TATA--CD CD –– the antithe anti--cocaine vaccinecocaine vaccine

Nicolette Ebsworth, PhDNicolette Ebsworth, PhD

Project LeaderProject Leader

Celtic Celtic PharmaPharma Development Services LtdDevelopment Services Ltd

SummarySummary

•• Cocaine addiction is a serious problem in the US and EU. Cocaine addiction is a serious problem in the US and EU.

•• There are currently no There are currently no pharmacotherapiespharmacotherapies to help addicts to to help addicts to quitquit

•• TATA--CD is a novel approach to treatment, targeting cocaine in CD is a novel approach to treatment, targeting cocaine in circulationcirculation

•• Proof of concept established in preclinical studiesProof of concept established in preclinical studies

•• Phase I and II studies have shown Phase I and II studies have shown

– vaccine is safe and well tolerated

– promising indications of efficacy

•• Phase Phase IIbIIb study (132 patients, randomised, placebostudy (132 patients, randomised, placebo--controlled) is due to report June 2006controlled) is due to report June 2006

Cocaine Addiction Cocaine Addiction –– the problemthe problem

•• USUS

– 2m regular cocaine users in US1

– 25% Americans between ages 26-34 used cocaine2

– 33.9m Americans age >12 reported lifetime use of cocaine3

– 500,000 emergency hospital visits annually2

•• EUEU

– Up to 10% lifetime prevalence in 15-34 age group4

– 4% recent prevalence in UK and Spain4

1 Office of Applied Studies, 2002 National Survey on Drug Use and Health2 Drug-Rehab.org3 NIDA, figures for 20024EMCDDA, 2004

The AThe A--Z (almost!) of cocaine treatment so farZ (almost!) of cocaine treatment so far

baclofenbaclofencabergolinecabergoline

disulfiramdisulfiram

effexoreffexorfluoxetinefluoxetine

GVGGVG

Help!Help!

isradipineisradipineJavaJava

ketoconazoleketoconazole

lamotraginelamotragine

modafinilmodafinil

naltrexonenaltrexoneondansetronondansetron

pergolidepergolide

quitiapinequitiapine

risperdolrisperdol

sertralinesertraline

tiagabinetiagabineUC2JokesUC2Jokes venlafaxinevenlafaxine

w

amantadineamantadine

x y z to follow!

Features of cocaine addictionFeatures of cocaine addiction

•• Addiction is a chronic relapsing disorderAddiction is a chronic relapsing disorder

•• When cocaine is taken, it is transported rapidly to the When cocaine is taken, it is transported rapidly to the brainbrain

•• Speed of transport depends on how cocaine is takenSpeed of transport depends on how cocaine is taken

•• It is the quantity and speed of delivery of cocaine into It is the quantity and speed of delivery of cocaine into the brain that is important in generating the highthe brain that is important in generating the high

•• ““PrimingPriming”” is associated with this effect, often leading is associated with this effect, often leading to bingingto binging

A strategy for cracking cocaine addictionA strategy for cracking cocaine addiction

•• Addiction is a chronic relapsing disorderAddiction is a chronic relapsing disorder

•• It is very unlikely that an addict will quit unless It is very unlikely that an addict will quit unless highly motivatedhighly motivated

•• It is expected that a patient will lapse during It is expected that a patient will lapse during treatmenttreatment

•• Priming contributes to turning a lapse into a bingePriming contributes to turning a lapse into a binge

•• Priming is a function of the rate and extent of cocaine Priming is a function of the rate and extent of cocaine entry into the brainentry into the brain

•• Blocking the priming effect can keep a lapse from Blocking the priming effect can keep a lapse from becoming a full blown relapsebecoming a full blown relapse

Vaccination Vaccination –– a novel approach to cocaine a novel approach to cocaine addictionaddiction

•• Vaccinate the patientVaccinate the patient

•• Patient makes antibodiesPatient makes antibodies

•• Antibodies remain in circulation for several monthsAntibodies remain in circulation for several months

•• If the patient takes cocaine, it is bound by circulating If the patient takes cocaine, it is bound by circulating antibodiesantibodies

•• Antibody:cocaineAntibody:cocaine complexes cannot cross the bloodcomplexes cannot cross the blood--brain barrier. The amount of cocaine reaching the brain barrier. The amount of cocaine reaching the brain and also the speed of delivery are thus reduced.brain and also the speed of delivery are thus reduced.

