?


Merck’s Peter Kim states, “People have been arguing about this for some time," Kim said. "We have no idea what target is being hit by torcetrapib. And when you don't know what's being hit, all bets are off.”

Staying the Course, Dec 20, 2006, Beth Herskovits, PharmExec Direct.




• Or is it the CETP target and potentially the whole class?– Does blocking CETP lead to increases in

dysfunctional HDL ?• Several recent studies have shown that

normal HDL is anti-inflammatory, but HDL from patients with cardiovascular disease is actually proinflammatory.


Nature Medicine. 2004;10(9).AAFP News Now, Clinical Trial Involving HDL-Raising Drug Halted December 6, 2006.




• Or is it the CETP target and potentially the whole class?– Does blocking CETP lead to increases in

dysfunctional HDL ?• Several recent studies have shown that

normal HDL is anti-inflammatory, but HDL from patients with cardiovascular disease is actually proinflammatory.


“Pfizer officials told the Washington Post they would comb through their research data to determine what had caused the heightened risk, but said that data gathered to date had not indicated blood pressure issues were related to an increased risk of death.”

Nature Medicine. 2004;10(9).AAFP News Now, Clinical Trial Involving HDL-Raising Drug Halted December 6, 2006.



Merck and Roche Are Cautiously Optimistic.

Staying the CourseDec 20, 2006 By: Beth Herskovits PharmExec Direct

Merck managers typically keep details of their R&D protocols close to the vest, but at their annual investors meeting last week, they confirmed rumors that they too are developing a CETP-inhibitor, the new class of anti-cholesterol drug whose fate has darkened since Pfizer pulled its much-hyped torceptrapib from Phase III trials two weeks ago.In announcing that Merck had entered the CETP-blocker race, the president of its research laboratories, Peter Kim, was uncharacteristically blunt about its prospects. "There is no question that there remain doubts, and that those doubts have been reinforced," he said. "We--like everyone else now--are waiting to see what additional information comes in." The company's MK-0859 has just completed an eight-week Phase IIb trial that showed no cardiovascular or blood pressure side effects.When pressed by an analyst, Kim acknowledged that he was one of the early skept ics of CETP-inhibitors. CETP, or cholesterol ester transfer protein, is involved in converting "good" HDL cholesterol into "bad" LDL cholesterol. But studies suggest that it also has a cardio-protective function, and that inhibiting it might produce defective HDL. Pfzer's large scale study--which saw a 50 percent greater mortality rate when torceptrapib was combined with Lipitor (atorvastatin)--has raised red flags among researchers, who now fear but that the entire approach causes more harm than good."You really have a big unknown," Kim said. "It is a field that is moving forward in terms of the characterization of HDL cells that are produced." Pfizer had been criticized for focusing its science on torceptrapib's ability to raise HDL rather than outcome studies on whether the drug could prevent heart attacks.Yet with the statin market crowded with brand and generic products, companies are still banking on HDL to breathe new life into the category."Raising HDL is a big field," said Allan Haberman, principal of Haberman Associates, a consulting firm that specializes in science and technology strategy. "People are certainly trying to do something beyond niacin," a popular HDL-raiser.Other leading CETP-inhibitor contenders include Roche, which is developing JTT705, and Avant Immunotherapeutics, which has an anti-CETP vaccine on deck, according to Haberman.Another approach to raising HDL involves the protein APOA-1, a major component of HDL. Pfizer-owned biotech Esperion Therapeutics is working on a recombinant version, but trials have been stalled by the expense and difficulty of making the large-molecule product. Novartis and Bruin are collaborating on a Phase I small-molecule drug that uses amino acid peptides to mimic APOA-1's effect.All of these programs are likely to continue--cauti ously--because of scant understanding of the catego ry. "People have been arguing about this for some time, " Kim said. "We have no idea what target is being h it by torceptrapib. And when you don't know what's being hit, all bets are off."

