A Randomized Placebo-Controlled Trial of Conjugate Nicotine Vaccine (Nicvax®) in Smokers Who Want to Quit: 12 Months Results
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AA RandomizedRandomized PlaceboPlacebo--ControlledControlled TrialTrial ofof aa ConjugateConjugate NicotineNicotine VaccineVaccine (NicVAX(NicVAX®)) inin SmokersSmokers WhoWho WantWant toto Quit:Quit: 1212 MonthMonth ResultsResults Stephen Rennard, Douglas Jorenby, David Gonzales, Nancy Rigotti, Arjen de Vos, Enoch Bortey, Roxanne Akhavain, Dorothy Hatsukami U. Nebraska, U. Wisconsin, Oregon Health & Sciences U., Massachusetts General Hospital, Nabi Biopharmaceuticals, and U. Minnesota Supported by a grant from the National Institute on Drug Abuse PresenterPresenter DisclosureDisclosure InformationInformation Stephen I Rennard A Randomized Placebo-Controlled Trial of Conjugate Nicotine Vaccine (NicVAX®) in Smokers Who Want to Quit: 12 Months Results NicVAX® is investigational DISCLOSURE INFORMATION: The following relationships exist related to this presentation: University of Nebraska Medical Center (S. Rennard, PI) received a research contract from Nabi to conduct this and one other clinical trial Since 2006, Dr. Rennard has conducted clinical trials or consulted with the following companies on the topic of smoking cessation: Pfizer, Novartis, GSK NicotineNicotine LevelsLevels inin aa SmokerSmoker Light Smoker High Withdrawal Nicotine Level Time of the day 33’’aminomethylaminomethyl NicotineNicotine –– RecombinantRecombinant Ps.Ps. aeruginosaaeruginosa ExoproteinExoprotein AA ((rEPArEPA)) ConjugateConjugate N NH2 O CH3 N + O + H2N rEPA N Nicotine O CH3 N 3’ aminomethyl Nicotine O NH NH AMNic O rEPA rEPA N CH3 N + alum (Adjuant) AMNicAMNic--rEPArEPA (NicVAX)(NicVAX) AntibodiesAntibodies Function:Function: CaptureCapture ReleaseRelease MechanismMechanism Blood Brain N I C V A X PhasePhase 22 Study:Study: KeyKey QuestionsQuestions ff DetermineDetermine mostmost effectiveeffective dosedose andand immunizationimmunization scheduleschedule ff DetermineDetermine ifif vaccinationvaccination isis associatedassociated withwith longlong termterm quitsquits ff DetermineDetermine ifif antibodyantibody responseresponse isis associatedassociated withwith longlong termterm quitsquits 6 NicVAXNicVAX PhasePhase IIbIIb TrialTrial DesignDesign A randomized, double-blind, placebo-controlled trial WeekWeek 0 4 8 12 16 20 24 26 52 Schedule 1 Schedule 1 N=50 400 µg NV TQD=7 weeks 400µg NicVAX N=50N=50 200 µg NV Follow Up N=50 200µg NicVAX Follow Up N=50N=50 Placebo (PBS + alum) TQD Week 7 Placebo (PBS) Schedule 2 26 N=51 400 µ 400 µg NV Follow Up N=50 200 µ 200 µg NV N=50 Placebo (PBS + alum) TQD Week 5 1° Endpoint Final 8 weeks Continuous Abstinence: 2 wk post TQD to 12 mo StudyStudy PopulationPopulation NicVax Placebo Demographics n=201 n=100 n=201 n=100 Baseline Smoking NicVAX Placebo Characteristics N=201 n=100 Males 54% 50% Gender Mean Number Females 46% 50% Mean Number Cigarettes 24.3 24.8 Age Mean Age 48 47 Smoked Per Day Ethnicity Not Hispanic 98% 98% Mean FTND Score 6.12 6.05 Asian 1% 3% Black 5% 7% Subjects with at Race Islander 1% 0% least 1 previous 96% 96% quit attempt White 91% 88% Other 2% 2% EarlyEarly TerminatedTerminated Subjects*Subjects* Schedule 1 Schedule 2 Placebo 200 µg 400 µg 200 µg 400 µg All Subjects 100 50 50 50 51 Early Terminated Total 33 (33%) 16 (32%) 12 (24%) 24 (48%) 22 (43%) Lost to Follow-Up 6 (6%) 5 (10%) 4 (8%) 5 (10%) 6 (12%) Non-Compliant with Protocol 1 (1%) 0 0 1 (2%) 2 (4%) Protocol Violation 000 02 (4%) Withdrawal of Consent 23 (23%) 11 (22%) 7 (14%) 16 (32%) 7 (14%) Adverse Event 2 (2%) 0 1 (2%) 2 (4%) 4 (8%) Other 1 (1%) 0 0 0 1 (2%) *All Early Terminations are coded as smoking thereafter. 