•• This reduces or prevents the high and the associated This reduces or prevents the high and the associated priming effectpriming effect

Vaccines of Addiction Vaccines of Addiction -- Product ConceptProduct Concept

Before vaccination After vaccination

Circulation

Blood:brainbarrier

Brain “reward”

Cocaine Antibodies produced

by immune system

Cocaine

no “reward”

TATA--CD Product DescriptionCD Product Description

•• Cocaine derivative (Cocaine derivative (succinylsuccinylnorcocainenorcocaine) coupled to ) coupled to recombinant cholera toxin B recombinant cholera toxin B ((rCTBrCTB))

•• Linked by a stable covalent Linked by a stable covalent bondbond

•• Aluminum hydroxide Aluminum hydroxide adjuvant addedadjuvant added

•• Given by intramuscular Given by intramuscular injectioninjection to upper armto upper arm

rCTB

SNC

TATA--CD CD –– PreclinicalPreclinical StudiesStudies

•• Proof of concept established in preProof of concept established in pre--clinical clinical modelsmodels– Vaccine induces cocaine specific antibodies

– Antibodies reduce levels of cocaine in brain

– Vaccination leads to a significant reduction in cocaine self administration in addicted rodents

Immunogenicity of TAImmunogenicity of TA--CD in miceCD in mice

10000001000001000010001000.0

0.5

1.0

1.5

2.0

2.5

IPC-14,551-immuneNormal Mouse Serum

1/Dilution

O.D

. 450

nm

TA-CD immunised

Non-immune

Duration of antibody response in miceDuration of antibody response in mice

200150100500100

1000

10000

100000

1000000

Day

Ant

i-coc

aine

ant

ibod

y tit

er

Mice bled on days25, 42, 70, 113, & 196

Day

Ant

i-coc

aine

ant

ibod

y tit

re

Specificity of immune responseSpecificity of immune response

1 0 0 0 01 0 0 01 0 01 01.1.0 1.0 0 10 .0

0 .2

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1 .0

1 .2

C o c a in eB e n z o y le c g o n in eE c g o n in e M e th y l E s te rN o rc o c a in eC o c a e th y le n eP ro c a in eC o c a in e -H E L c o n ju g a te

C o n c e n tra t io n (µ M )

O.D

. 450

nm

Concentration (µM)

OD

450

nm

● cocaine

norcocaine

▲ cocaethylene

ס benzoylecgonine

� ecgonine methyl ester

X procaine

∆ cocaine-HEL conjugate

Loss of cocaine from brain in immunised miceLoss of cocaine from brain in immunised mice

0

20

40

60

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0 10 20 30 40

Time (min)

Coc

aine

and

met

abol

ites

(ng/

g)

ControlImmunised

Effect of TAEffect of TA--CD on cocaine selfCD on cocaine self--administration administration in rats (i)in rats (i)

0

2

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IPC-14,551 with alum

Tota

l Inf

usio

ns

Bas

elin

e

Imm

une

No

coca

ine

Bas

elin

e

Imm

une

No

coca

ine

Alum

Effect of TAEffect of TA--CD on cocaine selfCD on cocaine self--administration administration in rats (ii)in rats (ii)

0

20

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60

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IPC-14,551 with alum

Bas

elin

e

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une

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coca

ine

Alum

Bas

elin

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Imm

une

No

coca

ine

Ave

rage

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n in

terv

al (m

in)

TATA--CD: Clinical Studies SummaryCD: Clinical Studies Summary

•• Completed:Completed:

– Phase I: TA-CD/01 - Safety and Immunogenicity (n = 30)

– Phase IIa: TA-CD/03 - Relapse Prevention (n = 9)

– Phase IIa: TA-CD/06 - Abstinence Initiation (n = 13)

•• In progress:In progress:

– Phase IIa: TA-CD/04 – Cocaine Challenge (n=11)

– Phase IIb: TA-CD/08 – Efficacy (randomised, double-blind placebo-controlled, n=132)

Phase I study designPhase I study design

•• PlaceboPlacebo--controlled double blind studycontrolled double blind study

•• 30 cocaine abstinent subjects in in30 cocaine abstinent subjects in in--patient facilitypatient facility