Staying the CourseDec 20, 2006 By: Beth Herskovits PharmExec Direct

Merck managers typically keep details of their R&D protocols close to the vest, but at their annual investors meeting last week, they confirmed rumors that they too are developing a CETP-inhibitor, the new class of anti-cholesterol drug whose fate has darkened since Pfizer pulled its much-hyped torceptrapib from Phase III trials two weeks ago.In announcing that Merck had entered the CETP-blocker race, the president of its research laboratories, Peter Kim, was uncharacteristically blunt about its prospects. "There is no question that there remain doubts, and that those doubts have been reinforced," he said. "We--like everyone else now--are waiting to see what additional information comes in." The company's MK-0859 has just completed an eight-week Phase IIb trial that showed no cardiovascular or blood pressure side effects.When pressed by an analyst, Kim acknowledged that he was one of the early skept ics of CETP-inhibitors. CETP, or cholesterol ester transfer protein, is involved in converting "good" HDL cholesterol into "bad" LDL cholesterol. But studies suggest that it also has a cardio-protective function, and that inhibiting it might produce defective HDL. Pfzer's large scale study--which saw a 50 percent greater mortality rate when torceptrapib was combined with Lipitor (atorvastatin)--has raised red flags among researchers, who now fear but that the entire approach causes more harm than good."You really have a big unknown," Kim said. "It is a field that is moving forward in terms of the characterization of HDL cells that are produced." Pfizer had been criticized for focusing its science on torceptrapib's ability to raise HDL rather than outcome studies on whether the drug could prevent heart attacks.Yet with the statin market crowded with brand and generic products, companies are still banking on HDL to breathe new life into the category."Raising HDL is a big field," said Allan Haberman, principal of Haberman Associates, a consulting firm that specializes in science and technology strategy. "People are certainly trying to do something beyond niacin," a popular HDL-raiser.Other leading CETP-inhibitor contenders include Roche, which is developing JTT705, and Avant Immunotherapeutics, which has an anti-CETP vaccine on deck, according to Haberman.Another approach to raising HDL involves the protein APOA-1, a major component of HDL. Pfizer-owned biotech Esperion Therapeutics is working on a recombinant version, but trials have been stalled by the expense and difficulty of making the large-molecule product. Novartis and Bruin are collaborating on a Phase I small-molecule drug that uses amino acid peptides to mimic APOA-1's effect.All of these programs are likely to continue--cauti ously--because of scant understanding of the catego ry. "People have been arguing about this for some time, " Kim said. "We have no idea what target is being h it by torceptrapib. And when you don't know what's being hit, all bets are off."

Kim acknowledged that he was one of the early skept ics of CETP-inhibitors. CETP, or cholesterol ester transfer pro tein, is involved in converting "good" HDL cholesterol into "bad" LDL ch olesterol. But studies suggest that it also has a cardio-protectiv e function, and that inhibiting it might produce defective HDL.




• What are the results on plaque regression by imaging?– IVUS + CIMT data to be presented at ACC meeting

(New Orleans, March 24, 2007).– What will it mean for imaging as a surrogate for

events?– Could rapid reduction in lipid content induce

arterial rupture and cardiac events?




We Are All Waiting for the Imaging Data, Especially IVUS



We Are All Waiting for the Imaging Data, Especially IVUSIf IVUS shows little or no effect, then…..

• HDL level as an independent CHD risk factor may be suspect.

• CETP inhibition and RCT are not simple.

• HDL-raising therapies need contextual validation.

• Torcetrapib lacks the ability to reverse atheroscle rosis.

If IVUS shows plaque reduction, then…

• The relationship between plaque burden as measured by IVUS and clinical events is in question.

• A setback for the validation of imaging as a surrog ate marker, and the possibility of reducing CHD drug development costs.

• There are consequences to CETP inhibition or torcet rapib therapy that offset disease reversal.

• The addition of torcetrapib worked, but off-target effects increased mortality.



Agenda




Potentially, Many People Could Benefit From HDL Therapeutics

• AHA estimates over 70M Americans have a cardiovascular condition.• Cardiovascular disease is the major cause of death in the US.

– In the US alone, heart disease accounts for nearly 700,000 deaths each year (51% of them women).

– Despite increased chance of survival of acute events, heart disease is still the leading cause of death for both women and men in the United States.

• Increased survival of acute events like myocardial infarction has increased the need for aggressive therapy for secondary prevention.

Causes of Deaths in US Annually (estimated 2006)

0

100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

Heart

Diseas

e

Cance

r

Stroke

COPDAcc

ident

sDiab

e tes

Lung

Infe

ction

Alzhe im

er's

Kidne

y dise

a seSep

ticem

ia

National Center for Health Statistics.