9 AntibodyAntibody ConcentrationConcentration OverOver TimeTime ScheduleSchedule 11 && ScheduleSchedule 22 200 µg/Schedule 1 400 µg/Schedule 1 ) 200 µg/Schedule 2 ml / TQD TQD 400 µg/Schedule 2 g µ ( C Ab M G 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Study Week Schedule 1 Schedule 2 1212--MonthMonth ContinuousContinuous AbstinenceAbstinence Intent to Treat Population SScchheedduullee 11 SScchheedduullee 22 NNiiccVVAAXX 6%6% 1166%% 440000 µµgg (n=3/50)(n=3/50) (( nn==88//5511)) pp==00..9966 pp==00..003388 NNiiccVVAAXX 6%6% 1144%% 220000 µµgg (n=3/50)(n=3/50) ((nn==77//5500)) pp==00..8888 pp==00..005566 PPllaacceebboo 66%% ((nn==66//110000)) ContinuousContinuous AbstinenceAbstinence atat 1212 MonthsMonths byby AntiAnti--NicotineNicotine AntibodyAntibody LevelsLevels 1122--MMoonntthh AAbbssttiinneennccee NNiiccVVAAXX 1166%% High Antibody* ((nn==1100//6611)) pp==00..0033 NNiiccVVAAXX 88%% Low Antibody ((nn==1111//114400)) pp==00..4499 PPllaacceebboo 66%% ((nn==66//110000)) *Top 30% by AUC per protocol 12 ContinuousContinuous AbstinenceAbstinence atat 1212 MonthsMonths byby AntiAnti-- NicotineNicotine AntibodyAntibody Levels,Levels, DoseDose && ScheduleSchedule 12-Month Schedule 2 Schedule 1 Continuous Abstinence 400 µg 200 µg 400 µg 200 µg Rates (44 wks) NicVAX 21% 19% 13% 10% High Antibody* (n=4/19) (n=3/16) (n=2/16) (n=1/10) p=0.038 p=0.056 p=0.57 p=0.84 NicVAX 13% 12% 3% 5% (n=4/32) (n=4/34) (n=1/34) (n=2/40) Low Antibody p=0.22 p=0.23 p=0.36 p=0.55 Placebo 6% (n=6/100) *Top 30% by AUC per protocol AntibodyAntibody--DependentDependent ReductionReduction inin CigaretteCigarette ConsumptionConsumption inin NonNon--QuittersQuitters Average Daily Cigarette Consumption (median, inter-quartile range) % Baseline @ Baseline 6-Months 12-Months 12-months NicVAX 20 7.5 10 High 50% Antibody* 18-25 4-16 4-19 NicVAX 20 13 16 Low 80% Antibody 20-30 6-18.5 5-20 Placebo 20 13 14 70% 20-30 5-19 7-20 *Top 30% by AUC per protocol 14 AdverseAdverse EventsEvents NNiiccVVAAXX PPllaacceebboo nn==220011 nn==110000 UUppppeerr RReessppiirraattoorryy 2299%% 3300%% IInnffeeccttiioonn HHeeaaddaacchhee 1122%% 1122%% IInnssoommnniiaa 1100%% 99%% NNaassoopphhaarryynnggiittiiss 99%% 1144%% NNaauusseeaa 77%% 1100%% DDiizzzziinneessss 66%% 1111%% All events ≥ 10% of either NicVAX or Placebo AdverseAdverse eventsevents leadingleading toto earlyearly terminationsterminations f Nicvax groups (7/201): ― Anaphylactic reaction ― Increasing frequency of migraine headaches ― Arthralgias in multiple joints ― Shingles ― Stiffness in left hand ― Dozing off at the wheel ― Atrial fibrillation f Placebo (2/100): ― Forgetfulness ― Exacerbation of Crohn’s disease 16 LocalLocal ReactogenicityReactogenicity –– PercentagePercentage ofof SubjectsSubjects ExperiencingExperiencing EventsEvents (ITT)(ITT) Injection 1 2 3 4 5 † ‡ NV Pbo NV Pbo NV Pbo NV Pbo NV Pbo Ache 75 83 84 85 73 81 77 69 79 68 Burning 19 17 21 24 24 19 28 13 28 6 Heat 17 18 28 30 32 21 32 20 29 15 Swelling 32 41 45 38 46 31 43 25 38 27 Redness 14 18 26 18 34 19 28 11 24 9 Tenderness 78 91 87 89 81 81 80 77 83 77 † NV = NicVAX ‡ Pbo = Placebo 17 SystemicSystemic ReactogenicityReactogenicity –– PercentagePercentage ofof SubjectsSubjects ExperiencingExperiencing EventsEvents (ITT)(ITT) Injection 1 2 3 4 5 ‡ NV† Pbo NV Pbo NV Pbo NV Pbo NV Pbo Fever 2 2 3 2 8 7 6 3 0 0 General Dis- comfort / Malaise 50 58 64 52 50 49 46 41 36 32 Headache 41 41 54 36 44 35 34 27 33 21 Muscle Aches / Myalgia 65 64 66 64 55 62 57 57 50 59 Nausea 18 22 28 21 18 13 12 12 19 15 Vomiting 1 2 5 2 1 0 4 5 4 3 † NV = NicVAX ‡ Pbo = Placebo 18 ConclusionsConclusions ffMostMost effectiveeffective dosedose andand scheduleschedule identified:identified: ScheduleSchedule 22 (5(5 injections),injections), 400400 µµgg ffAntibodyAntibody levellevel predictspredicts continuouscontinuous abstinenceabstinence ffSignificantlySignificantly increasedincreased abstinenceabstinence throughthrough 1212 monthsmonths ffSafetySafety profileprofile ――ReactogenicityReactogenicity andand adverseadverse eventsevents similarsimilar toto placeboplacebo ――NoNo evidenceevidence ofof compensatorycompensatory smokingsmoking oror increaseincrease inin withdrawalwithdrawal symptomssymptoms AcknowledgementsAcknowledgements f Clinical Investigators f National Institute on ― Dorothy Hatsukami Drug Abuse (NIDA) ― Stephen Rennard ― RO1 DA017894 ― Douglas Jorenby f Nabi ― Michael Fiore Biopharmaceuticals ― David Gonzales ― Ali Fattom ― Nancy Rigotti ― Mariya Charny ― Matt Hohenboken ― Victor Reus ― Matt Hohenboken ― Matthew Kalnik ― Cheryl Oncken ― Phyllis Link ― Donald Tashkin ― Sharon Sutton ― Mitchell Nides ― Scott Winston ― Elbert Glover ― Paul Pentel.