•• EndpointsEndpoints

– Safety

– Immunogenicity

•• 3 dose levels3 dose levels

– 13 µg, 82 µg, 709 µg

•• Newtown Ct, USA, Prof Tom Newtown Ct, USA, Prof Tom KostenKosten

TATA--CD Phase I study CD Phase I study -- safetysafety

•• Vaccine well toleratedVaccine well tolerated

– Mild injection site reactions, also found in placebo group

– No vaccine-related serious adverse events

•• No significant difference in adverse events between No significant difference in adverse events between placebo and active groupsplacebo and active groups

TATA--CD CD –– Phase I immunogenicityPhase I immunogenicity

0

50

100

150

200

0 50 100 150 200 250 300 350 400

Days

Anti-

coca

ine

antib

odie

s (u

nits

)

709µg82µg13µg

TATA--CD Phase CD Phase IIaIIa Study DesignStudy Design

•• Two studiesTwo studies

– Relapse Prevention (8 evaluable patients)

– Abstinence Initiation (12 evaluable patients)

•• EndpointsEndpoints

– Safety

– Immunogenicity

•• Two dose levelsTwo dose levels

– 82 µg, 360 µg

TATA--CD Phase CD Phase IIaIIa

•• SafetySafety

– Vaccine well tolerated

– No vaccine-related serious adverse events

– Some patients experienced mild injection site reactions

•• ImmunogenicityImmunogenicity

– Patients produced anti-cocaine antibodies in response to the vaccine

– Higher dose generally resulted in higher antibody levels

– Booster injection increased antibody levels which had dropped

Phase Phase IIaIIa –– ImmunogenicityImmunogenicity

M e a n R e s p o n s e s in 8 2 µ g a n d 3 6 0 µ g g r o u p s

0 2 4 6 8 1 0 1 2 1 4 1 60

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

3 0 0 0

3 6 0 µ g8 2 µ g

W e e k

Ant

ibod

y tit

re

Week

Ant

ibod

y tit

re

TATA--CD CD -- Phase Phase IIaIIa -- efficacyefficacy

•• Relapse prevention: Relapse prevention:

– 6/8 maintained abstinence during 12 wk study

•• Abstinence initiation: Abstinence initiation:

– 7/12 achieved & maintained abstinence during 12 wk study

– 5/12 remained cocaine free after 6 months

•• Indication that higher antibody response correlates with Indication that higher antibody response correlates with reduced likelihood of using cocainereduced likelihood of using cocaine

•• Some of those patients who relapsed post vaccination Some of those patients who relapsed post vaccination reported a reduction in euphoric effects of cocainereported a reduction in euphoric effects of cocaine

TATA--CD CD -- Phase Phase IIbIIb

•• Study designStudy design

– 132 methadone dependent cocaine addicts

– Placebo controlled, randomized, double blind study

•• Primary end pointPrimary end point

– Quit rate as determined by at least 3 consecutive weeks of negative urine samples between weeks 8-20

•• Supported by NIDASupported by NIDA

•• Results due June 2006Results due June 2006

TATA--CD CD –– Future plansFuture plans

•• If Phase II data are positiveIf Phase II data are positive……

•• Plan to move rapidly intoPlan to move rapidly into

– Phase III US

– Phase III EU

•• ChallengesChallenges

– Treatment of cocaine addicts varies from country to country

• medically• healthcare system

– Success depends on patient receiving full course of vaccinations

SummarySummary

•• Cocaine addiction is a serious problem in the US and EU. Cocaine addiction is a serious problem in the US and EU.

•• There are currently no There are currently no pharmacotherapiespharmacotherapies to help addicts to help addicts to quit.to quit.

•• TATA--CD is a novel approach to treatment, targeting cocaine CD is a novel approach to treatment, targeting cocaine in circulationin circulation

•• Proof of concept established in Proof of concept established in preclinicalpreclinical studiesstudies

•• Phase I and II studies have shown Phase I and II studies have shown

– vaccine is safe and well tolerated

– promising indications of efficacy

•• Phase Phase IIbIIb study (132 patients, randomised, placebostudy (132 patients, randomised, placebo--controlled) is due to report June 2006controlled) is due to report June 2006

•• Positive data will trigger a rapid move into Phase III Positive data will trigger a rapid move into Phase III studiesstudies