Nearly 40% of people who experience a cardiovascular event have low HDL levels



Forecasted Revenue by Therapeutic Category

0

20,000

40,000

60,000

80,000

100,000

120,000

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

US

$ (

mln

)

Hematology Cardiovascular Neurology Dermatology Endocrine Gastro-Intestinal

Genito-Urinary Musculoskeletal Oncology Respiratory Anti-infectives Others

Cardiovascular Disease as a Therapeutic Category is Declining in Revenue• CVD is a shrinking market among the therapeutic areas in terms of

share of contribution to the overall pharmaceutical market.– Decline is largely driven by generic erosion of off-patent products.– Genericization will greatly accelerate in 2011 when generic versions of

Lipitor (Pfizer) and Plavix (BMS, s-a) become available.

Evaluate Pharma, DH analysis.

22% Contribution

22% Contribution

19% Contribution



0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

US

$ (

mln

)

ACE inhibitors Angiotensin II antagonists Beta blockers Calcium antagonists Diuretics Anti-arrhythmics Nitrates/Nitrites Anti-hyperlipidaemics Cerebral & peripheral vasotherapeutics Antithrombotics Others

Statins, ARBs and Anti-thrombotics Have been Leading Growth, But Are Now Losing Ground

Total Worldwide CV Therapeutic Category Sales, 1987 - 2005

Evaluate Pharma

WW Sales ($M)

Evaluate Pharma, DH Analysis

Major categories of cardiopreventiondrugs are soon to be genericized.



Statins and the Transformation of CV Medicine

PhRMA: Value of Medicine 2006.



There is No More Statin Action

RIPRIPMevacor

1987 1987 1987 1987 ---- 2001200120012001

RIPRIP

Pravachol

1989 1989 1989 1989 ---- 2005200520052005

RIPRIPZocor

1988 1988 1988 1988 ---- 2005200520052005

RIPRIPLipitor

1997 1997 1997 1997 ---- 2010201020102010

RIPRIP

Crestor

2002 2002 2002 2002 ----2015201520152015

• In the next 4 years all statins except Crestor will be generic.• No late-stage follow-ons to the currently marketed s tatins.• According to the databases, at least 16 statins hav e been

discontinued or suspended.



0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2006E 2007E 2008E 2009E 2010E 2011E 2012E 2013E 2014E 2015E 2016E 2017E 2018E

All LDL Lowering Products - Patient Share (%)

Zetia

Vytorin

BAS (WelChol, etc.)

Lipitor

Crestor

Generic Statins

All Other LDL Lowering Drug Brands

Majority of Statin Scripts Are Forecasted to be for Generic Alternatives By 2011

Evaluate Pharma, DH analysis.

% T

otal

Tre

ated

Pat

ient

s



Today’s Cholesterol Drugs Account for a Large Proportion of Cardiovascular Franchise Sales...

Evaluate Pharma.

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

18,000

20,000

Pfizer

Merck

Novarti

sAstr

aZen

eca

BMSsa

nofi-

aven

tis

Servie

rDaii

chi S

ankyo

Bayer

GlaxoS

mithKl in

eU

S $

(m

ln)

Others

Cardiac therapy

Diuretics

Anti-hyperlipidaemics

Cerebral & peripheral vasotherapeutics

Beta blockers

Calcium antagonists

Angiotensin II antagonists

ACE inhibitors

WW CV Sales ($M, 2005)

…soon to be lost.



Agenda




Evaluate Pharma.

The Value of a Few Validated Surrogates?

Hyper-tension

Dys-lipidemia

LDL HDL

14%16%% of Pharma Market

$31.8B$29.5BCholesterol(LDL-C)

$38.5B$39.5BHypertension(Blood Pressure)

Sales 2010(E)Sales 2006

Surrogate

Could HDL be the next big surrogate?



Surrogate marker can be objectively measured as an independent indicator of a biological process.

1

Marker can be used to assess a pharmacological response.2

A change in the status of the surrogate marker is associated with clinical endpoints (i.e., how a pat ient feels, functions, survives).

3

What Are The Criteria to Validate a New Surrogate?

Hyper-tension

Dys-lipidemia

Diabetes

BP LDL HDL

LPAATrig

HbA1c

Basic Criteria for a Clinically Useful Surrogate Ma rker

Circulation 2006; 113:2936-2942.

Smoking Exercise Obesity

BMI WC



While LDL-C is Recognized as a Surrogate Marker, HDL-C Has Never Been Validated

• LDL– The outer layer of LDL contains free

cholesterol, ApoB, phospholipids and other proteins, such as the enzyme paraoxonase.

– The inner hydrophobic core of LDL is rich in cholesteryl esters and small amounts of triglycerides.

– Increased by a high fat diet, obesity, diabetes, thyroid disease, liver disease, renal disease.

