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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
0 .4
0 .6
0 .8
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
80
100
120
140
160
180
200
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
4
6
8
10
12
14
16
18
20
22
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
40
60
80
100
120
IPC-14,551 with alum
Bas
elin
e
Imm
une
No
coca
ine
Alum
Bas
elin
e
Imm
une
No
coca
ine
Ave
rage
inte
r-inf
usio
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