– Reduced by diet, exercise and pharmacotherapy.

• HDL– The outer layer of HDL contains

free cholesterol, Apo A-I, Apo A-II, Apo C, Apo E, phospholipids and other proteins, such as the enzyme paraoxonase.

– The inner hydrophobic core of HDL is rich in cholesteryl esters and small amounts of triglycerides.

– Reduced by diabetes, obesity, smoking, progesterone, lack of exercise.

– Increased by weight loss, exercise, smoking cessation, estrogen, alcohol consumption and pharmacotherapy.Lipidsonline.org; Resverlogix company website.



HDL Epidemiologic Data

Framingham Study

Lipid Research Clinic’sFollow-up Study

Multiple Risk Factor Intervention Trial

Coronary Primary Prevention Trial

ObservationalStudies

Randomized Controlled

Studies

Correlations

• Inverse relationship between HDL-C and CHD

• 2-3% decrease in CHD risk for each 1 mg/dL increase in HDL-C

Correlations

• Inverse relationship between HDL-C and CHD

• 2-3% decrease in CHD risk for each 1 mg/dL increase in HDL-C

The American Journal of Medicine (2005) 118, 1067-1077.

There is strong correlative evidence linking low HDL level to increased CHD risk.



“… LDL is the culprit behind the accumulation of atheroma, but it does not have any role in removing cholesterol. That is the job of HDL. We have to tar get both LDL and HDL. We're not going to abandon LDL an d the statins, but we need to add in HDL-raising ther apy. With LDL lowering we have been stuck with a 35% reduction in event rates. That is wonderful if you are one of those 35%, but it's not so great if you are one of the other 65%...”

Dr. Steven Nissen, 2004

“HDL cholesterol: The next target in the battle against heart disease,” HeartWire, Apr 21, 2004.

We Have to Target Both LDL and HDL



Cardiologists Accept the Use of HDL-Raising Therapies

In the survey of 50 cardiologists who routinely pre scribe statins, 88 percent agreed that raising HDL is a vital inter vention in decreasing the risk for coronary artery disease , while only 2 percent strongly disagreed . When asked about treatment preferences for patients with low HDL whose LDL and triglyceridelevels were being controlled by statins, cardiologists in the survey overwhelmingly said they would intervene to raise HDL. In a primary prevention setting – attempting to prevent a first h eart attack or stroke – 86 percent of physicians said they would pr escribe medicines to raise HDL, while a whopping 94 percent said the same about treating patients who have already had a heart attack or stroke.

Reuters, Nov 29, 2006.



A-I

Liver

CE

CEFCFC

LCATFC

Bile

SR-BI

A-I

ABC1

Macrophage

CE BCETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein

LDLR

VLDL/LDL

CETP

Mature HDLNascent HDL

CE

SRA

Oxidation

Multiple Benefits of Increased HDLIn-vitro and in-vivo studies lend support to epidemiologic and clinical data; demonstrating that the HDL particle may work against CVD at several levels.

Lipidsonline.org

Reducing Oxidation

Decreasing Inflammation

↑NO

↑NO↑NO

↑NO

↑NO↑NO

↑NO

Improving Endothelial Function



Clinical Trial Data on HDL Raising Therapies

Am J Cardiol. 2006;98:1542–1549.

Selected clinical trials of high-density lipoprotei n cholesterol-increasing therapy



Clinical Trial Data on HDL Raising Therapies

Am J Cardiol. 2006;98:1542–1549.

Selected clinical trials of high-density lipoprotei n cholesterol-increasing therapy

Several drugs that raise HDL reduce cardiac events!



Direct Evidence of Disease Reduction

Animals

Apo E-deficient, cholesterol-fed mice

Single 400 mg/Kg infusion

40-50% lowering of lipid content & 29-36% reduction of macrophages in

plaques

Increase in LDL at 48hrs

Animals

Apo E-deficient, cholesterol-fed mice

Single 400 mg/Kg infusion

40-50% lowering of lipid content & 29-36% reduction of macrophages in

plaques

Increase in LDL at 48hrs

Humans

Acute Coronary Syndrome patients

Single 15 or 45 mg/Kg infusion every week (5 wks)

1-4% reduction in atheroma volume

No change in lumen volume

No dose dependence

Humans

Acute Coronary Syndrome patients

Single 15 or 45 mg/Kg infusion every week (5 wks)

1-4% reduction in atheroma volume

No change in lumen volume

No dose dependence

The most direct evidence that raising HDL-C may benefit patients with CVD involved injection of Apo A-IMilano into animals and humans. In both cases, there was a rapid and significant reduction in plaque burden.

Circulation. 2001;103:3047-3050; JAMA 2003; 390(17):2292-2300.



Epidemiologic Data

Clinical Data Preclinical Data& Basic Research

Direct Injection &Imaging Studies

HDL, the “good” cholesterol

Convergence of Evidence:

• Implicates low HDL as a CVD risk factor• Suggests there is promise for HDL-raising therapy

• However, in the wake of torcetrabip, questions arise about the correlation between causality and this converging evidence.

Defined Health



Wait, the Epidemiologic Data Look More Complex Than Do Those for LDL-C

J Clin Invest. 1980 November; 66(5): 892–900.

• Familial inheritance of low HDL and reduced risk?

– In 1980, families were identified in Limone that had reduced CHD and increased longevity.

– Paradoxically, these patients had low Apo A-I and HDL-C levels (10-30 mg/dL) and moderate hypertriglyceridemia, but lacked preclinical atherosclerosis or premature CAD.

• Apo A-IMilano (Arg173→Cys)– The Cys allows disulfide bridges to form and

alters amphipathicity. – Facilitates increased cholesterol sequestration

from arteries.– Accelerates cholesterol clearance via RCT.– May have additional cardioprotective benefits.

Apo A-I Milano: Low HDL-C and Decreased CHD



Wait, the Epidemiologic Data Look More Complex Than do Those for LDL-C

• Conversely, in 2000 it was described that some people with high HDL are at increased risk– White women with higher HDL-C (homozygous CETP mutation)

were at 2.1-fold greater risk for CHD than the general population.– In another study, a CETP promoter polymorphism, which leads to

higher HDL-C, is associated with increased incidence of coronary disease in the general population.

• HDL particles from these people were shown to behave in ways that could promote the build up of cholesterol in the artery walls rather than protect against it.

Circulation. 2000;101:1907-1912; Circulation. 2003;108:2751–2756; J Clin Endocrinol Metab.2006;91:3382-3388.

Hyperalphalipoproteinemia (HALP): High HDL and Increased CHD



Basic Research Was Not Able to Identify the Rate-Limiting Step in RCT.

Khairul Alam, Robert S. Meidell, and David K. Spady ‡

Effect of Up-regulating Individual Steps in the Rev erse Cholesterol TransportPathway on Reverse Cholesterol Transport in Normoli pidemic Mice*

• Each step in RCT was upregulated to determine the relationship to serum HDL and sterol excretion.

• The study demonstrates that cholesterol can be compartmentalized and redistributed, but no individual step increases excretion.

JBC 2001; 276(19):15641–15649.



Basic Research Was Not Able to Identify the Rate-Limiting Step in RCT.

Khairul Alam, Robert S. Meidell, and David K. Spady ‡

Effect of Up-regulating Individual Steps in the Rev erse Cholesterol TransportPathway on Reverse Cholesterol Transport in Normoli pidemic Mice*

• Each step in RCT was upregulated to determine the relationship to serum HDL and sterol excretion.

• The study demonstrates that cholesterol can be compartmentalized and redistributed, but no individual step increases excretion.

JBC 2001; 276(19):15641–15649.

Conclusion: Although rHDLstimulated cholesterol efflux from most tissues and increased net cholesterol movement from extrahepatic tissues to the liver, cholesterol flux through the entire RCT pathway was not increased.



Relation of HDL-C Increase and Outcomes is MurkySelected clinical trials of high density lipoprotei n

cholesterol-increasing therapy

Am J Cardiol. 2006;98:1542–1549.



Relation of HDL-C Increase and Outcomes is MurkySelected clinical trials of high density lipoprotei n

cholesterol-increasing therapy

Many drugs that raise HDL reduce cardiac events, bu t not necessarily independently from other putative risk factors

Am J Cardiol. 2006;98:1542–1549.



Is CETP the Right Target?

Endogenous CholesterolProduction

Statins

A-I

Liver

CE

CEFCF

C

LCATFC

Bile

SR-BI

A-I

ABC1

Macrophage

CE BCETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein

LDLR

VLDL/LDL

CETP

Mature HDLNascent HDL

CE

SRA

Oxidation

Lipidsonline.org.

• There are many steps in RCT which may need to be stimulated to drive net removal of cholesterol.



• Torceptrapib achieved HDL increases, but may have done so without increasing the rate of RCT.

1. Atorvastatin reduces endogenous cholesterol production.

2. CETP inhibitors block the conversion of HDL to LDL/VDL.

3. CETP also potentially blocks hepatic uptake of cholesterol originating from HDL “offloaded” to VLDL.

4. However, torcetrapib does not significantly influence fecal sterol excretion.

Is CETP the Wrong Target?

• CETP inhibition increases particle size, leading to large dysfunctional, “Constipated HDL”.



When Good Cholesterol Goes Bad

• Products of an inflammatory enzyme, myeloperoxidase, are now shown to selectively target the main protein in HDL, apolipoprotein A-I.

• This turns the ‘good cholesterol’ bad, and the HDL particles may become proatherogenic.

Nature Medicine. 2004;10(9).



"We knew that torcetrapib increased blood pressure, so at least one possible explanation is that the increase in mortality is all blood-pressure related, and that it's not the mechanism of HDL raising," said Nissen. "However, I also think there is a distinct possibility that the type of HDL that is produced when you inhibit CETP is actually proatherogenic rather than antiatherosclerotic.”

Torcetrapib Torpedoed: Increased Risk of Mortality, Cardiovascular Events Ends Development; Dec 4, 2006, HeartWire.



Agenda




In the Wake of Torcetrapib, Have We Hit the Hitting the Wall in Cardioprevention?

• If failure of torcetrapib is target-based, the outlook for other CETP inhibitors could be quite cloudy.

Drug Company HighestPhaseJTT 705 Roche IIMK 0859 Merck & Co IIJTT 302 Japan Tobacco IResearch program Bayer PreclinicalResearch program Transition Therapeutics PreclinicalPD 140195 Pfizer No development reportedWiedendiol A Nonindustrial source, Schering-Plough No development reportedWiedendiol B Nonindustrial source, Schering-Plough No development reportedCGS 25159 Novartis No development reportedErabulenol A Nonindustrial source No development reportedSC 744 Pharmacia Corporation No development reported

Adis R&D Insight.



In the Wake of Torcetrapib, Have We Hit the Hitting the Wall in Cardioprevention?

• There are few truly innovative molecules in the clinic.• Developing new CVD drugs for the broad market will be

challenging:– New agents must be tested on top of an increasingly effective

SOC.– Since SOC therapy has already reduced hospitalization and

mortality dramatically, trials to collect enough events and demonstrate significant improvement are becoming increasingly large and expensive.

– Accordingly, the safety data collected from these large trials have increased the hurdles for new entrants in terms of toxicity.

• Few significant changes in the management of patients are foreseen over next 5 –10 years.



Clinical Trials in Cardiovascular Medicine in an Er a of Marginal Benefit, Bias, and Hyperbole

“Over the past three decades, mortality rates for highly prevalent cardiovascular diseases, including acute coronary syndromes, heart failure, and sudden death, have continuously improved owing to the clea r benefits of therapies proved to be efficacious in double-blind, randomized, controlled trials. With these mounting, cumulative successes, however, the marginal benefit of any proposed intervention decreases. Realistic limits, both operational and financial, to the size of study samples decrease th e statistical power and the absolute treatment effect detectable in these trials.” Joseph Loscalzo

Clinical Trials in Cardiovascular Medicine in an Era of Marginal Benefit, Bias, and hyperbole. Circulation 2005, 112:3026-3029



Continuing Late Stage Blow-ups

• Expensive late-stage CVD trial failures have been far too frequent.• The rising efficacy bar and safety hurdle have decreased the

predictability of Phase III success based on Phase II success.• In the debate of the value of surrogate markers, outcomes data have

become a prerequisite for FDA approval.

Short-acting GP IIb/IIIa Inhibitors (“Super Aspirins”)

(OPUS TIMI-16 (2000), EXITE, SYMPHONY I/II, BRAVO)

2001 2002 20052000 2003 2004

VasopeptidaseInhibitors

“Super ACEs”(OVERTURE)

Dual-Acting PPARs

(CV 168022)

Oral Factor Xa

(THRIVE-1, SPORTIF)

DH analysis, company news releases, clinicaltrials.gov.

CETP Inhibitors?

(ILLUMINATE)



NaturePublished online: 3 January 2007; | doi:10.1038/445013a

When the party's overA drug-trial failure leaves Pfizer in search of a n ew corporate strategy to deal with the post-blockbuster age, as Meredith Wadman reports.

The world's largest drug company starts 2007 in need of a fresh start. Most of all, Pfizer has to put aside the end of 2006, when it was forced to pull the plug on its eagerly anticipated cholesterol-lowering drug torcetrapib. The compound was found to be associated with unacceptably high death rates in a late-stage clinical trial involving 15,000 people (see Nature 444, 794–795; 2006).

This is no run-of-the-mill failure. Pfizer's current cholesterol drug Lipitor brings the company more than $12 billion in annual revenues, but loses patent protection in 2011. The company was counting on torcetrapib to replace those sales. The news sent Pfizer shares down 10% in a day, dissolving $21 billion in market capitalization.

There's still an outside chance that Pfizer could replace Lipitor: two chemical cousins of torcetrapib — known as cholesterol esterase transfer protein (CETP) inhibitors — are in early development. Steven Nissen at the Cleveland Clinic is using ultrasound scanning of torcetrapib's effect on plaque build-up in the coronary arteries to see if its toxicity was a quirk — in which case the other compounds might prove viable.

But no one is betting on it. For Pfizer's 106,000 staff, the failed trial was the culmination of an inauspicious year. Long-time chief executive Hank McKinnell was replaced in July by lawyer Jeffrey Kindler. And only days before the drug trial was abandoned on 2 December, the company said it would lay off more than 2,000 sales representatives — 20% of the sales force. This was seen as another move in Pfizer's quest to keep Wall Street satisfied in the face of expiring patents and anaemic drug pipelines.

In this environment the company's 13,000 researchers are entitled to worry about their future. "There appears to be a pattern to right-sizing the organization, that probably implies either trimming research and development or, at least, investigating whether it should be trimmed," says Tony Butler, a pharmaceuticals analyst with Lehman Brothers in New York.

Peter Rost, a company gadfly and former Pfizer marketing vice-president, now in litigation with the firm over the circumstances of his departure in 2005, is more direct. "It's very likely that Pfizer is going to pull back on personnel in all areas, including research," he says. Rost's blog, http://peterrost.blogspot.com, has been abuzz with chat on the circumstances and implications of the trial failure.











… putting its own laboratories on the chopping block won't help Pfizer unless it recognizes that the era of blockbuster drugs — those generating more than $1 billion in annual revenue — is over.











… putting its own laboratories on the chopping block won't help Pfizer unless it recognizes that the era of blockbuster drugs — those generating more than $1 billion in annual revenue — is over.

… Pfizer is not immune to the enormous risk and costliness of drug development — and the problems that come with late failures," Kenneth Kaitin of TCSDD says. "It must adapt its research and development strategy to focus on products that address smaller markets — and that can be brought to market more quickly, efficiently and at a lower cost."



Agenda




Nicotinic acid as an extended-release formulation has been developed by Kos Pharmaceuticals (a subsidiary of Abbott Laboratories) in the USA. Nicotinic acid has a positive effect on the complete lipid profile. However, as the immediate-release formulation it produces flushing, an intolerable adverse effect. To overcome this a sustained-release formulation was produced. This reduced flushing but was associated with a high incidence of adverse hepatic effects. With the extended-release formulation developed by Kos, there is a reduction in flushing and hepatotoxic events.

NCEP ATP III has recognized that niacin (the active ingredient in NIASPAN® niacin extended-release tablets), is one of the most effective lipid regulators for raising HDL-C. It also favorably affects lipid and lipoprotein parameters, including total cholesterol (TC), LDL-C, TG, and Lp(a).

Niacin alone reduces cardiac events and mortality versus placebo. This evidence was leveraged for Niaspan’s approval.

Would the failure of CETP inhibitors elevate niacin’s status within the primary prevention setting?

For the Near Term, HDL Therapeutics = Niacin

www.niaspan.com



Macromolecules Peptides Small Molecules

• Several interesting approaches to raising HDL-C or stimulating RCT are being tested.

• However, most candidates are early in development.

• Should torcetrapib’s failure prove to be target-based, there are no late-stage compounds outside of improved versions of niacin which can capitalize on the fall of CETP inhibitors.

• A gap in the primary prevention pipeline, following the genericizing of statins, may be inevitable.

Other Opportunities in the HDL/RCT Pipeline Are a Long Way Off




• Macromolecules including Apo A-I and HDL variants or mimetics and liposomes offer the potential to diminish CHD by stimulating RCT.

• Issues of delivery may hinder widespread use of these agents in the primary prevention setting.

• However, they may offer benefits to patients with advanced disease as well as a proof of principal for therapies that modulate RCT.

Drug Company Highest PhaseETC-216 Esperion/Pfizer Phase IIETC-588 - Liposome Esperion/Pfizer Phase IIETC-642 Esperion/Pfizer Phase ITrimeric ApoA-I Borean/Roche PreclinicalDelipidated HDL Lipid Sciences PreclinicalCerenis HDL Cerenis Therapeutics Preclinical

Adis R&D Insight.




• These candidates are short (<25 mer) peptide Apo A-I mimetics. • APP 018 (D 4-F) and reverse D-4F were shown to decrease

atherosclerotic lesion in apolipoprotein E knock-out mice. • Interestingly, they did not affect plasma total cholesterol, HDL-

cholesterol, or non-HDL-cholesterol levels like ETC-642. • APP 018 and reverse D-4F have the upside of oral bioavailability.

Drug Company Highest PhaseAPP 018 BruinPharma/Novartis Phase IReverse D-4F Arisaph/ Kos Pharmaceuticals Preclinical

Adis R&D Insight



Macromolecules Peptides

• Small molecule candidates may be sub-divided according to mechanism of action and include: PPARδ agonists, LXR agonists, and agents with miscellaneous mechanisms.

PPARδ Agonists Other MechanismsLXR Agonists

Small Molecules





Small Molecules

Drug Company Highest PhaseGW501516 GlaxoSmithKline, Ligand Pharmaceuticals Phase IIRWJ 800025 Ortho-McNeil/Metabolex Phase IKD-3010 Kalypsys Phase IResearch program Eli Lilly PreclinicalResearch program Metabolex PreclinicalResearch program Nippon Chemiphar/Cerenis PreclinicalResearch program sanofi-aventis Preclinical

Activation of PPARδ induces the expression of genes important for cellular fatty acid combustion and an associated increase in whole-body lipid dissipation. Apart from effects on fuel turnover, there is evidence for direct antiatherogenic properties, because PPARδ activation increases cholesterol export and represses inflammatory gene expression in macrophages and atherosclerotic lesions. In its first study in humans, GW501516 significantly raised HDL-C and reduced TGs in healthy volunteers.

Arterioscler Thromb Vasc Biol. 2006 Nov 16; [Epub ahead of print] ; Adis R&D Insight.





Small Molecules

Drug Company Highest PhaseLiver X receptor modulator Karo Bio/Wyeth Phase ILiver X receptor modulator Karo Bio/Wyeth PreclinicalLiver X receptor modulator Exelixis/Bristol-Myers Squibb PreclinicalGW-3965 GlaxoSmithKline PreclinicalLiver X receptor modulator 7TM Pharma PreclinicalLiver X receptor modulator Phenex Pharmaceuticals PreclinicalLiver X receptor modulator Roche Preclinical

LXR is an orphan nuclear receptor that has alpha and beta forms. Both forms are involved in controllingcholesterol metabolism by regulating the gene expression of proteins involved in cholesterol efflux from cells. Endogenous LXR ligands are oxidized sterols including oxycholesterols. LXR agonists may have the potential to lower cholesterol levels without increasing triglycerides. It has been shown that LXR's can stimulate reverse cholesterol transport from macrophages by upregulating ABCA1, ABCG1 and ApoE, thus LXR modulators could potentially have a dual effect by removing cholesterol from macrophages and inhibiting vascular inflammation. This could result in the inhibition of atherosclerotic lesion formation.

Adis R&D Insight.





Small Molecules

These compounds have less well-defined mechanisms of action but share in common the ability to raise HDL-C levels in humans or animal. GFT14 is a combination drug that raises HDL-C and lowers triglycerides. ETC-1011 is a novel lipid regulator that can raise HDL-C levels. AZD-2479 increased HDL-C and lowered LDL-C in animal models. Resverlogix is developing polyphenol compounds that stimulate production of ApoA-I and raise serum HDL-C.

Drug Company Highest PhaseGFT 14 Genfit Phase IIAZD-2479 Avanir/AstraZeneca Phase IETC-1001 Esperion/Pfizer Phase IResveratrol/Polyphenol compounds Resverlogix Corporation Preclinical

Adis R&D Insight.



Agenda




Documents

HDL Therapeutics in the Wake of Torcetrapibknowledgebase.definedhealth.net/wp-content/uploads/... · Dr. John LaMattina , Senior Vice President, Pfizer Inc. and President, Pfizer